<p><b>32</b></p><p><b>Population pharmacokinetics of ABC/DTG/3TC FDC to support dosing in PEDS with HIV-1 (IMPAACT 2019)</b></p><p>Hardik Chandasana<sup>1</sup>, Sven van Dijkman<sup>1</sup>, Rashmi Mehta<sup>1</sup>, Mark Bush<sup>2</sup>, Helena Rabie<sup>3</sup>, Patricia Flynn<sup>4</sup>, Tim Cressey<sup>5</sup>, Edward Acosta<sup>6</sup>, Kristina Brooks<sup>7</sup> and IMPAACT 2019 Protocol Team<sup>8</sup></p><p><sup>1</sup><i>GSK;</i> <sup>2</sup><i>ViiV Healthcare;</i> <sup>3</sup><i>University of Stellenbosch;</i> <sup>4</sup><i>St. Jude Children's Research Hospital;</i> <sup>5</sup><i>Chiang Mai University;</i> <sup>6</sup><i>University of Alabama at Birmingham;</i> <sup>7</sup><i>University of Colorado Anschutz Medical Campus;</i> <sup>8</sup><i>The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network</i></p><p><b>Background:</b> Once-daily fixed-dose combinations (FDC) containing abacavir (ABC), dolutegravir (DTG) and lamivudine (3TC) have been approved in the United States for adults and children with HIV weighing ≥6 kg (dispersible tablet [DT] and tablets). This analysis assessed the ability of previously developed ABC, DTG and 3TC paediatric population pharmacokinetic (PopPK) models using multiple formulations to describe and predict PK data in young children using DT and tablet formulations of ABC/DTG/3TC FDC in the IMPAACT 2019 study.</p><p><b>Methods:</b> IMPAACT 2019 was a phase I/II, multicentre, open-label study assessing the PK, safety, tolerability and efficacy of ABC/DTG/3TC FDC (tablets and DT) in children with HIV-1 aged <12 years and weighing ≥6 to <40 kg. Intensive and sparse PK samples were collected through 48 weeks (<i>N</i> = 55 participants with 590 ABC, 598 DTG and 597 3TC observations). Existing drug-specific paediatric PopPK models for ABC (two-compartment), DTG (one-compartment) and 3TC (one-compartment) were applied to the IMPAACT 2019 plasma drug concentrations data without re-estimation (external validation) of PopPK parameters. Exposures were then simulated across weight bands for each drug and compared with predefined exposure target ranges.</p><p><b>Results:</b> Goodness of fit and visual predictive check plots demonstrated good agreement between observed concentrations for ABC, DTG and 3TC from IMPAACT 2019 and the respective PopPK models. The post hoc PK parameter estimates were comparable to the NCA PK parameter estimates from IMPAACT 2019. Thus, new PopPK models to specifically describe the IMPAACT 2019 data were not necessary. Simulated geometric mean (GM) C24h DTG exposures were consistent across the weight bands (0.74–0.95 μg/mL) for both formulations. The predicted ABC GM AUC<sub>0–24</sub> ranged from 14.89 to 18.50 μg*h/mL for both formulations. Similarly, predicted GM AUC<sub>0–24</sub> ranges for 3TC were consistent across the weight bands (10.50–13.20 μg*h/mL). The predicted GM exposures were within the pre-defined GM target range set for each drug and c
{"title":"Population pharmacokinetics of ABC/DTG/3TC FDC to support dosing in PEDS with HIV-1 (IMPAACT 2019)","authors":"","doi":"10.1111/bcp.16311","DOIUrl":"10.1111/bcp.16311","url":null,"abstract":"<p><b>32</b></p><p><b>Population pharmacokinetics of ABC/DTG/3TC FDC to support dosing in PEDS with HIV-1 (IMPAACT 2019)</b></p><p>Hardik Chandasana<sup>1</sup>, Sven van Dijkman<sup>1</sup>, Rashmi Mehta<sup>1</sup>, Mark Bush<sup>2</sup>, Helena Rabie<sup>3</sup>, Patricia Flynn<sup>4</sup>, Tim Cressey<sup>5</sup>, Edward Acosta<sup>6</sup>, Kristina Brooks<sup>7</sup> and IMPAACT 2019 Protocol Team<sup>8</sup></p><p><sup>1</sup><i>GSK;</i> <sup>2</sup><i>ViiV Healthcare;</i> <sup>3</sup><i>University of Stellenbosch;</i> <sup>4</sup><i>St. Jude Children's Research Hospital;</i> <sup>5</sup><i>Chiang Mai University;</i> <sup>6</sup><i>University of Alabama at Birmingham;</i> <sup>7</sup><i>University of Colorado Anschutz Medical Campus;</i> <sup>8</sup><i>The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network</i></p><p><b>Background:</b> Once-daily fixed-dose combinations (FDC) containing abacavir (ABC), dolutegravir (DTG) and lamivudine (3TC) have been approved in the United States for adults and children with HIV weighing ≥6 kg (dispersible tablet [DT] and tablets). This analysis assessed the ability of previously developed ABC, DTG and 3TC paediatric population pharmacokinetic (PopPK) models using multiple formulations to describe and predict PK data in young children using DT and tablet formulations of ABC/DTG/3TC FDC in the IMPAACT 2019 study.</p><p><b>Methods:</b> IMPAACT 2019 was a phase I/II, multicentre, open-label study assessing the PK, safety, tolerability and efficacy of ABC/DTG/3TC FDC (tablets and DT) in children with HIV-1 aged <12 years and weighing ≥6 to <40 kg. Intensive and sparse PK samples were collected through 48 weeks (<i>N</i> = 55 participants with 590 ABC, 598 DTG and 597 3TC observations). Existing drug-specific paediatric PopPK models for ABC (two-compartment), DTG (one-compartment) and 3TC (one-compartment) were applied to the IMPAACT 2019 plasma drug concentrations data without re-estimation (external validation) of PopPK parameters. Exposures were then simulated across weight bands for each drug and compared with predefined exposure target ranges.</p><p><b>Results:</b> Goodness of fit and visual predictive check plots demonstrated good agreement between observed concentrations for ABC, DTG and 3TC from IMPAACT 2019 and the respective PopPK models. The post hoc PK parameter estimates were comparable to the NCA PK parameter estimates from IMPAACT 2019. Thus, new PopPK models to specifically describe the IMPAACT 2019 data were not necessary. Simulated geometric mean (GM) C24h DTG exposures were consistent across the weight bands (0.74–0.95 μg/mL) for both formulations. The predicted ABC GM AUC<sub>0–24</sub> ranged from 14.89 to 18.50 μg*h/mL for both formulations. Similarly, predicted GM AUC<sub>0–24</sub> ranges for 3TC were consistent across the weight bands (10.50–13.20 μg*h/mL). The predicted GM exposures were within the pre-defined GM target range set for each drug and c","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"22"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Absorption, distribution, metabolism and excretion of ainuovirine in healthy adults: A radiolabelled mass balance and biotransformation study
Miao Liyan1, Jiang Bin1, Sang Shibiao1, Qin Hong2 and Wu Yuechan2
1The First Affiliated Hospital of Soochow University;2Jiangsu Aidea Pharmaceutical Co., Ltd
Background: Ainuovirine (ANV) is a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of human immunodeficiency virus type 1 (HIV-1) infection. The absorption, distribution, metabolism and elimination of ANV was evaluated in a human radiolabelled mass balance and biotransformation study.
Methods: A single-centre, single-dose, non-randomized, open-label study was conducted, in which six healthy males received a single dose of oral suspension containing [14C]ANV at 150 mg/approximately 100 μCi on the first day in the study under fasting condition. Whole blood, plasma, urine and faecal samples were collected at the specific time points during the study. The data of pharmacokinetic (PK) parameters of the total radioactivity in plasma, concentration ratio of total radioactivity in whole blood to plasma and mass balance were obtained by measuring the total radioactivity of [14C]ANV in plasma, whole blood, urine and faeces. The main metabolic elimination pathways and characteristics of ANV in human body were obtained by analysing the radioactive metabolite profiles in plasma, urine and faeces; and the structure of major metabolites was identified using radioisotope and mass spectrometry.
Results: The time to maximum plasma total radioactivity (Tmax) was 3.42 h; the mean maximum concentration (Cmax) was 327 ng·eq./g; and the half-life of the total radioactivity terminal elimination phase (t½) was 43.5 h. Within 0–240 h, the mean cumulative excretion rate of total radioactivity was 101.64%. Specifically, the mean total excretion accounted for 28.10% of the administered dose in urine and 73.54% of the administered dose in faeces, suggesting that [14C]ANV was primarily excreted into faeces. The primary clearance pathway of [14C]ANV was mono-oxygenated to form M341, which was further glucuronidated, and metabolized by the liver, and excreted into faeces and urine. The secondary metabolic pathway was glucuronidation of the unchanged drug to form M501, which was excreted into urine.
Conclusions: Ainuovirine is primarily metabolized by the liver and excreted into faeces and urine, with a low plasma clearance, in the human body.
Keywords: ainuovirine, human immunodeficiency virus 1, mass balance, non-nucleoside reverse transcriptase inhibitor, pharmacokinetics
{"title":"Absorption, distribution, metabolism and excretion of ainuovirine in healthy adults: A radiolabelled mass balance and biotransformation study","authors":"","doi":"10.1111/bcp.16315","DOIUrl":"10.1111/bcp.16315","url":null,"abstract":"<p><b>36</b></p><p><b>Absorption, distribution, metabolism and excretion of ainuovirine in healthy adults: A radiolabelled mass balance and biotransformation study</b></p><p>Miao Liyan<sup>1</sup>, Jiang Bin<sup>1</sup>, Sang Shibiao<sup>1</sup>, Qin Hong<sup>2</sup> and Wu Yuechan<sup>2</sup></p><p><sup>1</sup><i>The First Affiliated Hospital of Soochow University;</i> <sup>2</sup><i>Jiangsu Aidea Pharmaceutical Co., Ltd</i></p><p><b>Background:</b> Ainuovirine (ANV) is a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of human immunodeficiency virus type 1 (HIV-1) infection. The absorption, distribution, metabolism and elimination of ANV was evaluated in a human radiolabelled mass balance and biotransformation study.</p><p><b>Methods:</b> A single-centre, single-dose, non-randomized, open-label study was conducted, in which six healthy males received a single dose of oral suspension containing [14C]ANV at 150 mg/approximately 100 μCi on the first day in the study under fasting condition. Whole blood, plasma, urine and faecal samples were collected at the specific time points during the study. The data of pharmacokinetic (PK) parameters of the total radioactivity in plasma, concentration ratio of total radioactivity in whole blood to plasma and mass balance were obtained by measuring the total radioactivity of [14C]ANV in plasma, whole blood, urine and faeces. The main metabolic elimination pathways and characteristics of ANV in human body were obtained by analysing the radioactive metabolite profiles in plasma, urine and faeces; and the structure of major metabolites was identified using radioisotope and mass spectrometry.</p><p><b>Results:</b> The time to maximum plasma total radioactivity (T<sub>max</sub>) was 3.42 h; the mean maximum concentration (C<sub>max</sub>) was 327 ng·eq./g; and the half-life of the total radioactivity terminal elimination phase (t½) was 43.5 h. Within 0–240 h, the mean cumulative excretion rate of total radioactivity was 101.64%. Specifically, the mean total excretion accounted for 28.10% of the administered dose in urine and 73.54% of the administered dose in faeces, suggesting that [14C]ANV was primarily excreted into faeces. The primary clearance pathway of [14C]ANV was mono-oxygenated to form M341, which was further glucuronidated, and metabolized by the liver, and excreted into faeces and urine. The secondary metabolic pathway was glucuronidation of the unchanged drug to form M501, which was excreted into urine.</p><p><b>Conclusions:</b> Ainuovirine is primarily metabolized by the liver and excreted into faeces and urine, with a low plasma clearance, in the human body.</p><p><b>Keywords:</b> ainuovirine, human immunodeficiency virus 1, mass balance, non-nucleoside reverse transcriptase inhibitor, pharmacokinetics</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"24"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16315","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><b>2</b></p><p><b>Dose linearity studies of a glecaprevir and pibrentasvir long-acting injectable formulation in Sprague Dawley rats</b></p><p>Eduardo Gallardo-Toledo<sup>1,2</sup>, Usman Arshad<sup>1,2</sup>, Henry Pertinez<sup>1,2</sup>, Joanne Sharp<sup>1,2</sup>, Joanne Herriott<sup>1,2</sup>, Edyta Kijak<sup>1,2</sup>, Helen Cox<sup>1,2</sup>, Alison Savage<sup>2,3</sup>, Catherine Unsworth<sup>2,3</sup>, Andrew Dwyer<sup>2,3</sup>, James Hobson<sup>2,3</sup>, Lee Tatham<sup>1,2</sup>, David Thomas<sup>4</sup>, Paul Curley<sup>1,2</sup>, Steve Rannard<sup>2,3</sup> and Andrew Owen<sup>1,2</sup></p><p><sup>1</sup><i>Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool;</i> <sup>2</sup><i>Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool;</i> <sup>3</sup><i>Department of Chemistry, University of Liverpool;</i> <sup>4</sup><i>Department of Infectious Diseases, John's Hopkins University School of Medicine</i></p><p><b>Background:</b> Glecaprevir (G) and pibrentasvir (P) is a fixed-dose combination (FDC) approved to treat all six types of hepatitis C. However, patient adherence to oral treatment regimens remains a major challenge with considerably lower efficacy in clinical use than reported in RCTs. Long-acting injectables (LAI) could address poor adherence through long-term exposure of both G and P after a single administration.</p><p><b>Materials and methods:</b> Male Sprague Dawley rats (<i>n</i> = 4 per group) were intramuscularly dosed into both thighs with LAI suspensions of G and P alone and both drugs in an FDC (GP-FDC, 1:1 ratio) as follows: GP-FDC group (75 mg G + 75 mg P, 150 μL/thigh), G group (150 mg G, 150 μL/thigh), P group (150 mg P, 150 μL/thigh) and GP group (75 mg G, 150 μL/left thigh + 75 mg P, 150 μL/right thigh). A second set of experiments evaluated the effects of different GP-FDC active doses (18.75, 37.5 and 75 mg) on the pharmacokinetics (PK) by changing the dosing volume (0.075, 0.15 and 0.3 mL of GP-FDC at 500 mg/mL) or GP-FDC suspension strength (0.3 mL of GP-FDC at 125, 250 and 500 mg/mL). For all studies, blood samples were collected from the lateral tail vein up to 90 days' post-dose. G and P concentrations were quantified in plasma using a validated method by LC-MS/MS.</p><p><b>Results:</b> GP-FDC showed plasma concentration–time profiles above the reported median human C<sub>trough</sub> for both G and P over the 90 days. However, for single drug-LAI suspensions, plasma concentrations of P were above the human Ctrough over 70 days for both P alone and GP groups, whereas a more rapid drop in plasma concentrations were observed for G in both G and GP groups, after 35 and 28 days, respectively. In the second set of experiments, a linear dose-dependent PK was observed with increasing volume, with a proportional increase in the AUC<sub>0-tlast</sub> for both G and P (G: 106, 220 and 390 μg·h/mL and P: 157, 346 a
格列卡韦和匹仑那韦长效注射制剂在 Sprague Dawley 大鼠体内的剂量线性研究Eduardo Gallardo-Toledo1,2, Usman Arshad1,2, Henry Pertinez1,2, Joanne Sharp1,2, Joanne Herriott1,2, Edyta Kijak1,2, Helen Cox1,2, Alison Savage2,3、Catherine Unsworth2,3、Andrew Dwyer2,3、James Hobson2,3、Lee Tatham1,2、David Thomas4、Paul Curley1,2、Steve Rannard2,3和Andrew Owen1,21利物浦大学系统、分子和整合生物学研究所药理学和治疗学系；2 利物浦大学长效治疗卓越中心（CELT）；3 利物浦大学化学系；4 约翰-霍普金斯大学医学院传染病系背景：Glecaprevir（G）和pibrentasvir（P）是一种固定剂量复方制剂（FDC），已被批准用于治疗所有六种类型的丙型肝炎。然而，患者对口服治疗方案的依从性仍然是一个重大挑战，临床使用中的疗效大大低于RCT报告的疗效。长效注射剂（LAI）可通过单次给药后G和P的长期暴露来解决依从性差的问题：雄性 Sprague Dawley 大鼠（每组 4 只）的两条大腿分别肌肉注射单独的 G 和 P LAI 悬浮液以及两种药物的 FDC（GP-FDC，1:1 比例），具体如下：GP-FDC组（75 mg G + 75 mg P，150 μL/大腿）、G组（150 mg G，150 μL/大腿）、P组（150 mg P，150 μL/大腿）和GP组（75 mg G，150 μL/左大腿 + 75 mg P，150 μL/右大腿）。第二组实验通过改变给药量（0.075、0.15 和 0.3 mL 的 GP-FDC，500 mg/mL）或 GP-FDC 悬浮液浓度（0.3 mL 的 GP-FDC，125、250 和 500 mg/mL），评估了不同 GP-FDC 活性剂量（18.75、37.5 和 75 mg）对药代动力学（PK）的影响。所有研究均从侧尾静脉采集血液样本，直至用药后 90 天。采用 LC-MS/MS 的验证方法对血浆中的 G 和 P 浓度进行量化：结果：GP-FDC 在 90 天内的血浆中 G 和 P 的浓度-时间曲线均高于所报告的人体 Ctrough 中值。然而，对于单药-LAI 悬浮液，单用 P 组和 GP 组的 P 血浆浓度在 70 天内均高于人体的 Ctrough 值，而 G 组和 GP 组的 G 血浆浓度则分别在 35 天和 28 天后迅速下降。在第二组实验中，随着容量的增加，观察到线性剂量依赖性 PK，G 和 P 的 AUC0-tlast 都成比例增加（G：106、220 和 390 μg-h/ml，P：157、346 和 513 μg-h/ml，分别为 0.075、0.15 和 0.3 mL）。相反，当剂量按 GP-FDC 悬浮液浓度滴定时，观察到 G 和 P 的 AUC0-tlast 均呈非剂量线性增长（G：156、325 和 390 μg-h/mL ；P：125、250 和 500 mg/mL 时分别为 200、400 和 513 μg-h/mL）。尽管如此，两种实验条件都提供了适当的血浆暴露量；18.75 毫克剂量可使 G 和 P 的暴露量分别在 5 周和 11 周内保持在人体中枢水平以上，37.5 毫克和 75 毫克剂量可使 G 和 P 的血浆暴露量在 90 天内保持在人体中枢水平以上：GP-FDC和单一药物-LAI混悬液之间G和P的血浆暴露量表明，P有助于延长G的终末半衰期。要推进人体临床试验，还需要优化药物配比和进行 GLP 毒理学评估。
{"title":"Dose linearity studies of a glecaprevir and pibrentasvir long-acting injectable formulation in Sprague Dawley rats","authors":"","doi":"10.1111/bcp.16281","DOIUrl":"10.1111/bcp.16281","url":null,"abstract":"<p><b>2</b></p><p><b>Dose linearity studies of a glecaprevir and pibrentasvir long-acting injectable formulation in Sprague Dawley rats</b></p><p>Eduardo Gallardo-Toledo<sup>1,2</sup>, Usman Arshad<sup>1,2</sup>, Henry Pertinez<sup>1,2</sup>, Joanne Sharp<sup>1,2</sup>, Joanne Herriott<sup>1,2</sup>, Edyta Kijak<sup>1,2</sup>, Helen Cox<sup>1,2</sup>, Alison Savage<sup>2,3</sup>, Catherine Unsworth<sup>2,3</sup>, Andrew Dwyer<sup>2,3</sup>, James Hobson<sup>2,3</sup>, Lee Tatham<sup>1,2</sup>, David Thomas<sup>4</sup>, Paul Curley<sup>1,2</sup>, Steve Rannard<sup>2,3</sup> and Andrew Owen<sup>1,2</sup></p><p><sup>1</sup><i>Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool;</i> <sup>2</sup><i>Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool;</i> <sup>3</sup><i>Department of Chemistry, University of Liverpool;</i> <sup>4</sup><i>Department of Infectious Diseases, John's Hopkins University School of Medicine</i></p><p><b>Background:</b> Glecaprevir (G) and pibrentasvir (P) is a fixed-dose combination (FDC) approved to treat all six types of hepatitis C. However, patient adherence to oral treatment regimens remains a major challenge with considerably lower efficacy in clinical use than reported in RCTs. Long-acting injectables (LAI) could address poor adherence through long-term exposure of both G and P after a single administration.</p><p><b>Materials and methods:</b> Male Sprague Dawley rats (<i>n</i> = 4 per group) were intramuscularly dosed into both thighs with LAI suspensions of G and P alone and both drugs in an FDC (GP-FDC, 1:1 ratio) as follows: GP-FDC group (75 mg G + 75 mg P, 150 μL/thigh), G group (150 mg G, 150 μL/thigh), P group (150 mg P, 150 μL/thigh) and GP group (75 mg G, 150 μL/left thigh + 75 mg P, 150 μL/right thigh). A second set of experiments evaluated the effects of different GP-FDC active doses (18.75, 37.5 and 75 mg) on the pharmacokinetics (PK) by changing the dosing volume (0.075, 0.15 and 0.3 mL of GP-FDC at 500 mg/mL) or GP-FDC suspension strength (0.3 mL of GP-FDC at 125, 250 and 500 mg/mL). For all studies, blood samples were collected from the lateral tail vein up to 90 days' post-dose. G and P concentrations were quantified in plasma using a validated method by LC-MS/MS.</p><p><b>Results:</b> GP-FDC showed plasma concentration–time profiles above the reported median human C<sub>trough</sub> for both G and P over the 90 days. However, for single drug-LAI suspensions, plasma concentrations of P were above the human Ctrough over 70 days for both P alone and GP groups, whereas a more rapid drop in plasma concentrations were observed for G in both G and GP groups, after 35 and 28 days, respectively. In the second set of experiments, a linear dose-dependent PK was observed with increasing volume, with a proportional increase in the AUC<sub>0-tlast</sub> for both G and P (G: 106, 220 and 390 μg·h/mL and P: 157, 346 a","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"3-4"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16281","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><b>6</b></p><p><b>Experience of a nirmatrelvir/ritonavir drug–drug interaction expert advice service</b></p><p>Florian Lemaitre, Camille Tron, Sébastien Lalanne, Bénédicte Franck, Christelle Boglione-Kerrien, Fabrice Taïeb and Marie-Clémence Verdier</p><p><i>Biological Pharmacologie Department, Rennes University Hospital</i></p><p><b>Background</b>: Nirmatrelvir/ritonavir is a protease inhibitor antiviral drug indicated in the treatment of severe acute respiratory syndrome coronavirus-2 infections in high-risk patients for a severe disease. Unfortunately, ritonavir, used to boost nirmatrelvir pharmacokinetics, can also inhibit or induce the metabolism of other co-administered drugs substrates. This may lead to a subsequent drug–drug interaction (DDI) risk and thus to adverse drug reaction. To secure the drug's prescription and help clinicians with drug indication, we developed a DDI expert advice service dedicated to nirmatrelvir/ritonavir. The aim of this study was to describe this service provided by the clinical pharmacology department of the Rennes University Hospital, Rennes, France.</p><p><b>Material and methods:</b> We collected all DDI advices provided by the five senior clinical pharmacologists of the department regarding nirmatrelvir/ritonavir in 2022 and 2023. These advices were given by phone, email or through a tele-expertise system. The following data were gathered: patient's age and sex, renal function, date of nirmatrelvir/ritonavir initiation, clinical department requiring the expert advice, patient's treatments and advice provided. Data were presented as medians and interquartile and percentages.</p><p><b>Results:</b> In 2022 and 2023, the expert advice services provided advices for 123 and 224 patients, respectively. These 347 advices relate on 2858 prescription lines. In 2022, advices were provided for 881 prescription lines for patients of median age of 69 years [57–76] and estimated glomerular filtration rate (eGFR) of 77 mL/min [59–91]. The main pharmacological classes were: cardiology drugs (26.8%), endocrinology drugs (16.9%) and immunosuppressive agents (13.6%). The advice was distributed as follows: treatment continuation, treatment discontinuation during the antiviral course, dosage adjustment and treatment switch in 71%, 19%, 7%, 3% of the cases, respectively. Only three patients (2.4%) were denied the drug due to contraindications. Drug monitoring was proposed in 5% of prescription lines. The top drug request was tacrolimus in 2022.</p><p>In 2023, advices were provided for 1977 prescription lines for patients of median age of 77 years [67–85] and estimated glomerular filtration rate (eGFR) of 77 mL/min [55–90]. The most common requests were for endocrinology drugs (22%), cardiac drugs (21%) and neurology drugs (18%). The advice was distributed as follows: treatment continuation, treatment discontinuation during the antiviral course, dosage adjustment and treatment switch in 77%, 14%, 6% and 3% of the cases, respec
{"title":"Experience of a nirmatrelvir/ritonavir drug–drug interaction expert advice service","authors":"","doi":"10.1111/bcp.16285","DOIUrl":"10.1111/bcp.16285","url":null,"abstract":"<p><b>6</b></p><p><b>Experience of a nirmatrelvir/ritonavir drug–drug interaction expert advice service</b></p><p>Florian Lemaitre, Camille Tron, Sébastien Lalanne, Bénédicte Franck, Christelle Boglione-Kerrien, Fabrice Taïeb and Marie-Clémence Verdier</p><p><i>Biological Pharmacologie Department, Rennes University Hospital</i></p><p><b>Background</b>: Nirmatrelvir/ritonavir is a protease inhibitor antiviral drug indicated in the treatment of severe acute respiratory syndrome coronavirus-2 infections in high-risk patients for a severe disease. Unfortunately, ritonavir, used to boost nirmatrelvir pharmacokinetics, can also inhibit or induce the metabolism of other co-administered drugs substrates. This may lead to a subsequent drug–drug interaction (DDI) risk and thus to adverse drug reaction. To secure the drug's prescription and help clinicians with drug indication, we developed a DDI expert advice service dedicated to nirmatrelvir/ritonavir. The aim of this study was to describe this service provided by the clinical pharmacology department of the Rennes University Hospital, Rennes, France.</p><p><b>Material and methods:</b> We collected all DDI advices provided by the five senior clinical pharmacologists of the department regarding nirmatrelvir/ritonavir in 2022 and 2023. These advices were given by phone, email or through a tele-expertise system. The following data were gathered: patient's age and sex, renal function, date of nirmatrelvir/ritonavir initiation, clinical department requiring the expert advice, patient's treatments and advice provided. Data were presented as medians and interquartile and percentages.</p><p><b>Results:</b> In 2022 and 2023, the expert advice services provided advices for 123 and 224 patients, respectively. These 347 advices relate on 2858 prescription lines. In 2022, advices were provided for 881 prescription lines for patients of median age of 69 years [57–76] and estimated glomerular filtration rate (eGFR) of 77 mL/min [59–91]. The main pharmacological classes were: cardiology drugs (26.8%), endocrinology drugs (16.9%) and immunosuppressive agents (13.6%). The advice was distributed as follows: treatment continuation, treatment discontinuation during the antiviral course, dosage adjustment and treatment switch in 71%, 19%, 7%, 3% of the cases, respectively. Only three patients (2.4%) were denied the drug due to contraindications. Drug monitoring was proposed in 5% of prescription lines. The top drug request was tacrolimus in 2022.</p><p>In 2023, advices were provided for 1977 prescription lines for patients of median age of 77 years [67–85] and estimated glomerular filtration rate (eGFR) of 77 mL/min [55–90]. The most common requests were for endocrinology drugs (22%), cardiac drugs (21%) and neurology drugs (18%). The advice was distributed as follows: treatment continuation, treatment discontinuation during the antiviral course, dosage adjustment and treatment switch in 77%, 14%, 6% and 3% of the cases, respec","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"6-7"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16285","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><b>13</b></p><p><b>Long-acting cabotegravir and rilpivirine plasma exposures in the clinical setting: The role of pharmacogenetics</b></p><p>Jessica Cusato<sup>1</sup>, Micol Ferrara<sup>2</sup>, Miriam Antonucci<sup>2</sup>, Razvan Goldan<sup>1</sup>, Sara Soloperto<sup>1</sup>, Giovanni Di Perri<sup>3</sup>, Antonio D'avolio<sup>1</sup>, Andrea Calcagno<sup>3</sup> and Stefano Bonora<sup>3</sup></p><p><sup>1</sup><i>Department of Medical Sciences, Laboratory of Clinical Pharmacology and Pharmacogenetics, University of Turin;</i> <sup>2</sup><i>ASL Città di Torino;</i> <sup>3</sup><i>Unit of Infectious Diseases, Department of Medical Sciences, University of Turin</i></p><p><b>Background:</b> Wide inter-individual variability in the pharmacokinetics of rilpivirine (RPV) and cabotegravir (CABO) has been reported in the first weeks after starting long acting injectable drugs (LAI) treatment. Furthermore, reduced RPV and/or CABO plasma trough concentrations combined with other risk factors (i.e. resistance-associated mutations, BMI ≥ 30 kg/m<sup>2</sup>) have been related with increased risk of virologic failure. However, data on the potential role of pharmacogenetics in affecting LAI pharmacokinetics and, possibly, the clinical outcome are lacking. Consequently, we aimed at evaluating the impact of genetic polymorphisms in affecting LAI drug exposure in PWH.</p><p><b>Material and methods:</b> RPV and CABO concentrations were quantified by chromatography, both in plasma and in peripheral blood mononuclear cells (PBMCs), before starting therapy (oral administration, baseline, only for RPV) and at 1, 3, 5, 7, 9 and 11 months (M) of therapy with LAI administration. The 4 × PA-IC90 were considered as the efficacy cut-off values, set at 50 and 664 ng/mL for RPV and CABO, respectively. Regression analysis was performed in order to evaluate which factors are able to predict the efficacy-related values of 50 ng/mL for RPV and 664 ng/mL for CABO respectively at 3 months of therapy.</p><p>Polymorphisms in genes encoding enzymes and transporters involved in drug metabolism and elimination (CYP2C19, CYP3A4, CYP3A5, UGT1A1, ABCB1, ABCG2) were analysed through real-time PCR.</p><p><b>Results:</b> One hundred and seventy-seven PWH were enrolled: 85.3% males with median age of 50.7 years (IQR 43.3; 59.1). Median plasma and PBMC antiretroviral drug levels at different timings are reported in Table 1. Following associations were found: baseline plasma RPV and ABCB1 3435 CT/TT (<i>p</i> = .039) and UGT1A1 023 TT (<i>p</i> = .028), 1 M CABO intracellular levels and ABCB1 1236 CT/TT (<i>p</i> = .047), M3 ratio CABO and CYP2C19 AA (<i>p</i> = .025) and UGT1A1 023 CT/TT (<i>p</i> = .009), M3 RPV plasma and CYP3A4*22 (<i>p</i> = .035), M5 ratio CABO and ABCG2 421 CA/AA (<i>p</i> = .020), M5 plasma CABO and UGT1A1 023 TT (<i>p</i> = .010), M9 plasma RPV and CYP3A4*22 (<i>p</i> = .046), M11 plasma RPV and ABCB1 1236 CT/TT (<i>p</i> = .042), M11 intracellular RPV and ABC
{"title":"Long-acting cabotegravir and rilpivirine plasma exposures in the clinical setting: The role of pharmacogenetics","authors":"","doi":"10.1111/bcp.16292","DOIUrl":"10.1111/bcp.16292","url":null,"abstract":"<p><b>13</b></p><p><b>Long-acting cabotegravir and rilpivirine plasma exposures in the clinical setting: The role of pharmacogenetics</b></p><p>Jessica Cusato<sup>1</sup>, Micol Ferrara<sup>2</sup>, Miriam Antonucci<sup>2</sup>, Razvan Goldan<sup>1</sup>, Sara Soloperto<sup>1</sup>, Giovanni Di Perri<sup>3</sup>, Antonio D'avolio<sup>1</sup>, Andrea Calcagno<sup>3</sup> and Stefano Bonora<sup>3</sup></p><p><sup>1</sup><i>Department of Medical Sciences, Laboratory of Clinical Pharmacology and Pharmacogenetics, University of Turin;</i> <sup>2</sup><i>ASL Città di Torino;</i> <sup>3</sup><i>Unit of Infectious Diseases, Department of Medical Sciences, University of Turin</i></p><p><b>Background:</b> Wide inter-individual variability in the pharmacokinetics of rilpivirine (RPV) and cabotegravir (CABO) has been reported in the first weeks after starting long acting injectable drugs (LAI) treatment. Furthermore, reduced RPV and/or CABO plasma trough concentrations combined with other risk factors (i.e. resistance-associated mutations, BMI ≥ 30 kg/m<sup>2</sup>) have been related with increased risk of virologic failure. However, data on the potential role of pharmacogenetics in affecting LAI pharmacokinetics and, possibly, the clinical outcome are lacking. Consequently, we aimed at evaluating the impact of genetic polymorphisms in affecting LAI drug exposure in PWH.</p><p><b>Material and methods:</b> RPV and CABO concentrations were quantified by chromatography, both in plasma and in peripheral blood mononuclear cells (PBMCs), before starting therapy (oral administration, baseline, only for RPV) and at 1, 3, 5, 7, 9 and 11 months (M) of therapy with LAI administration. The 4 × PA-IC90 were considered as the efficacy cut-off values, set at 50 and 664 ng/mL for RPV and CABO, respectively. Regression analysis was performed in order to evaluate which factors are able to predict the efficacy-related values of 50 ng/mL for RPV and 664 ng/mL for CABO respectively at 3 months of therapy.</p><p>Polymorphisms in genes encoding enzymes and transporters involved in drug metabolism and elimination (CYP2C19, CYP3A4, CYP3A5, UGT1A1, ABCB1, ABCG2) were analysed through real-time PCR.</p><p><b>Results:</b> One hundred and seventy-seven PWH were enrolled: 85.3% males with median age of 50.7 years (IQR 43.3; 59.1). Median plasma and PBMC antiretroviral drug levels at different timings are reported in Table 1. Following associations were found: baseline plasma RPV and ABCB1 3435 CT/TT (<i>p</i> = .039) and UGT1A1 023 TT (<i>p</i> = .028), 1 M CABO intracellular levels and ABCB1 1236 CT/TT (<i>p</i> = .047), M3 ratio CABO and CYP2C19 AA (<i>p</i> = .025) and UGT1A1 023 CT/TT (<i>p</i> = .009), M3 RPV plasma and CYP3A4*22 (<i>p</i> = .035), M5 ratio CABO and ABCG2 421 CA/AA (<i>p</i> = .020), M5 plasma CABO and UGT1A1 023 TT (<i>p</i> = .010), M9 plasma RPV and CYP3A4*22 (<i>p</i> = .046), M11 plasma RPV and ABCB1 1236 CT/TT (<i>p</i> = .042), M11 intracellular RPV and ABC","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"11"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16292","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><b>22</b></p><p><b>Pharmacometrics analyses and modelling of concentration-corrected QT interval and concentration-creatine kinase MB in healthy adults and treatment-naïve people with HIV-1 on ainuovirine monotherapy, and combined with lamivudine and tenofovir DF: The pooled analyses of early clinical pharmacology studies</b></p><p>Su Bin<sup>1</sup>, Wu Hao<sup>1</sup>, Wang Meixia<sup>1</sup>, Hao Xiaohua<sup>2</sup>, Hong Qin<sup>3</sup> and Wu Yuechan<sup>3</sup></p><p><sup>1</sup><i>Beijing Youan Hospital Affiliated to Capital Medical University;</i> <sup>2</sup><i>Beijing Ditan Hospital Affiliated to Capital Medical University;</i> <sup>3</sup><i>Jiangsu Aidea Pharmaceutical Co., Ltd</i></p><p><b>Background:</b> People with HIV-1 (PWH) are susceptible to corrected QT (QTc) interval prolongation, especially when on some specific antiretroviral regimens. Ainuovirine (ANV) is a new-generation NNRTI developed for HIV-1 treatment. The pooled analyses aimed to investigate effects of ainuovirine monotherapy and combined with lamivudine (3TC) and tenofovir DF (TDF) on electrocardiography and myocardial biomarker of healthy people and treatment-naïve PWH.</p><p><b>Methods:</b> Sixty-eight (<i>n</i> = 68) healthy adults were enrolled and exposed to ANV in single ascending dose (SAD), food effect (FE) and drug–drug interaction (DDI) with 3TC/TDF studies; 28 PWH were enrolled into multiple ascending dose (MAD) study and received ANV monotherapy for 10 successive days. ANV, 75–300 mg, was given to all participants under the fasting condition. A basic structure model (c-QTc) was established between observed plasma ANV concentration and change in corrected QT interval (ΔQTcF) with the linear mixed effect method. All model parameters were estimated using the first-order conditional estimation with interaction (FOCEI), with the linear model prioritized. An additional statistical random effect model was used to depict inter- and intra-individual variations without covariate adjusted. A simple linear regression model was also used to evaluate the correlation between ΔQTcF and plasma concentration, regardless of inter-individual variability. A 95% confidence interval containing 0 for the slope indicates negative QT prolongation. Changes in concentration-creatine kinase MB (c-CKMB) were also analysed using a similar methodology for evaluation of ANV myocardial safety.</p><p><b>Results:</b> A total of 492 post-dose ECG sampling points from 85 participants were included in the analysis. A linear population c-QTc model was established, which demonstrated the 95% CI of [−0.018, 0.0064] for the slope (containing 0), with favourable goodness of fit, precision and reliability. The simple linear regression model showed a slope of −0.003 [−0.010, 0.004], with no statistically significant difference from 0 (<i>p</i> = .409). CKMB levels did not change significantly with ACC007 monotherapy and remained well below the upper limit of normal (ULN, 3.6 ng/mL); CKMB levels
{"title":"Pharmacometrics analyses and modelling of concentration-corrected QT interval and concentration-creatine kinase MB in healthy adults and treatment-naïve people with HIV-1 on ainuovirine monotherapy, and combined with lamivudine and tenofovir DF: The pooled analyses of early clinical pharmacology studies","authors":"","doi":"10.1111/bcp.16301","DOIUrl":"10.1111/bcp.16301","url":null,"abstract":"<p><b>22</b></p><p><b>Pharmacometrics analyses and modelling of concentration-corrected QT interval and concentration-creatine kinase MB in healthy adults and treatment-naïve people with HIV-1 on ainuovirine monotherapy, and combined with lamivudine and tenofovir DF: The pooled analyses of early clinical pharmacology studies</b></p><p>Su Bin<sup>1</sup>, Wu Hao<sup>1</sup>, Wang Meixia<sup>1</sup>, Hao Xiaohua<sup>2</sup>, Hong Qin<sup>3</sup> and Wu Yuechan<sup>3</sup></p><p><sup>1</sup><i>Beijing Youan Hospital Affiliated to Capital Medical University;</i> <sup>2</sup><i>Beijing Ditan Hospital Affiliated to Capital Medical University;</i> <sup>3</sup><i>Jiangsu Aidea Pharmaceutical Co., Ltd</i></p><p><b>Background:</b> People with HIV-1 (PWH) are susceptible to corrected QT (QTc) interval prolongation, especially when on some specific antiretroviral regimens. Ainuovirine (ANV) is a new-generation NNRTI developed for HIV-1 treatment. The pooled analyses aimed to investigate effects of ainuovirine monotherapy and combined with lamivudine (3TC) and tenofovir DF (TDF) on electrocardiography and myocardial biomarker of healthy people and treatment-naïve PWH.</p><p><b>Methods:</b> Sixty-eight (<i>n</i> = 68) healthy adults were enrolled and exposed to ANV in single ascending dose (SAD), food effect (FE) and drug–drug interaction (DDI) with 3TC/TDF studies; 28 PWH were enrolled into multiple ascending dose (MAD) study and received ANV monotherapy for 10 successive days. ANV, 75–300 mg, was given to all participants under the fasting condition. A basic structure model (c-QTc) was established between observed plasma ANV concentration and change in corrected QT interval (ΔQTcF) with the linear mixed effect method. All model parameters were estimated using the first-order conditional estimation with interaction (FOCEI), with the linear model prioritized. An additional statistical random effect model was used to depict inter- and intra-individual variations without covariate adjusted. A simple linear regression model was also used to evaluate the correlation between ΔQTcF and plasma concentration, regardless of inter-individual variability. A 95% confidence interval containing 0 for the slope indicates negative QT prolongation. Changes in concentration-creatine kinase MB (c-CKMB) were also analysed using a similar methodology for evaluation of ANV myocardial safety.</p><p><b>Results:</b> A total of 492 post-dose ECG sampling points from 85 participants were included in the analysis. A linear population c-QTc model was established, which demonstrated the 95% CI of [−0.018, 0.0064] for the slope (containing 0), with favourable goodness of fit, precision and reliability. The simple linear regression model showed a slope of −0.003 [−0.010, 0.004], with no statistically significant difference from 0 (<i>p</i> = .409). CKMB levels did not change significantly with ACC007 monotherapy and remained well below the upper limit of normal (ULN, 3.6 ng/mL); CKMB levels ","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"17"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><b>34</b></p><p><b>TFV-DP adherence interpretations from TDF using an updated 50% methanol and 50% water extraction method for DBS</b></p><p>Corwin Coppinger<sup>1</sup>, Mary Morrow<sup>1</sup>, Samantha MaWhinney<sup>1</sup>, Martin Williams<sup>1</sup>, Lane Bushman<sup>1</sup>, Kristina Brooks<sup>1</sup>, Kenneth Mugwanya<sup>1,2</sup> and Peter Anderson<sup>1</sup></p><p><sup>1</sup><i>University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences;</i> <sup>2</sup><i>Department of Global Health, University of Washington</i></p><p><b>Background:</b> Intraerythrocytic tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) have been used in many clinical trials to better understand cumulative and recent adherence, respectively. The original validated extraction utilized 70% methanol and 30% water (70:30), which required controlled extraction conditions for reproducible results. We recently validated a 50% methanol and 50% water extraction (50:50), which yields better and more reproducible drug recoveries with fewer limitations on the control of extraction conditions. The aim of this study was to compare the extraction performances (70:30 <i>vs</i>. 50:50) and to adjust the original TFV-DP interpretations, which was based on 70:30, using the 50:50 extraction process.</p><p><b>Methods:</b> DBS from the Benchmark study were used for this analysis. The benchmark study included 53 African cisgender women without HIV randomized to two, four or seven doses per week, directly observed, for 8 weeks. An additional 17 pregnant women received 7 doses/week for 8 weeks. DBS samples were collected weekly; each sample included five 50uL spots. Three hundred ninety-six samples were available for this analysis. Both extraction methods were run in parallel to assess the relative efficiency of extracting TFV-DP and FTC-TP: Two 3-mm punches were removed from the same 50 μL spot from each card, and one punch was extracted with 70:30 and the other with 50:50. TFV-DP and FTC-TP concentrations were quantified using validated LC-MS/MS. A linear regression on the logarithmic scale was used to compare the results from the two extraction methods. The fold difference between extraction methods was applied to the original 70:30 TFV-DP adherence interpretations, which were <350 (<2 dose/week), 350–699 (2–3 doses/week), 700–1249 (4–6 doses/week) and ≥1250 fmol/punch (7 doses/week). These were generated from the DOT-DBS study conducted in the United States.</p><p><b>Results:</b> Data from the 70:30 extraction were within 10% of the original 70:30 TFV-DP adherence table estimates based on DOT-DBS, validating these interpretations for African cisgender women. The 50:50 extraction resulted in 1.27 (95% CI 1.25, 1.28) higher TFV-DP concentrations compared with the 70:30 extraction. The conversion factor of 1.27 was applied to the previous 70:30 TFV-DP benchmarks to produce the following interpretations for 50:50 ext
{"title":"TFV-DP adherence interpretations from TDF using an updated 50% methanol and 50% water extraction method for DBS","authors":"","doi":"10.1111/bcp.16313","DOIUrl":"10.1111/bcp.16313","url":null,"abstract":"<p><b>34</b></p><p><b>TFV-DP adherence interpretations from TDF using an updated 50% methanol and 50% water extraction method for DBS</b></p><p>Corwin Coppinger<sup>1</sup>, Mary Morrow<sup>1</sup>, Samantha MaWhinney<sup>1</sup>, Martin Williams<sup>1</sup>, Lane Bushman<sup>1</sup>, Kristina Brooks<sup>1</sup>, Kenneth Mugwanya<sup>1,2</sup> and Peter Anderson<sup>1</sup></p><p><sup>1</sup><i>University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences;</i> <sup>2</sup><i>Department of Global Health, University of Washington</i></p><p><b>Background:</b> Intraerythrocytic tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) have been used in many clinical trials to better understand cumulative and recent adherence, respectively. The original validated extraction utilized 70% methanol and 30% water (70:30), which required controlled extraction conditions for reproducible results. We recently validated a 50% methanol and 50% water extraction (50:50), which yields better and more reproducible drug recoveries with fewer limitations on the control of extraction conditions. The aim of this study was to compare the extraction performances (70:30 <i>vs</i>. 50:50) and to adjust the original TFV-DP interpretations, which was based on 70:30, using the 50:50 extraction process.</p><p><b>Methods:</b> DBS from the Benchmark study were used for this analysis. The benchmark study included 53 African cisgender women without HIV randomized to two, four or seven doses per week, directly observed, for 8 weeks. An additional 17 pregnant women received 7 doses/week for 8 weeks. DBS samples were collected weekly; each sample included five 50uL spots. Three hundred ninety-six samples were available for this analysis. Both extraction methods were run in parallel to assess the relative efficiency of extracting TFV-DP and FTC-TP: Two 3-mm punches were removed from the same 50 μL spot from each card, and one punch was extracted with 70:30 and the other with 50:50. TFV-DP and FTC-TP concentrations were quantified using validated LC-MS/MS. A linear regression on the logarithmic scale was used to compare the results from the two extraction methods. The fold difference between extraction methods was applied to the original 70:30 TFV-DP adherence interpretations, which were <350 (<2 dose/week), 350–699 (2–3 doses/week), 700–1249 (4–6 doses/week) and ≥1250 fmol/punch (7 doses/week). These were generated from the DOT-DBS study conducted in the United States.</p><p><b>Results:</b> Data from the 70:30 extraction were within 10% of the original 70:30 TFV-DP adherence table estimates based on DOT-DBS, validating these interpretations for African cisgender women. The 50:50 extraction resulted in 1.27 (95% CI 1.25, 1.28) higher TFV-DP concentrations compared with the 70:30 extraction. The conversion factor of 1.27 was applied to the previous 70:30 TFV-DP benchmarks to produce the following interpretations for 50:50 ext","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"23"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16313","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><b>5</b></p><p><b>Bictegravir exposures in adults with HIV and tuberculosis on a rifampicin-based tuberculosis treatment regimen</b></p><p>Anushka Naidoo<sup>1,2</sup>, Hylke Waalewijn<sup>3</sup>, Kogieleum Naidoo<sup>1,2</sup>, Marothi Letsoalo<sup>1</sup>, Gillian Dorse<sup>1</sup>, Rubeshan Perumal<sup>1,2</sup>, Emmanuella Osuala<sup>1</sup>, Nonpumelelo Zungu<sup>1</sup>, Phindile Msomi<sup>1</sup>, Paolo Denti<sup>3</sup> and Kelly Dooley<sup>4</sup></p><p><sup>1</sup><i>Center for the AIDS Program of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal;</i> <sup>2</sup><i>Centre for the AIDS Programme of Research in South Africa (CAPRISA), South African Medical Research Council (SAMRC)-CAPRISA-TB-HIV Pathogenesis and Treatment Research Unit, University of KwaZulu-Natal Nelson R Mandela School of Medicine;</i> <sup>3</sup><i>Division of Clinical Pharmacology, Department of Medicine, University of Cape Town;</i> <sup>4</sup><i>Vanderbilt University Medical Center</i></p><p><b>Background:</b> Bictegravir (BIC) has not been evaluated in people with HIV (PWH) and tuberculosis (TB) taking rifampicin-based TB treatment. Healthy volunteer data showed that rifampicin reduced BIC exposure by about 80%; however, trough concentrations remained threefold above the inhibitory quotient (IQ1) of 0.162 mg/L. Potential exposures below IQ1 in few individuals or breakthrough viremia may be mitigated by a long dissociation half-life of BIC from the HIV-1 integrase enzyme.</p><p><b>Methods:</b> INSIGHT (NCT04734652) is an open-label, non-comparative phase 2b randomized controlled trial in ART-naïve or non-naïve adults with HIV and TB, initiated on a rifampicin-based TB regimen (<8 weeks). Participants were randomized in a 2:1 ratio to either the BIC arm (bictegravir/emtricitabine/tenofovir alafenamide) or a standard of care dolutegravir arm (TLD), dosed twice daily until 2 weeks' post-TB treatment and once daily thereafter, until 48 weeks. Forty-three participants in the BIC arm were enrolled in a semi-intensive pharmacokinetic (PK) sub-study. Semi-intensive PK sampling was done at pre-dose, 1, 2, 4, 6 and 8–12 h post-dose during TB treatment and pre-dose, 1, 2, 4, 6–8 and 24–25 h post-dose after TB treatment. BIC concentrations were assayed using a validated LC-MS/MS method. Non-compartmental PK analyses for BIC were conducted in R using the PKNCA package (version 10.2). Participants underwent regular clinical and safety visits, including HIV viral load measurements at baseline, weeks 4, 8, 12, 24, 40 and 48. We report the preliminary PK data and primary endpoint results for the proportion of participants with plasma HIV-1-RNA < 50 copies/mL at the end of TB treatment (week 24).</p><p><b>Results:</b> We enrolled 122 participants: 80 in the BIC and 42 in the DTG arm. Forty-three (35%) were female, with median (IQR) baseline viral load (copies/mL) and CD4 + (cells/μL) of 75 649 (22 784–391 299) and 172 (1
5 以利福平为基础的结核病治疗方案中成人艾滋病病毒感染者和结核病患者的比特拉韦暴露Anushka Naidoo1,2、Hylke Waalewijn3、Kogieleum Naidoo1,2、Marothi Letsoalo1、Gillian Dorse1、Rubeshan Perumal1、2, Emmanuella Osuala1, Nonpumelelo Zungu1, Phindile Msomi1, Paolo Denti3 and Kelly Dooley41Center for the AIDS Program of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal；2 南非艾滋病研究计划中心 (CAPRISA)、南非医学研究理事会 (SAMRC)-CAPRISA-结核病-艾滋病毒发病机制和治疗研究组、夸祖鲁-纳塔尔大学纳尔逊-曼德拉医学院；3 开普敦大学医学系临床药理学部；4 范德比尔特大学医学中心背景：比特拉韦（BIC）尚未在接受利福平结核病治疗的艾滋病病毒感染者（PWH）和结核病患者中进行过评估。健康志愿者的数据显示，利福平可使 BIC 的暴露量减少约 80%；但谷浓度仍比 0.162 mg/L 的抑制商数（IQ1）高出三倍。BIC与HIV-1整合酶的解离半衰期较长，这可能会减轻少数个体低于IQ1的潜在暴露量或突破性病毒血症：INSIGHT（NCT04734652）是一项开放标签、非比较性的2b期随机对照试验，研究对象为抗逆转录病毒疗法（ART）无效或非无效的成人艾滋病病毒感染者和肺结核患者，以利福平为基础的肺结核治疗方案（8周）。参与者按2:1的比例随机分配到BIC治疗组（比特拉韦/恩曲他滨/替诺福韦-阿拉非那胺）或标准治疗多鲁特拉韦组（TLD），每天给药两次，直到结核病治疗后2周，之后每天给药一次，直到48周。43 名 BIC 组参与者参加了半强化药代动力学（PK）子研究。在结核病治疗期间的用药前、用药后 1、2、4、6 和 8-12 小时以及结核病治疗后的用药前、用药后 1、2、4、6-8 和 24-25 小时进行了半强化 PK 采样。采用经过验证的 LC-MS/MS 方法检测 BIC 浓度。在 R 中使用 PKNCA 软件包（10.2 版）对 BIC 进行了非室 PK 分析。参与者定期接受临床和安全访视，包括在基线、第 4、8、12、24、40 和 48 周进行 HIV 病毒载量测量。我们报告了初步的 PK 数据和主要终点结果，即在结核病治疗结束时（第 24 周）血浆 HIV-1-RNA 为 50 拷贝/毫升的参与者比例：我们招募了 122 名参与者：80 人参加 BIC 组，42 人参加 DTG 组。43人（35%）为女性，基线病毒载量（拷贝/毫升）和CD4 +（细胞/微升）的中位数（IQR）分别为75 649（22 784-391 299）和172（108-352）（BIC组），73 735（21 242-544 830）和139（97-237）（DTG组）。在半强化 PK 亚研究的参与者中，75 份 PK 资料在结核病治疗期间进行了评估，22 份 PK 资料在结核病治疗后进行了评估。在结核病治疗期间，每日两次 BIC 的 0 至 24 小时浓度-时间曲线下面积（AUC0-24）和谷浓度（Ctau）的几何平均数（GM）和（CV%）分别为 30.9 毫克*小时/升（42.2%）和 0.397 毫克/升（73.4%）；在结核病治疗后，每日一次 BIC 的 0 至 24 小时浓度-时间曲线下面积（AUC0-24）和谷浓度（Ctau）分别为 94.9 毫克*小时/升（35.9%）和 2.29 毫克/升（45.1%）。98%的参与者在结核病治疗期间的BIC Ctau有所降低，但仍高于IQ1。在第24周时，HIV-1-RNA为50拷贝/毫升，在按协议分析中，BIC组和DTG组分别为71/73（97%）和36/37（97%）人[在FDA快照分析中，BIC组为71/75（95%）人（2人提前退出），DTG组为36/38（95%）人（1人死亡）]。在报告的15起严重不良事件中，没有一起与研究治疗有关：INSIGHT中期研究结果表明，每日两次的比特拉韦/恩曲他滨/替诺福韦-阿拉非那胺与基于利福平的结核病治疗达到了病毒疗效的目标浓度。在Ctau低于IQ1的<2%参与者中，病毒抑制得以维持，这可能是由于BIC与HIV-1整合酶的解离半衰期较长（163小时）。PK、疗效和安全性数据都支持在PWH和肺结核患者中使用这种疗法。
{"title":"Bictegravir exposures in adults with HIV and tuberculosis on a rifampicin-based tuberculosis treatment regimen","authors":"","doi":"10.1111/bcp.16284","DOIUrl":"10.1111/bcp.16284","url":null,"abstract":"<p><b>5</b></p><p><b>Bictegravir exposures in adults with HIV and tuberculosis on a rifampicin-based tuberculosis treatment regimen</b></p><p>Anushka Naidoo<sup>1,2</sup>, Hylke Waalewijn<sup>3</sup>, Kogieleum Naidoo<sup>1,2</sup>, Marothi Letsoalo<sup>1</sup>, Gillian Dorse<sup>1</sup>, Rubeshan Perumal<sup>1,2</sup>, Emmanuella Osuala<sup>1</sup>, Nonpumelelo Zungu<sup>1</sup>, Phindile Msomi<sup>1</sup>, Paolo Denti<sup>3</sup> and Kelly Dooley<sup>4</sup></p><p><sup>1</sup><i>Center for the AIDS Program of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal;</i> <sup>2</sup><i>Centre for the AIDS Programme of Research in South Africa (CAPRISA), South African Medical Research Council (SAMRC)-CAPRISA-TB-HIV Pathogenesis and Treatment Research Unit, University of KwaZulu-Natal Nelson R Mandela School of Medicine;</i> <sup>3</sup><i>Division of Clinical Pharmacology, Department of Medicine, University of Cape Town;</i> <sup>4</sup><i>Vanderbilt University Medical Center</i></p><p><b>Background:</b> Bictegravir (BIC) has not been evaluated in people with HIV (PWH) and tuberculosis (TB) taking rifampicin-based TB treatment. Healthy volunteer data showed that rifampicin reduced BIC exposure by about 80%; however, trough concentrations remained threefold above the inhibitory quotient (IQ1) of 0.162 mg/L. Potential exposures below IQ1 in few individuals or breakthrough viremia may be mitigated by a long dissociation half-life of BIC from the HIV-1 integrase enzyme.</p><p><b>Methods:</b> INSIGHT (NCT04734652) is an open-label, non-comparative phase 2b randomized controlled trial in ART-naïve or non-naïve adults with HIV and TB, initiated on a rifampicin-based TB regimen (<8 weeks). Participants were randomized in a 2:1 ratio to either the BIC arm (bictegravir/emtricitabine/tenofovir alafenamide) or a standard of care dolutegravir arm (TLD), dosed twice daily until 2 weeks' post-TB treatment and once daily thereafter, until 48 weeks. Forty-three participants in the BIC arm were enrolled in a semi-intensive pharmacokinetic (PK) sub-study. Semi-intensive PK sampling was done at pre-dose, 1, 2, 4, 6 and 8–12 h post-dose during TB treatment and pre-dose, 1, 2, 4, 6–8 and 24–25 h post-dose after TB treatment. BIC concentrations were assayed using a validated LC-MS/MS method. Non-compartmental PK analyses for BIC were conducted in R using the PKNCA package (version 10.2). Participants underwent regular clinical and safety visits, including HIV viral load measurements at baseline, weeks 4, 8, 12, 24, 40 and 48. We report the preliminary PK data and primary endpoint results for the proportion of participants with plasma HIV-1-RNA < 50 copies/mL at the end of TB treatment (week 24).</p><p><b>Results:</b> We enrolled 122 participants: 80 in the BIC and 42 in the DTG arm. Forty-three (35%) were female, with median (IQR) baseline viral load (copies/mL) and CD4 + (cells/μL) of 75 649 (22 784–391 299) and 172 (1","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"6"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16284","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><b>18</b></p><p><b>Development of a USP-4 IVIVC methodology for LAI antivirals: Case studies with cabotegravir and rilpivirine</b></p><p>Emad Anaam, Henry Pertinez, Lee Tatham, Paul Curley, Paul Valentijn, Eduardo Gallardo Toledo, Joanne Sharp and Andrew Owen</p><p><i>University of Liverpool</i></p><p><b>Background:</b> Long-acting injectables (LAI) offer a promising approach to improving adherence and efficacy in the treatment of HIV. Establishing a reliable in vitro-in vivo correlation (IVIVC) is critical for predicting the in vivo performance of these formulations. This study aimed to develop a USP apparatus 4 (USP-4) IVIVC methodology specifically for LAI antivirals using cabotegravir (CAB) and rilpivirine (RPV) as model compounds.</p><p><b>Material and methods:</b> CAB and RPV formulations were subjected to in vitro release testing using the USP-4 apparatus with dose release from a float-a-lyzer dialysis device. Method optimization investigated adjustment of parameters such as temperature, dialysis membrane MWCO and flow rate, Tween 20 excipient concentration and pH of the circulating buffer. Cumulative release profiles were sampled and analysed over a period of 30 days and fitted with a bi-exponential mathematical model to allow extrapolation to estimate longer release durations. For in vivo analysis, clinical LAI pharmacokinetic (PK) data for CAB and RPV were obtained from literature, and in vivo release profiles derived through deconvolution using intravenous (IV) bolus disposition impulse responses estimated for both drugs via PBPK scaling due to lack of clinical IV data. IVIVC predictions and comparisons were made both by convolution of the in vitro release with IV disposition for direct comparison with the in vivo PK exposure profile and by Levy-plot correlations of in vitro and in vivo cumulative release.</p><p><b>Results:</b> Results obtained show sustained in vitro cumulative release for CAB and RPV over 30 days in the USP-4 system. However, in vitro cumulative release extrapolated for the duration of in vivo PK profiles was lower than cumulative release derived from in vivo data. Concordantly, convolution of the in vitro release profiles with estimated IV bolus disposition response underpredicted observed LAI PK exposure profiles. However, inclusion of a linear multiple scaling factor revealed the shape of the in vivo PK exposure profile was predicted by the in vitro release profile. This is illustrated in the Levy correlation plots showing partial correlation between in vitro and in vivo release but with deviation away from the line of unity.</p><p><b>Conclusions:</b> Initial results from developing a USP-4 methodology for application to LAI formulations and IVIVC to clinical LAI PK exposures indicate potential for prediction of in vivo PK exposure or utility as a means of ranking/comparing formulations by in vitro release. Work is ongoing to further investigate optimization of experimental parameters and to expand the library
18开发 LAI 抗病毒药物的 USP-4 IVIVC 方法：Emad Anaam、Henry Pertinez、Lee Tatham、Paul Curley、Paul Valentijn、Eduardo Gallardo Toledo、Joanne Sharp 和 Andrew Owen利物浦大学背景：长效注射剂（LAI）为提高艾滋病治疗的依从性和疗效提供了一种前景广阔的方法。建立可靠的体外-体内相关性（IVIVC）对于预测这些制剂的体内性能至关重要。本研究旨在以卡博特拉韦（CAB）和利匹韦林（RPV）为模型化合物，开发一种专门用于LAI抗病毒药物的USP仪器4（USP-4）IVIVC方法：使用 USP-4 仪器对 CAB 和 RPV 制剂进行了体外释放测试，测试结果显示，这两种药物可从浮动溶液透析装置中释放。方法优化研究了温度、透析膜截留分子量和流速、吐温 20 辅料浓度和循环缓冲液 pH 值等参数的调整。对 30 天内的累积释放曲线进行采样和分析，并采用双指数数学模型进行拟合，以推断出更长的释放持续时间。在体内分析方面，从文献中获得了 CAB 和 RPV 的临床 LAI 药代动力学 (PK) 数据，由于缺乏临床静脉注射数据，通过使用静脉注射 (IV) 药栓处置脉冲响应进行解卷积，得出了这两种药物的体内释放曲线。通过体外释放与静脉注射处置的卷积来预测和比较 IVIVC，以便与体内 PK 暴露曲线进行直接比较，还通过体外和体内累积释放的 Levy-plot 相关性来进行预测和比较：结果表明，在 USP-4 系统中，CAB 和 RPV 的体外累积释放可持续 30 天。然而，根据体内 PK 曲线推断出的体外累积释放量低于体内数据得出的累积释放量。同样，体外释放曲线与估计的静脉注射栓剂处置反应的卷积也低估了观察到的 LAI PK 暴露曲线。然而，加入一个线性多重比例因子后，体内 PK 暴露曲线的形状可由体外释放曲线预测。这在列维相关图中得到了说明，列维相关图显示体外和体内释放之间存在部分相关性，但偏离了统一线：开发用于 LAI 制剂的 USP-4 方法和用于临床 LAI PK 暴露的 IVIVC 的初步结果表明，该方法具有预测体内 PK 暴露的潜力，或可作为通过体外释放对制剂进行排序/比较的手段。目前正在进一步研究如何优化实验参数，并扩大正在研究的 LAI 制剂库，以确定各种 LAI 产品的趋势，并确认该方法的通用性。
{"title":"Development of a USP-4 IVIVC methodology for LAI antivirals: Case studies with cabotegravir and rilpivirine","authors":"","doi":"10.1111/bcp.16297","DOIUrl":"10.1111/bcp.16297","url":null,"abstract":"<p><b>18</b></p><p><b>Development of a USP-4 IVIVC methodology for LAI antivirals: Case studies with cabotegravir and rilpivirine</b></p><p>Emad Anaam, Henry Pertinez, Lee Tatham, Paul Curley, Paul Valentijn, Eduardo Gallardo Toledo, Joanne Sharp and Andrew Owen</p><p><i>University of Liverpool</i></p><p><b>Background:</b> Long-acting injectables (LAI) offer a promising approach to improving adherence and efficacy in the treatment of HIV. Establishing a reliable in vitro-in vivo correlation (IVIVC) is critical for predicting the in vivo performance of these formulations. This study aimed to develop a USP apparatus 4 (USP-4) IVIVC methodology specifically for LAI antivirals using cabotegravir (CAB) and rilpivirine (RPV) as model compounds.</p><p><b>Material and methods:</b> CAB and RPV formulations were subjected to in vitro release testing using the USP-4 apparatus with dose release from a float-a-lyzer dialysis device. Method optimization investigated adjustment of parameters such as temperature, dialysis membrane MWCO and flow rate, Tween 20 excipient concentration and pH of the circulating buffer. Cumulative release profiles were sampled and analysed over a period of 30 days and fitted with a bi-exponential mathematical model to allow extrapolation to estimate longer release durations. For in vivo analysis, clinical LAI pharmacokinetic (PK) data for CAB and RPV were obtained from literature, and in vivo release profiles derived through deconvolution using intravenous (IV) bolus disposition impulse responses estimated for both drugs via PBPK scaling due to lack of clinical IV data. IVIVC predictions and comparisons were made both by convolution of the in vitro release with IV disposition for direct comparison with the in vivo PK exposure profile and by Levy-plot correlations of in vitro and in vivo cumulative release.</p><p><b>Results:</b> Results obtained show sustained in vitro cumulative release for CAB and RPV over 30 days in the USP-4 system. However, in vitro cumulative release extrapolated for the duration of in vivo PK profiles was lower than cumulative release derived from in vivo data. Concordantly, convolution of the in vitro release profiles with estimated IV bolus disposition response underpredicted observed LAI PK exposure profiles. However, inclusion of a linear multiple scaling factor revealed the shape of the in vivo PK exposure profile was predicted by the in vitro release profile. This is illustrated in the Levy correlation plots showing partial correlation between in vitro and in vivo release but with deviation away from the line of unity.</p><p><b>Conclusions:</b> Initial results from developing a USP-4 methodology for application to LAI formulations and IVIVC to clinical LAI PK exposures indicate potential for prediction of in vivo PK exposure or utility as a means of ranking/comparing formulations by in vitro release. Work is ongoing to further investigate optimization of experimental parameters and to expand the library ","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"14-15"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16297","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><b>20</b></p><p><b>Dose proportionality and half-life of tenofovir in hair samples from those with differing adherence to TDF or TAF-based regimens monitored by directly observed therapy</b></p><p>David Nerguizian<sup>1</sup>, Mary Morrow<sup>1</sup>, Samantha MaWhinney<sup>1</sup>, Monica Gandhi<sup>2</sup>, Hideaki Okochi<sup>2</sup> and Peter Anderson<sup>1</sup></p><p><sup>1</sup><i>University of Colorado;</i> <sup>2</sup><i>University of California</i></p><p><b>Background:</b> Objective adherence metrics to antiretroviral therapy have been proven useful in interpreting clinical trial results. Hair tenofovir (TFV) concentrations are indicative of average adherence over approximately 1 month. The pharmacokinetics of TFV in hair have not been fully elucidated for TDF and TAF therapy following directly observed therapy (DOT) in people without HIV infection. The DOT-DBS and TAF-DBS studies, which used DOT to determine TFV-DP concentration benchmarks associated with variable adherence regimens, collected hair at regular intervals. This analysis aimed to assess concentrations, dose proportionality, comparability and the apparent half-life of TFV in hair from TDF and TAF.</p><p><b>Methods:</b> Hair samples were collected from adults without HIV in the DOT-DBS and TAF-DBS studies receiving either TDF 300 mg/FTC 200 mg or TAF 25 mg/FTC 200 mg, respectively, at 33%, 67% or 100% of daily doses. Participants were randomized to one adherence group for 12 weeks followed by a 12-week washout and then randomized to a different adherence group and followed for 12 additional weeks (36 weeks total). Approximately 100–200 hair strands were cut from the occipital portion of the scalp every 3 weeks. TFV concentrations were determined by a previously validated LC-MS/MS assay—reported as ng TFV/mg hair—and week 12 and 36 concentrations were summarized by treatment (TDF or TAF) and adherence group (33%, 67% or 100%). Dose proportionality was assessed using the power model. Ln TFV, concentrations were modelled linearly <i>vs</i>. Ln dose. Proportionality was assumed if the slope's 90% confidence interval (CI) was within 0.80 and 1.25. The apparent half-lives from TAF and TDF were determined assuming exponential decay during the 12-week washout phase.</p><p><b>Results:</b> Seventy samples were collected from 38 DOT-DBS participants (50% male; 7% Black, 55% White, 26% Hispanic) and 68 samples were collected from 35 TAF-DBS participants (51% male; 14% Black, 69% White, 17% Hispanic). Mean (%CV) TFV concentrations from TDF treatment were 0.0165 ng/mg (40.9%), 0.0454 (182%) and 0.0395 ng/mg (36.5%), while from TAF treatment they were 0.0142 ng/mg (30.9%), 0.0275 (28.5%) and 0.0409 ng/mg (42.1%) in the 33%, 67% and 100% adherence groups, respectively. Concentrations of TFV from TDF were less than dose proportional (slope 90% CI: 0.62, 0.96), and proportionality was still not achieved after removing one 67% dosing outlier (90% CI: 0.62, 0.94). TFV from TAF was dose propor
{"title":"Dose proportionality and half-life of tenofovir in hair samples from those with differing adherence to TDF or TAF-based regimens monitored by directly observed therapy","authors":"","doi":"10.1111/bcp.16299","DOIUrl":"10.1111/bcp.16299","url":null,"abstract":"<p><b>20</b></p><p><b>Dose proportionality and half-life of tenofovir in hair samples from those with differing adherence to TDF or TAF-based regimens monitored by directly observed therapy</b></p><p>David Nerguizian<sup>1</sup>, Mary Morrow<sup>1</sup>, Samantha MaWhinney<sup>1</sup>, Monica Gandhi<sup>2</sup>, Hideaki Okochi<sup>2</sup> and Peter Anderson<sup>1</sup></p><p><sup>1</sup><i>University of Colorado;</i> <sup>2</sup><i>University of California</i></p><p><b>Background:</b> Objective adherence metrics to antiretroviral therapy have been proven useful in interpreting clinical trial results. Hair tenofovir (TFV) concentrations are indicative of average adherence over approximately 1 month. The pharmacokinetics of TFV in hair have not been fully elucidated for TDF and TAF therapy following directly observed therapy (DOT) in people without HIV infection. The DOT-DBS and TAF-DBS studies, which used DOT to determine TFV-DP concentration benchmarks associated with variable adherence regimens, collected hair at regular intervals. This analysis aimed to assess concentrations, dose proportionality, comparability and the apparent half-life of TFV in hair from TDF and TAF.</p><p><b>Methods:</b> Hair samples were collected from adults without HIV in the DOT-DBS and TAF-DBS studies receiving either TDF 300 mg/FTC 200 mg or TAF 25 mg/FTC 200 mg, respectively, at 33%, 67% or 100% of daily doses. Participants were randomized to one adherence group for 12 weeks followed by a 12-week washout and then randomized to a different adherence group and followed for 12 additional weeks (36 weeks total). Approximately 100–200 hair strands were cut from the occipital portion of the scalp every 3 weeks. TFV concentrations were determined by a previously validated LC-MS/MS assay—reported as ng TFV/mg hair—and week 12 and 36 concentrations were summarized by treatment (TDF or TAF) and adherence group (33%, 67% or 100%). Dose proportionality was assessed using the power model. Ln TFV, concentrations were modelled linearly <i>vs</i>. Ln dose. Proportionality was assumed if the slope's 90% confidence interval (CI) was within 0.80 and 1.25. The apparent half-lives from TAF and TDF were determined assuming exponential decay during the 12-week washout phase.</p><p><b>Results:</b> Seventy samples were collected from 38 DOT-DBS participants (50% male; 7% Black, 55% White, 26% Hispanic) and 68 samples were collected from 35 TAF-DBS participants (51% male; 14% Black, 69% White, 17% Hispanic). Mean (%CV) TFV concentrations from TDF treatment were 0.0165 ng/mg (40.9%), 0.0454 (182%) and 0.0395 ng/mg (36.5%), while from TAF treatment they were 0.0142 ng/mg (30.9%), 0.0275 (28.5%) and 0.0409 ng/mg (42.1%) in the 33%, 67% and 100% adherence groups, respectively. Concentrations of TFV from TDF were less than dose proportional (slope 90% CI: 0.62, 0.96), and proportionality was still not achieved after removing one 67% dosing outlier (90% CI: 0.62, 0.94). TFV from TAF was dose propor","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"15-16"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16299","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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