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Pharmacokinetics, safety and efficacy study in pregnancy and existing cumulative data/evidence to support clinical use and labelling of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in pregnant women with HIV 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
British journal of clinical pharmacology
Pub Date : 2024-10-10 DOI: 10.1111/bcp.16305
<p><b>26</b></p><p><b>Pharmacokinetics, safety and efficacy study in pregnancy and existing cumulative data/evidence to support clinical use and labelling of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in pregnant women with HIV</b></p><p>Dhananjay Marathe, Priyanka Arora, Haeyoung Zhang, Jason Hindman, Hui Liu, Sandhya Girish, Casey Davis and Ramesh Palaparthy</p><p><i>Gilead Sciences, Inc</i></p><p><b>Background:</b> Safe, effective and convenient treatment options are needed for pregnant women with HIV. Bictegravir is metabolized by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and cytochrome P450 3A4 (CYP3A4). Pregnancy is associated with physiological changes, including increased CYP3A4 and UGT1A1 activities; however, limited data exist on the pharmacokinetics, safety and efficacy of B/F/TAF during pregnancy.</p><p><b>Material and methods:</b> An open-label study (NCT03960645) was conducted in virologically suppressed pregnant women with HIV-1 (<i>n</i> = 33). Steady-state plasma pharmacokinetic samples were collected over 24 h following once-daily oral B/F/TAF dosing during second/third trimesters of pregnancy and postpartum. Bictegravir exposure parameters during pregnancy and postpartum were compared and contextualized with prior pooled phase 3 data in non-pregnant participants. Plasma HIV-1 RNA/DNA was measured in mothers and their neonates. Efficacy response was calculated as the proportion of mothers with HIV-1 RNA < 50 copies/mL (missing = excluded) at delivery. Exposure-efficacy response (E-R) relationships were visualized and contextualized using pooled phase 3 data. Literature evidence from contemporary studies of B/F/TAF in different populations was collated for additional comparisons.</p><p><b>Results:</b> While plasma bictegravir AUC<sub>tau</sub> was lower (~59%) during pregnancy than postpartum, the difference was less pronounced when compared to non-pregnant adults with HIV (~40%). Bictegravir AUC<sub>tau</sub> was similar during second and third trimesters. Mean bictegravir Ctrough was >6 × inhibitory quotient (IQ)1 during pregnancy. All pregnant women maintained virologic suppression (VS), with HIV-1 RNA < 50 copies/mL at delivery (<i>n</i> = 32 [100%]) and no observed virologic failure or treatment-emergent resistance. B/F/TAF was well tolerated, with no adverse events (AEs) leading to premature discontinuation; AEs were consistent with those expected in this pregnant population. No cases of perinatal HIV transmission in neonates (<i>n</i> = 29) occurred. E-R relationship visualizations for once-daily B/F/TAF showed robustly high and plateaued responses over a large exposure range. Current literature is supportive of these data. In IMPAACT 2026 [1], similar efficacy/safety and bictegravir exposure changes during pregnancy were described in a different demographic population. In the INSIGHT trial [2], co-administration of twice-daily B/F/TAF with a rifampicin-based tuberculosis regimen in a
26妊娠期药代动力学、安全性和有效性研究以及支持比特拉韦/恩曲他滨/替诺福韦-阿拉非那胺（B/F/TAF）在感染艾滋病毒的孕妇中临床应用和标签的现有累积数据/证据Gilead Sciences, Inc背景：感染艾滋病病毒的孕妇需要安全、有效和方便的治疗方案。比特拉韦通过二磷酸尿苷葡萄糖醛酸转移酶 1A1 (UGT1A1) 和细胞色素 P450 3A4 (CYP3A4) 进行代谢。妊娠与生理变化有关，包括 CYP3A4 和 UGT1A1 活性增加；然而，关于妊娠期间 B/F/TAF 的药代动力学、安全性和有效性的数据有限：一项开放标签研究（NCT03960645）在病毒学抑制的 HIV-1 孕妇（33 人）中进行。在妊娠期第二/第三季度和产后，每天口服一次 B/F/TAF 后，在 24 小时内收集稳态血浆药代动力学样本。将妊娠期和产后的比特拉韦暴露参数与之前汇总的非妊娠参与者的第 3 期数据进行了比较和背景分析。测定了母亲及其新生儿的血浆 HIV-1 RNA/DNA。疗效反应按分娩时 HIV-1 RNA 为 50 拷贝/毫升（缺失 = 排除）的母亲比例计算。暴露-疗效反应（E-R）关系通过第 3 阶段的汇总数据进行可视化和背景化。为了进行更多比较，还整理了不同人群中B/F/TAF当代研究的文献证据：结果：虽然妊娠期血浆比特拉韦 AUCtau 比产后低（约 59%），但与非妊娠期成人艾滋病感染者（约 40%）相比，差异并不明显。比特拉韦的 AUCtau 在第二和第三孕期相似。妊娠期的平均比特拉韦Ctrough为6×抑制商数（IQ）1。所有孕妇都保持了病毒学抑制（VS），分娩时 HIV-1 RNA 为 50 拷贝/毫升（n = 32 [100%]），未观察到病毒学失败或治疗引发的耐药性。B/F/TAF的耐受性良好，没有导致过早停药的不良事件（AEs）；AEs符合该孕妇群体的预期。没有发生新生儿围产期 HIV 传播病例（29 例）。每日一次的 B/F/TAF 的 E-R 关系可视化显示，在较大的暴露范围内，反应强烈而平稳。目前的文献支持这些数据。在 IMPAACT 2026 [1]中，在不同的人群中描述了类似的疗效/安全性和妊娠期比特拉韦暴露变化。在INSIGHT试验[2]中，在成人HIV感染者和肺结核患者中联合使用每日两次的B/F/TAF和基于利福平的肺结核治疗方案，尽管比特拉韦的平均谷值暴露量（约2.5×IQ1）低得多，但在第24周时仍显示出持续的稳健疗效（约97%）：尽管孕期比特拉韦暴露量较低，但所有母亲都保持了VS，而且B/F/TAF的耐受性普遍良好，这表明孕期使用B/F/TAF是合适的，无需调整剂量。E-R分析和现有文献证据进一步证明，在妊娠期观察到的比特拉韦暴露量下，该药物可能具有很强的疗效。根据我们的妊娠研究数据[3]，美国卫生与公众服务部更新了围产期指南（2024 年 1 月 31 日），将比特拉韦作为一种替代整合酶链转移抑制剂，适用于某些妊娠人群和试图怀孕的非妊娠人群。此外，这些数据以及来自 IMPAACT 2026 和 INSIGHT 的证据支持了 FDA 最近（2024 年）对 B/F/TAF 用于妊娠亚人群的批准和标记。海报 783。[2] Naidoo, A. CROI 2024, Oral 211。[3] Zhang, H, Hindman, J.T., Lin, L., Davis, M., Shang, J., Xiao, D., Avihingsanon, A., Arora, P., Palaparthy, R., Girish, S., Marathe, D.D. Aids 2024; 38(1)：F1-9, A study of the pharmacokinetics, safety, and efficacy of bictegravir/emtricitabine/tenofovir alafenamide in virologically suppressed pregnant women with HIV, DOI: 10.1097/QAD.00000000003783.
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引用次数: 0
Favipiravir pharmacokinetics in saliva, tears and nasal secretions of hospitalized COVID-19 patients following intravenous favipiravir administration 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
British journal of clinical pharmacology
Pub Date : 2024-10-10 DOI: 10.1111/bcp.16287
<p><b>8</b></p><p><b>Favipiravir pharmacokinetics in saliva, tears and nasal secretions of hospitalized COVID-19 patients following intravenous favipiravir administration</b></p><p>Elizabeth Challenger<sup>1</sup>, Tim Rowland<sup>2,3</sup>, Laura Else<sup>1</sup>, Laura Dickinson<sup>1</sup>, Colin Hale<sup>2</sup>, Rebecca Lyon<sup>2</sup>, Henry Pertinez<sup>4</sup>, Andrew Owen<sup>4</sup>, Helen Reynolds<sup>1</sup>, Justin Chiong<sup>1</sup>, Richard FitzGerald<sup>1</sup>, Saye Khoo<sup>1</sup> and Tom Fletcher<sup>3</sup></p><p><sup>1</sup><i>Centre for Experimental Therapeutics, University Of Liverpool;</i> <sup>2</sup><i>Liverpool University Hospitals NHS Foundation Trust;</i> <sup>3</sup><i>Liverpool School of Tropical Medicine;</i> <sup>4</sup><i>Centre of Excellence for Long Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Integrative, Systems and Molecular Biology, University of Liverpool</i></p><p><b>Background:</b> SARS-CoV-2 is transmitted between individuals when virions trapped in aerosols or large droplets are expelled through conversation, coughing or sneezing. Due to consistent emergence of new variants, evaluation of therapeutics for SARS-CoV-2 is crucial to maximize treatment options should more virulent or treatment resistant strains arise. Establishing the concentration of potential therapeutics in sites of SARS-CoV-2 transmission is essential to assess compartmentalization and prophylactic potential. Here we report favipiravir (FVP) concentrations in saliva, tears and nasal secretions in hospitalized COVID-19 patients enrolled on the AGILE CST-6 clinical trial.</p><p><b>Materials and methods:</b> AGILE CST-6 is a randomized, multicentre, seamless, adaptive, phase I/II platform study to evaluate safety and efficacy of intravenous (IV) FVP for the treatment of COVID-19. Patients with laboratory confirmed COVID-19 were enrolled 2:1 to receive IV FVP or standard of care (SoC); four cohorts of six patients (<i>n</i> = 4 FVP, <i>n</i> = 2 SoC) were enrolled, with escalating doses per cohort (600 mg, 1200 mg, 1800 mg, 2400 mg). Patients received IV FVP twice daily over 7 days, with paired plasma and non-plasma samples (saliva, nasal swabs, tear strips) collected between 6 and 12 h post-completion of IV infusion on days 1 and 3. FVP was quantified using validated LC-MS methods and FVP concentrations expressed as ng/mL. Descriptive statistics were computed (Phoenix 64, WinNonlin, v8.3) and FVP non-plasma:plasma ratios (NP:P) determined. Relationships between paired quantifiable non-plasma and plasma concentrations were evaluated by linear regression.</p><p><b>Results:</b> Sixteen individuals [seven females at birth; median (range) age, weight, number of days with COVID-19 symptoms were 76.5 years (52–93), 78.6 kg (52.1–125) and 5 days (2–11), respectively] received at least six doses of IV FVP. Analysis included 32 plasma/nasal, 31 saliva and 30 tear samples. FVP was quantifiable in 100%/91%/
8 静脉注射法非拉韦后 COVID-19 住院患者唾液、眼泪和鼻腔分泌物中的法非拉韦药代动力学Colin Hale2、Rebecca Lyon2、Henry Pertinez4、Andrew Owen4、Helen Reynolds1、Justin Chiong1、Richard FitzGerald1、Saye Khoo1 和 Tom Fletcher31利物浦大学实验治疗中心；2 利物浦大学医院 NHS 基金会信托基金；3 利物浦热带医学院；4 利物浦大学综合、系统和分子生物学研究所药理学和治疗学系长效治疗卓越中心（CELT）背景：SARS-CoV-2 是通过交谈、咳嗽或打喷嚏时排出的滞留在气溶胶或大飞沫中的病毒在人与人之间传播。由于不断出现新的变种，因此评估 SARS-CoV-2 的治疗方法至关重要，以便在出现毒性更强或耐药性更强的病毒株时最大限度地增加治疗选择。确定潜在治疗药物在 SARS-CoV-2 传播场所的浓度对于评估分区和预防潜力至关重要。在此，我们报告了参加 AGILE CST-6 临床试验的 COVID-19 住院患者唾液、眼泪和鼻腔分泌物中的法非拉韦（FVP）浓度：AGILE CST-6 是一项随机、多中心、无缝、适应性 I/II 期平台研究，旨在评估静脉注射 (IV) FVP 治疗 COVID-19 的安全性和有效性。实验室确诊的COVID-19患者按2:1的比例入组，接受静脉注射FVP或标准治疗（SoC）；共入组四组，每组六名患者（n = 4名FVP患者，n = 2名SoC患者），剂量依次递增（600毫克、1200毫克、1800毫克、2400毫克）。患者在 7 天内每天接受两次静脉输注 FVP，并在第 1 天和第 3 天静脉输注结束后的 6 至 12 小时内采集配对的血浆和非血浆样本（唾液、鼻拭子、泪液条）。采用经过验证的 LC-MS 方法对 FVP 进行定量，FVP 浓度以纳克/毫升表示。计算描述性统计（Phoenix 64，WinNonlin，v8.3）并确定 FVP 非血浆与血浆比率（NP:P）。通过线性回归评估了可配对量化的非血浆浓度与血浆浓度之间的关系：16人[出生时为7名女性；年龄、体重和出现COVID-19症状天数的中位数（范围）分别为76.5岁（52-93岁）、78.6千克（52.1-125千克）和5天（2-11天）]接受了至少6次静脉注射FVP。分析包括 32 份血浆/鼻腔样本、31 份唾液样本和 30 份泪液样本。在静脉注射后 6.1-7.2 小时采集的唾液/鼻腔/泪液样本中，100%/91%/97% 的 FVP 均可定量。FVP浓度随剂量[600|1200|1800|2400 毫克/天]的增加而增加，但在剂量组群中，受试者内部和受试者之间存在显著差异。第 3 天，血浆中的 FVP 中位浓度分别为 1336/38 730/47 000/125 468 纳克/毫升，唾液中的 FVP 中位浓度分别为 69/1042/4218/9742 纳克/毫升，鼻腔分泌物中的 FVP 中位浓度分别为 2455/2247/7968/13 420 纳克/毫升，泪液中的 FVP 中位浓度分别为 693/5762/3620/34 985 纳克/毫升。从第 1 天到第 3 天，在所有基质中都观察到了 FVP 的累积。非血浆和血浆浓度在第 3 天显著相关（r > 0.724; p <.003）。第 1 天，13% 的血浆样本（均为 2400 毫克剂量）高于 FVP SARS-CoV-2 体外 EC90（24.9 微克/毫升）；所有非血浆浓度均低于该临界值。在第 3 天，56% 的血浆样本（≥1200 毫克剂量）、12% 的鼻腔样本和 6% 的泪液样本（2400 毫克剂量）超过了这一临界值：这是首次报道在 SARS-CoV-2 传播地点测量 FVP。这些数据表明，即使静脉注射较高剂量的 FVP（每日 2400 毫克），也很难在唾液、鼻腔和眼部达到相当于 EC90 的浓度。FVP 主要渗入鼻腔分泌物，其次是泪液和唾液，但个体间差异很大。目前正在评估静脉注射 FVP 的 PK/PD 关系。
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引用次数: 0
Optimal dose and safety of intravenous favipiravir in hospitalized patients with SARS-COV-2: A phase I, open-label, dose-escalating, randomized controlled study 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
British journal of clinical pharmacology
Pub Date : 2024-10-10 DOI: 10.1111/bcp.16288
<p><b>9</b></p><p><b>Optimal dose and safety of intravenous favipiravir in hospitalized patients with SARS-COV-2: A phase I, open-label, dose-escalating, randomized controlled study</b></p><p>Tim Rowland<sup>1,2</sup>, Richard FitzGerald<sup>2,3</sup>, Laura Else<sup>3</sup>, Elizabeth Challenger<sup>3</sup>, Laura Dickinson<sup>3</sup>, Lauren Walker<sup>2,3</sup>, Colin Hale<sup>2</sup>, Rebecca Lyon<sup>2</sup>, Karim Dhamani<sup>4</sup>, Margaret Irwin<sup>4</sup>, Yvanne Enever<sup>4</sup>, Michelle Tetlow<sup>3</sup>, Orod Osanlou<sup>5</sup>, Helen Reynolds<sup>3</sup>, Justin Chiong<sup>3</sup>, Henry Pertinez<sup>6</sup>, Andrew Owen<sup>6</sup>, Geoff Saunders<sup>7</sup>, Gareth Griffiths<sup>7</sup>, Saye Khoo<sup>3</sup> and Tom Fletcher<sup>1</sup></p><p><sup>1</sup><i>Liverpool School of Tropical Medicine;</i> <sup>2</sup><i>NIHR Liverpool Clinical Research Facility;</i> <sup>3</sup><i>Centre for Experimental Therapeutics (TherEx), Department of Pharmacology and Therapeutics, Institute of Integrative, Systems and Molecular Biology, University of Liverpool;</i> <sup>4</sup><i>PHARMExcel;</i> <sup>5</sup><i>Bangor University;</i> <sup>6</sup><i>Centre of Excellence for Long-acting Therapeutics (CELT), University of Liverpool;</i> <sup>7</sup><i>Southampton Clinical Trials Unit, University of Southampton</i></p><p><b>Background:</b> AGILE is a phase Ib/IIa platform for rapidly evaluating candidate therapeutics for the treatment of COVID-19. In this trial (NCT04746183), we evaluated the safety and optimal dose of a novel intravenous (IV) formulation of favipiravir (FVP) in hospitalized participants with SARS-CoV-2.</p><p><b>Materials and methods:</b> CST-6 was a dose-escalating, open-label, randomized, controlled Bayesian adaptive phase Ib trial carried out at the NIHR Liverpool Clinical Research Facility. Participants (hospitalized adults with PCR-confirmed SARS-CoV-2 infection within 14 days of onset of symptomatic COVID-19) were randomized 2:1 in groups of six participants (<i>n</i> = 4 FVP, <i>n</i> = 2 SoC) to 600, 1200, 1800 and 2400 mg doses of IV FVP twice daily for 7 days or standard of care (SoC). Throughout the study period, clinical data, safety evaluations, virology and pharmacokinetics were collected at predefined timepoints. FVP was quantified using validated LC-MS methods with FVP concentrations expressed as ng/mL. The primary outcome was safety, with toxicity considered to be unacceptable if the probability of 30% or greater dose-limiting toxicity related to FVP over controls was 25% or greater, as calculated by the Bayesian model. Secondary outcomes included clinical progression scores, pharmacokinetic parameters and virological endpoints.</p><p><b>Results:</b> Of 30 participants screened, 24 were enrolled between 10 September 2022 and 1 November 2023 [10/24 female; median age was 74 years (range 52–93)]. FVP was well tolerated at all doses, despite a high background rate of adverse events reflecting the frailty and c
9 SARS-COV-2 住院患者静脉注射法非拉韦的最佳剂量和安全性：一项 I 期、开放标签、剂量递增、随机对照研究Margaret Irwin4、Yvanne Enever4、Michelle Tetlow3、Orod Osanlou5、Helen Reynolds3、Justin Chiong3、Henry Pertinez6、Andrew Owen6、Geoff Saunders7、Gareth Griffiths7、Saye Khoo3 和 Tom Fletcher11利物浦热带医学院；2NIHR 利物浦临床研究机构；3Centre for Experimental Therapeutics (TherEx), Department of Pharmacology and Therapeutics, Institute of Integrative, Systems and Molecular Biology, University of Liverpool；4PHARMExcel；5Bangor University；6Centre of Excellence for Long-acting Therapeutics (CELT)，University of Liverpool；7Southampton Clinical Trials Unit，University of Southampton背景：AGILE 是一个 Ib/IIa 期平台，用于快速评估治疗 COVID-19 的候选疗法。在这项试验（NCT04746183）中，我们评估了新型静脉注射剂型法非比拉韦（FVP）在SARS-CoV-2住院患者中的安全性和最佳剂量：CST-6是一项剂量递增、开放标签、随机对照贝叶斯适应性Ib期试验，在利物浦NIHR临床研究机构进行。参与者（COVID-19 发病 14 天内经 PCR 证实感染 SARS-CoV-2 的住院成人）按 2:1 随机分为 6 组（n = 4 FVP，n = 2 SoC），分别接受 600、1200、1800 和 2400 毫克剂量的静脉注射 FVP，每天两次，连续 7 天或标准护理（SoC）。在整个研究期间，在预定的时间点收集临床数据、安全性评估、病毒学和药代动力学。采用经过验证的 LC-MS 方法对 FVP 进行定量，FVP 浓度以纳克/毫升表示。主要结果是安全性，根据贝叶斯模型计算，如果与 FVP 相关的 30% 或更大剂量限制性毒性超过对照组的概率为 25% 或更大，则认为毒性不可接受。次要结果包括临床进展评分、药代动力学参数和病毒学终点：在筛选出的 30 名参与者中，有 24 人在 2022 年 9 月 10 日至 2023 年 11 月 1 日期间入组[10/24 名女性；中位年龄为 74 岁（52-93 岁）]。所有剂量的 FVP 耐受性都很好，尽管不良反应发生率较高，这反映了参与者的体弱和合并症。与以往的 FVP 研究一样，治疗组群中的患者也出现了一过性高尿酸血症。所有病例均无症状，并在治疗结束后缓解。没有严重不良事件或严重（≥3 级）不良事件被独立的盲人评估员认为可能或很可能与 FVP 有关。根据贝叶斯模型的估计，2400 毫克的毒性超过对照组 30% 的概率为 2.7%。PK 暴露随剂量成比例增加，但每个队列中的参与者之间存在显著差异。血浆中出现了明显的FVP蓄积；1-4组（600/1200/1800/2400毫克BD）的第1天（输注后6-12小时）中位数为500（低于LLQ）/4242/5109/23 573纳克/毫升，第3天中位数为1335/38 730/47 000/125 468纳克/毫升：在这项新型静脉注射 FVP 制剂的 Ib 期多剂量递增研究中，我们给予了比以往更高的持续剂量，最高达 2400 毫克，每天两次。尽管COVID-19入院患者体弱多病，但静脉注射FVP在此剂量下安全且耐受性良好。血浆 PK 研究显示，与以往采用负荷剂量的研究不同，FVP 在第 3 天和第 5 天会出现蓄积。不同个体之间的 PK 存在显著差异。虽然耐受性良好，但根据 PK 数据，我们报告了最近的 FVP EC90 数据，我们不建议将 FVP 作为 COVID-19 的治疗方法进行后期临床试验评估。FVP 仍是治疗包括大流行性流感在内的新兴病毒威胁的潜在重要候选药物。
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引用次数: 0
Adherence insights from TAF/FTC-based art co-encapsulated with an ingestible sensor among virologically suppressed persons with HIV 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
British journal of clinical pharmacology
Pub Date : 2024-10-10 DOI: 10.1111/bcp.16291
<p><b>12</b></p><p><b>Adherence insights from TAF/FTC-based art co-encapsulated with an ingestible sensor among virologically suppressed persons with HIV</b></p><p>Ryan Coyle<sup>1</sup>, Vincent Mainella<sup>1</sup>, Mary Morrow<sup>1</sup>, Sarah Mann<sup>1</sup>, Stefanie Schwab<sup>1</sup>, Corwin Coppinger<sup>1</sup>, Nicholas Barker<sup>1</sup>, Samuel Ellis<sup>1</sup>, Tony Carnes<sup>2</sup>, Pamela Alpert<sup>2</sup>, Lucas Ellison<sup>1</sup>, Lane Bushman<sup>1</sup>, Kristina Brooks<sup>1</sup>, Samantha MaWhinney<sup>1</sup>, Jose Castillo-Mancilla<sup>1</sup> and Peter Anderson<sup>1</sup></p><p><sup>1</sup><i>University of Colorado Anschutz Medical Campus;</i> <sup>2</sup><i>etectRx</i></p><p><b>Background:</b> QUANTI-TAF (NCT04065347) measured adherence for approximately 16 weeks using digital pills with ingestible sensors (ID-Cap System, etectRx) paired with tenofovir diphosphate/emtricitabine triphosphate (TFV-DP/FTC-TP) concentrations in dried blood spots (DBS) among 84 persons with HIV (PWH) receiving daily oral tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART) for ≥6 months. This analysis focused on digital pill adherence patterns.</p><p><b>Material and methods:</b> We categorized each recorded dose by interval length (>36 h [late/missed]; 36–18 h [on-time]; <18 h [early/stacked]). Chi-squared tests compared the proportion of observed dosing intervals and detected <i>vs</i>. manually entered doses. Kaplan–Meier analysis evaluated digital pill system use from enrolment to end of study, censored at week 16. We used generalized estimating equations with a logit link to calculate the odds ratio (OR [95% CI]) of a missed dose according to day of the week, or between Sunday–Thursday and Friday–Saturday. We summarized HIV-1 RNA, adherence and TFV-DP/FTC-TP in DBS at visits with suppressed HIV-1 RNA (<200 copies/mL) and low (<85%) cumulative (enrolment to visit) digital pill adherence as proportion (%) or median (IQR).</p><p><b>Results:</b> Overall, adherence was 93% (8650 recorded doses/9280 expected). Dosing intervals were mostly on-time (7991 [92%]), with smaller numbers of late/missed doses (356 [4%]) or early/stacked doses (303 [4%]), <i>p</i> < .0001. Significantly more doses were detected (7948 [92%]) than manually entered (702 [8%]), <i>p</i> < .0001. The proportion of participants on-study was 84/84 (100%) at week 4, 81/84 (96%) at week 8, 77/84 (92%) at week 12 and 73/84 (87%) at week 16. Median (IQR) cumulative adherence was 100% (100%–100%) at week 4 and 99% (96%–100%) at week 12 and at week 16. The OR (95% CI) for a missed dose was higher on Friday compared with Monday (1.35 [1.02, 1.79]; <i>p</i> = .04) or Tuesday (1.34 [1.04, 1.73]; <i>p</i> = .03), and on Saturday compared with Sunday (1.39 [1.08, 1.79]; <i>p</i> = .01), Monday (1.58 [1.14, 2.19]; <i>p</i> = .006), Tuesday (1.57 [1.23, 2.02]; <i>p</i> = .0004), Wednesday (1.38 [1.01, 1.88]; <i>p</i> = .04), or Thursda
Nicholas Barker1、Samuel Ellis1、Tony Carnes2、Pamela Alpert2、Lucas Ellison1、Lane Bushman1、Kristina Brooks1、Samantha MaWhinney1、Jose Castillo-Mancilla1 和 Peter Anderson11科罗拉多大学安舒茨医学园区；2etectRx背景：QUANTI-TAF（NCT04065347）使用带有可摄取传感器的数字药丸（ID-Cap 系统）测量了约 16 周的依从性、etectRx）与干血斑（DBS）中的二磷酸替诺福韦/三磷酸恩曲他滨（TFV-DP/FTC-TP）浓度配对，测量了 84 名每天口服替诺福韦-阿拉芬酰胺/恩曲他滨（TAF/FTC）抗逆转录病毒疗法（ART）≥6 个月的 HIV 感染者（PWH）的依从性。本分析主要关注数字药片的依从性模式：我们将每次记录的服药时间按间隔长度分类（36 小时[迟到/错过]；36-18 小时[准时]；18 小时[提前/叠加]）。卡普兰-梅耶分析评估了观察到的用药间隔比例，以及检测到的剂量与手动输入的剂量之间的关系。卡普兰-梅耶分析评估了数字药丸系统从注册到研究结束的使用情况，并在第16周进行了删减。我们使用带有对数链接的广义估计方程，根据一周中的不同日期，或周日至周四和周五至周六，计算漏服剂量的几率比（OR [95% CI]）。我们以比例（%）或中位数（IQR）的形式总结了HIV-1 RNA、依从性和TFV-DP/FTC-TP在HIV-1 RNA抑制（200拷贝/毫升）和数字药片依从性较低（85%）的DBS就诊中的情况：总体而言，服药依从性为 93%（8650 次记录服药/9280 次预期服药）。服药间隔大多准时（7991 次[92%]），晚服/漏服（356 次[4%]）或早服/叠加服（303 次[4%]）的情况较少，P <.0001。检测到的剂量（7948 [92%]）明显多于手动输入的剂量（702 [8%]），p < .0001。第 4 周时，参与研究者的比例为 84/84 (100%)，第 8 周时为 81/84 (96%)，第 12 周时为 77/84 (92%)，第 16 周时为 73/84 (87%)。第 4 周的累计依从性中位数（IQR）为 100%（100%-100%），第 12 周和第 16 周为 99%（96%-100%）。与周一（1.35 [1.02, 1.79]；p = .04）或周二（1.34 [1.04, 1.73]；p = .03）相比，周五漏服的 OR 值（95% CI）更高；与周日相比，周六漏服的 OR 值（1.39 [1.08, 1.79]; p = .01）、周一（1.58 [1.14, 2.19]; p = .006）、周二（1.57 [1.23, 2.02]; p = .0004）、周三（1.38 [1.01, 1.88]; p = .04）或周四（1.47 [1.11, 1.96]; p = .008）。因此，与周日至周四相比，周五至周六漏服剂量的 OR 值（95% CI）更高（1.37 [1.15, 1.63]；p = .0005）。共有 335/404 人次（83%）评估了 HIV-1 RNA（均为 <200拷贝/毫升），其中 247/335 人次（74%）还获得了累积依从性结果（入组前未测定）。其中 19 次/247 人（8%）显示病毒学抑制，但累积依从性较低：在 9/19 次（47%）、4/19 次（21%）和 6/19 次（32%）就诊时，HIV-1 RNA 分别为 0、20 或 26 至 86 copies/mL。在这19次就诊中，DBS中TFV-DP和DBS中FTC-TP的累积依从性中位数（IQR）分别为79%（70%-82%）、2418（2039-3444）fmol/粒和2.79（2.20-3.94）pmol/粒：数字药丸系统的使用率在16周内保持较高水平，为接受TAF/FTC抗逆转录病毒疗法的病毒复制受到抑制的艾滋病患者提供了详细的依从性信息。接受每日口服抗逆转录病毒疗法的艾滋病感染者可能会叠加剂量，以弥补晚服/漏服的剂量；与周日至周四相比，漏服剂量更可能发生在周五至周六。现代抗逆转录病毒疗法的功效突出表现在即使间歇性不坚持治疗也能抑制病毒。未来的研究可以利用数字药丸系统对新型口服给药方案（如长效每周口服抗逆转录病毒疗法）的临床试验进行依从性监测。
{"title":"Adherence insights from TAF/FTC-based art co-encapsulated with an ingestible sensor among virologically suppressed persons with HIV","authors":"","doi":"10.1111/bcp.16291","DOIUrl":"10.1111/bcp.16291","url":null,"abstract":"&lt;p&gt;&lt;b&gt;12&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Adherence insights from TAF/FTC-based art co-encapsulated with an ingestible sensor among virologically suppressed persons with HIV&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Ryan Coyle&lt;sup&gt;1&lt;/sup&gt;, Vincent Mainella&lt;sup&gt;1&lt;/sup&gt;, Mary Morrow&lt;sup&gt;1&lt;/sup&gt;, Sarah Mann&lt;sup&gt;1&lt;/sup&gt;, Stefanie Schwab&lt;sup&gt;1&lt;/sup&gt;, Corwin Coppinger&lt;sup&gt;1&lt;/sup&gt;, Nicholas Barker&lt;sup&gt;1&lt;/sup&gt;, Samuel Ellis&lt;sup&gt;1&lt;/sup&gt;, Tony Carnes&lt;sup&gt;2&lt;/sup&gt;, Pamela Alpert&lt;sup&gt;2&lt;/sup&gt;, Lucas Ellison&lt;sup&gt;1&lt;/sup&gt;, Lane Bushman&lt;sup&gt;1&lt;/sup&gt;, Kristina Brooks&lt;sup&gt;1&lt;/sup&gt;, Samantha MaWhinney&lt;sup&gt;1&lt;/sup&gt;, Jose Castillo-Mancilla&lt;sup&gt;1&lt;/sup&gt; and Peter Anderson&lt;sup&gt;1&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;i&gt;University of Colorado Anschutz Medical Campus;&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt;&lt;i&gt;etectRx&lt;/i&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; QUANTI-TAF (NCT04065347) measured adherence for approximately 16 weeks using digital pills with ingestible sensors (ID-Cap System, etectRx) paired with tenofovir diphosphate/emtricitabine triphosphate (TFV-DP/FTC-TP) concentrations in dried blood spots (DBS) among 84 persons with HIV (PWH) receiving daily oral tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART) for ≥6 months. This analysis focused on digital pill adherence patterns.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Material and methods:&lt;/b&gt; We categorized each recorded dose by interval length (&gt;36 h [late/missed]; 36–18 h [on-time]; &lt;18 h [early/stacked]). Chi-squared tests compared the proportion of observed dosing intervals and detected &lt;i&gt;vs&lt;/i&gt;. manually entered doses. Kaplan–Meier analysis evaluated digital pill system use from enrolment to end of study, censored at week 16. We used generalized estimating equations with a logit link to calculate the odds ratio (OR [95% CI]) of a missed dose according to day of the week, or between Sunday–Thursday and Friday–Saturday. We summarized HIV-1 RNA, adherence and TFV-DP/FTC-TP in DBS at visits with suppressed HIV-1 RNA (&lt;200 copies/mL) and low (&lt;85%) cumulative (enrolment to visit) digital pill adherence as proportion (%) or median (IQR).&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Overall, adherence was 93% (8650 recorded doses/9280 expected). Dosing intervals were mostly on-time (7991 [92%]), with smaller numbers of late/missed doses (356 [4%]) or early/stacked doses (303 [4%]), &lt;i&gt;p&lt;/i&gt; &lt; .0001. Significantly more doses were detected (7948 [92%]) than manually entered (702 [8%]), &lt;i&gt;p&lt;/i&gt; &lt; .0001. The proportion of participants on-study was 84/84 (100%) at week 4, 81/84 (96%) at week 8, 77/84 (92%) at week 12 and 73/84 (87%) at week 16. Median (IQR) cumulative adherence was 100% (100%–100%) at week 4 and 99% (96%–100%) at week 12 and at week 16. The OR (95% CI) for a missed dose was higher on Friday compared with Monday (1.35 [1.02, 1.79]; &lt;i&gt;p&lt;/i&gt; = .04) or Tuesday (1.34 [1.04, 1.73]; &lt;i&gt;p&lt;/i&gt; = .03), and on Saturday compared with Sunday (1.39 [1.08, 1.79]; &lt;i&gt;p&lt;/i&gt; = .01), Monday (1.58 [1.14, 2.19]; &lt;i&gt;p&lt;/i&gt; = .006), Tuesday (1.57 [1.23, 2.02]; &lt;i&gt;p&lt;/i&gt; = .0004), Wednesday (1.38 [1.01, 1.88]; &lt;i&gt;p&lt;/i&gt; = .04), or Thursda","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"10-11"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16291","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399423","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}
引用次数: 0
Case report: Dolutegravir dosing post-Roux-en-Y gastric bypass surgery 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
British journal of clinical pharmacology
Pub Date : 2024-10-10 DOI: 10.1111/bcp.16314

35

Case report: Dolutegravir dosing post-Roux-en-Y gastric bypass surgery

Jennifer Hawkes

Northern Health

Background: Adequacy of dolutegravir drug exposure when administered after the duodenum (such as Roux-en-Y jejunostomy tube or Roux-en-Y gastric bypass surgery) is largely unknown. In addition, various gastrointestinal modifications including changes in gastric volume, acidity, emptying time, enterohepatic circulation and delayed entry of bile acids may be present post-surgery. Existing data are limited to individual case reports or case series with the timing of collection post-surgery varying. Pharmacokinetics are more likely to be altered in the early stages post-surgery. There is evidence of decreased exposure of dolutegravir following a Roux-en-Y gastric bypass surgery. In some cases, a temporary increase in dolutegravir dose to 50 mg BID may be considered.

Case report: A 53-year-old white male with HIV on antiretroviral therapy with dolutegravir/abacavir/lamivudine FDC and recent non-adherence with 1 month of missed doses is admitted for emergency Roux-en-Y gastric bypass surgery due to a septic shock and perforated gastric viscus with a suspected gastric tumour. He is non-obese and had a low BMI of 18.5. He was not virologically suppressed at the time of the surgery with an HIV VL 560 copies/mL and a CD4 count of 160 cells/mm3. The dolutegravir dose was increased to 50 mg BID with food post-surgery to mitigate potential decreased levels. Dolutegravir trough levels were measured at 7 days' post-dose increase (steady state), which was 2 weeks' post-surgery. A reduction in dolutegravir trough concentrations were observed compared to reference Cmin levels prior to the AM dose but not the supper dose (1137 and 2167 ng/mL vs. reference of 2120 ng/mL). A target dolutegravir trough has not yet been established nor has a dose limiting toxicity. His HIV viral load re-suppressed to <40 copies/mL at 1 month post-surgery and has remained suppressed at 2, 3 and 5 months' post-surgery with an increase of CD4 cells to 290 cells/mm3 at 5 months' post-surgery.

It was decided to continue dolutegravir BID long term in this patient due to one level being at reference and one below reference, the challenges with obtaining new steady-state levels, tolerability of the regimen and ongoing intermittent non-adherence.

Conclusion: This case study continues to highlight the importance of performing pharmacokinetic assessments in patients with the potential for impaired drug absorption to ensure antiretroviral success. Dolutegravir BID has been shown to be well tolerated for long-term use; however, there is the potential to reduce the dose in the future based on adherence and therapeutic drug monitoring.

35病例报告：Roux-en-Y 胃旁路手术后的多罗替拉韦剂量珍妮弗-霍克斯（Jennifer Hawkes）北方健康背景：在十二指肠（如 Roux-en-Y 空肠造口术管或 Roux-en-Y 胃旁路手术）术后给药时，多鲁曲韦药物暴露的充分性在很大程度上是未知的。此外，手术后可能会出现各种胃肠道变化，包括胃容量、酸度、排空时间、肠肝循环和胆汁酸进入延迟。现有数据仅限于个别病例报告或系列病例，手术后收集数据的时间也各不相同。药代动力学更有可能在术后早期阶段发生改变。有证据表明，Roux-en-Y 胃旁路手术后多鲁特韦的暴露量会减少。在某些情况下，可以考虑将多罗替拉韦的剂量暂时增加到 50 毫克，每日一次：病例报告：一名 53 岁的白人男性艾滋病患者正在接受多罗替韦/阿巴卡韦/拉米夫定 FDC 抗逆转录病毒治疗，最近因错过服药 1 个月而未坚持治疗，因脓毒性休克、胃粘膜穿孔和疑似胃肿瘤而入院接受紧急 Roux-en-Y 胃旁路手术。他并不肥胖，体重指数较低，仅为 18.5。手术时他的病毒未被抑制，HIV VL 为 560 copies/mL，CD4 细胞计数为 160 cells/mm3。手术后，多鲁曲韦的剂量增加到 50 毫克，每日两次，饭后服用，以减轻可能出现的药物浓度下降。多鲁曲韦谷浓度是在剂量增加后7天（稳态），即手术后2周测定的。与上午用药前的参考 Cmin 水平相比，多鲁曲韦谷浓度有所下降，但与晚餐用药前的参考 Cmin 水平相比，多鲁曲韦谷浓度并没有下降（1137 和 2167 纳克/毫升，参考值为 2120 纳克/毫升）。多鲁曲韦的目标谷值尚未确定，剂量限制毒性也未确定。术后1个月，他的HIV病毒载量恢复到40拷贝/毫升，术后2、3和5个月仍处于抑制状态，术后5个月CD4细胞增加到290个/立方毫米。由于多鲁曲韦的一个水平达到参考值，一个低于参考值，获得新的稳态水平面临挑战，治疗方案的耐受性以及间歇性不依从性，因此决定继续对该患者进行多鲁曲韦BID长期治疗：本病例研究继续强调了对药物吸收可能受损的患者进行药代动力学评估以确保抗逆转录病毒治疗成功的重要性。多罗替拉韦双剂量长期服用的耐受性良好，但未来有可能根据依从性和治疗药物监测情况减少剂量。
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引用次数: 0
Minimal impact of pregnancy on rilpivirine pharmacokinetics: A POPPK approach 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
British journal of clinical pharmacology
Pub Date : 2024-10-10 DOI: 10.1111/bcp.16293
<p><b>14</b></p><p><b>Minimal impact of pregnancy on rilpivirine pharmacokinetics: A POPPK approach</b></p><p>Minh Lê<sup>1</sup>, Benjamin Kably<sup>1</sup>, Roland Tubiana<sup>2</sup>, Jade Ghosn<sup>3</sup>, Quentin Le Hingrat<sup>4</sup>, Marc Wirden<sup>5</sup>, Zeliea Julia<sup>3</sup>, Naima Hamani<sup>2</sup>, Laurent Mandelbrot<sup>6</sup> and Gilles Peytavin<sup>1</sup></p><p><sup>1</sup><i>AP-HP, Hôpital Bichat, Pharmacology;</i> <sup>2</sup><i>AP-HP, Hôpital Pitié Salpétrière, Infectious Diseases;</i> <sup>3</sup><i>AP-HP, Hôpital Bichat, Infectious Diseases;</i> <sup>4</sup><i>AP-HP, Hôpital Bichat, Virology;</i> <sup>5</sup><i>AP-HP, Hôpital Pitié Salpétrière, Virology;</i> <sup>6</sup><i>AP-HP, Hôpital Louis Mourier, Obstetrics</i></p><p><b>Background:</b> Rilpivirine is the most popular non-nucleoside transcriptase inhibitor (NNRTI) recommended to prevent the risk of mother-to-child transmission of HIV. However, a decrease of rilpivirine plasma exposure in the second trimester could be expected due to an increased metabolism and/or elimination in pregnant women. The latter could compromise the efficacy of the ARV strategy. The objectives were to assess maternal rilpivirine plasma concentrations during pregnancy and postpartum.</p><p><b>Material and methods:</b> A multicentre, cross-sectional cohort was conducted from 2020 to 2023. Pregnant women living with HIV receiving rilpivirine 25 mg once-daily containing regimen were enrolled. Plasma concentrations of rilpivirine were determined by UPLC-MS/MS (Waters Acquity) during the three trimesters (Tn) of pregnancy and postpartum. The gestational age was recorded for each sample. A population pharmacokinetic approach was performed using Monolix 2023R1 suite to analyse the plasma concentrations. Rilpivirine trough plasma concentrations (C24h) were estimated using individual parameters. Rilpivirine C24h were interpreted using an efficacy threshold of 50 ng/mL. The results are presented as median (IQR).</p><p><b>Results:</b> Seventy-two (97% sub-Saharan African) pregnant women were enrolled: age 34 years old (28–38). All were receiving FTC/TFV (as TDF or TAF) associated NRTIs with no boosted PI/r or reported CYP3A4 inhibitor. For these women, 222 plasma concentrations were determined corresponding to 20 at T1, 85 at T2, 92 at T3 and 25 postpartum. Population pharmacokinetic parameters (RSE%) were ka 1 h-1 (fixed), V/F 727 L (10.7%), CL/F 6.4 L/h (9.1%). Inter-individual variabilities were 39% (22.7%) and 53% (14.5%) for V/F and CL/F, respectively. Between-occasion variabilities were 73% (8.2%) and 24% (14.1%) for V/F and CL/F, respectively. Additive and proportional errors were 3.7 ng/mL (46.5%) and 0.08 (36.1%), respectively. There was no effect of gestational age or trimester on ka, V/F or CL/F parameters to improve the between-occasion variabilities. Rilpivirine estimated C24h were 90 ng/mL (50–103). Among the 72 patients, 14% of patients presented C24h below the 50 ng/mL. All women pr
14 怀孕对利匹韦林药代动力学的影响最小：Minh Lê1, Benjamin Kably1, Roland Tubiana2, Jade Ghosn3, Quentin Le Hingrat4, Marc Wirden5, Zeliea Julia3, Naima Hamani2, Laurent Mandelbrot6 and Gilles Peytavin11AP-HP, Hôpital Bichat, Pharmacology；2AP-HP, Hôpital Pitié Salpétrière, Infectious Diseases; 3AP-HP, Hôpital Bichat, Infectious Diseases; 4AP-HP, Hôpital Bichat, Virology; 5AP-HP, Hôpital Pitié Salpétrière, Virology; 6AP-HP, Hôpital Louis Mourier, Obstetrics背景：利匹韦林是最常用的非核苷转录酶抑制剂（NNRTI），被推荐用于预防艾滋病母婴传播风险。然而，由于孕妇体内的新陈代谢和/或排出量增加，预计在妊娠后三个月里利匹韦林的血浆暴露量会减少。后者可能会影响抗逆转录病毒药物的疗效。研究目的是评估孕期和产后母体利匹韦林血浆浓度：在 2020 年至 2023 年期间进行了一项多中心横断面队列研究。招募了接受利匹韦林 25 毫克、每日一次含药方案的艾滋病病毒感染孕妇。通过 UPLC-MS/MS (Waters Acquity) 测定怀孕三个月（Tn）和产后的血浆中利匹韦林的浓度。每个样本都记录了孕龄。使用 Monolix 2023R1 套件采用群体药代动力学方法分析血浆浓度。利匹韦林谷血浆浓度（C24h）是利用单个参数估算的。利匹韦林 C24h 采用 50 纳克/毫升的疗效阈值进行解释。结果以中位数（IQR）表示：72名孕妇（97%为撒哈拉以南非洲孕妇）参加了研究，年龄为34岁（28-38岁）。所有孕妇都在接受 FTC/TFV（作为 TDF 或 TAF）相关的 NRTIs 治疗，但没有使用增强型 PI/r 或报告的 CYP3A4 抑制剂。对这些妇女的 222 例血浆浓度进行了测定，其中 20 例在 T1 期，85 例在 T2 期，92 例在 T3 期，25 例在产后。总体药代动力学参数（RSE%）为 ka 1 h-1（固定值）、V/F 727 L（10.7%）、CL/F 6.4 L/h（9.1%）。V/F 和 CL/F 的个体间变异率分别为 39% (22.7%) 和 53% (14.5%)。V/F和CL/F的个体间变异率分别为73%（8.2%）和24%（14.1%）。加性误差和比例误差分别为 3.7 纳克/毫升（46.5%）和 0.08（36.1%）。妊娠年龄或孕期对 ka、V/F 或 CL/F 参数没有影响，因而不会改善不同事件之间的变异性。利匹韦林估计的 C24h 为 90 纳克/毫升（50-103）。在 72 名患者中，14% 的患者 C24h 低于 50 纳克/毫升。所有妇女在怀孕期间均检测不到病毒载量：结论：在这群主要由撒哈拉以南非洲孕妇组成的艾滋病病毒感染者中，妊娠（孕期或胎龄）对利匹韦林药代动力学参数没有明显影响。令人惊讶的是，妊娠期间利匹韦林的血浆暴露量没有下降，所有患者在妊娠期间都保持了检测不到的病毒载量。这些结果表明，在这种情况下不建议进行系统的剂量调整。不过，考虑到利匹韦林的耐药性基因屏障较低，仍应进行密切的治疗药物监测。
{"title":"Minimal impact of pregnancy on rilpivirine pharmacokinetics: A POPPK approach","authors":"","doi":"10.1111/bcp.16293","DOIUrl":"10.1111/bcp.16293","url":null,"abstract":"&lt;p&gt;&lt;b&gt;14&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Minimal impact of pregnancy on rilpivirine pharmacokinetics: A POPPK approach&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Minh Lê&lt;sup&gt;1&lt;/sup&gt;, Benjamin Kably&lt;sup&gt;1&lt;/sup&gt;, Roland Tubiana&lt;sup&gt;2&lt;/sup&gt;, Jade Ghosn&lt;sup&gt;3&lt;/sup&gt;, Quentin Le Hingrat&lt;sup&gt;4&lt;/sup&gt;, Marc Wirden&lt;sup&gt;5&lt;/sup&gt;, Zeliea Julia&lt;sup&gt;3&lt;/sup&gt;, Naima Hamani&lt;sup&gt;2&lt;/sup&gt;, Laurent Mandelbrot&lt;sup&gt;6&lt;/sup&gt; and Gilles Peytavin&lt;sup&gt;1&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;i&gt;AP-HP, Hôpital Bichat, Pharmacology;&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt;&lt;i&gt;AP-HP, Hôpital Pitié Salpétrière, Infectious Diseases;&lt;/i&gt; &lt;sup&gt;3&lt;/sup&gt;&lt;i&gt;AP-HP, Hôpital Bichat, Infectious Diseases;&lt;/i&gt; &lt;sup&gt;4&lt;/sup&gt;&lt;i&gt;AP-HP, Hôpital Bichat, Virology;&lt;/i&gt; &lt;sup&gt;5&lt;/sup&gt;&lt;i&gt;AP-HP, Hôpital Pitié Salpétrière, Virology;&lt;/i&gt; &lt;sup&gt;6&lt;/sup&gt;&lt;i&gt;AP-HP, Hôpital Louis Mourier, Obstetrics&lt;/i&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Rilpivirine is the most popular non-nucleoside transcriptase inhibitor (NNRTI) recommended to prevent the risk of mother-to-child transmission of HIV. However, a decrease of rilpivirine plasma exposure in the second trimester could be expected due to an increased metabolism and/or elimination in pregnant women. The latter could compromise the efficacy of the ARV strategy. The objectives were to assess maternal rilpivirine plasma concentrations during pregnancy and postpartum.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Material and methods:&lt;/b&gt; A multicentre, cross-sectional cohort was conducted from 2020 to 2023. Pregnant women living with HIV receiving rilpivirine 25 mg once-daily containing regimen were enrolled. Plasma concentrations of rilpivirine were determined by UPLC-MS/MS (Waters Acquity) during the three trimesters (Tn) of pregnancy and postpartum. The gestational age was recorded for each sample. A population pharmacokinetic approach was performed using Monolix 2023R1 suite to analyse the plasma concentrations. Rilpivirine trough plasma concentrations (C24h) were estimated using individual parameters. Rilpivirine C24h were interpreted using an efficacy threshold of 50 ng/mL. The results are presented as median (IQR).&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Seventy-two (97% sub-Saharan African) pregnant women were enrolled: age 34 years old (28–38). All were receiving FTC/TFV (as TDF or TAF) associated NRTIs with no boosted PI/r or reported CYP3A4 inhibitor. For these women, 222 plasma concentrations were determined corresponding to 20 at T1, 85 at T2, 92 at T3 and 25 postpartum. Population pharmacokinetic parameters (RSE%) were ka 1 h-1 (fixed), V/F 727 L (10.7%), CL/F 6.4 L/h (9.1%). Inter-individual variabilities were 39% (22.7%) and 53% (14.5%) for V/F and CL/F, respectively. Between-occasion variabilities were 73% (8.2%) and 24% (14.1%) for V/F and CL/F, respectively. Additive and proportional errors were 3.7 ng/mL (46.5%) and 0.08 (36.1%), respectively. There was no effect of gestational age or trimester on ka, V/F or CL/F parameters to improve the between-occasion variabilities. Rilpivirine estimated C24h were 90 ng/mL (50–103). Among the 72 patients, 14% of patients presented C24h below the 50 ng/mL. All women pr","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"12"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16293","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399425","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}
引用次数: 0
Population pharmacokinetics of ainuovirine and exposure–response analysis in the HIV-infected individuals 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
British journal of clinical pharmacology
Pub Date : 2024-10-10 DOI: 10.1111/bcp.16309

30

Population pharmacokinetics of ainuovirine and exposure–response analysis in the HIV-infected individuals

Su Bin1, Sun Jin1, Zhang Yihang1, Jiang Taiyi1, Xia Wei1, Zhang Tong1, Sun Lijun1, Wu Hao1, Qin Hong2 and Yun Xinming2

1Beijing Youan Hospital, Capital Medical University; 2Jiangsu Aidea Pharmaceutical Co., Ltd

Objective: Ainuovirine (ANV) is a novel new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of human immunodeficiency virus type 1 (HIV-1) infection. This study aimed to evaluate the population pharmacokinetic profile and exposure-response relationship of ANV among people living with HIV (PLWH).

Methods: Plasma concentration–time data from phase 1 and phase 3 clinical trials of ANV were pooled for developing the population pharmacokinetic (PopPK) model. Exposure estimates obtained from the final model were used in exposure–response analysis for virologic and safety responses.

Results: ANV exhibited a non-linear pharmacokinetic profile, which was best described by a two-compartment model with first-order elimination. There were no significant covariates correlated to the pharmacokinetic parameters of ANV. The PopPK parameter estimate (RSE%) for CL/F was 6.46 L/h (15.0), and the clearance of ANV increased after multiple doses. The exposure–response model revealed no significant correlation between the virologic response (HIV-RNA < 50 copies/mL) at 48 weeks and the exposure, but the incidence of adverse events increased with the increasing exposure.

Conclusions: Our PopPK model supported ANV 150 mg once daily as the recommended dose for PLWH, requiring no dose adjustment for the studied factors. Optimization of ANV dose may be warranted in clinical practice due to an increasing trend in adverse reactions with increasing exposure.

Keywords: ainuovirine, expose–response model, HIV, population pharmacokinetics

30阿奴韦林在HIV感染者中的群体药代动力学及暴露-反应分析苏斌1, 孙进1, 张一航1, 蒋太一1, 夏伟1, 张彤1, 孙立军1, 吴昊1, 秦红2, 云新明21首都医科大学附属北京佑安医院；2江苏爱迪药业股份有限公司目的：阿奴韦林（ANV）是一种新型的新一代非核苷类逆转录酶抑制剂（NNRTI），用于治疗人类免疫缺陷病毒1型（HIV-1）感染：Ainuovirine（ANV）是一种新型的新一代非核苷类逆转录酶抑制剂（NNRTI），用于治疗人类免疫缺陷病毒1型（HIV-1）感染。本研究旨在评估 ANV 在 HIV 感染者（PLWH）中的群体药代动力学特征和暴露-反应关系：方法：汇集 ANV 1 期和 3 期临床试验的血浆浓度-时间数据，建立群体药代动力学（PopPK）模型。从最终模型中得到的暴露估计值被用于病毒学和安全性反应的暴露-反应分析：结果：ANV表现出非线性药代动力学特征，用一阶消除的两室模型对其进行了最佳描述。没有明显的协变量与 ANV 的药代动力学参数相关。CL/F的PopPK参数估计值（RSE%）为6.46升/小时（15.0），多次给药后ANV的清除率增加。暴露-反应模型显示，48周时的病毒学反应（HIV-RNA <50拷贝/毫升）与暴露量无显著相关性，但不良事件的发生率随着暴露量的增加而增加：我们的 PopPK 模型支持将 ANV 150 毫克、每日一次作为 PLWH 的推荐剂量，无需根据研究因素调整剂量。由于不良反应有随着暴露量增加而增加的趋势，因此在临床实践中可能需要优化ANV的剂量。
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引用次数: 0
Effect of fluconazole on the pharmacokinetics of ainuovirine in healthy adult subjects 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
British journal of clinical pharmacology
Pub Date : 2024-10-10 DOI: 10.1111/bcp.16316

37

Effect of fluconazole on the pharmacokinetics of ainuovirine in healthy adult subjects

Li Linghua, Huang Jianfei, Lei Yan, Cai Weiping, Meng Yu, Xiao Lei, Zhao Yi, Lin Weitong, He Yaozu, Huang Kaipeng and Qin Hong

Guangzhou Eighth People's Hospital, Guangzhou Medical University

Introduction: Ainuovirine (ANV) is a newly developed next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for used in combination therapy for people living with HIV (PLWH) in China, which is metabolized by CYP2C19. The aim of this phase 1 study was to assess the drug–drug interaction (DDI) and safety of ainuovirine when co-administered with fluconazole, a strong CYP2C19 inhibitor, by experimentally obtained in healthy adult subjects and a physiologically based pharmacokinetics (PBPK) model was developed for dose prediction of ainuovirine.

Methods: This was a single-centre, open-label, parallel-group, fixed-sequence, two-period study in healthy subjects (aged 20–45 years). Thirty-six healthy subjects were allocated into two groups. In group A, 18 healthy subjects received oral ainuovirine (150 mg) once daily in period 1 (days 1–7), followed by co-administration with oral fluconazole (200 mg) once daily in period 2 (days 8–14). In group B, 18 healthy subjects received oral fluconazole (200 mg) once daily in period 1 (days 1–7), followed by co-administration with oral ainuovirine (150 mg) once daily in period 2 (days 8–14). Blood samples were collected before and after dosing. A PBPK model (PK-SIM® version 11.2, Open Systems Pharmacology, USA) of ainuovirine and fluconazole was developed and validated to predict their DDIs.

Results: All subjects (N = 36) completed the study. In group A, when co-administered with fluconazole, geometric means of ainuovirine pharmacokinetics parameters Cmin,ss, AUC0–24,ss increased up to 233.0% and 349.6%, respectively, vs. ainuovirine alone, whereas the median Tmax,ss was unaffected. In group B, there were no apparent effects of ainuovirine on Cmax,ss, AUC0–24,ss and Tmax,ss for fluconazole. Possible treatment-related adverse events (AEs) assessed by investigators were fewer in group A (83.3%) vs. group B (94.4%), no death or grade ≥3 serious AE was reported. The PBPK modelling supports a dose reduction by half for co-administration of ainuovirine and strong CYP2C19 inhibitors such as fluconazole.

Conclusion: Co-administration of ainuovirine with fluconazole significantly increased ainuovirine systemic exposure, whereas ainuovirine did not appear to affect the exposure of fluconazole. The PBPK modelling supports a dose reduction by half (i.e. 75 mg) for coadministration of ainuovirine and strong CYP2C19 inhibitors such as fluconazole.

Keywords: ainuovirine, CPY2C19, drug–drug interactions, fluconazole, pharmacokinetics

37氟康唑对成人健康受试者服用阿奴韦林药代动力学的影响李玲华，黄剑飞，雷燕，蔡卫平，孟宇，肖磊，赵毅，林伟彤，何耀祖，黄凯鹏，覃宏广州医科大学附属广州市第八人民医院简介：阿奴韦林（Ainuovirine，ANV）是一种新开发的新一代非核苷类逆转录酶抑制剂（NNRTI），用于艾滋病病毒感染者（PLWH）的联合治疗：Ainuovirine（ANV）是中国新开发的新一代非核苷类逆转录酶抑制剂（NNRTI），用于艾滋病病毒感染者（PLWH）的联合治疗。这项1期研究的目的是通过在健康成人受试者中实验获得的数据，评估艾诺维林与氟康唑（一种强CYP2C19抑制剂）合用时的药物相互作用（DDI）和安全性，并建立一个基于生理学的药代动力学（PBPK）模型，用于预测艾诺维林的剂量：这是一项在健康受试者（20-45 岁）中进行的单中心、开放标签、平行分组、固定顺序、两阶段研究。36 名健康受试者被分为两组。在 A 组中，18 名健康受试者在第一阶段（第 1-7 天）每天一次口服阿奴韦林（150 毫克），然后在第二阶段（第 8-14 天）每天一次口服氟康唑（200 毫克）。在 B 组中，18 名健康受试者在第一阶段（第 1-7 天）每天一次口服氟康唑（200 毫克），然后在第二阶段（第 8-14 天）每天一次口服阿努韦林（150 毫克）。用药前后均采集血样。开发并验证了阿糖胞苷和氟康唑的 PBPK 模型（PK-SIM® 11.2 版，美国开放系统药理学公司），以预测它们的 DDI：所有受试者（36 人）均完成了研究。在 A 组中，与氟康唑联合用药时，与单独使用阿奴韦林相比，阿奴韦林药代动力学参数 Cmin,ss、AUC0-24,ss 的几何平均值分别增加了 233.0% 和 349.6%，而中位数 Tmax,ss 则不受影响。在 B 组中，伊诺韦林对氟康唑的 Cmax,ss、AUC0-24,ss 和 Tmax,ss 没有明显影响。研究人员评估的可能与治疗相关的不良事件（AEs）在 A 组（83.3%）少于 B 组（94.4%），没有死亡或等级≥3 的严重不良事件报告。PBPK模型支持阿奴韦林与氟康唑等强CYP2C19抑制剂合用时剂量减半：结论：艾诺韦林与氟康唑联合用药可显著增加艾诺韦林的全身暴露量，而艾诺韦林似乎不会影响氟康唑的暴露量。PBPK模型支持将阿奴韦林与氟康唑等强CYP2C19抑制剂联合用药的剂量减半（即75毫克）。关键词：阿奴韦林；CPY2C19；药物相互作用；氟康唑；药代动力学
{"title":"Effect of fluconazole on the pharmacokinetics of ainuovirine in healthy adult subjects","authors":"","doi":"10.1111/bcp.16316","DOIUrl":"10.1111/bcp.16316","url":null,"abstract":"<p><b>37</b></p><p><b>Effect of fluconazole on the pharmacokinetics of ainuovirine in healthy adult subjects</b></p><p>Li Linghua, Huang Jianfei, Lei Yan, Cai Weiping, Meng Yu, Xiao Lei, Zhao Yi, Lin Weitong, He Yaozu, Huang Kaipeng and Qin Hong</p><p><i>Guangzhou Eighth People's Hospital, Guangzhou Medical University</i></p><p><b>Introduction:</b> Ainuovirine (ANV) is a newly developed next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for used in combination therapy for people living with HIV (PLWH) in China, which is metabolized by CYP2C19. The aim of this phase 1 study was to assess the drug–drug interaction (DDI) and safety of ainuovirine when co-administered with fluconazole, a strong CYP2C19 inhibitor, by experimentally obtained in healthy adult subjects and a physiologically based pharmacokinetics (PBPK) model was developed for dose prediction of ainuovirine.</p><p><b>Methods:</b> This was a single-centre, open-label, parallel-group, fixed-sequence, two-period study in healthy subjects (aged 20–45 years). Thirty-six healthy subjects were allocated into two groups. In group A, 18 healthy subjects received oral ainuovirine (150 mg) once daily in period 1 (days 1–7), followed by co-administration with oral fluconazole (200 mg) once daily in period 2 (days 8–14). In group B, 18 healthy subjects received oral fluconazole (200 mg) once daily in period 1 (days 1–7), followed by co-administration with oral ainuovirine (150 mg) once daily in period 2 (days 8–14). Blood samples were collected before and after dosing. A PBPK model (PK-SIM® version 11.2, Open Systems Pharmacology, USA) of ainuovirine and fluconazole was developed and validated to predict their DDIs.</p><p><b>Results:</b> All subjects (<i>N</i> = 36) completed the study. In group A, when co-administered with fluconazole, geometric means of ainuovirine pharmacokinetics parameters C<sub>min,ss</sub>, AUC<sub>0–24,ss</sub> increased up to 233.0% and 349.6%, respectively, <i>vs</i>. ainuovirine alone, whereas the median T<sub>max,ss</sub> was unaffected. In group B, there were no apparent effects of ainuovirine on C<sub>max,ss</sub>, AUC<sub>0–24,ss</sub> and T<sub>max,ss</sub> for fluconazole. Possible treatment-related adverse events (AEs) assessed by investigators were fewer in group A (83.3%) <i>vs</i>. group B (94.4%), no death or grade ≥3 serious AE was reported. The PBPK modelling supports a dose reduction by half for co-administration of ainuovirine and strong CYP2C19 inhibitors such as fluconazole.</p><p><b>Conclusion:</b> Co-administration of ainuovirine with fluconazole significantly increased ainuovirine systemic exposure, whereas ainuovirine did not appear to affect the exposure of fluconazole. The PBPK modelling supports a dose reduction by half (i.e. 75 mg) for coadministration of ainuovirine and strong CYP2C19 inhibitors such as fluconazole.</p><p><b>Keywords:</b> ainuovirine, CPY2C19, drug–drug interactions, fluconazole, pharmacokinetics</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"24-25"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16316","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399448","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}
引用次数: 0
Cabotegravir PopPK analysis of adults and adolescents living with HIV/at risk for HIV receiving prep 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
British journal of clinical pharmacology
Pub Date : 2024-10-10 DOI: 10.1111/bcp.16317
<p><b>38</b></p><p><b>Cabotegravir PopPK analysis of adults and adolescents living with HIV/at risk for HIV receiving prep</b></p><p>Amy Cheung<sup>1,2</sup>, Yu-Wei Lin<sup>1,2</sup>, Isabelle Deprez<sup>1,2</sup>, Susan Ford<sup>2</sup>, Jon Collins<sup>3</sup>, Rashmi Mehta<sup>2</sup>, Mark Bush<sup>3</sup>, Kelong Han<sup>2</sup>, Cindy McCoig<sup>3</sup>, Conn Harrington<sup>3</sup>, Lionel Tan<sup>3</sup>, Aditya Gaur<sup>4</sup>, Carolyn Bolton<sup>5</sup>, Lynda Stranix-Chibanda<sup>6</sup>, Sybil Hosek<sup>7</sup>, Mark Marzinke<sup>8</sup>, Brookie Best<sup>9</sup>, Edmund Capparelli<sup>9</sup>, IMPAACT 2017 Study Team<sup>10</sup>, HPTN 084-01 Study Team<sup>11</sup> and HPTN 083-01 Study Team<sup>11</sup></p><p><sup>1</sup><i>Certara;</i> <sup>2</sup><i>GlaxoSmithKline;</i> <sup>3</sup><i>ViiV Healthcare;</i> <sup>4</sup><i>St. Jude Children's Hospital;</i> <sup>5</sup><i>Centre for Infectious Disease Research in Zambia;</i> <sup>6</sup><i>University of Zimbabwe;</i> <sup>7</sup><i>Stroger Hospital of Cook County;</i> <sup>8</sup><i>The John's Hopkins University;</i> <sup>9</sup><i>University of California;</i> <sup>10</sup><i>The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network;</i> <sup>11</sup><i>The HIV Prevention Trials Network (HPTN)</i></p><p><b>Background:</b> Cabotegravir (CAB) is an integrase strand transfer inhibitor approved in adults and adolescents (12 to <18 years) weighing >35 kg as long-acting injectable (LAI) HIV-1 prevention and for treatment in combination with rilpivirine. An existing CAB population pharmacokinetic (PopPK) model was limited to adult PK (Han 2023). We set out to extend and optimize that existing PopPK model for adolescents (12 to <18 years) by incorporating available adolescent PK data from the IMPAACT 2017/MOCHA (NCT03497676) and HPTN 083/084-01(NCT04824131/NCT02720094) clinical trials.</p><p><b>Materials and methods:</b> PK data following oral lead-in (30 mg once daily, QD for at least 4 weeks) and LAI treatment (an initial 600 mg 4-week loading dose followed by 400 mg Q4W or 600 mg Q8W) from 147 adolescents with HIV (IMPAACT 2017) and 62 HIV-negative adolescents (HPTN 083/084–01) with weight of 35.2–168 kg, body mass index (BMI) of 15.8–51.6 kg/m<sup>2</sup> and 12–17 years were added to adult data (<i>n</i> = 1647). The PopPK model parameters were re-estimated based on this pooled dataset using NONMEM 7.3. The updated PopPK model was used to simulate PK profiles for CAB for Q4W and Q8W regimens in adolescents and adults. Individual exposure metrics (e.g. C<sub>tau,ss</sub>) were derived and compared between adolescents and adults.</p><p><b>Results:</b> A two-compartment model with 1st-order absorption adequately described CAB PK in adolescents and adults. No new covariates were identified as compared to the adult PopPK model. Weight and smoking status were significant determinants of CL/F, and only weight was a determinant of Vc/F, Vp/F and Q/F. Need
38Cabotegravir PopPK Analysis of adults and adolesents living with HIV/at risk for HIV receiving prepAmy Cheung1,2, Yu-Wei Lin1,2, Isabelle Deprez1,2, Susan Ford2, Jon Collins3, Rashmi Mehta2, Mark Bush3, Kelong Han2, Cindy McCoig3、Conn Harrington3、Lionel Tan3、Aditya Gaur4、Carolyn Bolton5、Lynda Stranix-Chibanda6、Sybil Hosek7、Mark Marzinke8、Brookie Best9、Edmund Capparelli9、IMPAACT 2017 研究团队10、HPTN 084-01 研究团队11 和 HPTN 083-01 研究团队111Certara；2GlaxoSmithKline; 3ViiV Healthcare; 4St.Jude儿童医院；5Centre for Infectious Disease Research in Zambia；6University of Zimbabwe；7Stroger Hospital of Cook County；8The John's Hopkins University；9University of California；10The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network；11The HIV Prevention Trials Network (HPTN)背景：卡博特拉韦（CAB）是一种整合酶链转移抑制剂，已被批准用于成人和体重为35公斤的青少年（12至18岁），作为长效注射剂（LAI）预防HIV-1，并与利匹韦林联合治疗。现有的 CAB 群体药代动力学（PopPK）模型仅限于成人 PK 模型（Han 2023）。我们将 IMPAACT 2017/MOCHA (NCT03497676) 和 HPTN 083/084-01(NCT04824131/NCT02720094)临床试验中可用的青少年 PK 数据纳入其中，着手扩展和优化现有的青少年（12 至 18 岁）PopPK 模型：将147名HIV感染青少年（IMPAACT 2017）和62名HIV阴性青少年（HPTN 083/084-01）（体重35.2-168千克，体重指数（BMI）15.8-51.6千克/平方米，年龄12-17岁）口服前导剂量（30毫克，每日一次，QD，至少4周）和LAI治疗（初始600毫克，4周负荷剂量，随后400毫克Q4W或600毫克Q8W）后的PK数据添加到成人数据（n = 1647）中。使用 NONMEM 7.3 重新估计了基于该集合数据集的 PopPK 模型参数。更新后的 PopPK 模型用于模拟 CAB 在青少年和成人中 Q4W 和 Q8W 治疗方案的 PK 曲线。得出了个体暴露指标（如 Ctau,ss），并在青少年和成人之间进行了比较：结果：采用一阶吸收的二室模型充分描述了青少年和成人的 CAB PK。与成人 PopPK 模型相比，没有发现新的协变量。体重和吸烟状况是CL/F的重要决定因素，只有体重是Vc/F、Vp/F和Q/F的决定因素。针头长度、女性性别、分针和体重指数是 KA IM（LAI 的吸收率）的重要决定因素。青少年在稳态时的 CAB LA 暴露量（600 毫克 Q8W 的 Ctau,ss 中位数，第 5-95 位：2.36，0.849-4.13 微克/毫升）与成人（Q8W 的 Ctau,ss 中位数，第 5-95 位：1.91，0.786-3.33 微克/毫升）相当，在所有给药阶段，他们的暴露水平都在相同的范围内，并控制在 0.45 和 22.5 微克/毫升的既定疗效和安全性阈值内：将青少年数据添加到成人 PopPK 数据集后，可以将先前的 PopPK 模型扩展到 35 千克，并优化对青少年的预测。鉴于青少年和成人的 CAB PK 相似，因此成人和青少年适用相同的给药方案。
{"title":"Cabotegravir PopPK analysis of adults and adolescents living with HIV/at risk for HIV receiving prep","authors":"","doi":"10.1111/bcp.16317","DOIUrl":"10.1111/bcp.16317","url":null,"abstract":"&lt;p&gt;&lt;b&gt;38&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Cabotegravir PopPK analysis of adults and adolescents living with HIV/at risk for HIV receiving prep&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Amy Cheung&lt;sup&gt;1,2&lt;/sup&gt;, Yu-Wei Lin&lt;sup&gt;1,2&lt;/sup&gt;, Isabelle Deprez&lt;sup&gt;1,2&lt;/sup&gt;, Susan Ford&lt;sup&gt;2&lt;/sup&gt;, Jon Collins&lt;sup&gt;3&lt;/sup&gt;, Rashmi Mehta&lt;sup&gt;2&lt;/sup&gt;, Mark Bush&lt;sup&gt;3&lt;/sup&gt;, Kelong Han&lt;sup&gt;2&lt;/sup&gt;, Cindy McCoig&lt;sup&gt;3&lt;/sup&gt;, Conn Harrington&lt;sup&gt;3&lt;/sup&gt;, Lionel Tan&lt;sup&gt;3&lt;/sup&gt;, Aditya Gaur&lt;sup&gt;4&lt;/sup&gt;, Carolyn Bolton&lt;sup&gt;5&lt;/sup&gt;, Lynda Stranix-Chibanda&lt;sup&gt;6&lt;/sup&gt;, Sybil Hosek&lt;sup&gt;7&lt;/sup&gt;, Mark Marzinke&lt;sup&gt;8&lt;/sup&gt;, Brookie Best&lt;sup&gt;9&lt;/sup&gt;, Edmund Capparelli&lt;sup&gt;9&lt;/sup&gt;, IMPAACT 2017 Study Team&lt;sup&gt;10&lt;/sup&gt;, HPTN 084-01 Study Team&lt;sup&gt;11&lt;/sup&gt; and HPTN 083-01 Study Team&lt;sup&gt;11&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;i&gt;Certara;&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt;&lt;i&gt;GlaxoSmithKline;&lt;/i&gt; &lt;sup&gt;3&lt;/sup&gt;&lt;i&gt;ViiV Healthcare;&lt;/i&gt; &lt;sup&gt;4&lt;/sup&gt;&lt;i&gt;St. Jude Children's Hospital;&lt;/i&gt; &lt;sup&gt;5&lt;/sup&gt;&lt;i&gt;Centre for Infectious Disease Research in Zambia;&lt;/i&gt; &lt;sup&gt;6&lt;/sup&gt;&lt;i&gt;University of Zimbabwe;&lt;/i&gt; &lt;sup&gt;7&lt;/sup&gt;&lt;i&gt;Stroger Hospital of Cook County;&lt;/i&gt; &lt;sup&gt;8&lt;/sup&gt;&lt;i&gt;The John's Hopkins University;&lt;/i&gt; &lt;sup&gt;9&lt;/sup&gt;&lt;i&gt;University of California;&lt;/i&gt; &lt;sup&gt;10&lt;/sup&gt;&lt;i&gt;The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network;&lt;/i&gt; &lt;sup&gt;11&lt;/sup&gt;&lt;i&gt;The HIV Prevention Trials Network (HPTN)&lt;/i&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Cabotegravir (CAB) is an integrase strand transfer inhibitor approved in adults and adolescents (12 to &lt;18 years) weighing &gt;35 kg as long-acting injectable (LAI) HIV-1 prevention and for treatment in combination with rilpivirine. An existing CAB population pharmacokinetic (PopPK) model was limited to adult PK (Han 2023). We set out to extend and optimize that existing PopPK model for adolescents (12 to &lt;18 years) by incorporating available adolescent PK data from the IMPAACT 2017/MOCHA (NCT03497676) and HPTN 083/084-01(NCT04824131/NCT02720094) clinical trials.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Materials and methods:&lt;/b&gt; PK data following oral lead-in (30 mg once daily, QD for at least 4 weeks) and LAI treatment (an initial 600 mg 4-week loading dose followed by 400 mg Q4W or 600 mg Q8W) from 147 adolescents with HIV (IMPAACT 2017) and 62 HIV-negative adolescents (HPTN 083/084–01) with weight of 35.2–168 kg, body mass index (BMI) of 15.8–51.6 kg/m&lt;sup&gt;2&lt;/sup&gt; and 12–17 years were added to adult data (&lt;i&gt;n&lt;/i&gt; = 1647). The PopPK model parameters were re-estimated based on this pooled dataset using NONMEM 7.3. The updated PopPK model was used to simulate PK profiles for CAB for Q4W and Q8W regimens in adolescents and adults. Individual exposure metrics (e.g. C&lt;sub&gt;tau,ss&lt;/sub&gt;) were derived and compared between adolescents and adults.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; A two-compartment model with 1st-order absorption adequately described CAB PK in adolescents and adults. No new covariates were identified as compared to the adult PopPK model. Weight and smoking status were significant determinants of CL/F, and only weight was a determinant of Vc/F, Vp/F and Q/F. Need","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"25"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16317","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399449","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}
引用次数: 0
Evaluation of the effect of CYP2D6 and OCT1 polymorphisms on the pharmacokinetics of tramadol: Implications for clinical safety and dose rationale in paediatric chronic pain. 评估 CYP2D6 和 OCT1 多态性对曲马多药代动力学的影响：对儿科慢性疼痛的临床安全性和剂量合理性的影响。
IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
British journal of clinical pharmacology
Pub Date : 2024-10-09 DOI: 10.1111/bcp.16201
Paul Healy, Karel Allegaert, Oscar Della Pasqua

Aims: Our investigation aimed to assess the dose rationale of tramadol in paediatric patients considering the effect of CYP2D6/OCT1 polymorphisms on systemic exposure. Recommendations were made for the oral dose of tramadol to be used in a prospective study in children (3 months to < 18 years old) with chronic pain.

Methods: Intravenous pharmacokinetic and genotype data from neonatal patients (n = 46) were available for this analysis. The time course of tramadol and O-desmethyltramadol (M1) concentrations was characterized using a nonlinear mixed effects approach in conjunction with extrapolation principles. Clinical trial simulations were then implemented to explore the effects of polymorphism, maturation and developmental growth on the disposition of tramadol and M1. Reported efficacious exposure range in adult subjects were used as reference.

Results: The pharmacokinetics of tramadol and M1 was characterized by a two-compartment model. The total clearance of tramadol (CLPP) comprised CYP2D6-mediated metabolism (CLPM) and other pathways (CLPO). Age-related changes in CLPM, CLPO and M1 clearance (CLMO) were described by a sigmoid function, with CYP2D6 as a covariate on CLPP and CLPM,  and OCT1 on CLMO. Simulation scenarios including different CYP2D6/OCT1 combinations revealed that steady-state concentrations are above the putative ranges for analgesia in >15% and >70% of subjects after doses of 3 and 8 mg/kg, respectively.

Conclusions: In the absence of genotyping, reference exposure ranges can be used to define the dose rationale for tramadol in paediatric chronic pain. However, a starting dose of 0.5 mg/kg/day should be considered, followed by stepwise titration to the desired analgesic response.

目的：考虑到CYP2D6/OCT1多态性对全身暴露的影响，我们的调查旨在评估曲马多在儿童患者中的剂量合理性。在一项针对慢性疼痛儿童（3个月至18岁以下）的前瞻性研究中，对曲马多的口服剂量提出了建议：本研究分析了新生儿患者（46 人）的静脉药代动力学和基因型数据。采用非线性混合效应方法，结合外推法原理，描述了曲马多和O-去甲基曲马多（M1）浓度的时间过程。然后进行了临床试验模拟，以探索多态性、成熟度和发育成长对曲马多和 M1 药物处置的影响。结果表明，曲马多和M1的药代动力学是相同的：曲马多和M1的药代动力学以两室模型为特征。曲马多的总清除率（CLPP）包括CYP2D6介导的代谢（CLPM）和其他途径（CLPO）。CLPM、CLPO和M1清除率（CLMO）与年龄有关的变化用一个sigmoid函数来描述，CYP2D6是CLPP和CLPM的协变量，OCT1是CLMO的协变量。包括不同 CYP2D6/OCT1 组合在内的模拟情景显示，在服用 3 毫克/千克和 8 毫克/千克的剂量后，分别有超过 15% 和超过 70% 的受试者的稳态浓度高于镇痛的假定范围：结论：在没有进行基因分型的情况下，参考暴露范围可用于确定曲马多在儿科慢性疼痛中的合理剂量。不过，应考虑起始剂量为0.5毫克/千克/天，然后逐步滴定以达到理想的镇痛效果。
{"title":"Evaluation of the effect of CYP2D6 and OCT1 polymorphisms on the pharmacokinetics of tramadol: Implications for clinical safety and dose rationale in paediatric chronic pain.","authors":"Paul Healy, Karel Allegaert, Oscar Della Pasqua","doi":"10.1111/bcp.16201","DOIUrl":"https://doi.org/10.1111/bcp.16201","url":null,"abstract":"<p><strong>Aims: </strong>Our investigation aimed to assess the dose rationale of tramadol in paediatric patients considering the effect of CYP2D6/OCT1 polymorphisms on systemic exposure. Recommendations were made for the oral dose of tramadol to be used in a prospective study in children (3 months to < 18 years old) with chronic pain.</p><p><strong>Methods: </strong>Intravenous pharmacokinetic and genotype data from neonatal patients (n = 46) were available for this analysis. The time course of tramadol and O-desmethyltramadol (M1) concentrations was characterized using a nonlinear mixed effects approach in conjunction with extrapolation principles. Clinical trial simulations were then implemented to explore the effects of polymorphism, maturation and developmental growth on the disposition of tramadol and M1. Reported efficacious exposure range in adult subjects were used as reference.</p><p><strong>Results: </strong>The pharmacokinetics of tramadol and M1 was characterized by a two-compartment model. The total clearance of tramadol (CLPP) comprised CYP2D6-mediated metabolism (CLPM) and other pathways (CLPO). Age-related changes in CLPM, CLPO and M1 clearance (CLMO) were described by a sigmoid function, with CYP2D6 as a covariate on CLPP and CLPM,  and OCT1 on CLMO. Simulation scenarios including different CYP2D6/OCT1 combinations revealed that steady-state concentrations are above the putative ranges for analgesia in >15% and >70% of subjects after doses of 3 and 8 mg/kg, respectively.</p><p><strong>Conclusions: </strong>In the absence of genotyping, reference exposure ranges can be used to define the dose rationale for tramadol in paediatric chronic pain. However, a starting dose of 0.5 mg/kg/day should be considered, followed by stepwise titration to the desired analgesic response.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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