Pub Date : 2024-04-01Epub Date: 2024-03-22DOI: 10.1007/s11095-024-03678-2
Joseph R Cohen, Stephen R Brych, Siddharth Prabhu, Vivian Bi, Ahmed Elbaradei, Joshua M Tokuda, Cathie Xiang, Martha Hokom, Xiaohong Cui, Claudia Ly, Nathan Amos, Jilin Sun, Dominador Calamba, Jonathan Herskovitz, Allyson Capili, Kimya Nourbakhsh, Anthony Merlo, Julia Carreon, Jette Wypych, Linda O Narhi, Vibha Jawa, Marisa K Joubert
Background and purpose: There is concern that subvisible aggregates in biotherapeutic drug products pose a risk to patient safety. We investigated the threshold of biotherapeutic aggregates needed to induce immunogenic responses.
Methods and results: Highly aggregated samples were tested in cell-based assays and induced cellular responses in a manner that depended on the number of particles. The threshold of immune activation varied by disease state (cancer, rheumatoid arthritis, allergy), concomitant therapies, and particle number. Compared to healthy donors, disease state patients showed an equal or lower response at the late phase (7 days), suggesting they may not have a higher risk of responding to aggregates. Xeno-het mice were used to assess the threshold of immune activation in vivo. Although highly aggregated samples (~ 1,600,000 particles/mL) induced a weak and transient immunogenic response in mice, a 100-fold dilution of this sample (~ 16,000 particles/mL) did not induce immunogenicity. To confirm this result, subvisible particles (up to ~ 18,000 particles/mL, containing aggregates and silicone oil droplets) produced under representative administration practices (created upon infusion of a drug product through an IV catheter) did not induce a response in cell-based assays or appear to increase the rate of adverse events or immunogenicity during phase 3 clinical trials.
Conclusion: The ability of biotherapeutic aggregates to elicit an immune response in vitro, in vivo, and in the clinic depends on high numbers of particles. This suggests that there is a high threshold for aggregates to induce an immunogenic response which is well beyond that seen in standard biotherapeutic drug products.
{"title":"A High Threshold of Biotherapeutic Aggregate Numbers is Needed to Induce an Immunogenic Response In Vitro, In Vivo, and in the Clinic.","authors":"Joseph R Cohen, Stephen R Brych, Siddharth Prabhu, Vivian Bi, Ahmed Elbaradei, Joshua M Tokuda, Cathie Xiang, Martha Hokom, Xiaohong Cui, Claudia Ly, Nathan Amos, Jilin Sun, Dominador Calamba, Jonathan Herskovitz, Allyson Capili, Kimya Nourbakhsh, Anthony Merlo, Julia Carreon, Jette Wypych, Linda O Narhi, Vibha Jawa, Marisa K Joubert","doi":"10.1007/s11095-024-03678-2","DOIUrl":"10.1007/s11095-024-03678-2","url":null,"abstract":"<p><strong>Background and purpose: </strong>There is concern that subvisible aggregates in biotherapeutic drug products pose a risk to patient safety. We investigated the threshold of biotherapeutic aggregates needed to induce immunogenic responses.</p><p><strong>Methods and results: </strong>Highly aggregated samples were tested in cell-based assays and induced cellular responses in a manner that depended on the number of particles. The threshold of immune activation varied by disease state (cancer, rheumatoid arthritis, allergy), concomitant therapies, and particle number. Compared to healthy donors, disease state patients showed an equal or lower response at the late phase (7 days), suggesting they may not have a higher risk of responding to aggregates. Xeno-het mice were used to assess the threshold of immune activation in vivo. Although highly aggregated samples (~ 1,600,000 particles/mL) induced a weak and transient immunogenic response in mice, a 100-fold dilution of this sample (~ 16,000 particles/mL) did not induce immunogenicity. To confirm this result, subvisible particles (up to ~ 18,000 particles/mL, containing aggregates and silicone oil droplets) produced under representative administration practices (created upon infusion of a drug product through an IV catheter) did not induce a response in cell-based assays or appear to increase the rate of adverse events or immunogenicity during phase 3 clinical trials.</p><p><strong>Conclusion: </strong>The ability of biotherapeutic aggregates to elicit an immune response in vitro, in vivo, and in the clinic depends on high numbers of particles. This suggests that there is a high threshold for aggregates to induce an immunogenic response which is well beyond that seen in standard biotherapeutic drug products.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194418","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}
Pub Date : 2024-04-01Epub Date: 2024-03-22DOI: 10.1007/s11095-024-03690-6
Avinash Y Gahane, Devesh Pratap Verma, Swagata Sarkar, Ashwani K Thakur
Objective: To assess the pharmacokinetic profile, in-vivo toxicity, and efficacy of 9-Fluorenylmethoxycarbonyl-L-phenylalanine (Fmoc-F) as a potential antibacterial agent, with a focus on its suitability for clinical translation.
Methods: An RP-HPLC-based bio-analytical method was developed and qualified to quantify Fmoc-F levels in mouse plasma for pharmacokinetic analysis. Oral bioavailability was determined, and in-vivo toxicity was evaluated following intra-peritoneal administration. Efficacy was assessed by measuring the reduction in Staphylococcus aureus burden and survival rates in BALB/c mice.
Results: The RP-HPLC method is highly sensitive, detecting as low as 0.8 µg mL-1 (~ 2 µM) of Fmoc-F in blood plasma. This study revealed that Fmoc-F has an oral bioavailability of 65 ± 18% and suitable pharmacokinetic profile. Further, we showed that intra-peritoneal administration of Fmoc-F is well tolerated by BALB/c mice and Fmoc-F treatment (100 mg/kg, i.p.) significantly reduces Staphylococcus aureus burden from visceral organs in BALB/c mice but falls short in enhancing survival rates at higher bacterial loads.
Conclusions: The study provides crucial insights into the pharmacokinetic and pharmacodynamic properties of Fmoc-F. The compound displayed favourable oral bioavailability and in-vivo tolerance. Its significant reduction of bacterial burden underscores its potential as a treatment for systemic infections. However, limited effectiveness for severe infections, short half-life, and inflammatory response at higher doses need to be addressed for its clinical application.
{"title":"Evaluation of Pharmacokinetic and Pharmacodynamic (PK/PD) of Novel Fluorenylmethoxycarbonyl- Phenylalanine Antimicrobial Agent.","authors":"Avinash Y Gahane, Devesh Pratap Verma, Swagata Sarkar, Ashwani K Thakur","doi":"10.1007/s11095-024-03690-6","DOIUrl":"10.1007/s11095-024-03690-6","url":null,"abstract":"<p><strong>Objective: </strong>To assess the pharmacokinetic profile, in-vivo toxicity, and efficacy of 9-Fluorenylmethoxycarbonyl-L-phenylalanine (Fmoc-F) as a potential antibacterial agent, with a focus on its suitability for clinical translation.</p><p><strong>Methods: </strong>An RP-HPLC-based bio-analytical method was developed and qualified to quantify Fmoc-F levels in mouse plasma for pharmacokinetic analysis. Oral bioavailability was determined, and in-vivo toxicity was evaluated following intra-peritoneal administration. Efficacy was assessed by measuring the reduction in Staphylococcus aureus burden and survival rates in BALB/c mice.</p><p><strong>Results: </strong>The RP-HPLC method is highly sensitive, detecting as low as 0.8 µg mL-1 (~ 2 µM) of Fmoc-F in blood plasma. This study revealed that Fmoc-F has an oral bioavailability of 65 ± 18% and suitable pharmacokinetic profile. Further, we showed that intra-peritoneal administration of Fmoc-F is well tolerated by BALB/c mice and Fmoc-F treatment (100 mg/kg, i.p.) significantly reduces Staphylococcus aureus burden from visceral organs in BALB/c mice but falls short in enhancing survival rates at higher bacterial loads.</p><p><strong>Conclusions: </strong>The study provides crucial insights into the pharmacokinetic and pharmacodynamic properties of Fmoc-F. The compound displayed favourable oral bioavailability and in-vivo tolerance. Its significant reduction of bacterial burden underscores its potential as a treatment for systemic infections. However, limited effectiveness for severe infections, short half-life, and inflammatory response at higher doses need to be addressed for its clinical application.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194419","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}
Pub Date : 2024-04-01Epub Date: 2024-03-12DOI: 10.1007/s11095-024-03677-3
Yunjiao Wu, Karel Allegaert, Robert B Flint, Sebastiaan C Goulooze, Pyry A J Välitalo, Matthijs de Hoog, Hussain Mulla, Catherine M T Sherwin, Sinno H P Simons, Elke H J Krekels, Catherijne A J Knibbe, Swantje Völler
Aims: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs.
Methods: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFRbirth (GFR at birth), and an Emax model dependent on PNA (with GFRmax, PNA50 (PNA at which half of is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations.
Result: In the GFR model, GFRbirth varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA50, and current weight for GFRmax. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well.
Conclusions: GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.
目的:早产儿的肾小球滤过率(GFR)是否以及何时赶上足月儿还不得而知。本研究旨在为(足月儿)从出生到 18 岁建立一个肾小球滤过率成熟模型。其次,将该函数应用于不同肾脏排泄药物的数据:方法:我们将已公布的菊粉清除率值和血清肌酐(Scr)浓度结合起来,观察(足月前)出生的婴儿在整个儿童期的情况。假定菊粉清除率等于肾小球滤过率,Scr反映肌酐合成率/肾小球滤过率。我们建立了一个 GFR 函数,包括 GFRbirth(出生时的 GFR)和一个取决于 PNA 的 Emax 模型(包括 GFRmax、PNA50(达到 GFR 最大值一半的 PNA)和希尔系数)。最终的 GFR 模型用于预测庆大霉素、妥布霉素和万古霉素的浓度:结果:在 GFR 模型中,出生 GFR 与出生体重呈线性变化,而在基于 PNA 的 Emax 方程中,GA 是 PNA50 的最佳协变量,而当前体重是 GFRmax 的最佳协变量。最终模型显示,GA 为 26 周时出生的儿童,其 1 个月、6 个月、1 年、3 年和 12 年的绝对 GFR 分别是 GA 为 40 周时出生儿童的 18%、63%、80%、92% 和 96%。使用 GFR 成熟方程建立的 PopPK 模型可以很好地预测(早产)足月新生儿肾脏清除的抗生素浓度,直至 18 岁:早产儿的肾小球滤过率在三岁左右会赶上足月儿,这意味着在此年龄段以下应考虑减少肾脏清除药物的剂量。
{"title":"When will the Glomerular Filtration Rate in Former Preterm Neonates Catch up with Their Term Peers?","authors":"Yunjiao Wu, Karel Allegaert, Robert B Flint, Sebastiaan C Goulooze, Pyry A J Välitalo, Matthijs de Hoog, Hussain Mulla, Catherine M T Sherwin, Sinno H P Simons, Elke H J Krekels, Catherijne A J Knibbe, Swantje Völler","doi":"10.1007/s11095-024-03677-3","DOIUrl":"10.1007/s11095-024-03677-3","url":null,"abstract":"<p><strong>Aims: </strong>Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs.</p><p><strong>Methods: </strong>We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFR<sub>birth</sub> (GFR at birth), and an Emax model dependent on PNA (with GFR<sub>max</sub>, PNA<sub>50</sub> (PNA at which half of <math> <msub><mrow><mi>GFR</mi></mrow> <mrow><mi>max</mi></mrow> </msub> </math> is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations.</p><p><strong>Result: </strong>In the GFR model, GFR<sub>birth</sub> varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA<sub>50</sub>, and current weight for GFR<sub>max</sub>. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well.</p><p><strong>Conclusions: </strong>GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11024008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140111121","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}
Pub Date : 2024-04-01Epub Date: 2024-03-22DOI: 10.1007/s11095-024-03654-w
Farzaneh Maleki, Cheng Chang, Vivek S Purohit, Timothy Nicholas
Introduction: Topical brepocitinib, a tyrosine kinase (TYK)2/Janus kinase (JAK)1 inhibitor, is in development for psoriasis (PsO) and atopic dermatitis (AD). Quantitative analyses of prior clinical trial data were used to inform future clinical trial designs.
Methods: Two phase 2b studies in patients with AD and PsO were used to characterize the amount of topical brepocitinib and the resultant systemic trough concentration (CTrough) using a linear mixed-effects regression (LMER). This model was used to predict brepocitinib systemic CTrough for higher treated body surface areas (BSAs) in adults and children. Information from non-clinical and clinical trials with oral brepocitinib was leveraged to set safety thresholds. This combined approach was used to inform future dose-strength selection and treated BSA limits.
Results: Data from 256 patients were analyzed. Patient type, dose strength, and frequency had significant impacts on the dose-exposure relationship. Systemic concentration in patients with PsO was predicted to be 45% lower than in patients with AD from the same dose. When topically applied to the same percentage BSA, brepocitinib systemic exposures are expected to be comparable between adults and children. The systemic steady-state exposure after 3% once daily and twice daily (2 mg/cm2) cream applied to less than 50% BSA in patients with AD and PsO, respectively, maintains at least a threefold margin to non-clinical safety findings and clinical hematologic markers.
Conclusion: The relationship between the amount of active drug applied and brepocitinib systemic CTrough, described by LMER, may inform the development strategy for dose optimization in the brepocitinib topical program.
{"title":"Pharmacokinetic Profile of Brepocitinib with Topical Administration in Atopic Dermatitis and Psoriasis Populations: Strategy to Inform Clinical Trial Design in Adult and Pediatric Populations.","authors":"Farzaneh Maleki, Cheng Chang, Vivek S Purohit, Timothy Nicholas","doi":"10.1007/s11095-024-03654-w","DOIUrl":"10.1007/s11095-024-03654-w","url":null,"abstract":"<p><strong>Introduction: </strong>Topical brepocitinib, a tyrosine kinase (TYK)2/Janus kinase (JAK)1 inhibitor, is in development for psoriasis (PsO) and atopic dermatitis (AD). Quantitative analyses of prior clinical trial data were used to inform future clinical trial designs.</p><p><strong>Methods: </strong>Two phase 2b studies in patients with AD and PsO were used to characterize the amount of topical brepocitinib and the resultant systemic trough concentration (C<sub>Trough</sub>) using a linear mixed-effects regression (LMER). This model was used to predict brepocitinib systemic C<sub>Trough</sub> for higher treated body surface areas (BSAs) in adults and children. Information from non-clinical and clinical trials with oral brepocitinib was leveraged to set safety thresholds. This combined approach was used to inform future dose-strength selection and treated BSA limits.</p><p><strong>Results: </strong>Data from 256 patients were analyzed. Patient type, dose strength, and frequency had significant impacts on the dose-exposure relationship. Systemic concentration in patients with PsO was predicted to be 45% lower than in patients with AD from the same dose. When topically applied to the same percentage BSA, brepocitinib systemic exposures are expected to be comparable between adults and children. The systemic steady-state exposure after 3% once daily and twice daily (2 mg/cm<sup>2</sup>) cream applied to less than 50% BSA in patients with AD and PsO, respectively, maintains at least a threefold margin to non-clinical safety findings and clinical hematologic markers.</p><p><strong>Conclusion: </strong>The relationship between the amount of active drug applied and brepocitinib systemic C<sub>Trough</sub>, described by LMER, may inform the development strategy for dose optimization in the brepocitinib topical program.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11024034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194355","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}
Pub Date : 2024-04-01Epub Date: 2024-03-27DOI: 10.1007/s11095-024-03693-3
Leiah J Brigitha, Veerle Mondelaers, Yiwei Liu, Birgitte K Albertsen, Beata Zalewska-Szewczyk, Carmelo Rizzari, Rishi S Kotecha, Rob Pieters, Alwin D R Huitema, Inge M van der Sluis
Background: PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population.
Methods: Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM).
Results: 68 infants with ALL, with a total of 388 asparaginase activity samples, were included. PEGasparaginase doses ranging from 400 to 3,663 IU/m2 were administered either intravenously or intramuscularly. A one-compartment model with time-dependent clearance, modeled using a transit model, provided the best fit to the data. Body weight was significantly correlated with clearance and volume of distribution. The final model estimated a half-life of 11.7 days just after administration, which decreased to 1.8 days 14 days after administration. Clearance was 19.5% lower during the post-induction treatment phase compared to induction.
Conclusion: The pharmacokinetics of PEGasparaginase in infants diagnosed under one year of age with ALL is comparable to that of older children (1-18 years). We recommend a PEGasparaginase dosing at 1,500 IU/m2 for infants without dose adaptations according to age, and implementing therapeutic drug monitoring as standard practice.
背景:众所周知,PEGasparaginase是治疗小儿急性淋巴细胞白血病(ALL)的关键药物,然而,目前还没有足够的证据来确定诊断时年龄小于1岁的婴儿的最佳剂量。这项国际研究旨在确定新诊断为ALL的婴儿服用PEG天冬酰胺酶的药代动力学,并了解这一人群的清除率和用药剂量:我们采用非线性混合效应模型(NONMEM)对接受 PEGasparaginase 治疗的 ALL 婴儿进行了群体药代动力学评估:结果:共纳入了 68 名患有 ALL 的婴儿,共采集了 388 份天冬酰胺酶活性样本。PEG天冬酰胺酶的剂量为400至3,663 IU/m2,通过静脉或肌肉注射给药。采用转运模型建立的单室模型与时间相关的清除率最符合数据。体重与清除率和分布容积有明显的相关性。最终模型估计,刚给药后的半衰期为 11.7 天,给药 14 天后降至 1.8 天。与诱导相比,诱导后治疗阶段的清除率降低了 19.5%:结论:PEGasparaginase 在一岁以下确诊为 ALL 的婴儿中的药代动力学与较大儿童(1-18 岁)相当。我们建议婴儿的 PEG 天冬酰胺酶剂量为 1,500 IU/m2,无需根据年龄调整剂量,并将治疗药物监测作为标准做法。
{"title":"Pharmacokinetics of PEGasparaginase in Infants with Acute Lymphoblastic Leukemia.","authors":"Leiah J Brigitha, Veerle Mondelaers, Yiwei Liu, Birgitte K Albertsen, Beata Zalewska-Szewczyk, Carmelo Rizzari, Rishi S Kotecha, Rob Pieters, Alwin D R Huitema, Inge M van der Sluis","doi":"10.1007/s11095-024-03693-3","DOIUrl":"10.1007/s11095-024-03693-3","url":null,"abstract":"<p><strong>Background: </strong>PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population.</p><p><strong>Methods: </strong>Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM).</p><p><strong>Results: </strong>68 infants with ALL, with a total of 388 asparaginase activity samples, were included. PEGasparaginase doses ranging from 400 to 3,663 IU/m<sup>2</sup> were administered either intravenously or intramuscularly. A one-compartment model with time-dependent clearance, modeled using a transit model, provided the best fit to the data. Body weight was significantly correlated with clearance and volume of distribution. The final model estimated a half-life of 11.7 days just after administration, which decreased to 1.8 days 14 days after administration. Clearance was 19.5% lower during the post-induction treatment phase compared to induction.</p><p><strong>Conclusion: </strong>The pharmacokinetics of PEGasparaginase in infants diagnosed under one year of age with ALL is comparable to that of older children (1-18 years). We recommend a PEGasparaginase dosing at 1,500 IU/m<sup>2</sup> for infants without dose adaptations according to age, and implementing therapeutic drug monitoring as standard practice.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306439","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}
Pub Date : 2024-04-01Epub Date: 2024-03-22DOI: 10.1007/s11095-024-03684-4
Kaizhu Guo, Jing Song, Petra Bennington, Alexander J Pavon, Jameson R Bothe, Hanmi Xi, Rico C Gunawan
Purpose or objective: Surfactants, including polysorbates and poloxamers, play a crucial role in the formulation of therapeutic proteins by acting as solubilizing and stabilizing agents. They help prevent protein aggregation and adsorption, thereby enhancing the stability of drug substance and products., However, it is important to note that utilizing high concentrations of surfactants in protein formulations can present significant analytical challenges, which can ultimately affect the product characterization.
Methods: In our study, we specifically investigated the impact of elevated surfactant concentrations on the characterization of monoclonal antibodies. We employed various analytical techniques including size-exclusion chromatography (SEC), capillary electrophoresis (CE-SDS), a cell based functional assay, and biophysical characterization.
Results: The findings of our study indicate that higher levels of Polysorbate 80 (PS-80) have adverse effects on the measured purity, biological activity, and biophysical characterization of biologic samples. Specifically, the elevated levels of PS-80 cause analytical interferences, which can significantly impact the accuracy and reliability of analytical studies.
Conclusions: Our study results highlight a significant risk in analytical investigations, especially in studies involving the isolation and characterization of impurities. It is important to be cautious of surfactant concentrations, as they can become more concentrated during common sample manipulations like buffer exchange. Indeed, the research presented in this work emphasizes the necessity to evaluate the impact on analytical assays when there are substantial alternations in the matrix composition. By doing so, valuable insights can be gained regarding potential challenges associated with assay development and characterization of biologics with complex formulations.
{"title":"Identification of Surfactant Impact on a Monoclonal Antibody Characterization via HPLC-Separation Based and Biophysical Methods.","authors":"Kaizhu Guo, Jing Song, Petra Bennington, Alexander J Pavon, Jameson R Bothe, Hanmi Xi, Rico C Gunawan","doi":"10.1007/s11095-024-03684-4","DOIUrl":"10.1007/s11095-024-03684-4","url":null,"abstract":"<p><strong>Purpose or objective: </strong>Surfactants, including polysorbates and poloxamers, play a crucial role in the formulation of therapeutic proteins by acting as solubilizing and stabilizing agents. They help prevent protein aggregation and adsorption, thereby enhancing the stability of drug substance and products., However, it is important to note that utilizing high concentrations of surfactants in protein formulations can present significant analytical challenges, which can ultimately affect the product characterization.</p><p><strong>Methods: </strong>In our study, we specifically investigated the impact of elevated surfactant concentrations on the characterization of monoclonal antibodies. We employed various analytical techniques including size-exclusion chromatography (SEC), capillary electrophoresis (CE-SDS), a cell based functional assay, and biophysical characterization.</p><p><strong>Results: </strong>The findings of our study indicate that higher levels of Polysorbate 80 (PS-80) have adverse effects on the measured purity, biological activity, and biophysical characterization of biologic samples. Specifically, the elevated levels of PS-80 cause analytical interferences, which can significantly impact the accuracy and reliability of analytical studies.</p><p><strong>Conclusions: </strong>Our study results highlight a significant risk in analytical investigations, especially in studies involving the isolation and characterization of impurities. It is important to be cautious of surfactant concentrations, as they can become more concentrated during common sample manipulations like buffer exchange. Indeed, the research presented in this work emphasizes the necessity to evaluate the impact on analytical assays when there are substantial alternations in the matrix composition. By doing so, valuable insights can be gained regarding potential challenges associated with assay development and characterization of biologics with complex formulations.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194420","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}
Purpose: Quantifying unencapsulated drug concentrations in tissues is crucial for understanding the mechanisms underlying the efficacy and safety of liposomal drugs; however, the methodology for this has not been fully established. Herein, we aimed to investigate the enhanced therapeutic potential of a pegylated liposomal formulation of topotecan (FF-10850) by analyzing the concentrations of the unencapsulated drug in target tissues, to guide the improvement of its dosing regimen.
Methods: We developed a method for measuring unencapsulated topotecan concentrations in tumor and bone marrow interstitial fluid (BM-ISF) and applied this method to pharmacokinetic assessments. The ratios of the area under the concentration-time curves (AUCs) between tumor and BM-ISF were calculated for total and unencapsulated topotecan. DNA damage and antitumor effects of FF-10850 or non-liposomal topotecan (TPT) were evaluated in an ES-2 mice xenograft model.
Results: FF-10850 exhibited a much larger AUC ratio between tumor and BM-ISF for unencapsulated topotecan (2.96), but not for total topotecan (0.752), than TPT (0.833). FF-10850 promoted milder DNA damage in the bone marrow than TPT; however, FF-10850 and TPT elicited comparable DNA damage in the tumor. These findings highlight the greater tumor exposure to unencapsulated topotecan and lower bone marrow exposure to FF-10850 than TPT. The dosing regimen was successfully improved based on the kinetics of unencapsulated topotecan and DNA damage.
Conclusions: Tissue pharmacokinetics of unencapsulated topotecan elucidated the favorable pharmacological properties of FF-10850. Evaluation of tissue exposure to an unencapsulated drug with appropriate pharmacodynamic markers can be valuable in optimizing liposomal drugs and dosing regimens.
目的量化组织中的未包封药物浓度对于了解脂质体药物的疗效和安全性机制至关重要;然而,这方面的方法尚未完全确立。在此,我们旨在通过分析托泊替康(FF-10850)未胶囊化药物在靶组织中的浓度,研究托泊替康聚乙二醇脂质体制剂的增强治疗潜力,从而指导改进其给药方案:我们开发了一种测量肿瘤和骨髓间质(BM-ISF)中未包封托泊替康浓度的方法,并将此方法应用于药代动力学评估。计算了肿瘤和骨髓间质液中总托泊替康和未包囊托泊替康的浓度-时间曲线下面积(AUC)的比率。在 ES-2 小鼠异种移植模型中评估了 FF-10850 或非脂质体托泊替康 (TPT) 的 DNA 损伤和抗肿瘤效果:与 TPT(0.833)相比,FF-10850 对未包封的拓扑替康(2.96),但对全部拓扑替康(0.752)而言,在肿瘤和 BM-ISF 之间显示出更大的 AUC 比值。与 TPT 相比,FF-10850 对骨髓中 DNA 损伤的促进作用较轻;但是,FF-10850 和 TPT 在肿瘤中引起的 DNA 损伤程度相当。这些发现突出表明,与TPT相比,未包囊的托泊替康对肿瘤的暴露更大,而FF-10850对骨髓的暴露更小。根据未包封的托泊替康和DNA损伤的动力学,成功改进了给药方案:结论:未包封的托泊替康的组织药代动力学阐明了FF-10850的良好药理特性。用适当的药效学指标评估组织对未包封药物的暴露,对优化脂质体药物和给药方案很有价值。
{"title":"Quantification of Unencapsulated Drug in Target Tissues Demonstrates Pharmacological Properties and Therapeutic Effects of Liposomal Topotecan (FF-10850).","authors":"Toshifumi Kimura, Ken Okada, Yasushi Morohashi, Yukio Kato, Mikinaga Mori, Hiroshi Kato, Takeshi Matsumoto, Susumu Shimoyama","doi":"10.1007/s11095-023-03652-4","DOIUrl":"10.1007/s11095-023-03652-4","url":null,"abstract":"<p><strong>Purpose: </strong>Quantifying unencapsulated drug concentrations in tissues is crucial for understanding the mechanisms underlying the efficacy and safety of liposomal drugs; however, the methodology for this has not been fully established. Herein, we aimed to investigate the enhanced therapeutic potential of a pegylated liposomal formulation of topotecan (FF-10850) by analyzing the concentrations of the unencapsulated drug in target tissues, to guide the improvement of its dosing regimen.</p><p><strong>Methods: </strong>We developed a method for measuring unencapsulated topotecan concentrations in tumor and bone marrow interstitial fluid (BM-ISF) and applied this method to pharmacokinetic assessments. The ratios of the area under the concentration-time curves (AUCs) between tumor and BM-ISF were calculated for total and unencapsulated topotecan. DNA damage and antitumor effects of FF-10850 or non-liposomal topotecan (TPT) were evaluated in an ES-2 mice xenograft model.</p><p><strong>Results: </strong>FF-10850 exhibited a much larger AUC ratio between tumor and BM-ISF for unencapsulated topotecan (2.96), but not for total topotecan (0.752), than TPT (0.833). FF-10850 promoted milder DNA damage in the bone marrow than TPT; however, FF-10850 and TPT elicited comparable DNA damage in the tumor. These findings highlight the greater tumor exposure to unencapsulated topotecan and lower bone marrow exposure to FF-10850 than TPT. The dosing regimen was successfully improved based on the kinetics of unencapsulated topotecan and DNA damage.</p><p><strong>Conclusions: </strong>Tissue pharmacokinetics of unencapsulated topotecan elucidated the favorable pharmacological properties of FF-10850. Evaluation of tissue exposure to an unencapsulated drug with appropriate pharmacodynamic markers can be valuable in optimizing liposomal drugs and dosing regimens.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11024016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306440","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}
Pub Date : 2024-04-01Epub Date: 2024-03-22DOI: 10.1007/s11095-024-03691-5
Jingxi Li, Xue Li, Keheng Wu, Sihui Long, Youni Zhao, Xiong Jin, Mengjun Zhang, Xinyi Wu, Zhijun Huang, Zhou Zhou, Jack Liu, Bo Liu
Aims: To develop a semi-mechanistic hepatic compartmental model to predict the effects of rifampicin, a known inducer of CYP3A4 enzyme, on the metabolism of five drugs, in the hope of informing dose adjustments to avoid potential drug-drug interactions.
Methods: A search was conducted for DDI studies on the interactions between rifampicin and CYP substrates that met specific criteria, including the availability of plasma concentration-time profiles, physical and absorption parameters, pharmacokinetic parameters, and the use of healthy subjects at therapeutic doses. The semi-mechanistic model utilized in this study was improved from its predecessors, incorporating additional parameters such as population data (specifically for Chinese and Caucasians), virtual individuals, gender distribution, age range, dosing time points, and coefficients of variation.
Results: Optimal parameters were identified for our semi-mechanistic model by validating it with clinical data, resulting in a maximum difference of approximately 2-fold between simulated and observed values. PK data of healthy subjects were used for most CYP3A4 substrates, except for gilteritinib, which showed no significant difference between patients and healthy subjects. Dose adjustment of gilteritinib co-administered with rifampicin required a 3-fold increase of the initial dose, while other substrates were further tuned to achieve the desired drug exposure.
Conclusions: The pharmacokinetic parameters AUCR and CmaxR of drugs metabolized by CYP3A4, when influenced by Rifampicin, were predicted by the semi-mechanistic model to be approximately twice the empirically observed values, which suggests that the semi-mechanistic model was able to reasonably simulate the effect. The doses of four drugs adjusted via simulation to reduce rifampicin interaction.
{"title":"Predicting Drug-Drug Interactions Involving Rifampicin Using a Semi-mechanistic Hepatic Compartmental Model.","authors":"Jingxi Li, Xue Li, Keheng Wu, Sihui Long, Youni Zhao, Xiong Jin, Mengjun Zhang, Xinyi Wu, Zhijun Huang, Zhou Zhou, Jack Liu, Bo Liu","doi":"10.1007/s11095-024-03691-5","DOIUrl":"10.1007/s11095-024-03691-5","url":null,"abstract":"<p><strong>Aims: </strong>To develop a semi-mechanistic hepatic compartmental model to predict the effects of rifampicin, a known inducer of CYP3A4 enzyme, on the metabolism of five drugs, in the hope of informing dose adjustments to avoid potential drug-drug interactions.</p><p><strong>Methods: </strong>A search was conducted for DDI studies on the interactions between rifampicin and CYP substrates that met specific criteria, including the availability of plasma concentration-time profiles, physical and absorption parameters, pharmacokinetic parameters, and the use of healthy subjects at therapeutic doses. The semi-mechanistic model utilized in this study was improved from its predecessors, incorporating additional parameters such as population data (specifically for Chinese and Caucasians), virtual individuals, gender distribution, age range, dosing time points, and coefficients of variation.</p><p><strong>Results: </strong>Optimal parameters were identified for our semi-mechanistic model by validating it with clinical data, resulting in a maximum difference of approximately 2-fold between simulated and observed values. PK data of healthy subjects were used for most CYP3A4 substrates, except for gilteritinib, which showed no significant difference between patients and healthy subjects. Dose adjustment of gilteritinib co-administered with rifampicin required a 3-fold increase of the initial dose, while other substrates were further tuned to achieve the desired drug exposure.</p><p><strong>Conclusions: </strong>The pharmacokinetic parameters AUCR and CmaxR of drugs metabolized by CYP3A4, when influenced by Rifampicin, were predicted by the semi-mechanistic model to be approximately twice the empirically observed values, which suggests that the semi-mechanistic model was able to reasonably simulate the effect. The doses of four drugs adjusted via simulation to reduce rifampicin interaction.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194356","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}
PDX-02 (Flurbiprofen sodium) is a topical nonsteroidal anti-inflammatory drug in gel formulation for local analgesia and anti-inflammation. A Phase I clinical trial was conducted to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of PDX-02 gel in Chinese healthy adults.
Methods
The trial comprised three parts: (1) a single-dose ascending study with three dose levels (0.5%, 1% to 2% PDX-02 gel) applied on a 136 cm2 skin area; (2) a multiple-dose study with either 1% or 2% PDX-02 gel applied on a 136 cm2 skin area for 7 consecutive days; and (3) a high dose group with 2% PDX-02 gel on an 816 cm2 skin area and a frequent multiple dose group with 2% PDX-02 gel on a 272 cm2 skin area four times a day for 7 consecutive days. The safety, tolerability and pharmacokinetics of the PDX-02 gel were evaluated in each part.
Results
A total of sixty participants completed the trial, with all adverse events recovered and all positive skin reaction being transient and recovered. The overall absorption of topical PDX-02 gel was slow with a mean peak time exceeding 9 h. The elimination rate remained consistent between dose groups. A less-than-dose-proportional nonlinear pharmacokinetics relationship was observed within the studied dose range, and this is likely due to the autoinduction of skin first-pass metabolism.
Conclusion
The topical PDX-02 gel showed favorable safety and tolerability in both single and multiple dosing studies, with a less-than-dose-proportional nonlinear pharmacokinetics observed.
{"title":"Nonlinear Pharmacokinetics of Topical Flurbiprofen Gel in a Phase I Study Among Chinese Healthy Adults","authors":"Wending Xiao, Zhihong Zhu, Feifan Xie, Feiyan Liu, Zeneng Cheng","doi":"10.1007/s11095-024-03692-4","DOIUrl":"https://doi.org/10.1007/s11095-024-03692-4","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Introduction</h3><p>PDX-02 (Flurbiprofen sodium) is a topical nonsteroidal anti-inflammatory drug in gel formulation for local analgesia and anti-inflammation. A Phase I clinical trial was conducted to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of PDX-02 gel in Chinese healthy adults.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>The trial comprised three parts: (1) a single-dose ascending study with three dose levels (0.5%, 1% to 2% PDX-02 gel) applied on a 136 cm<sup>2</sup> skin area; (2) a multiple-dose study with either 1% or 2% PDX-02 gel applied on a 136 cm<sup>2</sup> skin area for 7 consecutive days; and (3) a high dose group with 2% PDX-02 gel on an 816 cm<sup>2</sup> skin area and a frequent multiple dose group with 2% PDX-02 gel on a 272 cm<sup>2</sup> skin area four times a day for 7 consecutive days. The safety, tolerability and pharmacokinetics of the PDX-02 gel were evaluated in each part.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>A total of sixty participants completed the trial, with all adverse events recovered and all positive skin reaction being transient and recovered. The overall absorption of topical PDX-02 gel was slow with a mean peak time exceeding 9 h. The elimination rate remained consistent between dose groups. A less-than-dose-proportional nonlinear pharmacokinetics relationship was observed within the studied dose range, and this is likely due to the autoinduction of skin first-pass metabolism.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>The topical PDX-02 gel showed favorable safety and tolerability in both single and multiple dosing studies, with a less-than-dose-proportional nonlinear pharmacokinetics observed.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140169287","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}
Biodegradable polyesters are widely employed in the development of controlled release systems for peptide drugs. However, one of the challenges in developing a polyester-based delivery system for peptides is the acylation reaction between peptides and polymers. Peptide acylation is an important factor that affects formulation stability and can occur during storage, in vitro release, and after drug administration. This review focuses on the mechanisms and parameters that influence the rate of peptide acylation within polyesters. Furthermore, it discusses reported strategies to minimize the acylation reaction.
{"title":"Peptide Acylation in Aliphatic Polyesters: a Review of Mechanisms and Inhibition Strategies","authors":"Mojgan Sheikhi, Nasrin Nemayandeh, Mehrnoosh Shirangi","doi":"10.1007/s11095-024-03682-6","DOIUrl":"https://doi.org/10.1007/s11095-024-03682-6","url":null,"abstract":"<p>Biodegradable polyesters are widely employed in the development of controlled release systems for peptide drugs. However, one of the challenges in developing a polyester-based delivery system for peptides is the acylation reaction between peptides and polymers. Peptide acylation is an important factor that affects formulation stability and can occur during storage, <i>in vitro</i> release, and after drug administration. This review focuses on the mechanisms and parameters that influence the rate of peptide acylation within polyesters. Furthermore, it discusses reported strategies to minimize the acylation reaction.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140169121","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}