CPT: Pharmacometrics & Systems Pharmacology最新文献

{"title":"From In Vitro Efficacy to Long-Term HbA1c Response for GLP-1R/GlucagonR Agonism Using the 4GI-HbA1c Systems Model.","authors":"Rolien Bosch, Marcella Petrone, Rosalin Arends, Eric J G Sijbrands, Sven Hoefman, Nelleke Snelder","doi":"10.1002/psp4.70074","DOIUrl":"https://doi.org/10.1002/psp4.70074","url":null,"abstract":"<p><p>For the treatment of Type 2 Diabetes, high efficacy approaches such as Glucagon-like peptide 1 (GLP-1)-based therapies are recommended for glucose control. Prediction of the clinical outcome of these therapies on glucose and hemoglobin A1c (HbA1c), using early available pharmacokinetic and in vitro efficacy information, can be a valuable tool for compound selection and supporting drug development. Our previously developed glucose homeostasis model (the 4GI model) is a systems model that is able to quantify drug effects on glucose based on in vitro potency and PK information. In this research, the model was coupled to an existing integrated glucose-red blood cell-HbA1c (IGRH) model for predicting the effects of GLP-1 and GLP-1/glucagon (dual) receptor agonists, liraglutide and cotadutide, on glucose and HbA1c. The 4GI model was validated for predicting 24-h glucose (C_glc,av) with minimal model calibration using short-term Ph2a continuous glucose monitoring (CGM) data. Subsequently, the predicted C_glc,av served as input for the HbA1c model to assess the predictiveness of the combined 4GI-HbA1c model on HbA1c. The resulting combined model was used in cotadutide's clinical development by providing predictive insights into the 26 weeks glucose and HbA1c dynamics of the Ph2b study prior to its initiation. Retrospective analysis showed that the model adequately predicted the effect of cotadutide and liraglutide on fasting plasma glucose and HbA1c (Root Means Square Percent Error (RMSPE) 5.9% and 13%, respectively). This demonstrates the potential of the 4GI-HbA1c systems model as a valuable tool in supporting the clinical development of novel GLP-1 and/or glucagon agonists.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642034","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}

{"title":"Continuous-Time Markov Population PK/PD Modeling of Longitudinal EASI Categorical Score in Atopic Dermatitis Treated With Rocatinlimab, an Anti-OX40 Monoclonal Antibody.","authors":"Hiroki Okada, Sam Liao, Lisa Khouri, Lori Liao, Matthew W Hruska, Yoshinori Nagata, Maki Hasegawa, Andrew Gewitz, Douglas Marsteller","doi":"10.1002/psp4.70069","DOIUrl":"https://doi.org/10.1002/psp4.70069","url":null,"abstract":"<p><p>Rocatinlimab (AMG 451/KHK4083) is a potential T-cell rebalancing therapy that inhibits and reduces the number of pathogenic T cells by targeting the OX40 receptor; it is associated with a progressive and sustained response for patients with moderate-to-severe atopic dermatitis (AD). This population pharmacokinetic-pharmacodynamic (PPK-PD) analysis of rocatinlimab analyzed the longitudinal relationship between drug exposure and response using a four-state continuous-time Markov model. The model was developed using a two-compartment PPK model for exposure based on five clinical studies and the categorical scores of Eczema Area and Severity Index (EASI) response from two clinical studies in AD (NCT03096223/NCT03703102). EASI categorical score was classified by percentage reduction from baseline (EASI₀: < 50%; EASI₅₀: ≥ 50% to < 75%; EASI₇₅: ≥ 75% to < 90%; EASI₉₀: ≥ 90%) following rocatinlimab exposure. Overall, 413 patients/healthy subjects were included in the full PPK dataset. The observed serum concentration-time data following rocatinlimab exposure was well described using the two-compartment PPK model. For PPK-PD analysis, EC₅₀ and E_max estimates were 24.0 μg/mL (% relative standard error [RSE]: 32.4) and 1.26 (%RSE: 25.4), respectively, with dropout probability for EASI₀ (0.0291) greater than for other EASI categories. Race was identified as a covariate but was not clinically meaningful. The PPK-PD model adequately described the time course and drug-related change in EASI score and was used to simulate various dosage regimens to predict the time course of EASI response. The identified parameters and drug-exposure relationship were considered to potentially support dose revisions and optimization for phase 3 trials in patients with moderate-to-severe AD that are utilizing a subcutaneous regimen with dosing every 4 weeks.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636437","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}

{"title":"Predicting Drug Transfer Into Human Milk With the Simcyp Simulator: A Contribution From the ConcePTION Project.","authors":"Julia Macente, Nina Nauwelaerts, Justine Marine Badée, Rodolfo Hernandes Bonan, Miao-Chan Huang, Martje Van Neste, Anne Smits, Karel Allegaert, Hedvig Nordeng, Markus Hovd, Frederico Severino Martins, Pieter Annaert","doi":"10.1002/psp4.70066","DOIUrl":"https://doi.org/10.1002/psp4.70066","url":null,"abstract":"<p><p>Physiologically-based pharmacokinetic (PBPK) modeling can support decision-making on maternal medication use during breastfeeding. This study aimed to enhance lactation PBPK models in two ways. First, the utility of integrating permeability- versus perfusion-limited distribution to human milk was explored using the Simcyp Simulator. Secondly, for permeability-limited models, drug-specific bidirectional intrinsic clearance across the blood-milk barrier, predicted from drug physicochemical properties, was incorporated into lactation PBPK models. Initially, reference PBPK models were developed and verified against published clinical data. Geometric Mean Fold Error (GMFE; ~accuracy) and Average Fold Error (AFE; ~bias) for these models ranged from 1.13-1.51 and 0.68-1.42, respectively. These verified models were then extended to lactation PBPK models applying either permeability- or perfusion-limited assumptions for drug distribution across the blood-milk barrier. The lactation PBPK models were applied to predict drug concentrations in human milk and relative infant doses (RID) for 11 small molecule drugs with diverse physicochemical and disposition profiles. The models successfully predicted observed plasma PK, human milk concentration-time profiles, and milk-to-plasma ratios. Nine drugs had RID values below the safety threshold of 25%, while levetiracetam and nevirapine showed relatively higher RIDs (up to 21%). Based on these findings, a decision tree is proposed to guide the selection between permeability- or perfusion-limited distribution models in future lactation PBPK applications using Simcyp. This workflow can be extended beyond the 11 model drugs evaluated, supporting broader infant risk assessment for maternal medication during lactation.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590632","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}

{"title":"Pharmacokinetics of Intrapartum Benzylpenicillin: Insights Into Candidate Regimens to Prevent Early Onset Neonatal Group B Streptococcus Disease.","authors":"Bonniface Obura, Jennifer Unsworth, Ana Jimenez-Valverde, Catriona Waitt, Shampa Das, William Hope, Kate Navaratnam","doi":"10.1002/psp4.70072","DOIUrl":"https://doi.org/10.1002/psp4.70072","url":null,"abstract":"<p><p>Early onset neonatal Group B Streptococcus (GBS) infection accounts for significant global morbidity and mortality. Intrapartum prophylaxis with benzylpenicillin is advised for women at high risk of having a baby affected by early onset GBS disease. Pregnancy-related physiological changes can alter pharmacokinetics. To estimate the intrapartum pharmacokinetics of penicillin, women (n = 12) at risk of GBS disease were enrolled. A fixed regimen of intravenous benzylpenicillin 3 g at onset of labor and 1.5 g every 4 h until delivery was used. Benzylpenicillin concentrations in plasma and umbilical cord were quantified. A nonparametric population pharmacokinetic model was fitted to the data and regimens that optimized drug exposure (fC_min > MIC for 100% of the dosing interval) were determined using Monte Carlo simulation. Benzylpenicillin pharmacokinetics were well described using a two-compartment model with a linked umbilical cord compartment. The mean volume of the central compartment and first-order clearance were 16.55 L and 41.24 L/h, respectively. Simulations showed that a lower regimen of benzylpenicillin 2.4 g followed by 1.2 g every 4 h resulted in adequate drug exposure-with plasma fC_min > 0.125 mg/L for 100% of the dosing interval in > 90% of the simulated population. Simulations of a continuous infusion of benzylpenicillin resulted in higher target attainment rates when compared to intermittent dosing. Alternative intrapartum regimens of penicillin that are efficacious but require less total daily drug amounts appear feasible. Further research evaluating alternative regimens on clinical outcomes is required.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590631","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}

{"title":"Prognostic Value of a Joint K-PD Model With Tumor Size Dynamics and CA-125 Kinetics in Recurrent Ovarian Cancer Patients: BOLD Phase II GINECO Study.","authors":"Aurore Carrot, Pauline Corbaux, Olivier Colomban, Coriolan Lebreton, Laurence Gladieff, Olivier Tredan, Frédéric Selle, Cyril Abdeddaim, Alexandra Leary, Véronique D'Hondt, Coraline Dubot, Thibaut Reverdy, Benoit You, Gilles Freyer","doi":"10.1002/psp4.70025","DOIUrl":"https://doi.org/10.1002/psp4.70025","url":null,"abstract":"<p><p>In patients with recurrent advanced ovarian cancer, there is a need for companion tests to guide the development of innovative chemotherapy-free treatments. The modeled longitudinal CA-125 ELIMination rate constant K KELIM-B was a major prognostic factor for progression-free survival (PFS) and overall survival (OS) in recurrent advanced ovarian cancer patients treated with bevacizumab, olaparib, and durvalumab in the BOLD trial. The objective was to determine if a joint semi-mechanistic model with tumor size and CA-125 kinetics would increase KELIM-B accuracy/prognostic value. The BOLD phase II trial (NCT04015739) investigated the triplet regimen in 74 patients with recurrent platinum-sensitive/resistant advanced ovarian cancer. Two kinetic-pharmacodynamic models were developed to fit the data collected during the first 100 treatment days: (1) a CA-125 longitudinal kinetics model, and (2) a joint model integrating both CA-125 kinetics and tumor size. The prognostic value of KELIM-B and KELIM-joint was assessed using univariate/multivariate analyses (PFS/OS). The modeling of CA-125 and tumor size dynamics was feasible with adequate quality checks. The prognostic value of the categorical KELIM-joint, binarized by the median (PFS, HR = 0.29, 95% CI [0.12-0.72]; OS, HR = 0.24, 95% CI [0.08-0.74]), was not clinically different from that of KELIM-B (PFS, HR = 0.35, 95% CI [0.14-0.84]; OS, HR = 0.34, 95% CI [0.12-0.99]). Interactions between tumor size changes and CA-125 kinetics could be assessed in the joint model. However, the improvement in prognostic value was not sufficient to justify the higher complexity of the joint model. Assessing early longitudinal CA-125 kinetics alone remains the best pragmatic strategy for future development.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583320","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}

{"title":"Quantitative Systems Pharmacology Modeling of Platelet Responses to Recombinant ADAMTS13 in Patients With Congenital Thrombotic Thrombocytopenic Purpura.","authors":"Cameron McBride, Jiaolong Jiang, Zhiwei Zhang, John Tolsma, Parth Patwari, Björn Mellgård, Majid Vakilynejad, Indranil Bhattacharya, Andy Z X Zhu","doi":"10.1002/psp4.70063","DOIUrl":"https://doi.org/10.1002/psp4.70063","url":null,"abstract":"<p><p>Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening thrombotic microangiopathy caused by a severe inherited deficiency of ADAMTS13, a von Willebrand factor (VWF) cleaving enzyme. Inadequate clinical endpoint data often make it challenging to statistically power clinical trials in ultra-rare diseases. Therefore, utilizing in vitro, adamts13-knockout mouse, literature-based, and clinical data, a quantitative systems pharmacology (QSP) model was developed to describe the mechanistic relationship between ADAMTS13, VWF, and platelet count, and to supplement evidence from clinical trials of recombinant ADAMTS13 (rADAMTS13) for the treatment of cTTP. The effect of long-term prophylaxis with rADAMTS13 versus plasma-based therapies (PBT) on platelet count in patients with cTTP was investigated. One-year clinical trial simulations of thrombocytopenia occurrences in 1000 virtual patients, phenotype-matched to a cTTP Phase 3 study population (NCT03393975), were produced. Simulations suggested that once-weekly (Q1W) or once every 2 weeks (Q2W) rADAMTS13 administered over 1 year resulted in fewer patients experiencing thrombocytopenia versus patients treated with PBT (e.g., Q2W [rADAMTS13] relative to Q2W [PBT], HR = 0.47 [platelet count drop to < 150 × 10⁹/L], HR = 0.41 [< 100 × 10⁹/L]). These results provide confirmative evidence to support the use of rADAMTS13 in cTTP by integrating the current mechanistic understanding of interactions between ADAMTS13 and VWF multimers as its substrate, as well as key downstream parameters, primarily platelet count. Virtual patient clinical simulations from the QSP model supported the regulatory approval of rADAMTS13 in cTTP, highlighting the significant potential of QSP modeling to supplement clinical trial data in rare disease drug development.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564642","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}

{"title":"Population Pharmacokinetic and Exposure-Response Analyses of Ibrutinib Combined With Bendamustine and Rituximab in Patients With Mantle Cell Lymphoma.","authors":"Per Olsson Gisleskog, Belén Valenzuela, Nicoline Treijtel, Sanjay Deshpande, Todd Henninger, Juan José Perez-Ruixo","doi":"10.1002/psp4.70061","DOIUrl":"https://doi.org/10.1002/psp4.70061","url":null,"abstract":"<p><p>Efficacy and safety of ibrutinib 560 mg once daily or placebo combined with bendamustine and rituximab (BR) were assessed in patients with mantle cell lymphoma in a randomized phase 3 study (SHINE). The analysis described explores the ibrutinib population pharmacokinetics (PK) and exposure-response (E-R) relationships of selected efficacy and safety endpoints. Ibrutinib PK was consistent with previous assessments, characterized by an open two-compartment disposition model with sequential zero-first order oral absorption after a lag time. Ibrutinib treatment was efficacious in extending PFS versus placebo (HR: 0.75; 95% CI: 0.59 to 0.96), although similar OS, CRR, and ORR were observed. PFS benefit was similar across the quartiles of ibrutinib exposure, suggesting that systemic exposures obtained provide maximal clinical response. There was no association between ibrutinib exposure and incidence of major hemorrhage, Grade ≥ 3 liver function test abnormalities, Grade ≥ 3 neutropenia, Grade ≥ 2 diarrhea, treatment-emergent adverse events (TEAEs) leading to death, and TEAEs leading to ibrutinib dose reduction. However, the incidence of all Grade ≥ 3 TEAEs, all serious TEAEs, TEAEs leading to ibrutinib discontinuation, Grade ≥ 1 atrial fibrillation, any hemorrhage, and Grade ≥ 3 infection was higher in the ibrutinib than placebo arm. Of these, only atrial fibrillation and any hemorrhage increased with increasing exposure. Overall, ibrutinib 560 mg, combined with BR, consistently improves PFS across the ibrutinib exposure range evaluated. According to the results of the exposure-response analysis, for patients who develop specific toxicities, dose reduction according to the prescribing information may improve the ibrutinib tolerability while keeping adequate exposure to maintain efficacy.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559463","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}

{"title":"Prediction of a CLDN18.2 Targeted Antibody Drug Conjugate Pharmacokinetics in Cancer Patients Using PBPK Modeling and Simulation.","authors":"Chiara Zunino, Sichen Wang, Yanyan Zhang, Séverine Urdy, Wilhelmus E A de Witte, Xavier Declèves, Alicja Puszkiel, Nassim Djebli","doi":"10.1002/psp4.70071","DOIUrl":"https://doi.org/10.1002/psp4.70071","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) represent a promising anticancer approach. Although physiologically based pharmacokinetics (PBPK) modeling became essential in Pharmacometrics to characterize exposure in different tissues, very few PBPK models have been published for ADCs, none within the PK-Sim/MoBi software. To capture the pharmacokinetics (PK) of an anti-Claudin 18.2 ADC, a PBPK model was built in PK-Sim and MoBi and compared to observations from three clinical studies after intravenous (IV) administration in 109 patients with cancer. The PK parameters were considered inaccurate if the predicted error ratios were outside the two-fold error range (0.5-2). In PK-Sim, we defined one PBPK model comprising three compounds (ADC, payload, and naked antibody), which were mechanistically linked. This model captured the ADC PK profile. However, additional clearance mechanisms were essential to improve the fit of the ADC elimination phase. After integration of target-mediated drug disposition (TMDD) and deconjugation of the payload in MoBi, 3 parameters were optimized for each of the ADC and the payload (degradation rate constant and reference concentration of the target, deconjugation rate constant, lipophilicity, nonspecific hepatic clearance rate constant and passive renal clearance of the payload). The PK data were adequately captured for both observed compounds, with a predicted error ratio within the two-fold range: C_max__ADC (1.07-1.50), C_{max_Payload} (0.56-1.18), AUC_{0-504h_ADC} (0.73-1.23) and AUC_{0-504h_payload} (0.77-1.37). The \"parameter optimization\" of different parameters allowed accurately capturing the observed data for both ADC and payload in cancer patients for an anti-Claudin 18.2 ADC. This analysis paves the way for PBPK modeling of other ADCs currently in development.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559464","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}

{"title":"Population Pharmacokinetics and Exposure-Response Relationships of Maribavir in Transplant Recipients With First Episode or Refractory Cytomegalovirus.","authors":"Kefeng Sun, Claudia Jomphe, Nathalie H Gosselin, Leon Pheng, Chandrasekar Durairaj, Yaming Hang, Indranil Bhattacharya","doi":"10.1002/psp4.70054","DOIUrl":"https://doi.org/10.1002/psp4.70054","url":null,"abstract":"<p><p>Maribavir's anti-cytomegalovirus (CMV) activity and favorable safety/tolerability profile is a welcomed addition to the CMV treatment armamentarium. To further characterize pharmacokinetic (PK) and exposure-response relationships of maribavir in transplant recipients with CMV, a population PK model was updated with data from the AURORA study, using non-linear mixed-effect modeling. Covariates were tested using a stepwise procedure. In exposure-response analyses, relationships between maribavir exposure metrics and the primary and key secondary response endpoints and safety data from AURORA were characterized. The final model was a two-compartment disposition model with first-order elimination, first-order absorption and an absorption lag-time. Exposure levels were similar irrespective of transplant type and in patients with refractory CMV infection versus those receiving first-line maribavir. Concomitant administration of proton-pump inhibitors resulted in reduced maribavir exposure that was not clinically significant. There was no apparent relationship between maribavir exposure and the primary or key secondary endpoints of the AURORA study. Steady-state maribavir exposures were not significantly associated with any adverse events other than nausea and vomiting. In conclusion, maribavir's efficacy, safety, and favorable tolerability profile in transplant recipients with first CMV infection after transplant or refractory CMV infection is supported by PK exposure metrics. Higher maribavir steady-state concentrations were not associated with greater efficacy or a higher frequency of adverse events other than nausea and vomiting.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564641","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}

{"title":"Population Pharmacokinetic Modeling of the Oral Calcitonin Gene-Related Peptide Receptor Antagonist Rimegepant in Adults.","authors":"Craig M Comisar, Jim H Hughes, Jose Francis, Yorinao Chinda, Yamato Sano, Chieko Muto, Christine Neumar, Rajinder Bhardwaj, Richard Bertz, Jing Liu","doi":"10.1002/psp4.70051","DOIUrl":"https://doi.org/10.1002/psp4.70051","url":null,"abstract":"<p><p>Rimegepant is a small-molecule calcitonin gene-related peptide receptor antagonist approved for acute and preventive migraine treatment in adults, administered as an orally disintegrating tablet (ODT). A population pharmacokinetic analysis was performed to describe rimegepant's plasma concentration-time course and to estimate covariate effects on rimegepant exposure. The model was developed/evaluated in 3 stages using data from 11 phase 1 clinical studies, wherein rimegepant was administered orally to healthy adults, elderly people with stable chronic illness(es), adults with renal or hepatic dysfunction, and healthy adults with Japanese or Chinese ethnicity. Plasma concentration-time data were analyzed using nonlinear mixed effects modeling. A 2-compartment model with 4 transit compartments and a first-order absorption best described the rimegepant plasma concentration-time course. Estimated typical values (%relative standard error) were apparent clearance (CL/F) = 24.1 L/h (4.86%), apparent central volume of distribution (V_c/F) = 114.0 L (5.36%), apparent inter-compartmental clearance (Q/F) = 3.94 L/h (6.37%), apparent peripheral volume of distribution (V_p/F) = 46.0 L (5.30%), absorption rate constant (k_a) = 3.86 h^-1 (28.4%), and transit absorption rate constant (ktr) = 8.23 h^-1 (8.24%). Statistically significant covariates included empirical allometric body weight-based scaling exponents (0.75 for CL/F and Q/F and 1 for V_c/F and V_p/F); severe/moderate hepatic impairment and fluconazole/itraconazole co-administration on CL/F; fed status, dose on relative bioavailability; and fed status, itraconazole co-administration, and capsule and ODT formulations on transition absorption rate constant. Only severe hepatic impairment and co-administration of itraconazole resulted in a clinically significant decrease in rimegepant CL/F, supporting the recommendation to avoid rimegepant administration in patients with severe hepatic impairment or with a strong CYP3A4 inhibitor.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564640","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}