Jerry Li, Li Zhou, Abraham C. F. Leung, Donghua Yin, Xiaoying Chen
{"title":"Adaptive Dosing Trial Simulation Framework to Inform Dose Optimization: Case Study Using Longitudinal PKPD Models With PF-06804103 Phase 1 Data in Participants With Human Epidermal Growth Factor Receptor 2 (HER2) Positive and Low Solid Tumors","authors":"Jerry Li, Li Zhou, Abraham C. F. Leung, Donghua Yin, Xiaoying Chen","doi":"10.1002/psp4.70261","DOIUrl":"10.1002/psp4.70261","url":null,"abstract":"<p>Population models to identify optimal dosages typically include the evaluation of a drug's pharmacokinetics and the relationships with efficacy and safety. Dose modifications due to intolerable toxicities are frequently required for oncology therapeutics taken chronically and may impact antitumor activity and subsequent occurrences of adverse events. Model-based simulations must account for the impact of dose modifications to provide meaningful predictions that capture the dynamic interplay between pharmacokinetics, safety, and efficacy. While static dose modification schedules may be incorporated into simulations, these pre-determined scenarios are empiric and may not adequately capture the time-dependent and stochastic nature of adverse events that lead to dose modifications. PF-06804103 is an anti-HER2 antibody-drug conjugate that demonstrated dose-dependent antitumor activity and safety events. PF-06804103 appeared to have a narrow therapeutic window, which made it difficult to identify the optimal starting dosing regimen and dose modification schedule. Thus, quantitative modeling approaches were explored to better understand exposure-response relationships. An adaptive clinical trial simulation framework consisting of pharmacokinetic, tumor dynamic, and repeated time-to-event peripheral neuropathy longitudinal models was developed to guide the dose optimization of PF-06804103. This framework provides the advantage of accounting for adverse event-driven dose modifications and their real-time impact of safety on PK and efficacy, and can be adapted to other oncology therapeutics with time-dependent and exposure-related safety and efficacy profiles. The framework could be particularly beneficial to inform dose optimization, by integrating multi-dimensional early clinical data to evaluate different dosage regimens and define the regimen with the best benefit/risk ratio for further investigation.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 5","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70261","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147927289","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}
Yu-Jou Lin, Frances Okibedi, Mats O. Karlsson, Elin M. Svensson
{"title":"An Interactive Pharmacokinetic-Pharmacodynamic Framework to Evaluate Bedaquiline Dose Modifications in Adults With Tuberculosis","authors":"Yu-Jou Lin, Frances Okibedi, Mats O. Karlsson, Elin M. Svensson","doi":"10.1002/psp4.70264","DOIUrl":"10.1002/psp4.70264","url":null,"abstract":"<p>Bedaquiline is approved for use in a thrice-weekly dosing schedule; simpler once-daily dosing strategies could enable fixed-dose combinations and improve patient adherence. We developed an interactive R Shiny simulation tool to enable the evaluation of different bedaquiline dosing schedules within an integrated dose-pharmacokinetic-efficacy-safety-outcome framework. Four models describing bedaquiline and its metabolite M2 concentrations, time-to-positivity sputum culture results, QTc intervals, and long-term outcomes were incorporated in the framework. A virtual population representative of tuberculosis patients was generated for simulation. Two case studies were investigated: (1) alternative bedaquiline dosing regimens and (2) bedaquiline treatment interruption and reinitiation. The ZeNix once-daily dosing (200 mg once daily for 8 weeks, followed by 100 mg once daily for 16 weeks) yielded 50% lower median bedaquiline and M2 weekly average concentrations compared to the registered (approved) and standard-loading once-daily dosing (400 mg once daily for 2 weeks, followed by 100 mg once daily for 22 weeks) at 2 weeks. The exposure difference was predicted to lead to 11% fewer patients with negative cultures at 2 weeks and 5.8% fewer patients having sputum culture conversions at 8 weeks under the ZeNix dosing. The QTcF intervals were predicted from 376 to 442 ms (5th to 95th percentile of the population) for the three evaluated strategies. We also demonstrated that the Shiny application could guide decisions on the timing and doses for reloading bedaquiline after treatment interruption. The developed Shiny platform supports future exploration of bedaquiline treatment under different scenarios, for example, potential drug–drug interactions and clinical trial simulations.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 5","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70264","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873591","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}
Akshanth R. Polepally, Aline Goebel, Maulik Patel, Carla Biesdorf, Jalaja Potluri, Rajeev M. Menon, Sven Mensing, Benjamin Engelhardt
{"title":"Semi-Mechanistic PK/PD Modeling of Platelets and Spleen Volume With Navitoclax in Combination With Ruxolitinib in Patients With Myelofibrosis","authors":"Akshanth R. Polepally, Aline Goebel, Maulik Patel, Carla Biesdorf, Jalaja Potluri, Rajeev M. Menon, Sven Mensing, Benjamin Engelhardt","doi":"10.1002/psp4.70260","DOIUrl":"10.1002/psp4.70260","url":null,"abstract":"<p>Navitoclax, an oral small molecule BCL-X<sub>L</sub>/BCL-2 inhibitor evaluated in myelofibrosis, was assessed through integrated PK/PD modeling to guide starting dose and dose-reduction decisions when combined with ruxolitinib. An integrated sequential PK/PD model was developed to describe the relationships between navitoclax and ruxolitinib exposure, platelet count, and spleen volume. Simulations were conducted to assess spleen volume reductions of ≥ 35% at week 24 (SVR<sub>35W24</sub>) and incidences of ≥ grade 3 or grade 4 thrombocytopenia. The population PKs were adequately characterized by two-compartment models, and the subsequent integrated PK/PD model adequately described the platelet and spleen volume data. Model simulations indicated that the incidence of ≥ grade 3 or grade 4 thrombocytopenia during a weekly ramp-up from navitoclax 100 to 200 mg once daily (QD) was similar to that predicted with a flat 200 mg QD starting dose. Simulations suggested that reducing doses of navitoclax by 25 mg for patients with baseline platelet counts ≤ 150 × 10<sup>9</sup>/L (starting at 100 mg) and by 50 mg, with an additional 25 mg if needed, for those > 150 × 10<sup>9</sup>/L (starting at 200 mg) effectively minimized ≥ grade 3 thrombocytopenia while maintaining SVR<sub>35W24</sub>. Integrated PK/PD model simulations suggested that a flat starting dose of navitoclax 200 mg for baseline platelets > 150 × 10<sup>9</sup>/L, and 100 mg for ≤ 150 × 10<sup>9</sup>/L with ruxolitinib minimized thrombocytopenia risk while maintaining efficacy. Dose reductions of 25 mg for the 100 mg start and 50 mg (plus 25 mg if needed) for the 200 mg start optimized the benefit–risk balance.</p>","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"15 5","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70260","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147867137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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