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Pediatric model ‐based dose optimization using a pooled exposure‐response safety analysis for nivolumab and nivolumab plus ipilimumab combination in melanoma
AbstractAn exposure –response (E-R) safety analysis was conducted across adult and pediatric (<18  years) studies to evaluate the potential impact of higher nivolumab and/or ipilimumab exposures in adolescents (≥12 to<18  years ) versus adults with melanoma using the approved adult dosing regimens for nivolumab alone or in combination with ipilimumab. Data from 3507 patients across 15 studies were used to examine the relationship between nivolumab–ipilimumab daily average exposure (Cavg) and time to grade 2+ immune-mediated adverse events (gr2+ IMAEs). Results from the E-R safety model showed ipilimumab, bu...
Source: CPT: Pharmacometrics and Systems Pharmacology - October 24, 2023 Category: Drugs & Pharmacology Authors: Shengnan Du, Yue Zhao, Zheyi Hu, Sihang Liu, Amit Roy, Jun Shen, Li Zhu, Lora Hamuro Tags: ARTICLE Source Type: research

A Convolution ‐based In Vitro‐In Vivo Correlation (IVIVC) Model for Methylphenidate Hydrochloride Delayed‐release and Extended‐release Capsule
(Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - October 21, 2023 Category: Drugs & Pharmacology Authors: Pawan Kumar Gupta, Bev Incledon, Jogarao V. S. Gobburu, Roberto Gomeni Tags: ARTICLE Source Type: research

A Multistate Platform Model for Time ‐To‐Event Endpoints in Oncology Clinical Trials
AbstractA multistate platform model was developed to describe time-to-event (TTE) endpoints in an oncology trial through the following states: initial, tumor response (TR), progressive disease (PD), overall survival (OS) event (death), censor to the last evaluable tumor assessment (progression free survival [PFS] censor), and censor to study end (OS censor), using an ordinary differential equation framework. Two types of piecewise functions were used to describe the hazards for different events. Piecewise surge functions were used for events that require tumor assessments at the scheduled study visit times (TR, PD, and PFS...
Source: CPT: Pharmacometrics and Systems Pharmacology - October 20, 2023 Category: Drugs & Pharmacology Authors: Chih ‐Wei Lin, Mario Nagase, Sameer Doshi, Sandeep Dutta Tags: ARTICLE Source Type: research

Toward improved predictions of pharmacokinetics of  transported drugs in hepatic impairment: Insights from the extended clearance model
AbstractHepatic impairment (HI) moderately (<5-fold) affects the systemic exposure (i.e., area under the plasma concentration –time curve [AUC]) of drugs that are substrates of the hepatic sinusoidal organic anion transporting polypeptide (OATP) transporters and are excreted unchanged in the bile and/or urine. However, the effect of HI on their AUC is much greater (>10-fold) for drugs that are also substrates of cytochrome P450 (CYP) 3A enzymes. Using the extended clearance model, through simulations, we identified the ratio of sinusoidal efflux clearance (CL) over the sum of metabolic and biliary CLs as important ...
Source: CPT: Pharmacometrics and Systems Pharmacology - October 20, 2023 Category: Drugs & Pharmacology Authors: Flavia Storelli, Mayur K. Ladumor, Xiaomin Liang, Yurong Lai, Paresh P. Chothe, Osatohanmwen J. Enogieru, Raymond Evers, Jashvant D. Unadkat Tags: ARTICLE Source Type: research

Cluster Gauss ‐Newton method for a quick approximation of profile likelihood: With application to physiologically‐based pharmacokinetic models
In this study, we propose a method that approximates the profile likelihood by reusing intermediate computation results from CGNM, allowing us to obtain the upper bounds of the profile likelihood without conducting additional model evaluation. This method allows us to quickly draw approximate profile likelihoods for all unknown parameters. Additionally, the same approach can be used to draw two-dimensional profile likelihoods for all parameter combinations within seconds. We demonstrate the effectiveness of this method on three PBPK models. (Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - October 19, 2023 Category: Drugs & Pharmacology Authors: Yasunori Aoki, Yuichi Sugiyama Tags: ARTICLE Source Type: research

Issue Information
(Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - October 18, 2023 Category: Drugs & Pharmacology Tags: ISSUE INFORMATION Source Type: research

Role of Pharmacometrics and Systems Pharmacology in Facilitating Efficient Dose Optimization in Oncology
(Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - October 18, 2023 Category: Drugs & Pharmacology Authors: Priya Jayachandran, Rajat Desikan, Sriram Krishnaswami, Stefanie Hennig Tags: EDITORIAL Source Type: research

Integrating machine learning with pharmacokinetic models: Benefits of scientific machine learning in adding neural networks components to existing PK models
AbstractRecently, the use of machine-learning (ML) models for pharmacokinetic (PK) modeling has grown significantly. Although most of the current approaches use ML techniques as black boxes, there are only a few that have proposed interpretable architectures which integrate mechanistic knowledge. In this work, we use as the test case a one-compartment PK model using a scientific machine learning (SciML) framework and consider learning an unknown absorption using neural networks, while simultaneously estimating other parameters of drug distribution and elimination. We generate simulated data with different sampling strategi...
Source: CPT: Pharmacometrics and Systems Pharmacology - October 16, 2023 Category: Drugs & Pharmacology Authors: Diego Valderrama, Ana Victoria Ponce ‐Bobadilla, Sven Mensing, Holger Fröhlich, Sven Stodtmann Tags: ARTICLE Source Type: research

Towards improved predictions of pharmacokinetics of transported drugs in hepatic impairment: insights from the extended clearance model
AbstractHepatic impairment (HI) moderately (<  5-fold) affects the systemic exposure (i.e. area under the plasma concentration-time curve, AUC) of drugs that are substrates of the hepatic sinusoidal organic anion transporting polypeptide (OATP) transporters and are excreted unchanged in the bile and/or urine. However, the effect of HI on their AUC is much greater (>  10-fold) for drugs that are also substrates of cytochrome P450 (CYP) 3A enzymes. Using the extended clearance model, through simulations, we identified the ratio of sinusoidal efflux clearance (CL) and the sum of metabolic and biliary CLs as importan...
Source: CPT: Pharmacometrics and Systems Pharmacology - October 14, 2023 Category: Drugs & Pharmacology Authors: Flavia Storelli, Mayur K. Ladumor, Xiaomin Liang, Yurong Lai, Paresh P. Chothe, Osatohanmwen J. Enogieru, Raymond Evers, Jashvant D. Unadkat Tags: ARTICLE Source Type: research