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Population pharmacokinetic and exposure ‐response analyses of pemigatinib in patients with advanced solid tumors including cholangiocarcinoma
AbstractPemigatinib is a selective, potent, oral inhibitor of fibroblast growth factor receptor (FGFR)1 –3 with efficacy in patients with previously treated, advanced/metastatic cholangiocarcinoma (CCA) withFGFR2 alterations. A previously developed population pharmacokinetic (PK) model of pemigatinib was refined using an updated dataset with 467 participants from seven clinical studies, including patients with CCA. Updated PK model parameters were used to evaluate the association between pemigatinib exposure and efficacy and safety. Pemigatinib PK was adequately described by a two-compartment model with linear eliminatio...
Source: CPT: Pharmacometrics and Systems Pharmacology - November 16, 2023 Category: Drugs & Pharmacology Authors: Xiaohua Gong, Ayman Akil, Andre Ndi, Tao Ji, Xiang Liu, Mark Lovern, Xuejun Chen Tags: ARTICLE Source Type: research

Realizing the Promise of Project Optimus: Challenges and Emerging Opportunities for Dose Optimization in Oncology Drug Development
AbstractProject Optimus is a U.S. Food and Drug Administration Oncology Center of Excellence initiative aimed at reforming the dose selection and optimization paradigm in oncology drug development. This project seeks to bring together pharmaceutical companies, international regulatory agencies, academic institutions, patient advocates, and other stakeholders. While there is much promise in this initiative, there are several challenges that need to be addressed, including multi-dimensionality of the dose optimization problem in oncology, the heterogeneity of cancer and patients, importance of evaluating long-term tolerabili...
Source: CPT: Pharmacometrics and Systems Pharmacology - November 16, 2023 Category: Drugs & Pharmacology Authors: Wei Gao, Jiang Liu, Blerta Shtylla, Karthik Venkatakrishnan, Donghua Yin, Mirat Shah, Timothy Nicholas, Yanguang Cao Tags: REVIEW Source Type: research

A model ‐based approach leveraging in vitro data to support dose selection from the outset: A framework for bispecific antibodies in immuno‐oncology
AbstractFAP-4-1BBL is a bispecific antibody exerting 4-1BB-associated T-cell activation only while simultaneously bound to the fibroblast activation protein (FAP) receptor, expressed on the surface of cancer-associated fibroblasts. The trimeric complex formed when FAP-4-1BBL is simultaneously bound to FAP and 4-1BB represents a promising mechanism to achieve tumor-specific 4-1BB stimulation. We integrated in  vitro data with mathematical modeling to characterize the pharmacology of FAP-4-1BBL as a function of trimeric complex formation when combined with the T-cell engager cibisatamab. This relationship was used to prospe...
Source: CPT: Pharmacometrics and Systems Pharmacology - November 15, 2023 Category: Drugs & Pharmacology Authors: Javier S ánchez, Christina Claus, Rosmarie Albrecht, Brenda C. Gaillard, Joana Marinho, Christine McIntyre, Tamara Tanos, Axel Boehnke, Lena E. Friberg, Siv Jönsson, Nicolas Frances Tags: ARTICLE Source Type: research

Correction to Network module ‐based drug repositioning for pulmonary arterial hypertension
(Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - November 14, 2023 Category: Drugs & Pharmacology Tags: CORRIGENDUM Source Type: research

A tutorial for model ‐based evaluation and translation of cardiovascular safety in preclinical trials
AbstractAssessment of drug-induced effects on the cardiovascular (CV) system remains a critical component of the drug discovery process enabling refinement of the therapeutic index. Predicting potential drug related unintended CV effects in the preclinical stage is necessary for first-in-human dose selection and preclusion of adverse CV effects in the clinical stage. According to the current guidelines for small molecules, non-clinical CV safety assessment conducted via telemetry analyses should be included in the safety pharmacology core battery studies. However, the manual for quantitative evaluation of the CV safety sig...
Source: CPT: Pharmacometrics and Systems Pharmacology - November 14, 2023 Category: Drugs & Pharmacology Authors: Victoria Kulesh, Igor Vasyutin, Alina Volkova, Kirill Peskov, Holly Kimko, Victor Sokolov, Ravindra Alluri Tags: TUTORIAL Source Type: research

Machine Learning ‐based Integration of Network Features and Chemical Structure of Compounds for SARS‐CoV‐2 Drug Effect Analysis
AbstractHigh drug development costs and the limited number of new annual drug approvals increase the need for innovative approaches for drug effect prediction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), led to a global pandemic with high morbidity and mortality. While effective preventive measures exist, there are few effective treatments for hospitalized patients with SARS-CoV-2 infection. Drug effect prediction are promising strategies that could shorten development time and reduce costs compared tode novo drug discovery. In this work, we present a mach...
Source: CPT: Pharmacometrics and Systems Pharmacology - November 11, 2023 Category: Drugs & Pharmacology Authors: Julian Sp äth, Rui‐Sheng Wang, Maeve Humphrey, Jan Baumbach, Joseph Loscalzo Tags: ARTICLE Source Type: research

Optimizing the Design of a Pharmacokinetic Trial to Evaluate the Dosing Scheme of a Novel Tuberculosis Drug in Children Living with or without HIV
AbstractPharmacokinetic (PK) studies in children are usually small and have ethical constraints due to the medical complexities of drawing blood in this special population. Often population PK models for the drug(s) of interest are available in adults, and these models can be extended to incorporate the expected deviations seen in children. As a consequence, there is increasing interest in the use of optimal design methodology to design PK sampling schemes in children that maximize information using a small sample size and limited number of sampling times per dosing period. As a case study, we use the novel TB drug delaman...
Source: CPT: Pharmacometrics and Systems Pharmacology - November 10, 2023 Category: Drugs & Pharmacology Authors: Grace Montepiedra, Elin M. Svensson, Weng Kee Wong, Andrew C. Hooker Tags: ARTICLE Source Type: research

Correction to: Consistent methods for fat free mass, creatinine clearance, and glomerular filtration rate to describe renal function from neonates to adults
(Source: CPT: Pharmacometrics and Systems Pharmacology)
Source: CPT: Pharmacometrics and Systems Pharmacology - November 10, 2023 Category: Drugs & Pharmacology Tags: CORRIGENDUM 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 - November 9, 2023 Category: Drugs & Pharmacology Authors: Chih ‐Wei Lin, Mario Nagase, Sameer Doshi, Sandeep Dutta Tags: ARTICLE Source Type: research