Assessment of quinidine-induced TdP risks using a whole-body physiologically based pharmacokinetic model linked to cardiac ionic current inhibition
In conclusion, the developed PBPK-PD model may be applied to predict the quinidine pharmacokinetics and quinidine-induced TdP risks in healthy subjects, but also simulate quinidine-induced TdP risks under disease conditions such as hypokalemia and alkalosis.PMID:38117225 | DOI:10.1002/cpt.3156 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - December 20, 2023 Category: Drugs & Pharmacology Authors: Zexin Zhang Han Zhou Yiting Yang Li Liu Xiaodong Liu Source Type: research

Model-Based Dose Selection of Subcutaneous Nivolumab in Patients with Advanced Solid Tumors
Clin Pharmacol Ther. 2023 Dec 19. doi: 10.1002/cpt.3148. Online ahead of print.ABSTRACTThe pharmacokinetics (PK) of intravenous (IV) nivolumab is well characterized. A subcutaneous (SC) nivolumab formulation with and without recombinant human hyaluronidase PH20 enzyme is being evaluated in CheckMate 8KX (NCT03656718). A model-based analysis was conducted to characterize the PK of nivolumab SC and predict systemic exposures after IV and SC administration to guide dosing regimen selection for nivolumab SC. A prior IV model was modified to incorporate an SC extravascular compartment and estimate the absorption rate constant (...
Source: Clinical Pharmacology and Therapeutics - December 20, 2023 Category: Drugs & Pharmacology Authors: Yue Zhao Kinjal Sanghavi Amit Roy Bindu Murthy Akintunde Bello Urvi Aras Heather Vezina Source Type: research

A randomized phase 1 study of the anti-interleukin-33 antibody tozorakimab in healthy adults and patients with chronic obstructive pulmonary disease
Clin Pharmacol Ther. 2023 Dec 19. doi: 10.1002/cpt.3147. Online ahead of print.ABSTRACTTozorakimab is a human monoclonal antibody that neutralizes interleukin (IL)-33. IL-33 is a broad-acting epithelial 'alarmin' cytokine upregulated in lung tissue of patients with chronic obstructive pulmonary disease (COPD). This first-in-human, phase 1, randomized, double-blind, placebo-controlled study (NCT03096795) evaluated the safety, tolerability, pharmacokinetics, immunogenicity, target engagement, and pharmacodynamics of tozorakimab. This was a three-part study. In part 1, 56 healthy participants with a history of atopy received ...
Source: Clinical Pharmacology and Therapeutics - December 20, 2023 Category: Drugs & Pharmacology Authors: Fred Reid Dave Singh Muna Albayaty Rachel Moate Eulalia Jimenez Muhammad Waqas Sadiq David Howe Monica Gavala Helen Killick Adam Williams Surekha Krishnan Alex Godwood Animesh Shukla Lisa Hewitt Alejhandra Lei Chris Kell Hitesh Pandya Paul Newcombe Nichol Source Type: research

Population Pharmacokinetic Analysis of Atomoxetine and its Metabolites in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder
The objective of this study was to characterize the time course of ATX and metabolites (4-hydroxyatomoxetine, 4-OH; N-desmethylatomoxetine, NDA; and 2- carboxymethylatomoxetine, 2-COOH) exposure following oral ATX dosing in ADHD children to support individualized dosing. A nonlinear mixed-effect modeling approach was used to analyze ATX, 4-OH and NDA plasma and urine, and 2-COOH urine profiles obtained over 24-72 hours from ADHD children (n=23) following a single oral ATX dose. Demographics and CYP2D6 activity score (AS) were evaluated as covariates. Simulations were performed to explore the ATX dosing in subjects with var...
Source: Clinical Pharmacology and Therapeutics - December 20, 2023 Category: Drugs & Pharmacology Authors: Shen Cheng Mahmoud Al-Kofahi J Steven Leeder Jacob T Brown Source Type: research

Assessment of quinidine-induced TdP risks using a whole-body physiologically based pharmacokinetic model linked to cardiac ionic current inhibition
In conclusion, the developed PBPK-PD model may be applied to predict the quinidine pharmacokinetics and quinidine-induced TdP risks in healthy subjects, but also simulate quinidine-induced TdP risks under disease conditions such as hypokalemia and alkalosis.PMID:38117225 | DOI:10.1002/cpt.3156 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - December 20, 2023 Category: Drugs & Pharmacology Authors: Zexin Zhang Han Zhou Yiting Yang Li Liu Xiaodong Liu Source Type: research

Correction to Exploring the Use of Serum-Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Hepatic Cytochromes P450 and Organic Anion Transporting Polypeptides
Clin Pharmacol Ther. 2023 Dec 18. doi: 10.1002/cpt.3141. Online ahead of print.NO ABSTRACTPMID:38111152 | DOI:10.1002/cpt.3141 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - December 19, 2023 Category: Drugs & Pharmacology Source Type: research

Assessment of the CYP3A4 Induction Potential by Carbamazepine: Insights from two Clinical DDI Studies and PBPK Modeling
Clin Pharmacol Ther. 2023 Dec 17. doi: 10.1002/cpt.3151. Online ahead of print.ABSTRACTIn the past, rifampicin was well established as strong index CYP3A inducer in clinical drug-drug interaction (DDI) studies. However, due to identified potentially genotoxic nitrosamine impurities, it should not any longer be used in healthy volunteer studies. Available clinical data suggest carbamazepine as an alternative to rifampicin as strong index CYP3A4 inducer in clinical DDI studies. Further, physiologically based pharmacokinetic (PBPK) modeling is a tool with increasing importance to support the DDI risk assessment of drugs durin...
Source: Clinical Pharmacology and Therapeutics - December 18, 2023 Category: Drugs & Pharmacology Authors: Friederike Kanefendt Andr é Dallmann Huijun Chen Klaus Francke Tianxing Liu Christine Brase Sebastian Frechen Marcus-Hillert Schultze-Mosgau Source Type: research

Machine Learning in Modeling Disease Trajectory and Treatment Outcomes: An Emerging Enabler for Model-Informed Precision Medicine
Clin Pharmacol Ther. 2023 Dec 17. doi: 10.1002/cpt.3153. Online ahead of print.ABSTRACTThe increasing breadth and depth of resolution in biological and clinical data, including -omics and real-world data, requires advanced analytical techniques like artificial intelligence (AI) and machine learning (ML) to fully appreciate the impact of multi-dimensional population variability in intrinsic and extrinsic factors on disease progression and treatment outcomes. Integration of advanced data analytics in Quantitative Pharmacology is crucial for drug-disease knowledge management, enabling precise, efficient and inclusive drug dev...
Source: Clinical Pharmacology and Therapeutics - December 18, 2023 Category: Drugs & Pharmacology Authors: Nadia Terranova Karthik Venkatakrishnan Source Type: research

Correction to Leveraging Human Plasma-Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Cytochrome P450 3A4 by Modafinil
Clin Pharmacol Ther. 2023 Dec 18. doi: 10.1002/cpt.3142. Online ahead of print.NO ABSTRACTPMID:38108195 | DOI:10.1002/cpt.3142 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - December 18, 2023 Category: Drugs & Pharmacology Source Type: research

Correction to Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3  Months and Older
Clin Pharmacol Ther. 2023 Dec 18. doi: 10.1002/cpt.3143. Online ahead of print.NO ABSTRACTPMID:38108553 | DOI:10.1002/cpt.3143 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - December 18, 2023 Category: Drugs & Pharmacology Source Type: research

Assessment of the CYP3A4 Induction Potential by Carbamazepine: Insights from two Clinical DDI Studies and PBPK Modeling
Clin Pharmacol Ther. 2023 Dec 17. doi: 10.1002/cpt.3151. Online ahead of print.ABSTRACTIn the past, rifampicin was well established as strong index CYP3A inducer in clinical drug-drug interaction (DDI) studies. However, due to identified potentially genotoxic nitrosamine impurities, it should not any longer be used in healthy volunteer studies. Available clinical data suggest carbamazepine as an alternative to rifampicin as strong index CYP3A4 inducer in clinical DDI studies. Further, physiologically based pharmacokinetic (PBPK) modeling is a tool with increasing importance to support the DDI risk assessment of drugs durin...
Source: Clinical Pharmacology and Therapeutics - December 18, 2023 Category: Drugs & Pharmacology Authors: Friederike Kanefendt Andr é Dallmann Huijun Chen Klaus Francke Tianxing Liu Christine Brase Sebastian Frechen Marcus-Hillert Schultze-Mosgau Source Type: research

Machine Learning in Modeling Disease Trajectory and Treatment Outcomes: An Emerging Enabler for Model-Informed Precision Medicine
Clin Pharmacol Ther. 2023 Dec 17. doi: 10.1002/cpt.3153. Online ahead of print.ABSTRACTThe increasing breadth and depth of resolution in biological and clinical data, including -omics and real-world data, requires advanced analytical techniques like artificial intelligence (AI) and machine learning (ML) to fully appreciate the impact of multi-dimensional population variability in intrinsic and extrinsic factors on disease progression and treatment outcomes. Integration of advanced data analytics in Quantitative Pharmacology is crucial for drug-disease knowledge management, enabling precise, efficient and inclusive drug dev...
Source: Clinical Pharmacology and Therapeutics - December 18, 2023 Category: Drugs & Pharmacology Authors: Nadia Terranova Karthik Venkatakrishnan Source Type: research

Correction to Leveraging Human Plasma-Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Cytochrome P450 3A4 by Modafinil
Clin Pharmacol Ther. 2023 Dec 18. doi: 10.1002/cpt.3142. Online ahead of print.NO ABSTRACTPMID:38108195 | DOI:10.1002/cpt.3142 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - December 18, 2023 Category: Drugs & Pharmacology Source Type: research

Correction to Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3  Months and Older
Clin Pharmacol Ther. 2023 Dec 18. doi: 10.1002/cpt.3143. Online ahead of print.NO ABSTRACTPMID:38108553 | DOI:10.1002/cpt.3143 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - December 18, 2023 Category: Drugs & Pharmacology Source Type: research

Broadly Implementing "At-Home Sampling" in Clinical Trials: What's Holding Us Back?
Clin Pharmacol Ther. 2024 Jan;115(1):11-13. doi: 10.1002/cpt.3090.NO ABSTRACTPMID:38102787 | DOI:10.1002/cpt.3090 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - December 16, 2023 Category: Drugs & Pharmacology Authors: Amita Joshi Source Type: research