In Memoriam Michelle A. Rudek (1972 - 2023)
Clin Pharmacol Ther. 2023 Dec 7. doi: 10.1002/cpt.3137. Online ahead of print.NO ABSTRACTPMID:38062790 | DOI:10.1002/cpt.3137 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - December 8, 2023 Category: Drugs & Pharmacology Authors: Sharyn D Baker William D Figg Source Type: research

Machine Learning-led Optimization of Combination Therapy: Confronting the Public Health Threat of Extensively Drug Resistant Gram Negative Bacteria
This study utilized human population PK (PopPK) of aztreonam, ceftazidime/avibactam, and polymyxin B along with in vitro pharmacodynamics from the Hollow Fiber Infection Model (HFIM) to derive optimal multi-drug regimens de novo through implementation of a genetic algorithm (GA). The mechanism-based PD model was constructed based on 7-day HFIM experiments across four clinical, extensively drug resistant K. pneumoniae isolates. GA-led optimization was performed using thirteen different fitness functions to compare the effects of different efficacy (60%, 70%, 80% or 90% of simulated subjects achieving bacterial counts of 102...
Source: Clinical Pharmacology and Therapeutics - December 8, 2023 Category: Drugs & Pharmacology Authors: Nicholas M Smith Thomas D Nguyen Thomas P Lodise Liang Chen Jan Naseer Kaur John F Klem Katie Rose Boissonneault Patricia N Holden Dwayne R Roach Brian T Tsuji Source Type: research

Quantitative Systems Toxicology Modeling Informed Safe Dose Selection of Emvododstat in Acute Myeloid Leukemia Patients
Clin Pharmacol Ther. 2023 Dec 8. doi: 10.1002/cpt.3136. Online ahead of print.ABSTRACTClinical investigation of emvododstat for the treatment of solid tumors was halted after two patients who were heavily treated with other anticancer therapies experienced drug-induced liver failure. However preclinical investigations supported that emvododstat at lower doses might be effective in treating acute myeloid leukemia (AML) and against SARS-CoV-2 as a dihydroorotate dehydrogenase inhibitor. Therefore, a quantitative systems toxicology model, DILIsym, was employed to predict liver safety of the proposed dosing of emvododstat in A...
Source: Clinical Pharmacology and Therapeutics - December 8, 2023 Category: Drugs & Pharmacology Authors: Kyunghee Yang Ronald Kong Robert Spiegel John D Baird Kylie O'Keefe Brett A Howell Paul B Watkins Source Type: research

The European List of Essential Medicines for Medical Education: a modified Delphi study
Clin Pharmacol Ther. 2023 Dec 7. doi: 10.1002/cpt.3132. Online ahead of print.ABSTRACTRational prescribing is essential for the quality of health care. However, many final-year medical students and junior doctors lack prescribing competence to perform this task. The availability of a list of medicines that a junior doctor working in Europe should be able to independently prescribe safely and effectively without supervision could support and harmonize teaching and training in clinical pharmacology and therapeutics (CPT) in Europe. Therefore, our aim was to achieve consensus on such a list of medicines that are widely access...
Source: Clinical Pharmacology and Therapeutics - December 8, 2023 Category: Drugs & Pharmacology Authors: Erik M Donker Pietro Spitaleri Timpone David J Brinkman Milan C Richir Paraskevi Papaioannidou Robert Likic Emilio J Sanz Thierry Christiaens Jo ão N Costa Fabrizio De Ponti Milo Gatti Ylva B öttiger Cornelis Kramers Rahul Pandit Michiel A van Agtmael J Source Type: research

In Memoriam Michelle A. Rudek (1972 - 2023)
Clin Pharmacol Ther. 2023 Dec 7. doi: 10.1002/cpt.3137. Online ahead of print.NO ABSTRACTPMID:38062790 | DOI:10.1002/cpt.3137 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - December 8, 2023 Category: Drugs & Pharmacology Authors: Sharyn D Baker William D Figg Source Type: research

Machine Learning-led Optimization of Combination Therapy: Confronting the Public Health Threat of Extensively Drug Resistant Gram Negative Bacteria
This study utilized human population PK (PopPK) of aztreonam, ceftazidime/avibactam, and polymyxin B along with in vitro pharmacodynamics from the Hollow Fiber Infection Model (HFIM) to derive optimal multi-drug regimens de novo through implementation of a genetic algorithm (GA). The mechanism-based PD model was constructed based on 7-day HFIM experiments across four clinical, extensively drug resistant K. pneumoniae isolates. GA-led optimization was performed using thirteen different fitness functions to compare the effects of different efficacy (60%, 70%, 80% or 90% of simulated subjects achieving bacterial counts of 102...
Source: Clinical Pharmacology and Therapeutics - December 8, 2023 Category: Drugs & Pharmacology Authors: Nicholas M Smith Thomas D Nguyen Thomas P Lodise Liang Chen Jan Naseer Kaur John F Klem Katie Rose Boissonneault Patricia N Holden Dwayne R Roach Brian T Tsuji Source Type: research

Highlights
Clin Pharmacol Ther. 2023 Dec 8. doi: 10.1002/cpt.3122. Online ahead of print.NO ABSTRACTPMID:38063482 | DOI:10.1002/cpt.3122 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - December 8, 2023 Category: Drugs & Pharmacology Source Type: research

Risk of Toxicity from Topical 5-Fluorouracil Treatment in Patients Carrying DPYD Variant Alleles
The objective of this retrospective cohort study was to investigate whether DPYD variant allele carriers have increased risk of toxicity from topical 5-FU. Treatment and toxicity data were retrospectively abstracted from the electronic medical records. Genotypes for the five DPYD variants that are associated with increased toxicity from systemic fluoropyrimidine chemotherapy (DPYD*2A, DPYD*13, DPYD p.D949V, DPYD HapB3, and DPYD p.Y186C) were collected from a genetic data repository. Incidence of grade 3+ (primary endpoint) and 1+ (secondary endpoint) toxicity was compared between DPYD variant carriers vs. wild-type patient...
Source: Clinical Pharmacology and Therapeutics - December 7, 2023 Category: Drugs & Pharmacology Authors: Javier Granados Amy L Pasternak N Lynn Henry Vaibhav Sahai Daniel L Hertz Source Type: research

Characterisation of CYP2B6 and CYP2A6 pharmacogenetic variation in sub-Saharan African populations
This study therefore aimed to characterise the star allele (haplotype) distribution in CYP2B6 and CYP2A6 across diverse and understudied sub-Saharan African (SSA) populations. We called star alleles from 961 high-depth full genomes using StellarPGx, Aldy and PyPGx. In addition, we performed CYP2B6 and CYP2A6 star allele frequency comparisons between SSA and other global biogeographical groups represented in the new 1000 Genomes Project high-coverage dataset (n=2000). This study presents frequency information for star alleles in CYP2B6 (e.g. *6 and *18; frequency of 21-47% and 2-19%, respectively) and CYP2A6 (e.g. *4, *9 an...
Source: Clinical Pharmacology and Therapeutics - December 4, 2023 Category: Drugs & Pharmacology Authors: David Twesigomwe Britt I Dr ögemöller Galen E B Wright Clement Adebamowo Godfred Agongo Palwend é R Boua Mogomotsi Matshaba Maria Paximadis Mich èle Ramsay Gustave Simo Martin C Simuunza Caroline T Tiemessen Zan é Lombard Scott Hazelhurst Source Type: research

Characterisation of CYP2B6 and CYP2A6 pharmacogenetic variation in sub-Saharan African populations
This study therefore aimed to characterise the star allele (haplotype) distribution in CYP2B6 and CYP2A6 across diverse and understudied sub-Saharan African (SSA) populations. We called star alleles from 961 high-depth full genomes using StellarPGx, Aldy and PyPGx. In addition, we performed CYP2B6 and CYP2A6 star allele frequency comparisons between SSA and other global biogeographical groups represented in the new 1000 Genomes Project high-coverage dataset (n=2000). This study presents frequency information for star alleles in CYP2B6 (e.g. *6 and *18; frequency of 21-47% and 2-19%, respectively) and CYP2A6 (e.g. *4, *9 an...
Source: Clinical Pharmacology and Therapeutics - December 4, 2023 Category: Drugs & Pharmacology Authors: David Twesigomwe Britt I Dr ögemöller Galen E B Wright Clement Adebamowo Godfred Agongo Palwend é R Boua Mogomotsi Matshaba Maria Paximadis Mich èle Ramsay Gustave Simo Martin C Simuunza Caroline T Tiemessen Zan é Lombard Scott Hazelhurst Source Type: research

Characterisation of CYP2B6 and CYP2A6 pharmacogenetic variation in sub-Saharan African populations
This study therefore aimed to characterise the star allele (haplotype) distribution in CYP2B6 and CYP2A6 across diverse and understudied sub-Saharan African (SSA) populations. We called star alleles from 961 high-depth full genomes using StellarPGx, Aldy and PyPGx. In addition, we performed CYP2B6 and CYP2A6 star allele frequency comparisons between SSA and other global biogeographical groups represented in the new 1000 Genomes Project high-coverage dataset (n=2000). This study presents frequency information for star alleles in CYP2B6 (e.g. *6 and *18; frequency of 21-47% and 2-19%, respectively) and CYP2A6 (e.g. *4, *9 an...
Source: Clinical Pharmacology and Therapeutics - December 4, 2023 Category: Drugs & Pharmacology Authors: David Twesigomwe Britt I Dr ögemöller Galen E B Wright Clement Adebamowo Godfred Agongo Palwend é R Boua Mogomotsi Matshaba Maria Paximadis Mich èle Ramsay Gustave Simo Martin C Simuunza Caroline T Tiemessen Zan é Lombard Scott Hazelhurst Source Type: research

pyDarwin: A Machine Learning Enhanced Automated Nonlinear Mixed-effect Model Selection Toolbox
Clin Pharmacol Ther. 2023 Dec 1. doi: 10.1002/cpt.3114. Online ahead of print.ABSTRACTpyDarwin is an open-source Python package for nonlinear mixed-effect model selection. pyDarwin combines machine learning (ML) algorithms and NONMEM to perform a global search in a user-defined model search space. Compared with traditional stepwise search, pyDarwin provides an efficient platform for conducting an objective, robust, less labor-intensive model selection process without compromising model interpretability. In this tutorial, we will begin by introducing the essential components and concepts within the package. Subsequently, we...
Source: Clinical Pharmacology and Therapeutics - December 1, 2023 Category: Drugs & Pharmacology Authors: Xinnong Li Mark Sale Keith Nieforth Kristin L Bigos James Craig Fenggong Wang Kairui Feng Meng Hu Robert Bies Liang Zhao Source Type: research

Successful Prediction of Human Hepatic Concentrations of Transported Drugs Using the Proteomics-Informed Relative Expression Factor Approach
Clin Pharmacol Ther. 2023 Dec 1. doi: 10.1002/cpt.3123. Online ahead of print.ABSTRACTTissue drug concentrations determine the efficacy and toxicity of drugs. When a drug is the substrate of transporters that are present at the blood:tissue barrier, the steady-state unbound tissue drug concentrations cannot be predicted from their corresponding plasma concentrations. To accurately predict transporter-modulated tissue drug concentrations, all clearances (CLs) mediating the drug's entry and exit (including metabolism) from the tissue must be accurately predicted. Since primary cells of most tissues are not available, we have...
Source: Clinical Pharmacology and Therapeutics - December 1, 2023 Category: Drugs & Pharmacology Authors: Mengyue Yin Ankit Balhara Sol ène Marie Nicolas Tournier Zsuzsanna G áborik Jashvant D Unadkat Source Type: research

Circulating tumor DNA profiling approach based on in silico background elimination guides chemotherapy in nasopharyngeal carcinoma
This study has the potential to enhance the sensitivity and expand the application scope of ctDNA detection, independently of other paired genome sequencing methods. As a result, it might further increase the clinical utilization of liquid biopsy based on ctDNA.PMID:38037868 | DOI:10.1002/cpt.3125 (Source: Clinical Pharmacology and Therapeutics)
Source: Clinical Pharmacology and Therapeutics - December 1, 2023 Category: Drugs & Pharmacology Authors: Ming Li Sisi Xie Tao Hou Tong Shao Jingyu Kuang Chuanyang Liu Ying Qu Chenyu Lu Jiali Liu Xianling Liu Lingyun Zhu Lvyun Zhu Source Type: research

pyDarwin: A Machine Learning Enhanced Automated Nonlinear Mixed-effect Model Selection Toolbox
Clin Pharmacol Ther. 2023 Dec 1. doi: 10.1002/cpt.3114. Online ahead of print.ABSTRACTpyDarwin is an open-source Python package for nonlinear mixed-effect model selection. pyDarwin combines machine learning (ML) algorithms and NONMEM to perform a global search in a user-defined model search space. Compared with traditional stepwise search, pyDarwin provides an efficient platform for conducting an objective, robust, less labor-intensive model selection process without compromising model interpretability. In this tutorial, we will begin by introducing the essential components and concepts within the package. Subsequently, we...
Source: Clinical Pharmacology and Therapeutics - December 1, 2023 Category: Drugs & Pharmacology Authors: Xinnong Li Mark Sale Keith Nieforth Kristin L Bigos James Craig Fenggong Wang Kairui Feng Meng Hu Robert Bies Liang Zhao Source Type: research