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Model-Informed Drug Development Applications and Opportunities in mRNA-LNP Therapeutics.
Clin Pharmacol Ther
March 2025
Pfizer Inc, Groton, Connecticut, USA.
The utilization of lipid nanoparticles (LNP) for encapsulating mRNA has revolutionized the field of therapeutics, enabling the rapid development of COVID-19 vaccines and cancer vaccines. However, the clinical development of mRNA-LNP therapeutics faces numerous challenges due to their complex mechanisms of action and limited clinical experience. To overcome these hurdles, Model-Informed Drug Development (MIDD) emerges as a valuable tool that can be applied to mRNA-LNP therapeutics, facilitating the evaluation of their safety and efficacy through the integration of data from all stages into appropriate modeling and simulation techniques.
View Article and Find Full Text PDFContinuous Nicotine Monitors for Personal Nicotine Pharmacokinetics: A Receptor-Aware Research Agenda.
Nicotine Tob Res
March 2025
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena CA 91125 USA.
A minimally invasive "continuous nicotine monitor" (CNM) would resolve the dynamic nicotine concentration, [nicotine]t, faced by high-sensitivity nicotinic acetylcholine receptors (nAChRs) during and after nicotine intake by individual subjects. Motivations: "Know the potential enemy at an individual level". Smoking or vaping produces an initial "bolus" of nicotine in the blood and brain, lasting ~5 min with a peak concentration of ~ 100-200 nM.
View Article and Find Full Text PDFHigh-performance PBPK model for predicting CYP3A4 induction-mediated drug interactions: a refined and validated approach.
Front Pharmacol
February 2025
Department of Drug Discovery and Development, GenFleet Therapeutics (Shanghai) Inc., Shanghai, China.
Introduction: The cytochrome P450 enzyme 3A4 (CYP3A4) mediates numerous drug-drug interactions (DDIs) by inducing the metabolism of co-administered drugs, which can result in reduced therapeutic efficacy or increased toxicity. This study developed and validated a Physiologically Based Pharmacokinetic (PBPK) model to predict CYP3A4 induction-mediated DDIs, focusing on the early stages of clinical drug development.
Methods: The PBPK model for rifampicin, a potent CYP3A4 inducer, was developed and validated using human pharmacokinetic data.
Bayesian inference informed by parameter subset selection for a minimal PBPK brain model.
Philos Trans A Math Phys Eng Sci
March 2025
Department of Statistics, North Carolina State University, Raleigh, NC 27695, USA.
Physiologically based pharmacokinetic (PBPK) models use a mechanistic approach to delineate the processes of the absorption, distribution, metabolism and excretion of biological substances in various species. These models generally comprise coupled systems of ordinary differential equations involving multiple states and a moderate to a large number of parameters. Such models contain compartments corresponding to various organs or tissues in the body.
View Article and Find Full Text PDFPBPK Modeling to Recommend Nevirapine Dosing in HIV and HIV-TB Co-infected Patients: Leveraging Enzyme Auto-Induction, Drug Interactions, and Ethnic Variability.
AAPS J
March 2025
Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China.
Nevirapine, primarily metabolized by CYP2B6 and CYP3A4, exhibits enzyme auto-induction and significant ethnic variability in its pharmacokinetics (PK). These complexities are further exacerbated in HIV-TB co-infected patients, where nevirapine is often co-administered with rifampicin/isoniazid-based anti-tuberculosis (TB) therapies. Rifampicin, a strong CYP3A4 inducer and moderate CYP2B6 inducer, and isoniazid, a moderate CYP3A4 inhibitor, create intricate drug interactions that challenge optimal nevirapine dosing strategies, leading to clinical uncertainty and debate.
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