Leveraging Physiologically Based Pharmacokinetic Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions in the Pediatric Population.
Drug Metab Dispos
; 49(9): 844-855, 2021 09.
Article
en En
| MEDLINE
| ID: mdl-34154994
ABSTRACT
Solithromycin is a novel fluoroketolide antibiotic that is both a substrate and time-dependent inhibitor of CYP3A. Solithromycin has demonstrated efficacy in adults with community-acquired bacterial pneumonia and has also been investigated in pediatric patients. The objective of this study was to develop a framework for leveraging physiologically based pharmacokinetic (PBPK) modeling to predict CYP3A-mediated drug-drug interaction (DDI) potential in the pediatric population using solithromycin as a case study. To account for age, we performed in vitro metabolism and time-dependent inhibition studies for solithromycin for CYP3A4, CYP3A5, and CYP3A7. The PBPK model included CYP3A4 and CYP3A5 metabolism and time-dependent inhibition, glomerular filtration, P-glycoprotein transport, and enterohepatic recirculation. The average fold error of simulated and observed plasma concentrations of solithromycin in both adults (1966 plasma samples) and pediatric patients from 4 days to 17.9 years (684 plasma samples) were within 0.5- to 2.0-fold. The geometric mean ratios for the simulated area under the concentration versus time curve (AUC) extrapolated to infinity were within 0.75- to 1.25-fold of observed values in healthy adults receiving solithromycin with midazolam or ketoconazole. DDI potential was simulated in pediatric patients (1 month to 17 years of age) and adults. Solithromycin increased the simulated midazolam AUC 4- to 6-fold, and ketoconazole increased the simulated solithromycin AUC 1- to 2-fold in virtual subjects ranging from 1 month to 65 years of age. This study presents a systematic approach for incorporating CYP3A in vitro data into adult and pediatric PBPK models to predict pediatric CYP3A-mediated DDI potential. SIGNIFICANCE STATEMENT Using solithromycin, this study presents a framework for investigating and incorporating CYP3A4, CYP3A5, and CYP3A7 in vitro data into adult and pediatric physiologically based pharmacokinetic models to predict CYP3A-mediated DDI potential in adult and pediatric subjects during drug development. In this study, minor age-related differences in inhibitor concentration resulted in differences in the magnitude of the DDI. Therefore, age-related differences in DDI potential for substrates metabolized primarily by CYP3A4 can be minimized by closely matching adult and pediatric inhibitor concentrations.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Triazoles
/
Macrólidos
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Interacciones Farmacológicas
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Citocromo P-450 CYP3A
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Inhibidores del Citocromo P-450 CYP3A
Tipo de estudio:
Prognostic_studies
Límite:
Adolescent
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Adult
/
Child
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Child, preschool
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Humans
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Infant
Idioma:
En
Revista:
Drug Metab Dispos
Asunto de la revista:
FARMACOLOGIA
Año:
2021
Tipo del documento:
Article