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A Physiologically Based Pharmacokinetic Model to Describe Artemether Pharmacokinetics in Adult and Pediatric Patients

Lin, Wen and Heimbach, Tycho and Jain, Jay Prakash and Hamed, Kamal and Sunkara, Gangadhar and He, Handan (2016) A Physiologically Based Pharmacokinetic Model to Describe Artemether Pharmacokinetics in Adult and Pediatric Patients. Journal of Pharmaceutical Sciences, 105 (10). pp. 3205-3213. ISSN 1520-6017

Abstract

Artemether is co-administered with lumefantrine as part of a fixed-dose combination therapy for malaria in both adult and pediatric patients. However, artemether exposure is higher in younger infants (1-3 months) with a lower body weight (<5 kg) as compared to older infants (3-6 months) with a higher body weight (≥5 to <10 kg), children, and adults. In contrast, lumefantrine exposure is similar in all age groups. This article describes the clinically observed artemether exposure data in pediatric populations across various age groups (1 month to 12 years) and body weights (<5 or ≥5 kg) using physiologically based pharmacokinetic (PBPK) mechanistic models. A PBPK model was developed using artemether physicochemical, biopharmaceutic, and metabolic properties together with known enzyme ontogeny and pediatric physiology. The model was verified using clinical data from adult patients after multiple doses of oral artemether, and was then applied to simulate the exposure in children and infants. The simulated PBPK concentration-time profiles captured observed clinical data. Consistent with the clinical data, the PBPK model simulations indicated a higher artemether exposure for younger infants with lower body weight. A PBPK model developed for artemether reliably described the clinical data from adult and pediatric patients.

Item Type: Article
Keywords: clinical pharmacokinetics CYP enzymes drug metabolizing enzymes elimination hepatic clearance interspecies scaling physiologically based pharmacokinetic modeling preclinical pharmacokinetics simulations
Date Deposited: 25 Oct 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/29066

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