title: A Physiologically Based Pharmacokinetic Model to Describe Artemether Pharmacokinetics in Adult and Pediatric Patients.
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.
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors: Wen
authors: W
authors: Lin
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936. Electronic address: tycho.heimbach@novartis.com.
authors: Tycho
authors: T
authors: Heimbach
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, Novartis Healthcare Pvt. Ltd., Hyderabad, India.
authors: Jay Prakash
authors: JP
authors: Jain
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors: Rakesh
authors: R
authors: Awasthi
authors: Global Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936.
authors: Kamal
authors: K
authors: Hamed
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors: Gangadhar
authors: G
authors: Sunkara
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936.
authors: Handan
authors: H
authors: He
mesh_terms: D000328:Adult; D000367:Age Factors; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics*; D000077549:Artemether; D037621:Artemisinins / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077549:Artemether
keywords: CYP enzymes; clinical pharmacokinetics; drug metabolizing enzymes; elimination; hepatic clearance; interspecies scaling; physiologically based pharmacokinetic modeling; preclinical pharmacokinetics; simulations