title: Development of a physiologically based pharmacokinetic model to predict the effects of flavin-containing monooxygenase 3 (FMO3) polymorphisms on itopride exposure.
abstract: Itopride, a substrate of FMO3, has been used for the symptomatic treatment of various gastrointestinal disorders. Physiologically based pharmacokinetic (PBPK) modeling was applied to evaluate the impact of FMO3 polymorphism on itopride pharmacokinetics (PK). The Asian populations within the Simcyp simulator were updated to incorporate information on the frequency, activity and abundance of FMO3 enzyme with different phenotypes. A meta-analysis of relative enzyme activities suggested that FMO3 activity in subjects with homozygous Glu158Lys and Glu308Gly mutations (Lys158 and Gly308) in both alleles is ~47% lower than those carrying two wild-type FMO3 alleles. Individuals with homozygous Lys158 and Gly308 mutations account for about 5% of the total population in Asian populations. A CLintof 9 μl/min/pmol was optimised for itopride via a retrograde approach as human liver microsomal results would under-predict its clearance by ~7.9-fold. The developed itopride PBPK model was first verified with three additional clinical studies in Korean and Japanese subjects resulting in a predicted clearance of 52 to 69 l/h, which was comparable to those observed (55 to 88 l/h). The model was then applied to predict plasma concentration-time profiles of itopride in Chinese subjects with wild type or homozygous Lys158 and Gly308 FMO3 genotypes. The ratios of predicted to observed AUC of itopride in subjects with each genotype were 1.23 and 0.94, respectively. In addition, the results also suggested that for FMO3 metabolised drugs with a safety margin of 2 or more, proactive genotyping FMO3 to exclude subjects with homozygous Lys158/Gly308 alleles may not be necessary.
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: Wangda
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Simcyp (A Certara Company), Sheffield, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Humphries
authors.affiliation: Simcyp (A Certara Company), Sheffield, UK.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Neuhoff
authors.affiliation: Simcyp (A Certara Company), Sheffield, UK.
authors.forename: Iain
authors.initials: I
authors.lastname: Gardner
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Masson
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: Nidal
authors.initials: N
authors.lastname: Al-Huniti
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: Diansong
authors.identifier: http://orcid.org/0000-0002-2673-1069
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D001549:Benzamides / Q000097:blood / Q000493:pharmacokinetics*; D001593:Benzyl Compounds / Q000097:blood / Q000493:pharmacokinetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010105:Oxygenases / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: D001549:Benzamides; D001593:Benzyl Compounds; C102254:itopride; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)
keywords: FMO3; PBPK; itopride; polymorphisms