title: Semiphysiologically Based Pharmacokinetic Model of Leflunomide Disposition in Rheumatoid Arthritis Patients.
abstract: A semiphysiologically based pharmacokinetic (semi-PBPK) population model was used to evaluate the influence of enterohepatic recycling and protein binding, as well as the effect of genetic variability in CYP1A2, CYP2C19, and ABCG2, on the large interindividual variability of teriflunomide (active metabolite) concentrations following leflunomide administration in rheumatoid arthritis (RA) patients. The model was developed with total and free teriflunomide concentrations determined in RA patients taking leflunomide, as well as mean teriflunomide concentrations following the administration of leflunomide or teriflunomide extracted from the literature. Once developed, the 15-compartment model was able to predict total and free teriflunomide concentrations and was used to screen demographic and genotypic covariates, of which only fat-free mass and liver function (ALT) improved prediction. This approach effectively evaluated the effects of multiple covariates on both total and free teriflunomide concentrations, which have only been explored previously through simplistic one-compartment models for total teriflunomide.
authors.affiliation: University of South Australia, Australian Centre for Pharmacometrics, School of Pharmacy and Medical Sciences Adelaide, South Australia, Australia ; University of South Australia, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences Adelaide, South Australia, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: Hopkins
authors.affiliation: University of South Australia, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences Adelaide, South Australia, Australia.
authors.forename: M D
authors.initials: MD
authors.lastname: Wiese
authors.affiliation: Royal Adelaide Hospital, Department of Rheumatology Adelaide, South Australia, Australia ; Adelaide University, Discipline of Medicine Adelaide, South Australia, Australia.
authors.forename: S M
authors.initials: SM
authors.lastname: Proudman
authors.affiliation: University of South Australia, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences Adelaide, South Australia, Australia.
authors.forename: C E
authors.initials: CE
authors.lastname: O'Doherty
authors.affiliation: University of South Australia, Australian Centre for Pharmacometrics, School of Pharmacy and Medical Sciences Adelaide, South Australia, Australia.
authors.forename: Djr
authors.initials: D
authors.lastname: Foster
authors.affiliation: University of South Australia, Australian Centre for Pharmacometrics, School of Pharmacy and Medical Sciences Adelaide, South Australia, Australia.
authors.forename: R N
authors.initials: RN
authors.lastname: Upton