Modeling of the induction of CYP2B6 and CYP2C19 by artemisinin antimalarials
Elsherbiny, D.(1), S. Asimus(2), M.O. Karlsson(1), M. Ashton(2), U. S. H. Simonsson(1)
(1)Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, BMC, 751 24 Uppsala, Sweden; (2) Unit for Pharmacokinetics and Drug Metabolism, Sahlgrenska Academy at G÷teborg University, Box 431, 405 30 Gothenburg, Sweden.
Introduction: Malaria is a global health problem with about 1-2 million deaths annually. Parasite resistance has been reported to existing antimalarials except for the artemisinin drugs . In sub-Saharan
Objective: To model the induction of CYP2C19 and CYP2B6 activities by artemisinin antimalarials by developing a model to describe the pharmacokinetics of S-mephenytoin, a probe of CYP2B6 and CYP2C19 activities, and its metabolites S-nirvanol and S-4┤-hydroxymephenytoin before and after administration of the antimalarials artemisinin, dihydroartemisinin, artemether, arteether or artesunate to healthy volunteers.
Methods: The population pharmacokinetics of S-mephenytoin and its metabolites S-nirvanol and S-4┤-hydroxymephenytoin and enzyme turn-over models of CYP2B6 and CYP2C19 induction were described by nonlinear mixed effects modeling using NONMEM. Data were pooled from two studies. One dataset contained data from 14 healthy volunteers, 6 CYP2C19 poor metabolizers (PMs) and 8 CYP2C19 extensive metabolizers (EMs), phenotyped using 3 hour plasma omeprazole/hydroxyomeprazole concentration ratio. Subjects had received a single oral dose of 200 mg racemic mephenytoin. Artemisinin (500 mg) were administered orally, simultaneously with mephenytoin. Twenty eight days later, artemisinin was given (250 mg/day) for 9 days and a 500 mg dose on the tenth day. Mephenytoin (200 mg) was given on the fourth day of the 10-day artemisinin administration. In PMs, blood samples for the determination of plasma concentrations of S-mephenytoin, S-4'-hydroxymephenytoin and S-nirvanol were taken immediately before and at 10 hours after mephenytoin administration, and then one sample was taken in the morning 1, 2, 3, 5, 9 and 13 days after mephenytoin administration. In EMs, additional blood samples were taken at 1, 2, 3, 4, 5, 6, 7 and 8 after mephenytoin administration (rich data study). The second dataset contained data from 74 healthy volunteers who had received a single oral dose of 100 mg racemic mephenytoin among a cocktail of enzymes probes. Six days later, volunteers received artemisinin (500 mg), dihydroartemisinin (60 mg), artemether (100 mg), arteether (100 mg) or artesunate (100 mg) for 5 days. On the first and fifth days of the antimalarial administration, the probes cocktail was re-administered, one hour after intake of the artemisinin drugs. After a five-day wash-out period, administration of the probes cocktail was repeated. S-mephenytoin, S-4'-hydroxymephenytoin and S-nirvanol plasma concentrations were obtained immediately before and at 4 and 8 hours after intake of the probes cocktail (sparse data study). In the sparse data study, subjects were not phenotyped. $MIXTURE subroutine was used for the assignment of individuals to subpopulations. The data were analyzed sequentially by first fitting uninduced S-mephenytoin concentration-time data followed by simultaneously fitting data from all three substances using fixed mephenytoin pharmacokinetic parameters. Finally, mephenytoin, S-4'-hydroxymephenytoin and S-nirvanol data during and after antimalarials administration were incorporated to develop the induction model. S-mephenytoin has high oral first-pass effect in EMs. The need for a hypothetical absorption compartment to account for significant first-pass formation of S-4'-hydroxymephenytoin and S-nirvanol were tested in the model. Graphical analysis revealed that the formation of S-nirvanol was slow in PMs. The need of up to ten transit compartments between the central compartments of S-mephenytoin and S-nirvanol was tested. Two enzyme compartments representing CYP2C19 and CYP2B6 amounts influencing either the formation of S-4┤-hydroxymephenytoin or S-nirvanol, respectively, accounted for potential induction of these pathways by artemisinin antimalarials. The enzyme turn-over models, with enzyme amount at start of antimalarials administration normalized to 1, were expressed as:
where Aenz is the amount of enzyme in the enzyme pool. kenz is the rate constant for production and degradation of the enzyme (day-1), DRUG is a factor describing induction of the enzyme.
Results: The S-mephenytoin data were analysed with a three-compartment model with first-order absorption and 3 elimination pathways, two of which describe the formation of S-nirvanol and S-4┤-hydroxymephenytoin. The S-4┤-hydroxymephenytoin and the S-nirvanol data were analysed with two-compartment models. Two transit compartments were used between the central compartments of S-mephenytoin and S-nirvanol to account for probable enterohepatic recirculation of S-nirvanol. The $MIXTURE subroutine was used to estimate 3 subpopulations of CYP2C19 phenotype; EMs, intermediate metabolizers and PMs representing 60, 23 and 17% of the individuals, respectively. In the rich data study, all individuals phenotyped as PMs were correctly estimated to be PMs by $MIXTURE. Out of the 8 subjects phenotyped as EMs, 2 were estimated to be IMs. Due to too long run times with FOCE and $MIXTURE, the full uninduced model with all data was run with FO and $MIXTURE. The individual phenotypes estimated with FO, were used with FOCE as a covariate to re-evaluate the pharmacokinetic parameters that were different between the three subpopulations. The parameters that differed among the three subpopulations and estimated separately for the subpopulations were formation clearance of S-4┤-hydroxymephenytoin, S-4┤-hydroxymephenytoin central volume and the third S-mephenytoin clearance pathway. First-pass formation of S-4┤-hydroxymephenytoin was not supported by the data. Since artemisinin dose regimen was different between the rich data and sparse data studies, the DRUG factor describing enzyme induction was estimated separately for the 2 studies. DRUG factor describing induction of CYP2C19 by artemisinin was not supported in the rich data study. DRUG factor describing induction of CYP2B6 by artemisinin was about 5 fold higher in the rich data study representing a time-dependent induction. The data supported CYP2B6 induction by arteether and artemether but not by artesunate or dihydroartemisinin.
Conclusions: The model adequately described the population pharmacokinetics of S-mephenytoin and its metabolites S-nirvanol and S-4┤-hydroxymephenytoin before and after administration of the artemisinin antimalarials. The clinical consequences of a potential interaction due to enzyme induction by artemisinin, arteether or artemether will depend on the therapeutic index of the co-administered drug. Artesunate and dihydroartemisinin seem to be a better choice for combination therapy with respect to the risk of drug-drug interactions involving CYP2B6 and/or CYP2C19.