The results of in vitro studies indicated that ARIPIPRAZOLE, a newly developed antipsychotic, is mainly metabolized by the human cytochrome P450 isozymes CYP3A4 and CYP2D6. The objective of the present study was to investigate the influence of itraconazole (hereafter referred to as ITZ) co-administration (CYP3A4 inhibition) on the pharmacokinetics of ARIPIPRAZOLE administered to 24 healthy adult male volunteers in a fasting condition. The influence of CYP3A4 inhibition was also examined by CYP2D6 genotype. All subjects were administered a single oral dose of ARIPIPRAZOLE alone in Period I and a single oral dose of ARIPIPRAZOLE following administration of ITZ at 100 mg/day for 7 consecutive days in Period II. The pharmacokinetic parameters of ARIPIPRAZOLE and its main metabolite OPC-14857 were determined. Co-administration of ITZ increased the Cmax, AUC336 hr, and t1/2,z of ARIPIPRAZOLE and OPC-14857 by 19.4%, 48.0%, and 18.6% and by 18.6%, 38.8%, and 53.4%, respectively. By co-administration of ITZ, the CL/F of ARIPIPRAZOLE in extensive metabolizers was decreased by 26.6%, with an even greater decrease (47.3%) in intermediate metabolizers. For the co-administration period, the CL/F of ARIPIPRAZOLE in intermediate metabolizers was about half of that in extensive metabolizers. For Cmax, there was no significant difference between extensive metabolizers and intermediate metabolizers, and the percent change by co-administration of ITZ was less than 20% in both extensive metabolizers and intermediate metabolizers. For OPC-14857, the t(max) in intermediate metabolizers was longer than that in extensive metabolizers, with the difference being amplified by co-administration of ITZ. The AUC336 hr showed similar increases by co-administration of ITZ in all genotypes. The urinary 6beta-hydroxycortisol/cortisol concentration ratio following ITZ administration for 7 consecutive days was about half of that before the start of ITZ administration, indicating that CYP3A4 metabolic activity was inhibited by administration of ITZ. The influence of CYP3A4 inhibition on the pharmacokinetics of ARIPIPRAZOLE was not considered to be clinically significant. On the other hand, definite differences in pharmacokinetics were observed between CYP2D6 genotypes.
We investigated the pharmacokinetics (PK) of aripiprazole, a newly developed antipsychotic, and its active metabolite in healthy Japanese, and the influence of CYP2D6 polymorphism on the PK of aripiprazole. Following a single oral 6 mg dose, the mean C(max), t(max), and t(1/2, z) (terminal phase half life) of aripiprazole were 31.0 ng/mL, 3.6 hr, and 61.0 hr, respectively. The t(1/2, z) in CYP2D6 IM subjects (75.2 hr) was significantly (p<0.01) longer than that in CYP2D6 EM subjects (45.8 hr), and the systemic clearance of IM subjects was approximately 60% that of EM subjects. The PK in one subject with the CYP2D6*41 homozygote was similar to that of IM subjects. In repeated oral administration, plasma concentrations of aripiprazole and active metabolite both reached a steady state by Day 14. The half-life of aripiprazole following repeated administration was similar to that following single administration, suggesting that pharmacokinetics was constant during 14-day administration. Our investigations revealed that there is no clear ethnic difference between Japanese and Western subjects in terms of mean plasma PK, while the CYP2D6*10 allele distinctive to Asian populations influences the PK of aripiprazole. Moreover, our observations suggest that the CYP2D6*41 allele significantly affects drug-metabolizing activity.
PurposeTo investigate the effects of coadministration of paroxetine or fluvoxamine on the pharmacokinetics of aripiprazole in healthy adult Japanese with different CYP2D6 genotypes.MethodsFourteen CYP2D6 extensive metabolizer (EM) and 14 CYP2D6 intermediate metabolizer (IM) subjects were coadministered a single oral dose of aripiprazole 3 mg after steady-state plasma concentrations of the SSRIs paroxetine (20 mg/day) or fluvoxamine (100 mg/day) were reached by repeated oral doses for 6–7 days. The pharmacokinetics of aripiprazole with and without coadministration of SSRIs were compared according to CYP2D6 genotypes.ResultsCoadministration of paroxetine, a potent CYP2D6 inhibitor, decreased systemic clearance (CL/F) of aripiprazole by 58 and 23% in CYP2D6 EMs and IMs, respectively, demonstrating that the percentage inhibition of CYP2D6 activity by coadministration of paroxetine was apparently greater in CYP2D6 EMs than in IMs. Coadministration of fluvoxamine, a less potent CYP3A4 inhibitor, decreased the CL/F of aripiprazole by 39% in CYP2D6 EMs and 40% in IMs, indicating the same inhibitory effect on CYP enzymes, regardless of the CYP2D6 genotype. Percent contribution of CYP2D6 to total CL/F (CYP2D6 plus CYP3A4) of aripiprazole estimated as a reduced percentage of CL/F by CYP enzyme inhibition was 62% for CYP2D6 EMs and 24% for IMs in paroxetine coadministration, and 40% for CYP2D6 EMs and 18% for IMs in fluvoxamine coadministration.ConclusionsThere were marked differences in the degree of influence of paroxetine coadministration on the pharmacokinetics of aripiprazole between CYP2D6 EMs and IMs, but no apparent differences were found between two CYP2D6 genotypes in fluvoxamine coadministration. Aripiprazole can be used safely in combination with SSRIs that have a CYP enzyme-inhibitory action.
A method for predicting the interindividual variability of human exposure for CYP3A4 substrates using Monte Carlo simulation was developed based on relevant factors. The coefficient of variation (CV) values for CYP3A4 content in human liver microsomes, hepatic blood flow, liver volume and body weight, and the unbound blood fraction were collected from the published literature. The parallel tube and dispersion models were found to be appropriate mathematical models to describe the pharmacokinetics (PK). Simulation results using 33% as the CV for CYP3A4 content reflected reported CV values of the area under the curve (AUC) for 40 CYP3A4 substrates for both intravenous and oral administration. We also successfully predicted the clearance of midazolam in Japanese and in European American subjects. In all cases, the simulated mean and SD values reflected the reported values. Thus, the interindividual variability of the AUC of CYP3A4 substrates was predictable for both intravenous and oral administration.
The population pharmacokinetic parameters of phenytoin were estimated using routine therapeutic drug monitoring data from 116 epileptic patients. The 531 serum concentration values at steady-state after repetitive oral administration were analyzed using a nonlinear mixed effects model (NONMEM) program designed for estimation of population pharmacokinetic parameters. A one-compartment model with dose-dependent clearance was used for the pharmacokinetic analysis of phenytoin. The volume of distribution (V) was estimated to be 1.231/kg in a typical 42-kg patient, assuming that the bioavailability of orally administered phenytoin is 100%. The maximal elimination rate (V(max)) and the Michaelis-Menten constant (K(m)) were 9.80 mg/d/kg and 9.19 micrograms/ml, respectively. The parameter of power function of weight to adjust V and V(max) was estimated to be 0.463. In addition, K(m) for phenytoin appeared to be 16% increased in patients receiving zonisamide concurrently. The population pharmacokinetic parameters of phenytoin will be useful for designing dosage regimens in epileptic patients.
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