Population Pharmacokinetics of Midazolam in Healthy Koreans: Effect of Cytochrome P450 3A-mediated Drug-drug Interaction.
- Author:
Kwang Hee SHIN
1
Author Information
1. College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea. kshin@knu.ac.kr
- Publication Type:Original Article
- Keywords:
Midazolam;
population pharmacokinetics;
drug-drug interaction;
CYP3A;
healthy subjects
- MeSH:
Cross-Over Studies;
Cytochrome P-450 CYP3A;
Cytochrome P-450 Enzyme System*;
Cytochromes*;
Drug Interactions;
Genotype;
Healthy Volunteers;
Humans;
Ketoconazole;
Male;
Midazolam*;
Pharmacokinetics*;
Plasma;
Rifampin
- From:Korean Journal of Clinical Pharmacy
2016;26(4):312-317
- CountryRepublic of Korea
- Language:English
-
Abstract:
OBJECTIVE: Midazolam is mainly metabolized by cytochrome P450 (CYP) 3A. Inhibition or induction of CYP3A can affect the pharmacological activity of midazolam. The aims of this study were to develop a population pharmacokinetic (PK) model and evaluate the effect of CYP3A-mediated interactions among ketoconazole, rifampicin, and midazolam. METHODS: Three-treatment, three-period, crossover study was conducted in 24 healthy male subjects. Each subject received 1 mg midazolam (control), 1 mg midazolam after pretreatment with 400 mg ketoconazole once daily for 4 days (CYP3A inhibition phase), and 2.5 mg midazolam after pretreatment with 600 mg rifampicin once daily for 10 days (CYP3A induction phase). The population PK analysis was performed using a nonlinear mixed effect model (NONMEM® 7.2) based on plasma midazolam concentrations. The PK model was developed, and the first-order conditional estimation with interaction was applied for the model run. A three-compartment model with first-order elimination described the PK. The influence of ketoconazole and rifampicin, CYP3A5 genotype, and demographic characteristics on PK parameters was examined. Goodness-of-fit (GOF) diagnostics and visual predictive checks, as well as bootstrap were used to evaluate the adequacy of the model fit and predictions. RESULTS: Twenty-four subjects contributed to 900 midazolam concentrations. The final parameter estimates (% relative standard error, RSE) were as follows; clearance (CL), 31.8 L/h (6.0%); inter-compartmental clearance (Q) 2, 36.4 L/h (9.7%); Q3, 7.37 L/h (12.0%), volume of distribution (V) 1, 70.7 L (3.6%), V2, 32.9 L (8.8%); and V3, 44.4 L (6.7%). The midazolam CL decreased and increased to 32.5 and 199.9% in the inhibition and induction phases, respectively, compared to that in control phase. CONCLUSION: A PK model for midazolam co-treatment with ketoconazole and rifampicin was developed using data of healthy volunteers, and the subject's CYP3A status influenced the midazolam PK parameters. Therefore, a population PK model with enzyme-mediated drug interactions may be useful for quantitatively predicting PK alterations.
