Prediction of inter-individual variability on the pharmacokinetics of CYP1A2 substrates in non-smoking healthy volunteers.
The activity of CYP1A2, a major drug-metabolizing enzyme, is known to be affected by various environmental factors. Our study aimed to predict inter-individual variability of AUC/Dose of CYP1A2 substrates in non-smoking healthy volunteers using the Monte Carlo simulation. Inter-individual variability in hepatic intrinsic clearance of CYP1A2 substrates (CLint,h,1A2) was estimated using dispersion model based on the inter-individual variability (N = 96) of the AUC of caffeine, a major CYP1A2 substrate. The estimated coefficient of variation (CV) of CLint,h,1A2 was 55%, similar to previously reported CLint,h,2D6 (60%) but larger than CLint,h,3A4 (33%). Then, this estimated CV was validated by predicting the CVs of AUC/Dose of tizanidine and phenacetin, which are mainly metabolized by CYP1A2 and have negligible renal clearance. As a result, reported CVs were successfully predicted within 2.5-97.5 percentile range of predicted values. Moreover, CVs for AUC/Dose of the CYP1A2 substrates theophylline and lidocaine, which are affected by other CYPs and renal clearance, were also successfully predicted. The inter-individual variability of AUC/Dose of CYP1A2 substrates was successfully predicted using 55% CV for CLint,h,1A2, and the results, along with those reported by our group for other CYPs, support the prediction of inter-individual variability of pharmacokinetics in the clinical setting.
Chugai Pharmabody Research Pte. Ltd., Singapore. Electronic address: haraya.kenta@chugai-pharm.co.jp.
Kenta
K
Haraya
Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
Motohiro
M
Kato
Laboratory of Clinical Pharmacology, Yokohama University of Pharmacy, Yokohama, Japan; Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Japan.
Koji
K
Chiba
Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Japan.
Yuichi
Y
Sugiyama
D019540:Area Under Curve; D002110:Caffeine / Q000493:pharmacokinetics; D003000:Clonidine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D008012:Lidocaine / Q000493:pharmacokinetics; D009010:Monte Carlo Method; D010615:Phenacetin / Q000493:pharmacokinetics; D013806:Theophylline / Q000493:pharmacokinetics
D002110:Caffeine; C023754:tizanidine; D008012:Lidocaine; D013806:Theophylline; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D010615:Phenacetin; D003000:Clonidine
CYP1A2; Drug development; Human pharmacokinetics; Inter-individual variability; Monte Carlo simulation