CYP3A5*3 and bilirubin predict midazolam population pharmacokinetics in Asian cancer patients.
We aim to evaluate the influence of covariates, including cytochrome P450 3A (CYP3A) genetic polymorphisms, on the pharmacokinetics of midazolam (MDZ) in Asian cancer patients, using a population pharmacokinetic approach. Pharmacokinetic data were obtained from 24 adult cancer patients who received an intravenous bolus dose of 1 mg MDZ as a CYP3A phenotyping probe, 1-day before starting FOLFIRI chemotherapy. Concentrations of MDZ and its major metabolites, 1'-hydroxymidazolam (1OHM) and 1'-hydroxymidazolam glucuronide (HMG) were measured using liquid chromatography/mass spectrometry. The population pharmacokinetic study was conducted using NONMEM. Demographics, clinical characteristics, and genetic polymorphisms were screened as covariates. A two-compartment model for MDZ and two sequential compartments representing 1OHM and HMG best described the data. The CYP3A5*3 and total bilirubin level significantly influenced MDZ clearance. The population typical MDZ clearance for CYP3A5*3 expressers was 22% lower than non-expressers. Baseline bodyweight was a statistically significant covariate for clearance and distribution volume of 1OHM. Creatinine clearance was positively correlated with HMG clearance. Our data indicate that CYP3A5*3, total bilirubin, bodyweight, and creatinine clearance are important predictors of MDZ and metabolite pharmacokinetics. Further studies in more patients are needed to explore the links between the identified covariates and the disposition of MDZ and its metabolites.
Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Defence Medical & Environmental Research Institute, DSO National Laboratories, Singapore, Singapore.
Kok-Yong
KY
Seng
Kim-Hor
KH
Hee
Gaik Hong
GH
Soon
Nur Sabrina
NS
Sapari
Richie
R
Soong
Boon-Cher
BC
Goh
Lawrence Soon-U
LS
Lee
D000328:Adult; D000368:Aged; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D044466:Asian People / Q000235:genetics*; D001663:Bilirubin / Q000097:blood*; D001835:Body Weight; D003404:Creatinine / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000378:metabolism*; D011110:Polymorphism, Genetic
D014151:Anti-Anxiety Agents; C061795:1-hydroxymethylmidazolam glucuronide; D003404:Creatinine; C040081:1-hydroxymethylmidazolam; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D008874:Midazolam; D001663:Bilirubin
Asian patients; cancer; cytochrome P450 3A; midazolam; pharmacogenetics; population pharmacokinetics