Kok-Yong Seng (1, 2), Daryl Kim-Hor Hee (1), Boon-Cher Goh (3, 4), Soo-Chin Lee (3, 4) and Lawrence Soon-U Lee (1)
(1) Yong Loo Lin School of Medicine, National University of Singapore, Singapore, (2) Defence Medical & Environmental Research Institute, DSO National Laboratories, Singapore, (3) National University Cancer Institute, National University Health System, Singapore, (4) Cancer Science Institute, Singapore, Singapore
Objectives: The objectives of this analysis were: (i) development of a linked population pharmacokinetic model for midazolam (MDZ) and its two major metabolites, 1’-hydroxymidazolam (1OHM) and 1’-hydroxymidazolam glucuronide (HMG); and (ii) evaluation of ethnicity differences in the modulation of intestinal and hepatic activity of human cytochrome P450 3A (CYP3A) by ritonavir, ketoconazole and rifampicin in healthy Chinese, Malay, Indian and Caucasian adults.
Methods: 52 subjects underwent pretreatments with probe drugs on 4 separate occasions (i) reference (no pretreatment); (ii) ritonavir 100 mg twice daily given for 3 days; (iii) ketoconazole given for 3 days [(ii) and (iii) in a randomised crossover design]; and (iv) rifampicin 600 mg given nightly for 2 weeks. At the end of pretreatment, each subject received intravenous 0.75mg midazolam and oral 400mg raltegravir followed by oral 1.5mg midazolam 4h later. Plasma concentrations of MDZ, 1OHM and HMG (0–12h) were measured by LC/MS/MS. A pharmacokinetic model of MDZ, 1OHM and HMG was built using nonlinear mixed effect modelling in NONMEM. The covariate model was built using the generalised additive modelling and forward selection-backward elimination [1].
Results: In the final model, the type of probe drug used in pretreatment was a significant covariate for MDZ and 1OHM clearances, and MDZ oral bioavailability. Additionally, MDZ and HMG clearances in Chinese were lower than the other ethnicity groups following ketoconazole pretreatment. Overall, ritonavir reduced hepatic and intestinal CYP3A activity to 0.18-fold (90% CI, 0.15–0.21) and to 0.75-fold (0.73–0.78), respectively. Ketoconazole reduced hepatic and intestinal CYP3A activity to 0.53-fold (90% CI, 0.4–0.66) and 0.76-fold (0.74–0.78), respectively. In agreement with [2], hepatic CYP3A activity in the Chinese was found to be reduced to a greater extent than the rest of the ethnicity groups following ketoconazole pretreatment (0.27 and 0.62, respectively). Rifampicin increased hepatic and intestinal CYP3A activity by 2.92-fold (90% CI, 2.38–3.45) and 1.32-fold (1.25–1.39), respectively.
Conclusions: Ritonavir inhibits hepatic CYP3A activity more profoundly than ketoconazole. Ketoconazole reduces MDZ and HMG clearances to a greater extent in Chinese than Malay, Indian and Caucasian adults. Rifampicin induces intestinal and hepatic CYP3A activity by the same extent among the studied ethnicity groups.
References:
[1] Seng KY, Hee KH, Soon GH, Sapari NS, Soong R, Goh BC, Lee LS. CYP3A5*3 and bilirubin predict midazolam population pharmacokinetics in Asian cancer patients. J Clin Pharmacol (2014) 54(2): 215-24.
[2] Lim YW, Goh BC, Wang LZ, Tan SH, Chuah BY, Lim SE, Iau P, Buhari SA, Chan CW, Sukri NB, Cordero MT, Soo R, Lee SC. Pharmacokinetics and pharmacodynamics of docetaxel with or without ketoconazole modulation in chemonaive breast cancer patients. Ann Oncol (2010) 21(11): 2175-82.
Reference: PAGE 24 () Abstr 3492 [www.page-meeting.org/?abstract=3492]
Poster: Drug/Disease modeling - Other topics