2010 - Berlin - Germany

PAGE 2010: Physiology-based modelling
Stefan Willmann

Investigation of the Influence of CYP3A4 Inhibition and Renal Impairment on Morphine and M6G Formation after Codeine Administration using Coupled Whole-Body PBPK Modelling

T. Eissing, J. Lippert, S. Willmann

Systems Biology and Computational Solutions, Bayer Technology Services GmbH, 51368 Leverkusen, Germany

Objectives: The objective of this study was to systematically investigate the influence of UGT2B7 activity, CYP3A4 inhibition, and renal impairment on the extent of morphine and morphine-6-glucuronide (M6G) exposure after oral codeine administration by means of a virtual trial using coupled whole-body physiologically-based pharmacokinetic (WB-PBPK) simulations.

Methods: A coupled WB-PBPK model for codeine, its primary metabolite morphine (formed by the polymorphic enzyme CYP2D6) and its secondary metabolite M6G (formed by UGT2B7 from morphine) was developed. Plasma concentration time profiles of codeine, morphine, and M6G after oral codeine administration were simulated in virtual populations of female and male adult individuals representing poor (PM), intermediate (IM), extensive (EM), and ultrarapid (UM) CYP2D6 metabolizers for different degrees of UGT2B7 activity, renal impairment and CYP3A4 inhibition.

Results: The simulated plasma pharmacokinetics of codeine, morphine, and M6G were in very good agreement with published data obtained in vivo by several authors in CYP2D6 genotyped or phenotyped individuals with normal kidney function and no co-administration of a CYP3A4 inhibitor [1-4]. The simulations further demonstrated that a decreasing kidney function leads to an increase of morphine and, in particular, M6G concentrations. Co-administration of a CYP3A4 inhibitor further increases the plasma exposure of morphine and M6G due to a (partial) block of codeine and morphine metabolization pathways that produce inactive metabolites (norcodeine and normorphine). UGT2B7 activity has nonlinear and opposing effects on morphine and M6G exposure, as this enzyme also catalyzes the formation of codeine-6-glucuronide, the major (inactive) primary codeine metabolite.

Conclusions: In conclusion, the developed coupled WB-PBPK model is capable of simulating the plasma pharmacokinetics of codeine, morphine, and M6G after oral codeine administration in dependence of the CYP2D6 phenotype, UGT2B7 activity, and the degree of renal function and CYP3A4 inhibition. This clinical trial simulation allows a quantitative assessment of safety and efficacy aspects of codeine administration in adult populations considering various covariates.

[1] Kirchheiner J, Schmidt H, Tzvetkov M, Keulen JT, Loetsch J, Roots I, Brockmoller J: Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J 2007, 7(4):257-265.
[2] Yue QY, Alm C, Svensson JO, Sawe J: Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators. Ther Drug Monit 1997, 19(5):539-542.
[3] Caraco Y, Sheller J, Wood AJ: Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 1996, 278(3):1165-1174.
[4] Loetsch J, Rohrbacher M, Schmidt H, Doehring A, Brockmoller J, Geisslinger G: Can extremely low or high morphine formation from codeine be predicted prior to therapy initiation? Pain 2009, 144(1-2):119-124.

Reference: PAGE 19 (2010) Abstr 1861 [www.page-meeting.org/?abstract=1861]
Oral presentation: Physiology-based modelling