Kenichi Umehara (1), Felix Huth (1), Kim Crewe (2), Karen Rowland-Yeo (2) and Gian Camenisch (1)
(1) Novartis Pharma AG, Basel, Switzerland, (2) Simcyp Limited (A Certara Company), Sheffield, UK
Objectives: With the physiologically-based pharmacokinetic (PBPK) model, the drug-drug interaction (DDI) potential of ruxolitinib for CYP3A4 and CYP2C9 was evaluated at the recommended doses in the drug prescribing label.
Methods: Simcyp software (V15) was used. Fractions metabolized by CYP enzymes (fm,CYP) calculated from in vitro phenotyping data in the initial ruxolitinib model were revised to the optimized in vivo fm,CYP – i.e. estimated based on the clinical DDI study results with ketoconazole. The verified model was used to simulate DDI effects of erythromycin, rifampicin and fluconazole. The CYP2C9 Ki in the original fluconazole model was updated from 7.92 µM to 20.4 µM to capture the clinical DDI effects on the probe substrates of CYP2C9.
Results: The initial ruxolitinib model based on in vitro fm,CYP3A4 (0.75) and fm,CYP2C9 (0.19) over-estimated AUC increase with ketoconazole (2.92-fold), compared to the observed ratio (1.91) [1]. With optimized fm,CYP3A4 (0.54) and fm,CYP2C9 (0.40), the predicted AUC ratio was 1.98. The DDI effects of erythromycin and rifampicin on ruxolitinib were well-predicted. The AUC increase with fluconazole (100-400 mg p.o., q.d.) was estimated to be 1.72-3.40-fold using the updated fluconazole model.
Conclusions: Verification of PBPK models by e.g. fm,CYP optimization is an important step to justify dose recommendations or substitute DDI studies. FDA accepted the current model, which was used for the dose adjustment for co-administration of a strong CYP3A inhibitor as ketoconazole, and a dual inhibitor for CYP3A4 and CYP2C9 as fluconazole.
References:
[1] Shi JG, Chen X, Emm T, Scherle PA, McGee RF, Lo Y, Landman RR, McKeever EG Jr, Punwani NG, Williams WV, Yeleswaram S. The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers. J Clin Pharmacol (2012) 52(6):809-18.
Reference: PAGE 25 () Abstr 3690 [www.page-meeting.org/?abstract=3690]
Poster: Drug/Disease modeling - Absorption & PBPK