CYP3A Induction Can Predict P-gp Induction: An Example of Sofosbuvir (a P-gp Substrate) with Rifampin, Carbamazepine or Rifabutin

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1 CYP3A Induction Can Predict P-gp Induction: An Example of ofosbuvir (a P-gp ubstrate) with Rifampin, Carbamazepine or Rifabutin Justin D. Lutz, Brian J. Kirby, Benedetta assetto, Qinghua ong, Angela orth, Brian P. Kearney, Anita athias Gilead ciences, Inc., Foster City, CA ICPAT 207, Chicago

2 Conservative Labeling Due to Lack of Transporter Induction Data Assumed parity between transporters and CYP3A induction Potentially conservative label recommendations adopted Known or potential strong CYP3A inducers assumed to be strong P-gp inducers Rifampin Rifabutin Rifapentine t. John s ort Co-regulation of many transporters and CYPs Carbamazepine Phenytoin Phenobarbital Tipranavir/Ritonavir Can CYP induction data be leveraged to predict transporter induction? 2

3 Cocktail Rifampin (RIF): a Prototypical Inducer and PXR Agonist ultiple RIF dose levels (2, 0, 75, 600 mg) to elicit weak to strong CYP3A induction Probe Drug Cassette Dose CYP/Transporter Cassette Day Dabigatran etexilate (DE)* 75 mg P-gp Pravastatin (PRA) 20 mg OATP 3 Rosuvastatin (RO) 0 mg OATP/BCRP 5 idazolam (DZ) 2 mg CYP3A Tolbutamide (TOL 500 mg CYP2C9 7 Caffeine (CAF) 200 mg CYPA2 *DE was analyzed as total dabigatran (TDAB), the sum of conjugated and unconjugated active species. Are transporters as inducible as CYP3A? Can transport induction be predicted by CYP3A? 3

4 P-gp TDAB AUCR P-gp TDAB AUCR CYP3A DZ AUCR P-gp Induction is One DDI Category Less Potent Than CYP3A ean observed ± 90% CI Corrected Individual observed trong (AUCR <0.2) oderate (AUCR ) eak (AUCR ) 0. ED 50 = 66 mg E max = 3 E max,ri = ED 50 = 3 mg E max = 2.0 E max,ri = RIF Dose, mg CYP3A DZ AUCR 0. Combining E max /ED 50 curves allows for evaluation of relative induction potency Gray areas represent induction parity between probes This relationship holds true even after accounting for probe sensitivity (ie f m and f t ) 4

5 OATP and CYP2C9 Induction is One DDI Category Less Potent Than CYP3A OATP PRA AUCR CYP2C9 TOL AUCR OATP/BCRP RO AUCR ean observed ± 90% CI Corrected CYP3A DZ AUCR 0. imilar effects on PRA and RO suggest BCRP not inducible by RIF Data not shown Only weak induction of CYPA2 CYP3A 0. DZ AUCR Parity between P-gp, OATP and CYP2C9 suggests clinical simplicity in interpretation and prediction 5

6 Do the RIF Relationships Predict Other Inducers: Carbamazepine and Rifabutin? tudy Design Days OF + Cassette OF + Cassette Cohort, n=24 Escalated to CBZ 300 mg bid Days OF + Cassette OF + Cassette Cohort 2, n=20 RBT 300 mg qd Do the relationships observed with RIF (relative induction potency) apply to and/or predict: Other inducers: carbamazepine (CBZ) and rifabutin (RBT)? Other object drugs: ofosbuvir, a P-gp substrate 6

7 P -g p T D A B A U C R P-gp Induction by CBZ and RBT is Predicted by the RIF CYP3A P-gp Relationship Predicted ean observed ± 90% CI R B T C B Z Blue line /shaded area RIF CYP3A P-gp relationship 0. CBZ and RBT P-gp induction is well predicted by the RIF CYP3A P-gp relationship 0. C Y P 3 A D Z A U C R 7

8 C Y P 2 C 9 CBZ-ediated OATP Induction is Under-Predicted by RIF CYP3A OATP Relationship O A T P T O L A U C R P R A A U C R O A T P /B C R P R O A U C R R B T R B T ean observed ± 90% CI Predicted C B Z C B Z C Y P 3 A D Z A U C R 0. C Y P 3 A D Z A U C R C B Z R B T C Y P 3 A D Z A U C R Faucette et al. J Pharmacol Exper Ther 2007; voboda et al. Curr Drug etab 20. CBZ: CYP3A OATP parity Both moderate Is CBZ inducing via a non-pxr pathway? OATP is regulated by several non-pxr pathways RBT: Follows RIF relationships 8

9 O F A U C R Effect of CBZ and RBT on OF is Predicted by RIF CYP3A P-gp Relationship Blue line / shaded area = predicted relationship between induction of CYP3A and OF based on RIF CYP3A P-gp relationship adjusted for OF ft Predicted ean observed ± 90% CI R B T R IF C B Z DZ AUC GR OF AUC GR RIF CBZ RBT C Y P 3 A D Z A U C R CBZ and RBT considered moderate CYP3A inducers elicit weak induction of OF clearance (AUC GR 0.50) are not expected to significantly reduce therapeutic effect of OF based on the known PK/PD relationship for OF GR, geometric least-squares mean ratio. Kirby et al. Clin Pharmacokinet 205 9

10 hat are the Clinical Implications? Carbamazepine and rifabutin induction categorization: CYP3A P-gp OATP CYP2C9 CYPA2 OF Carbamazepine oderate eak oderate eak eak eak Rifabutin oderate eak None eak None eak Nuclear receptor involvement is important for predictability Primarily PXR involvement: CYP3A predicts P-gp, OATP, CYP2C9 as one DDI class less potent strong CYP3A = moderate P-gp, OATP, CYP2C9 Additional non-pxr agonism: CYP3A may under-predict OATP induction magnitude Application of these results could provide for ore informed label recommendations for drug transport substrates with inducers Decreased # of DDI studies via better leveraging available data 0

11 Acknowledgments e extend our thanks to the study participants and study team. This study was funded by Gilead ciences, Inc.

12 Thank You ICPAT 207, Chicago