Blisse Vakkalagadda1, Charles Frost2, Wonkyung Byon3, Rebecca A Boyd3, Jessie Wang4, Donglu Zhang5, Zhigang Yu1, Clapton Dias1, Andrew Shenker1, Frank LaCreta1. 1. Research and Development, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Mail Stop E12-16, Route 206 and Province Line Road, Princeton, NJ, 08543-4000, USA. 2. Research and Development, Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Mail Stop E12-16, Route 206 and Province Line Road, Princeton, NJ, 08543-4000, USA. charles.frost@bms.com. 3. Global Innovative Pharma Business Clinical Pharmacology, Pfizer Inc, Groton, CT, USA. 4. Global Biometric Sciences, Bristol-Myers Squibb Company, Princeton, NJ, USA. 5. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, NJ, USA.
Abstract
OBJECTIVE:Apixaban is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. The effects of rifampin, a strong inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics of oral and intravenous apixaban were evaluated in an open-label, randomized, sequential crossover study. METHODS:Twenty healthy participants received single doses of apixaban 5 mg intravenously on day 1 and 10 mg orally on day 3, followed by rifampin 600 mg once daily on days 5-15. Finally, participants received single doses of apixaban 5 mg intravenously and 10 mg orally separately on days 12 and 14 in one of two randomized sequences. RESULTS:Apixaban, given intravenously and orally, was safe and well tolerated when administered in the presence and absence of rifampin. Apixaban absolute oral bioavailability was 49 % when administered alone and 39 % following induction by rifampin. Rifampin reduced apixaban area under the plasma concentration-time curve from time zero to infinity (AUC∞) by 39 % after intravenous administration and by 54 % after oral administration. Rifampin induction increased mean clearance by 1.6-fold for intravenous apixaban and mean apparent clearance by 2.1-fold for oral apixaban, indicating rifampin affected both pre-systemic and systemic apixaban elimination pathways. CONCLUSION: Co-administration of apixaban with rifampin reduced apixaban exposure via both decreased bioavailability and increased systemic clearance.
RCT Entities:
OBJECTIVE:Apixaban is a substrate of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. The effects of rifampin, a strong inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics of oral and intravenous apixaban were evaluated in an open-label, randomized, sequential crossover study. METHODS: Twenty healthy participants received single doses of apixaban 5 mg intravenously on day 1 and 10 mg orally on day 3, followed by rifampin 600 mg once daily on days 5-15. Finally, participants received single doses of apixaban 5 mg intravenously and 10 mg orally separately on days 12 and 14 in one of two randomized sequences. RESULTS:Apixaban, given intravenously and orally, was safe and well tolerated when administered in the presence and absence of rifampin. Apixaban absolute oral bioavailability was 49 % when administered alone and 39 % following induction by rifampin. Rifampin reduced apixaban area under the plasma concentration-time curve from time zero to infinity (AUC∞) by 39 % after intravenous administration and by 54 % after oral administration. Rifampin induction increased mean clearance by 1.6-fold for intravenous apixaban and mean apparent clearance by 2.1-fold for oral apixaban, indicating rifampin affected both pre-systemic and systemic apixaban elimination pathways. CONCLUSION: Co-administration of apixaban with rifampin reduced apixaban exposure via both decreased bioavailability and increased systemic clearance.
Authors: Sarah Hanigan; Jessica Das; Kristen Pogue; Geoffrey D Barnes; Michael P Dorsch Journal: J Thromb Thrombolysis Date: 2020-05 Impact factor: 2.300
Authors: Markus Gulilat; Denise Keller; Bradley Linton; A Demetri Pananos; Daniel Lizotte; George K Dresser; Jeffrey Alfonsi; Rommel G Tirona; Richard B Kim; Ute I Schwarz Journal: J Thromb Thrombolysis Date: 2020-02 Impact factor: 2.300