Drug-Drug Interaction Study of Apixaban with Cyclosporine and Tacrolimus in Healthy Volunteers

Babar Bashir, Douglas F Stickle, Inna Chervoneva, Walter K Kraft, Babar Bashir, Douglas F Stickle, Inna Chervoneva, Walter K Kraft

Abstract

Apixaban is metabolized by cytochrome P450 (CYP) 3A4 in the liver and intestine, undergoes direct intestinal excretion, and is a substrate to permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. We examined the drug interactions between cyclosporine and tacrolimus (combined inhibitors of CYP3A4, P-gp, and BCRP) with apixaban in 12 healthy adult male volunteers. Apixaban 10 mg was administered orally alone, in combination with 100 mg cyclosporine or 5 mg tacrolimus. Co-administration with cyclosporine resulted in increase in apixaban maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC(0-tlast) ) with associated geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of 143% (112, 183) and 120% (97, 148), respectively. Co-administration with tacrolimus resulted in reduction in apixaban Cmax and AUC(0-tlast) with associated GMRs (90% CI) of 87% (69, 112) and 78% (63, 97), respectively. The observed changes in apixaban exposure margins with cyclosporine or tacrolimus are within the range of the historical clinical development program, therefore, apixaban dose adjustments are not warranted.

© 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Study design and treatment schedules. Apixaban (APX) was administered as a single 10 mg oral dose in three treatment periods in both sequences, alone; with 100 mg oral cyclosporine (CsA) administered daily for 3 days; with 5 mg oral tacrolimus (Tac) administered daily for 3 days. APX pharmacokinetic (PK) blood samples were collected predose through 72 hours after each administration. CsA and Tac trough concentrations were measured before their respective third dose.
Figure 2
Figure 2
Plasma concentration‐time profiles and pharmacokinetic parameters of apixaban (APX) with and without cyclosporine (CsA). Mean plasma concentration‐time profiles of apixaban in 12 healthy subjects following a single 10 mg oral dose of apixaban alone or in the presence of 3 daily doses of 100 mg cyclosporine; apixaban plasma concentration is presented on a linear scale (a) and log‐transformed scale (b), error bars show SD; comparison of area under the plasma concentration‐time curve from time zero to the last quantifiable concentration (AUC (0–tlast)) (c) and maximum plasma concentration (Cmax) (d) with and without cyclosporine.
Figure 3
Figure 3
Plasma concentration‐time profiles and pharmacokinetic parameters of apixaban with and without tacrolimus. Mean plasma concentration‐time profiles of apixaban in 12 healthy subjects following a single 10 mg oral dose of apixaban alone or in the presence of 3 daily doses of 5 mg tacrolimus; apixaban plasma concentration is presented on a linear scale (a) and log‐transformed scale (b), error bars show SD; comparison of area under the plasma concentration‐time curve from time zero to the last quantifiable concentration (AUC (0–tlast)) (c) and maximum plasma concentration (Cmax) (d) with and without tacrolimus.

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