The pharmacokinetics of darexaban are not affected to a clinically relevant degree by rifampicin, a strong inducer of P-glycoprotein and CYP3A4.
OBJECTIVE
We investigated the effects of rifampicin on the pharmacokinetics (PK) of the direct clotting factor Xa inhibitor darexaban (YM150) and its main active metabolite, darexaban glucuronide (YM-222714), which almost entirely determines the antithrombotic effect.


METHODS
In this open-label, single-sequence study, 26 healthy men received one dose of darexaban 60 mg on day 1 and oral rifampicin 600 mg once daily on days 4-14. On day 11, a second dose of darexaban 60 mg was given with rifampicin. Blood and urine were collected after study drug administration on days 1-14. The maximal plasma drug concentration (C(max)) and exposure [area under the plasma concentration-time curve from time zero to time of quantifiable measurable concentration; (AUC(last)) or AUC(last) extrapolated to infinity (AUC(∞))] were assessed by analysis of variance of PK. Limits for statistical significance of 90% confidence intervals for AUC and C(max) ratios were predefined as 80-125%.


RESULTS
Darexaban glucuronide plasma exposure was not affected by rifampicin; the geometric mean ratio (90% confidence interval) of AUC(last) with/without rifampicin was 1.08 (1.00, 1.16). The C(max) of darexaban glucuronide increased by 54% after rifampicin [ratio 1.54 (1.37, 1.73)]. The plasma concentrations of darexaban were very low (<1% of darexaban glucuronide concentrations) with and without rifampicin. Darexaban alone or in combination with rifampicin was generally safe and well tolerated.


CONCLUSIONS
Overall, rifampicin did not affect the PK profiles of darexaban glucuronide and darexaban to a clinically relevant degree, suggesting that the potential for drug-drug interactions between darexaban and CYP3A4 or P-glycoprotein-inducing agents is low.
Global Clinical Pharmacology and Exploratory Development, Astellas Pharma Global Development Europe, Leiderdorp, The Netherlands. dorien.groenendaal@astellas.com
Dorien
D
Groenendaal
Gregory
G
Strabach
Alberto
A
Garcia-Hernandez
Takeshi
T
Kadokura
Marten
M
Heeringa
Roelof
R
Mol
Charlotte
C
Eltink
Hartmut
H
Onkels
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001381:Azepines / Q000493:pharmacokinetics*; D001549:Benzamides / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005170:Factor X / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000494:pharmacology*; D055815:Young Adult
D018435:ATP Binding Cassette Transporter, Subfamily B; D001381:Azepines; D001549:Benzamides; D004791:Enzyme Inhibitors; D005170:Factor X; D051544:Cytochrome P-450 CYP3A; C569750:darexaban; D012293:Rifampin