Effect of food on the pharmacokinetics and pharmacodynamics of R1663, an oral factor Xa inhibitor, in healthy male volunteers.
OBJECTIVE
To explore the effect of food intake on the relative bioavailability of R1663 and on its pharmacodynamic effects (prothrombin time (PT) and activated partial thromboplastin time (aPTT)) after a single oral dose of 200 mg.


METHODS
This was a prospective, open-label, randomized, two-way crossover study. Eight healthy male volunteers received R1663 on two occasions, after a high fat/high calorie breakfast and after an overnight fast of 10 h, with a 7-day washout between doses. Blood was sampled up to 48 h for the pharmacokinetic and pharmacodynamic evaluation of R1663. Pharmacokinetic parameters (area under the plasma concentration-time curve from Time 0 extrapolated to infinity (AUC(0-∞)) and maximal concentration (C(max)) as well as pharmacodynamic parameters (area under the effect curve over 48 h (AUE(0-48)) and maximal effect (E(max)) were determined on both occasions. Geometric mean ratios fed/ fasted (GMR) and 90% confidence intervals (CI) were calculated for AUC(0-∞) and C(max) of R1663 and AUE(0-48) and E(max) of PT and aPTT.


RESULTS
Following food intake, C(max) was reduced by 10% with CI extended outside the bioequivalence range (GMR, 0.90; CI 0.72 - 1.13). R1663 t(max) was delayed in the fed state (4 h) as compared to the fasted state (1 h). There was no significant food effect on R1663 AUC(0-∞) (GMR, 1.09; CI 0.97 - 1.24). Although the Emax of PT showed statistically significant reduction with food, the 90% CIs for Emax and AUE(0-48) of PT and aPTT were all contained within the bioequivalence range (0.80 - 1.25).


CONCLUSIONS
These findings will allow the administration of R1663 without regard to food in the upcoming trials.
F. Hoffmann-La Roche AG, Basel, Switzerland. christophe.schmitt@roche.com
Christophe
C
Schmitt
Anne
A
Charoin-Pannier
Christine
C
McIntyre
Hagen
H
Zandt
Cornelia
C
Ciorciaro
Lydia
L
Zweigler
Katie
K
Winters
Tom
T
Pepper
D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D059305:Diet, High-Fat; D002149:Energy Intake; D065427:Factor Xa Inhibitors; D005215:Fasting; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D010314:Partial Thromboplastin Time / Q000706:statistics & numerical data; D011517:Prothrombin Time / Q000706:statistics & numerical data; D011728:Pyridones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011759:Pyrrolidines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*
C573820:1-(2,2-difluoroethyl)pyrrolidine-3,4-dicarboxylic acid 3-((5-chloropyridin-2-yl)amide) 4-((2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl)amide); D065427:Factor Xa Inhibitors; D011728:Pyridones; D011759:Pyrrolidines