Author: Charoin-Pannier, Anne ; McIntyre, Christine ; Ciorciaro, Cornelia ; Zandt, Hagen ; Pepper, Tom ; Zweigler, Lydia ; Schmitt, Christophe ; Winters, Katie

AIMSTo 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.METHODSThis 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.RESULTSFollowing 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).CONCLUSIONSThese findings will allow the administration of R1663 without regard to food in the upcoming trials.

01 Apr 2012·The Journal of Clinical PharmacologyQ3 · MEDICINE

Crossover Dose Escalation Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of R1663, an Oral Factor Xa Inhibitor, in Healthy Male Volunteers

Q3 · MEDICINE

Article

Author: Tom Pepper ; Katie Winters ; Hagen Zandt ; Christophe Schmitt ; Anne Pannier ; Christine McIntyre ; Cornelia Ciorciaro

This study investigated the safety, pharmacokinetics, and pharmacodynamics of single oral doses of R1663, a factor Xa inhibitor, in healthy volunteers. It was a single‐blind, randomized, crossover, placebo‐controlled, dose escalation study in 33 healthy male volunteers aged 18 to 45 years. Each volunteer was dosed on 3 occasions with R1663 or placebo. Single oral doses of R1663 were safe and well tolerated. R1663 did not affect bleeding time. Pharmacodynamic effects (prothrombin time [PT], activated partial thromboplastin time [aPTT]), parameters of thrombogram, and anti‐factor Xa activity) and plasma concentrations of R1663 were dose‐dependent and showed low to moderate (<40%) intersubject and intrasubject variability. Maximum factor Xa inhibition was achieved 3 hours post dose (time to maximum concentration of R1663): clotting times were prolonged up to 2.5‐fold, whereas endogenous thrombin potential (ETP) and peak height were decreased by 48% and 85% from their baseline values, respectively. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations, with IC50 values of 182 and 2680 ng/mL for peak height and ETP, respectively. Oral doses of R1663 up to 480 mg were well tolerated, with predictable pharmacodynamics and pharmacokinetics. R1663 prolonged clotting times (PT, aPTT) and inhibited thrombin generation without increasing bleeding time.

01 Jan 2012·Thrombosis and HaemostasisQ2 · MEDICINE

Safety, pharmacokinetics and pharmacodynamics of multiple ascending doses of R1663, an oral factor Xa inhibitor, in healthy young subjects coupled with exploration of influence of gender and age

Q2 · MEDICINE

Article

Author: Pepper, Tom ; Charoin-Pannier, Anne ; McIntyre, Christine ; Ciorciaro, Cornelia ; Zandt, Hagen ; Winters, Katie ; Schmitt, Christophe

SummaryThis study investigated the safety, pharmacokinetics and pharmacodynamics of multiple oral doses of R1663, a factor Xa inhibitor, and explored the influence of age and gender on pharmacokinetics and pharmacodynamics of R1663. This was a single-blind, randomised, placebo-controlled, dose escalation study in 48 healthy male volunteers aged 18 to 44 years. R1663 doses up to 300 mg twice daily or 400 mg once daily were administered for seven days. The exploration of gender and age effect was carried out in separate cohorts of eight male and eight female volunteers aged 45 to 65 years. Multiple oral doses of R1663 were safe and well tolerated. Pharmacokinetics was linear and showed moderate variability. Plasma concentrations peaked at 3 hour. Terminal half-life at steady state was 3–5 hours. Accumulation of R1663 was minimal. R1663 prolonged clotting times, inhibited thrombin generation (peak height and endogenous thrombin potential [ETP]) and anti-factor Xa activity in a concentration-dependent manner without increasing bleeding time. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations. The inhibition was more pronounced on peak height (IC50 = 194 ng/ml) than on ETP (2790 ng/ml). Pharmacokinetics and pharmacodynamics of R1663 appeared not to be substantially affected by age or gender but remained to be confirmed in larger clinical trials including older patients. Meanwhile, dose adjustments based on age and gender are not anticipated.

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Indication	Highest Phase	Country/Location	Organization	Date
Thrombosis	Phase 1	-	F. Hoffmann-La Roche Ltd.	-
Thrombosis	Discovery	US	Roche Holding AG	-
Thrombosis	Discovery	GB	Roche Holding AG	-

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