Effects of lasofoxifene on the pharmacokinetics and pharmacodynamics of single‐dose warfarin

Ouellet, Danièle; Bramson, Candace; Carvajal‐Gonzalez, Santos; Roman, D.; Randinitis, Edward J.; Remmers, Ann E.; Gardner, Mark

doi:10.1111/j.1365-2125.2006.02589.x

Cited by 14 publications

(9 citation statements)

References 8 publications

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“…The pharmacokinetics of warfarin in the absence of almorexant were in good agreement with previously reported results [19, 21]. Almorexant was not expected to influence the pharmacokinetics of R-warfarin as this compound is mainly metabolized by CYP1A2 [16], an enzyme that is not inhibited by almorexant.…”

Section: Discussionsupporting

confidence: 89%

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Absence of Pharmacokinetic and Pharmacodynamic Interactions between Almorexant and Warfarin in Healthy Subjects

Dingemanse

Hoever

2013

Drugs R D

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Background and Objective Almorexant is the first representative of the new class of orexin receptor antagonists, which could become a new treatment option for insomnia. The present study investigated the potential interaction between almorexant and warfarin.Methods In this open-label, two-way crossover, drugdrug interaction study, healthy male subjects received, in a randomized fashion, almorexant 200 mg once daily for 10 days and a single dose of 25 mg warfarin co-administered on day 5 (treatment A) and a single dose of 25 mg warfarin on day 1 (treatment B). Serial blood samples for warfarin pharmacokinetics and pharmacodynamics were drawn during both treatments. Results Of the 14 enrolled subjects, one withdrew due to an adverse event and 13 completed the study. Almorexant had no effect on the pharmacokinetics of warfarin. The geometric mean ratios (90 % confidence interval) for the area under the plasma concentration-time curve to infinity (AUC 0-? ) of S-and R-warfarin were 0.99 (0.89, 1.09) and 1.05 (0.95, 1.16), respectively, and for the maximum plasma concentration (C max ) were 0.99 (0.86, 1.14) and 1.00 (0.88, 1.13), respectively. The main pharmacodynamic variable was the AUC for the international normalized ratio (AUC INR ). Almorexant had no effect on this variable as demonstrated by a geometric mean ratio of 0.99 (0.82, 1.19). Secondary pharmacodynamic variables including maximum effect (E max ), the time to the maximum INR, and factor VII plasma concentrations were also not affected by almorexant. ConclusionNo dose adjustment of warfarin is necessary when concomitantly administered with almorexant.

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Section: Discussionsupporting

confidence: 89%

“…The type-I error was set to 0.05 and the power to 90 %. A sample size of 12 provided more than 95 % power to reject the null hypothesis assuming a standard deviation of the difference (in log scale) equal to 0.13 [19]. …”

Section: Methodsmentioning

confidence: 99%

Absence of Pharmacokinetic and Pharmacodynamic Interactions between Almorexant and Warfarin in Healthy Subjects

Dingemanse

Hoever

2013

Drugs R D

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“…Several published studies have successfully employed a similar single-dose warfarin/multiple-dose study paradigm to evaluate possible warfarin-drug interactions. 38,[40][41][42] Furthermore, it has been demonstrated that the single-dose warfarin study paradigm yields findings similar to those obtained from a multiple-dose study design. 43 The single-dose study design has the advantage of allowing for the investigation of possible drug interactions while mitigating the safety risks associated with exposing healthy subjects to multiple doses of warfarin.…”

Section: Discussionmentioning

confidence: 62%

Influence of Laropiprant, a Selective Prostaglandin D2 Receptor 1 Antagonist, on the Pharmacokinetics and Pharmacodynamics of Warfarin

Schwartz

Liu²,

Stroh³

et al. 2009

American Journal of Therapeutics

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Laropiprant (LRPT), a prostaglandin D2 receptor 1 antagonist shown to reduce niacin-induced flushing symptoms, is being developed in combination with niacin for the treatment of dyslipidemia. This study assessed the pharmacokinetics/pharmacodynamics of single-dose warfarin in the presence/absence of multiple-dose LRPT. Thirteen subjects received 2 treatments in random order separated by > or =10-day washout: (1) multiple-dose LRPT 40 mg/d for 12 days (days -5 to 7) with coadministered single-dose warfarin 30 mg (day 6) and (2) single-dose warfarin 30 mg (day 1). R+- and S(-)-warfarin and international normalized ratio (INR) were assayed predose and up to 168 hours postdose. Comparability was declared if the 90% confidence intervals (CIs) for the geometric mean ratio (GMR; warfarin + LRPT/warfarin alone) of area under the plasma concentration curve from zero to infinity (AUC0-infinity) for R+- and S(-)-warfarin were contained within (0.80, 1.25). The estimated GMRs of AUC0-infinity (90% CIs) were 1.02 (0.96, 1.09) and 1.04 (0.98, 1.09) for R+- and S(-)-warfarin, respectively. The estimated GMRs of maximum plasma concentration (Cmax) (90% CIs) were 1.13 (1.02, 1.26) and 1.11 (0.99, 1.24) for R+- and S(-)-warfarin, respectively. The estimated GMRs of area under the prothrombin time INR curve from 0 to 168 hours on day 21 (INR AUC0-168 h) and average maximum observed prothrombin time INR (INRmax) were 1.02 (0.99, 1.05) and 1.04 (0.98, 1.10), respectively. There was no evidence of clinically meaningful alterations in the pharmacokinetics and pharmacodynamics (ie, INR) of R(+)- or S(-)-warfarin after coadministration of multiple-dose LRPT and single-dose warfarin.

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“…11,13 Several published studies have successfully employed a similar single-dose warfarin/multiple-dose drug study design as a means to probe for possible warfarin-drug interactions. 22,23,25,26 Schwartz et al demonstrated that the single-dose model is predictive of the results obtained from a multiple-dose design. 27 This single-dose study design paradigm facilitates the investigation of possible interactions while mitigating the safety risks associated with exposing healthy subjects to multiple doses of warfarin.…”

Section: Discussionmentioning

confidence: 97%

Influence of taranabant, a cannabinoid-1 receptor inverse agonist, on pharmacokinetics and pharmacodynamics of warfarin

et al. 2008

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Effects of lasofoxifene on the pharmacokinetics and pharmacodynamics of single‐dose warfarin

Cited by 14 publications

References 8 publications

Absence of Pharmacokinetic and Pharmacodynamic Interactions between Almorexant and Warfarin in Healthy Subjects

Absence of Pharmacokinetic and Pharmacodynamic Interactions between Almorexant and Warfarin in Healthy Subjects

Influence of Laropiprant, a Selective Prostaglandin D2 Receptor 1 Antagonist, on the Pharmacokinetics and Pharmacodynamics of Warfarin

Influence of taranabant, a cannabinoid-1 receptor inverse agonist, on pharmacokinetics and pharmacodynamics of warfarin

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