Oral bioavailability of dabigatran etexilate (Pradaxa^®) after co‐medication with verapamil in healthy subjects

Abstract

AIMTo investigate the effect of the P-glycoprotein inhibitor verapamil on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DE). METHODIn this two part multiple crossover trial in 40 healthy subjects, DE 150 mg was given alone or with verapamil at different doses, duration of treatment (single vs. multiple dosing), formulations, and timings (before, concurrently or after DE). Primary pharmacokinetic endpoints were determined from concentrations of total dabigatran (unconjugated plus conjugated). Pharmacodynamic endpoints were determined from clotting time. RESULTSThe greatest effect was observed with single dose verapamil 120 mg immediate release given 1 h before single dose DE. Geometric mean area under the plasma concentration curve [AUC(0,•)] and maximum analyte concentration in the plasma (Cmax) were increased by 143% [90% confidence interval (CI) 91, 208] and 179% (90% CI 115, 262), respectively. The effect was reduced to a 71% and 91% increase in AUC and Cmax, respectively, when DE was administered with verapamil 240 mg extended release. After multiple verapamil dosing, DE AUC(0,•) and Cmax increases were 54% and 63%, respectively. However, DE given 2 h before verapamil increased DE AUC(0,•) and Cmax by <20%. With regard to clotting prolongation, the dabigatran plasma concentration-effect relationship was generally not affected by the co-administration of verapamil. Concomitant administration of DE and verapamil did not reveal any unexpected safety findings. CONCLUSIONVerapamil increased DE bioavailability, likely due to inhibition of P-glycoprotein. Our results suggest that an interaction between verapamil and DE can be minimized if DE is administered 2 h prior to verapamil. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Dabigatran, the active principle of the oral prodrug dabigatran etexilate (DE), is a direct and reversible thrombin inhibitor with potent antithrombotic effects.• DE and dabigatran are not metabolized by hepatic cytochrome P450 isoenzymes and do not affect the metabolism of other drugs that utilize the cytochrome P450 system. • DE, but not dabigatran, is a substrate of the efflux transporter P-glycoprotein (P-gp) and drugs that affect P-gp may alter the bioavailability of dabigatran. WHAT THIS STUDY ADDS• The bioavailability of dabigatran is increased when co-administered with a P-gp inhibitor, such as verapamil. Several factors affected the interaction: (i) the dosing interval between the two drugs, such that the maximum increase in dabigatran exposure occurred when verapamil was given 1 h before DE, whereas there was virtually no effect on exposure when DE was given 2 h before verapamil, (ii) the formulation of verapamil, with the immediate release (IR) formulation having a greater effect than the extended release (ER) formulation and (iii) verapamil dosing, with a single dose having a greater effect on the PK of dabigatran than multiple dosing.• An interaction between verapamil and DE might be minimized if DE is administered in the fasted state 2 h prior to verapamil.

Photodynamic therapy of cancer — Challenges of multidrug resistance

“…Preliminary data suggest that for P-gp, a single dose of verapamil 120 mg or 80 mg three times daily (total daily doses of 240 mg) for 6 days could improve bioavailability of P-gp substrates or chemotherapy drugs. 52,53 It is noteworthy that clinical trials indicated that the Pgp-modulating agent Valspodar did not improve the treatment outcome of refractory multiple myeloma and P-gp inhibitors may not be a practical solution to MDR. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative and proapoptotic functions.…”

Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation

“…This is important because the safety and efficacy of dabigatran etexilate are related to its plasma concentrations, single-nucleotide polymorphisms in the gene encoding P-glycoprotein are associated with a 12% increase in peak dabigatran concentration per minor allele carried, studies with other P-glycoprotein inhibitors have found increases in dabigatran exposure ranging from 30% to 171%, and the likelihood of concomitant statin use among these patients is high. [13][14][15][16] We examined the association between statin use and subsequent hospital admissions or emergency department visits for ischemic stroke or major hemorrhage in patients with atrial fibrillation treated with dabigatran etexilate. Owing to their inhibitory effects on P-glycoprotein, we hypothesized that simvastatin and lovastatin would increase the risk of major hemorrhage in patients taking dabigatran.…”

Drug Interactions of New Oral Anticoagulants: Inside and Outside Table Cells

“…Приведенный в переработанной таблице диапазон влияния верапамила на AUC дабигатрана (+18-143%) менее широк, чем в европейской таблице (+12-180% [3,4]). Исправление внесено потому, что в европейской таблице неверно процитированы ре-зультаты исследования S. Hartter et al [13]. В этом ис-следовании с участием здоровых добровольцев наи-меньшее увеличение AUC дабигатрана (+18%) реги-стрировалось при назначении верапамила немедлен-ного высвобождения (immediate release -IR) по 120 мг 2 раза в день (р/д) спустя 2 ч после приема дабигат-рана.…”

“…Наибольшее увеличение AUC дабигатрана (+143%) наблюдалось при однократном назначении верапамила IR в дозе 120 мг за 1 ч до приема даби-гатрана. Причем в первом случае прирост пиковой кон-центрации дабигатрана составлял 12%, тогда как во вто-ром -179% [13]. Именно два последних показателя (+12% и +179% с округлением до +180%) и были по ошибке включены в европейскую таблицу вместо по-казателей наименьшего и наибольшего увеличения AUC.…”

“…Однако не-обходимо иметь в виду, что увеличение AUC дабигат-рана на 143%, зарегистрированное в исследовании S. Hartter и соавт., отмечалось только в случае одно-кратного назначения верапамила IR за 1 ч до дабигат-рана. Продолжение приема верапамила IR в дозе 120 мг 2 р/д сопровождалось быстрым и значительным ослаблением эффекта взаимодействия: уже на 4-е сут увеличение AUC дабигатрана, принятого через 1 ч после верапамила IR, составляло +54% [13], что вполне со-поставимо с увеличением AUC эдоксабана в ответ на прием верапамила SR в дозе 240 мг/сут. По мнению ав-торов исследования, ослабление эффекта взаимо-действия обусловлено тем, что верапамил при не-однократном назначении, наряду с ингибированием P-gp, индуцирует экспрессию P-gp в стенках кишечника [13].…”