Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB1 genetic polymorphisms and interaction with clarithromycin

Abstract

Background The direct oral anticoagulants (DOACs) dabigatran and rivaroxaban are both substrates of the P-glycoprotein (P-gp) transporter, encoded by the ABCB1 gene. Rivaroxaban is metabolized by cytochrome P450 A4 (CYP3A4). Interindividual variability in DOAC exposure and frequent P-gp-associated drug-drug interactions have been described in patients. Objective To assess the influence of ABCB1 polymorphisms on the pharmacokinetics of dabigatran and rivaroxaban, associated or not with clarithromycin, a P-gp and CYP3A4 inhibitor. Methods Sixty healthy male volunteers, selected according to ABCB1 genotype (20 homozygous mutated, 20 heterozygous mutated, and 20 wild-type for haplotype 2677-3435), were included in this randomized, two-center, crossover study. All received sequentially a single dose of dabigatran etexilate (300 mg) and rivaroxaban (40 mg) associated or not with clarithromycin. Peak plasma concentration and area under the curve (AUC) were compared across the three ABCB1 genotypes. The effect of clarithromycin on dabigatran or rivaroxaban pharmacokinetics was assessed. Results Interindividual coefficients of variation for AUC were 77% for dabigatran and 51% for rivaroxaban. ABCB1 genotype did not significantly affect drug pharmacokinetics: AUC ratios between mutant-allele carriers and wild-type volunteers were 1.27 (95% confidence interval [CI] 0.84-1.92) and 1.20 (95% CI 0.96-1.51) for dabigatran and rivaroxaban, respectively. Clarithromycin coadministration led to a two-fold increase in both drugs' AUC, irrespective of ABCB1 genotype: ratios of geometric means were 2.0 (95% CI 1.15-3.60) and 1.94 (95% CI 1.42-2.63) for dabigatran and rivaroxaban, respectively. Conclusions ABCB1 genotype is not a significant determinant of interindividual variability in dabigatran and rivaroxaban pharmacokinetics. The levels of one drug did not predict the levels of the other. Coadministration of a P-gp/CYP3A4 inhibitor with dabigatran or rivaroxaban may warrant caution in patients at risk of overexposure.

Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability

“…Among the 60 volunteers enrolled in the DRIVING study, of 18 subjects had TG analyzed at all 11 time points. In the case of one volunteer, (P‐gp 2 group, low Cmax), TG could not be assessed because of insufficient plasma sample quantity.…”

“…The DRIVING study was a randomized, open crossover study with four treatment sequences. The protocol has been described elsewhere . Briefly, 60 healthy male volunteers were recruited at two academic clinical investigation centers in Paris (Hôpital Européen Georges Pompidou and Hôpital Pitié‐Salpêtrière).…”

“…Tubes were gently inverted five times to ensure adequate mixing. Tubes were immediately double centrifuged at 2000 g for 15 min at 20°C and platelet poor plasma (PPP) was aliquoted, frozen, and stored at −80°C until use . All PPP samples were thawed 3 min in a 37°C water bath just before use.…”

“…Pharmacokinetic parameters were derived from rivaroxaban plasma concentration time profiles obtained by serial blood sampling at predefined sampling time points (T): at baseline (T0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h after rivaroxaban intake. Plasma rivaroxaban concentrations were quantified using an ultrahigh‐pressure liquid chromatography system coupled with a Quattro micro triple quadrupole mass spectrometer (Waters, Saint‐Quentin en Yvelines, France) …”

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

“…В исследовании с ривароксабаном кларит-ромицин приводил к приросту AUC ривароксабана на 54% [6]. В более позднем перекрестном исследовании, результаты которого опубликованы в 2017 г., оцени-валось взаимодействие кларитромицина с обоими препаратами, при этом было обнаружено практически одинаковое влияние кларитромицина и на тот, и на дру-гой НОАК: AUC дабигатрана увеличивалась на 100%, AUC ривароксабана -на 94% [22].…”