European journal of clinical pharmacology · 2013
Interaction of ambrisentan with clarithromycin and its modulation by polymorphic SLCO1B1.
Клиническое исследованиеСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Markert Christoph, Hellwig Regina, Burhenne Jürgen, Hoffmann Michael Marcus, Weiss Johanna, Mikus Gerd, Haefeli Walter E
Аннотация
PURPOSE: We assessed the effect of cytochrome P450 (CYP) 3A4 and the OATP1B1 inhibitor clarithromycin on ambrisentan steady-state kinetics and its relationship to the SLCO1B1 15 haplotype in healthy volunteers.
METHODS: In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 (n = 6), with CYP2C19 1/1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 (n = 4), with CYP2C19 EM and homozygous (n = 3) or heterozygous for SLCO1B1 15 (n = 1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3-14 and twice-daily oral doses of 500 mg clarithromycin on study days 11-14. To monitor CYP3A activity 3 mg midazolam was given orally 1 day before the first ambrisentan administration and on days 1, 10, and 14 of ambrisentan treatment. Ambrisentan plasma kinetics was assessed on days 1 (single dose), 10 (steady-state), and 14 (CYP3A4/OATP1B1 inhibition by clarithromycin).
RESULTS: Consistent with the expectation that ambrisentan does not induce its own metabolism, ambrisentan exposure and peak concentration (Cmax) were similar after the first dose and at steady-state. Clarithromycin increased the area under the plasma concentration-time curve of ambrisentan by 41 % and Cmax by 27 % (n = 10, both p < 0.05). No contribution of SLCO1B1*15 to the extent of this interaction was observed.
CONCLUSIONS: Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.
METHODS: In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 (n = 6), with CYP2C19 1/1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 (n = 4), with CYP2C19 EM and homozygous (n = 3) or heterozygous for SLCO1B1 15 (n = 1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3-14 and twice-daily oral doses of 500 mg clarithromycin on study days 11-14. To monitor CYP3A activity 3 mg midazolam was given orally 1 day before the first ambrisentan administration and on days 1, 10, and 14 of ambrisentan treatment. Ambrisentan plasma kinetics was assessed on days 1 (single dose), 10 (steady-state), and 14 (CYP3A4/OATP1B1 inhibition by clarithromycin).
RESULTS: Consistent with the expectation that ambrisentan does not induce its own metabolism, ambrisentan exposure and peak concentration (Cmax) were similar after the first dose and at steady-state. Clarithromycin increased the area under the plasma concentration-time curve of ambrisentan by 41 % and Cmax by 27 % (n = 10, both p < 0.05). No contribution of SLCO1B1*15 to the extent of this interaction was observed.
CONCLUSIONS: Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.
Предметные рубрики MeSH
Administration, OralAdultArea Under CurveClarithromycinCross-Over StudiesCytochrome P-450 CYP3ACytochrome P-450 CYP3A InhibitorsDrug Administration ScheduleDrug InteractionsFemaleGene FrequencyHumansLiver-Specific Organic Anion Transporter 1MaleMetabolic Clearance RateMidazolamNontherapeutic Human ExperimentationOrganic Anion TransportersPhenylpropionatesPolymorphism, GeneticPyridazines