Dataset Information

The Effects of Clarithromycin on the Pharmacokinetics of Apixaban in Healthy Volunteers: A Single-Sequence Crossover Study.

ABSTRACT: BACKGROUND:This was an open-label, phase I, nonrandomized, single-sequence, crossover study to evaluate the effect of concomitant administration of multiple doses of clarithromycin on the single-dose exposure, safety, and tolerability of apixaban in healthy subjects. METHODS:In total, 19 subjects received a single oral dose of apixaban 10 mg on day 1. On day 4, subjects began receiving oral clarithromycin immediate release (IR) 500 mg twice daily (bid) for 4 days. On day 8, subjects received oral apixaban 10 mg and oral clarithromycin IR 500 mg bid. Oral clarithromycin IR 500 mg bid was given alone on days 9 and 10. RESULTS:Compared with apixaban alone, coadministration of apixaban with clarithromycin resulted in increased apixaban exposure. The adjusted geometric mean ratio (GMR) was 1.299 (90% confidence interval [CI] 1.220-1.384) for peak plasma concentration (Cmax), whereas the adjusted GMR for the area under the concentration curve (AUC(INF)) was 1.595 (90% CI 1.506-1.698). The mean half-life and median time to Cmax of apixaban were comparable with and without concomitant administration of clarithromycin. Administration of apixaban and clarithromycin concomitantly did not result in increased adverse events compared with administration of either agent alone. All adverse events were mild in intensity. CONCLUSIONS:Apixaban Cmax and AUC(INF) increased 30% and 60%, respectively, when multiple doses of clarithromycin were coadministered with apixaban versus administration of apixaban alone. The increase in apixaban Cmax and AUC(INF) with concomitant clarithromycin was less than that which has been observed when apixaban was given with ketoconazole. Administration of apixaban alone and in combination with clarithromycin bid was safe and generally well-tolerated by the healthy adult subjects in this study. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov identifier number NCT02912234.

SUBMITTER: Garonzik S

PROVIDER: S-EPMC6885504 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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The Effects of Clarithromycin on the Pharmacokinetics of Apixaban in Healthy Volunteers: A Single-Sequence Crossover Study.

Garonzik Samira S Byon Wonkyung W Myers Elsa E Li Xiodong X Marchisin David D Murthy Bindu B

American journal of cardiovascular drugs : drugs, devices, and other interventions 20191201 6

<h4>Background</h4>This was an open-label, phase I, nonrandomized, single-sequence, crossover study to evaluate the effect of concomitant administration of multiple doses of clarithromycin on the single-dose exposure, safety, and tolerability of apixaban in healthy subjects.<h4>Methods</h4>In total, 19 subjects received a single oral dose of apixaban 10 mg on day 1. On day 4, subjects began receiving oral clarithromycin immediate release (IR) 500 mg twice daily (bid) for 4 days. On day 8, subjec ...[more]

PMID: 31030414

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Project description:Background: Voriconazole an antifungal drug, has a potential for drug-drug interactions (DDIs) with administered drugs. Clarithromycin is a Cytochromes P450 CYP (3A4 and 2C19) enzyme inhibitor, and voriconazole is a substrate and inhibitor of these two enzymes. Being a substrate of the same enzyme for metabolism and transport, the chemical nature and pKa of both interacting drugs make these drugs better candidates for potential pharmacokinetic drug-drug interactions (PK-DDIs). This study aimed to evaluate the effect of clarithromycin on the pharmacokinetic profile of voriconazole in healthy volunteers. Methods: A single oral dose, open-label, randomized, crossover study was designed for assessing PK-DDI in healthy volunteers, consisting of 2 weeks washout period. Voriconazole, either alone (2 mg × 200 mg, tablet, P/O) or along with clarithromycin (voriconazole 2 mg × 200 mg, tablet + clarithromycin 500 mg, tablet, P/O), was administered to enrolled volunteers in two sequences. The blood samples (approximately 3 cc) were collected from volunteers for up to 24 h. Plasma concentrations of voriconazole were analyzed by an isocratic, reversed-phase high-performance-liquid chromatography ultraviolet-visible detector (RP HPLC UV-Vis) and a non-compartmental method. Results: In the present study, when voriconazole was administered with clarithromycin versus administered alone, a significant increase in peak plasma concentration (Cmax) of voriconazole by 52% (geometric mean ratio GMR: 1.52; 90% CI 1.04, 1.55; p = 0.000) was observed. Similarly, the area under the curve from time zero to infinity (AUC0-∞) and the area under the concentration-time curve from time zero to time-t (AUC0-t) of voriconazole also significantly increased by 21% (GMR: 1.14; 90% CI 9.09, 10.02; p = 0.013), and 16% (GMR: 1.15; 90% CI 8.08, 10.02; p = 0.007), respectively. In addition, the results also showed a reduction in the apparent volume of distribution (Vd) by 23% (GMR: 0.76; 90% CI 5.00, 6.20; p = 0.051), and apparent clearance (CL) by 13% (GMR: 0.87; 90% CI 41.95, 45.73; p = 0.019) of voriconazole. Conclusion: The alterations in PK parameters of voriconazole after concomitant administration of clarithromycin are of clinical significance. Therefore, adjustments in dosage regimens are warranted. In addition, extreme caution and therapeutic drug monitoring are necessary while co-prescribing both drugs. Clinical Trial Registration: clinicalTrials.gov, Identifier NCT05380245.

Dataset Information

The Effects of Clarithromycin on the Pharmacokinetics of Apixaban in Healthy Volunteers: A Single-Sequence Crossover Study.

Publications

The Effects of Clarithromycin on the Pharmacokinetics of Apixaban in Healthy Volunteers: A Single-Sequence Crossover Study.

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