Coadministration of probenecid and cimetidine with mirogabalin in healthy subjects: A phase 1, randomized, open‐label, drug–drug interaction study

Aims The primary aim of this study was to assess the individual effects of probenecid and cimetidine on mirogabalin exposure. Methods This phase 1, open‐label, crossover study randomized healthy adults to receive three treatment regimens, each separated by ≥5‐day washout: a single oral dose of mirogabalin 15 mg on day 2, mirogabalin 15 mg on day 2 plus probenecid 500 mg every 6 h from days 1 to 4, and mirogabalin 15 mg on day 2 plus cimetidine 400 mg every 6 h from days 1 to 4. Results Coadministration of mirogabalin with probenecid or cimetidine increased the maximum and total mirogabalin exposure. The geometric mean ratios of C max and AUC (0‐t) (90% CI) with and without coadministration of probenecid were 128.7% (121.9–135.7%) and 176.1% (171.9–180.3%), respectively. The geometric mean ratios of C max and AUC (0‐t) (90% CI) with and without coadministration of cimetidine were 117.1% (111.0–123.6%) and 143.7% (140.3–147.2%), respectively. Mean (standard deviation) renal clearance of mirogabalin (l h –1 ) was substantially slower after probenecid [6.67 (1.53)] or cimetidine [7.17 (1.68)] coadministration, compared with mirogabalin alone [11.3 (2.39)]. Coadministration of probenecid or cimetidine decreased mirogabalin mean (standard deviation) apparent total body clearance [10.5 (2.33) and 12.8 (2.67) l h –1 , respectively, vs . 18.4 (3.93) for mirogabalin alone]. Conclusions A greater magnitude of change in mirogabalin exposure was observed when coadministered with a drug that inhibits both renal and metabolic clearance (probenecid) vs . a drug that only affects renal clearance (cimetidine). However, as the increase in exposure is not clinically significant (>2‐fold), no a priori dose adjustment is recommended.