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

Abstract

AimsThe primary aim of this study was to assess the individual effects of probenecid and cimetidine on mirogabalin exposure.MethodsThis 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.ResultsCoadministration of mirogabalin with probenecid or cimetidine increased the maximum and total mirogabalin exposure. The geometric mean ratios of Cmax 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 Cmax 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].ConclusionsA 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.

Mirogabalin—A Novel Selective Ligand for the α2δ Calcium Channel Subunit

“…Coadministration of mirogabalin with cimetidine or probenecid may raise the mirogabalin plasma concentration [ 5 ], although this increase in exposure may not be clinically relevant [ 5 , 47 ]. In 2018, Tachibana et al [ 47 ] studied drug-to-drug interaction between mirogabalin and probenecid or cimetidine. Probenecid and cimetidine are known to inhibit renal clearance, probenecid also diminished metabolic clearance.…”

“…The increase in mirogabalin exposure when coadministered with cimetidine was like that observed with mild renal impairment, but in these patients mirogabalin dose adjustments are not necessary. Similarly, the effect of probenecid on mirogabalin exposure is not significant [ 47 ].…”

A review of a new voltage-gated Ca2+ channel α2δ ligand, mirogabalin, for the treatment of peripheral neuropathic pain

“…In a cross-over phase 1 study on 30 healthy adult volunteers, C max and AUC last of mirogabalin increased by 29% and 76%, respectively, when mirogabalin (15 mg) was administered with probenecid (500 mg), and by 17% and 44%, respectively, with co-administration of cimetidine (400 mg) [58]. No apparent effect on the pharmacokinetic parameters of mirogabalin was observed with the co-administration of ethanol or lorazepam in healthy adult volunteers (16 and 20 participants, respectively), but reductions in attentiveness and balance functions were observed in the combination groups compared with the mirogabalin alone group [29].…”

Mirogabalin: could it be the next generation gabapentin or pregabalin?

“…Probenecid, treating gout and hyperuricemia, has known interactions with some commonly-used drugs, such as non-steroidal anti-inflammatory drugs (indomethacin, ketoprofen, ketorolac, and naproxen), antibiotics (cephalosporins, quinolones, and penicillins), methotrexate, acyclovir, and lorazepam, and reduces excretion of these drugs [42].…”

“…Probenecid inhibits both renal and metabolic clearance; cimetidine reduces renal clearance. Even though renal excretion of a single oral dose of mirogabalin 15 mg in healthy volunteers was slightly decreased with coadministration of both probenecid 500 mg and cimetidine 400 mg, adjustment of the dose of mirogabalin was not recommended clinically in a phase 1 study [42].…”