Coadministration of probenecid and cimetidine with mirogabalin in healthy subjects: A phase 1, randomized, open-label, drug-drug interaction study.
Br J Clin Pharmacol
; 84(10): 2317-2324, 2018 10.
Article
in En
| MEDLINE
| ID: mdl-29920736
ABSTRACT
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 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].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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Bridged Bicyclo Compounds
/
Metabolic Clearance Rate
/
Probenecid
/
Cimetidine
Type of study:
Clinical_trials
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Etiology_studies
/
Prognostic_studies
Limits:
Adult
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Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
Br J Clin Pharmacol
Year:
2018
Document type:
Article
Affiliation country:
Japón
Publication country:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
/
SCOTLAND
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UK
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UNITED KINGDOM