期刊
CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT
卷 6, 期 6, 页码 592-603出版社
WILEY
DOI: 10.1002/cpdd.378
关键词
multiple-ascending-dose study; pharmacokinetics; QT/QTc study; tolerability; tramadol
资金
- Janssen Scientific Affairs, LLC
- Valeant Pharmaceuticals International Inc
- Cipher Pharmaceuticals Inc.
- SIRO Clinpharm Pvt. Ltd., Thane, India
This randomized, double-blind, parallel-group multiple-ascending-dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthymen and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200,400, or 600 mg/day treatment cohort and within each cohort, randomized (4: 1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUC(tau,ss) of tramadol increased approximately 2.2- and 3.6-fold for the (+) enantiomer and 2.0- and 3.5-fold for the (-) enantiomer with increasing dose from 200 to 400 and 600 mg/day, whereas the C-max,C-ss increased 2.1- and 3.3-fold for the (+) enantiomer and 2.0- and 3.2-fold for the (-) enantiomer. Overall, 21 participants (87.5%) participants reported >= 1 treatment-emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study.
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