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Peripheral selectivity of the novel cannabinoid receptor antagonist TM 38837 in healthy subjects
Author(s) -
Klumpers Linda E.,
Fridberg Marianne,
Kam Marieke L.,
Little Paul B.,
Jensen Niels Ole,
Kleinloog Hendrik D.,
Elling Christian E.,
Gerven Joop M. A.
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12141
Subject(s) - rimonabant , placebo , crossover study , cannabinoid , antagonist , pharmacodynamics , medicine , population , pharmacology , cannabinoid receptor antagonist , heart rate , pharmacokinetics , cannabinoid receptor , endocrinology , receptor , blood pressure , alternative medicine , environmental health , pathology
Aim Cannabinoid receptor type 1 ( CB 1 ) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB 1 antagonist TM 38837 was studied in humans. Methods This was a double‐blind, randomized, placebo‐controlled, crossover study. On occasions 1–4, 24 healthy subjects received 5 × 4 mg THC with TM 38837 100 mg, 500 mg or placebo, or placebos only. During occasion 5, subjects received placebo TM 38837 + THC with rimonabant 60 mg or placebo in parallel groups. Blood collections and pharmacodynamic ( PD ) effects were assessed frequently. Pharmacokinetics ( PK ) and PD were quantified using population PK − PD modelling. Results The TM 38837 plasma concentration profile was relatively flat compared with rimonabant. TM 38837 showed an estimated terminal half‐life of 771 h. THC induced effects on VAS feeling high, body sway and heart rate were partly antagonized by rimonabant 60 mg [−26.70% [90% confidence interval (CI) −40.9, −12.6%]; −7.10%, (90% CI −18.1, 5.3%); −7.30%, (90% CI −11.5%, −3.0%) respectively] and TM 38837 500 mg [−22.10% (90% CI −34.9, −9.4%); −12.20% (90% CI −21.6%, −1.7%); −8.90% (90% CI −12.8%, −5.1%) respectively]. TM 38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects. Conclusions Rimonabant showed larger effects than TM 38837, but the heart rate effects were similar. TM 38837 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. This TM 38837 dose is predicted to be at least equipotent to rimonabant with regard to metabolic disorders in rodent models. These results provide support for further development of TM 38837 as a peripherally selective CB 1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects.