title: Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects.
abstract: OBJECTIVE
  Cannabinoid receptor type 1 (CB1 ) antagonists show central side effects, whereas beneficial effects are most likely peripherally mediated. In this study, the peripherally selective CB1 antagonist TM38837 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 TM38837 100 mg, 500 mg or placebo, or placebos only. During occasion 5, subjects received placebo TM38837 + 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 TM38837 plasma concentration profile was relatively flat compared with rimonabant. TM38837 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 TM38837 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]. TM38837 100 mg had no measurable feeling high or body sway effects and limited heart rate effects.
  
  
  CONCLUSIONS
  Rimonabant showed larger effects than TM38837, but the heart rate effects were similar. TM38837 100 mg had no impact on CNS effects, suggesting that this dose does not penetrate the brain. This TM38837 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 TM38837 as a peripherally selective CB1 antagonist for indications such as metabolic disorders, with a reduced propensity for psychiatric side effects.
authors.affiliation: Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: Linda E
authors.initials: LE
authors.lastname: Klumpers
authors.forename: Marianne
authors.initials: M
authors.lastname: Fridberg
authors.forename: Marieke L
authors.initials: ML
authors.lastname: de Kam
authors.forename: Paul B
authors.initials: PB
authors.lastname: Little
authors.forename: Niels Ole
authors.initials: NO
authors.lastname: Jensen
authors.forename: Hendrik D
authors.initials: HD
authors.lastname: Kleinloog
authors.forename: Christian E
authors.initials: CE
authors.lastname: Elling
authors.forename: Joop M A
authors.initials: JM
authors.lastname: van Gerven
mesh_terms: D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D013759:Dronabinol / Q000494:pharmacology; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017933:Peripheral Nervous System / Q000187:drug effects*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D055815:Young Adult
chemical_list: D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C000591691:TM38837; D013759:Dronabinol; D000077285:Rimonabant
keywords: PK−PD; TM38837; cannabinoid receptor type 1 antagonist; peripheral CB1 antagonist; pharmacokinetics; rimonabant