Purpose: Cannabis is a well-known, plant-based product, although clinical usage remains to be confirmed. With expectation of cannabis legalization, industry and regulators expect to obtain adequate information on the clinical pharmacology of the product. One of the objectives of this study was to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of cannabis following single and multiple ascending doses (SAD/MAD) in healthy volunteers. The present mainly describes the PK and safety following the MAD portion of the study.
Methods: Following completion of the first SAD portion of the study, it was agreed to proceed to MAD portion comparing PK, PD and safety of cannabis. This portion was to include up to 24 healthy subjects (who had a history of cannabis use) in a Phase 1, randomized, double-blinded, placebo-controlled study. The first three cohorts were to smoke/inhale with a titanium pipe, a 25 mg/5.5 mg dose of cannabis (Tetrahydrocannabinol [THC]/Cannabinoid[CBD]) or placebo given die, bid or tid (4 hrs apart) over seven consecutive days. Each cohort was to include eight subjects (6A:2P). Also, the main objective of the trial was to assess safety through adverse events, vital signs, electrocardiograms, physical examination and laboratory tests. THC and CBD were to be assayed with a validated HPLC method using MS/MS detection. PD (cognitive tests) was evaluated.
Results: Procedure for the smoking/inhalation was to be adapted to ensure study objectives were met and were related to results of the SAD portion of the study. Difficulty of the clinical process will be presented. For the MAD, predefined stopping criteria were not met in any dosing cohort. Overall, 24 (100%) subjects experienced at least treatment-emergent adverse event (TEAE) during the study (six [100%] subjects in the THC/cannabidiol 25 mg die Group, six [100%] subjects in the THC/cannabidiol 25 mg bid Group, six [100%] subjects in the THC/cannabidiol 25 mg tid Group and six [100%] subjects in the placebo Group); a total of 354 TEAEs were reported. The percentage distribution of TEAEs for the 25 mg die, bid or tid cohorts was 21% (74/354), 28% (98/354) and 36% (126/354), respectively and 16% (56/354) for the placebo cohort. The majority of TEAEs were mild in intensity (94%; 332/354). One severe TEAE was experienced by a subject on placebo. One subject was withdrawn from the study due to a TEAE. On Day 7, Tmax ranged from 0.05–0.17 hrs and AUC increased from 5.3 to 30.6 ng*h/mL across cohorts. For CBD, Tmax ranged from 0.02–0.17 h and AUC increased from 3.0 to 9.5 ng*h/mL across cohorts. Half-life was short with both THC and CBD eliminated from plasma in less than 0.81 and 1.25 hrs postdose, respectively. As expected, no significant accumulation was noted after seven consecutive days.
Conclusion: Cannabis administered as a multiple 25 mg die, bid or tid over seven days was generally safe and well tolerated. Pharmacokinetics of THC and CBD were similar across cohorts as the dosing interval (4 hrs) allowed returning to baseline between each administration reflecting high clearance, no accumulation and rapid elimination. Pharmacodynamic responses remain to be evaluated.
Josée Michaud
РAssociate Director, Altasciences, Laval, QuebecJos̩e Michaud
– Associate Director, Altasciences, Laval, QuebecAnastasia Papageorgiou
– Medical Writer, AltasciencesGraham Wood
– Chief Research and Development Officer, AltasciencesIngrid Holmes
– Vice-President, AltasciencesÉric Sicard
– Principal Investigator, AltasciencesÉric Sicard
– Principal Investigator, AltasciencesGuy Chamberland
РChief Executive Officer, Tetra Bio-PharmaJos̩e Michaud
– Associate Director, Altasciences, Laval, Quebec388 Views