Rimonabant

Rimonabant is a selective cannabinoid-1 receptor (CB1) antagonist that inhibits the pharmacological effects of cannabinoid agonists in vitro and in vivo. The endocannabinoid system is a physiological system present in brain and peripheral tissues (including adipocytes) that affects energy balance, glucose and lipid metabolism and body weight, and in neurons of the mesolimbic system modulates the intake of highly palatable, sweet or fatty foods.

Rimonabant pharmacokinetics are fairly dose proportional up to about 20 mg. AUC increased less than in proportion to dose above 20 mg.

Absorption

Rimonabant displays high in vitro permeability and is not a substrate of P-glycoprotein. The absolute bioavailability of rimonabant has not been determined. Following multiple once-daily doses of 20 mg to healthy subjects in the fasted state, maximum plasma concentrations of rimonabant are achieved in approximately 2 hours with steady state plasma levels achieved within 13 days (C_max = 196 ± 28.1 ng/ml; C_trough = 91.6 ± 14.1 ng/ml; AUC_0-24 = 2960 ± 268 ng.h/ml). Steady state rimonabant exposures are 3.3-fold higher than those observed after the first dose. Population pharmacokinetic analysis demonstrated less fluctuation in peak to trough plasma concentration but no differences in steady state AUC as weight increases. As weight increases from 65 to 200 kg, C_max is expected to decrease 24% and C_trough is expected to increase by 5%. Time to steady state is longer in obese patients (25 days) as a consequence of the higher volume of distribution in these patients. Population pharmacokinetic analysis indicated that rimonabant pharmacokinetics are similar between healthy non-smoking subjects and patients who smoke.

Effect of food

Administration of rimonabant to healthy subjects in the fasted state or with a high fat meal demonstrated that C_max and AUC were increased 67% and 48% respectively, under fed conditions. In clinical studies, rimonabant 20 mg was taken in the morning usually before breakfast.

Distribution

The in vitro human plasma protein binding of rimonabant is high (>99.9%) and non-saturable over a wide concentration range. The apparent peripheral volume of distribution of rimonabant appears to be related to body weight, with obese patients having a higher volume of distribution than normal-weight subjects.

Biotransformation

Rimonabant is metabolized by both CYP3A and amidohydrolase (predominantly hepatic) pathways in vitro. Circulating metabolites do not contribute to its pharmacologic activity.

Elimination

Rimonabant is mainly eliminated by metabolism and subsequent biliary excretion of metabolites. Only an approximate 3% of the dose of rimonabant is eliminated in the urine, while approximately 86% of the dose is excreted in the faeces as unchanged drug and metabolites. In obese patients, the elimination half-life is longer (about 16 days) than in non-obese patients (about 9 days) due to a larger volume of distribution.

Special Populations

Race

In single- and repeat-dose studies, the C_max and AUC of rimonabant were similar in healthy Japanese and Caucasian subjects, whereas elimination half-life was shorter in Japanese subjects (3-4 days) compared to Caucasian subjects (about 9 days). The difference in half-life was due to differences in peripheral volume of distribution as a consequence of lower weight in Japanese subjects. Black patients may have up to a 31% lower C_max and a 43% lower AUC than patients of other races.

Gender

The pharmacokinetics of rimonabant are similar in female and male patients.

Elderly

Elderly patients have slightly higher exposure than young patients. Based on a population pharmacokinetic analysis (age range 18-81 years) a 75 year old patient is estimated to have a 21% higher C_max and a 27% higher AUC than a 40 year old patient.

Patients with hepatic insufficiency

Mild hepatic impairment does not alter rimonabant exposure. Data are insufficient to draw conclusions regarding pharmacokinetics in moderate hepatic impairment. Patients with severe hepatic impairment were not evaluated.

Patients with renal impairment

The effect of renal function on the pharmacokinetics of rimonabant has not been studied specifically. Based on data from population pharmacokinetic studies, mild renal impairment do not seem to affect the pharmacokinetics of rimonabant. Limited data suggest an increased exposure in patients with moderate renal impairment (40% increase in AUC). There are no data in severe renal impairment.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: Convulsions were observed sporadically in studies in rodents and macaques. No convulsions were observed in dogs during a 3 month study. In some, but not all cases, initiation of convulsions appeared to be associated with procedural stress such as handling of the animals. A proconvulsant activity of rimonabant was found in one of two safety pharmacology studies. No adverse effect of rimonabant treatment was observed on EEG patterns in rats.

Increased incidence and/or severity of clinical signs suggestive of increased tactile hyperesthesia were observed in rodent studies. A direct effect of rimonabant cannot be ruled out.

Liver steatosis and a dose-related increase in centrilobular necrosis were observed in long-term studies in the rat. A direct effect of rimonabant cannot be ruled out.

In standard fertility studies in female rats (dosing for 2 weeks prior to mating) there was abnormal oestrous cyclicity and a decrease in corpora lutea and fertility index at doses of rimonabant that induced maternal toxicity (30 and 60 mg/kg/day). Following dosing for a longer treatment duration prior to mating (9 weeks) that permitted recovery from the initial effects of rimonabant, no adverse effects were seen on fertility or oestrous cyclicity. Regarding reproductive parameters, at 30 mg/kg no differences were observed between treated animals and controls, at 60 mg/kg effects were still observed (decreased number of corpora lutea, implantations, total and viable fetuses).

Sporadic malformations (anencephaly, micro-ophthalmia, widened brain ventricles and omphalocele) were observed in the rabbit embryofetal toxicity studies at doses resulting in exposures comparable with the clinical exposures. Although maternal toxicity was observed at these doses, a relation to treatment cannot be excluded. No treatment-related malformations were seen in the rat.

Effects of rimonabant on pre- and post-natal development were assessed in the rat at doses up to 10 mg/kg/day. There was a treatment related increase in pup mortality in the pre-weaning period. The increased pup mortality might be attributable to a failure of the dam to nurse or ingestion of rimonabant in milk and/or inhibition of the suckling reflex that is reported in the literature to be initiated in neonatal mice by endocannabinoid signalling via CB1 receptors. There are reports in the literature that, in both rodents and humans, the spatial distribution and density of CB1 receptors in the brain changes during development. The potential relevance of this to administration of a CB1 antagonist is unknown. In the pre- and post-natal development study in rats, exposure to rimonabant in utero and via lactation produced no alterations on learning or memory, but equivocal effects on motor activity and auditory startle response were observed in the pups as a result of rimonabant exposure.