Bexarotene

Bexarotene is a synthetic compound that exerts its biological action through selective binding and activation of the three RXRs: α, β, and γ. Once activated, these receptors function as transcription factors that regulate processes such as cellular differentiation and proliferation, apoptosis, and insulin sensitisation. The ability of the RXRs to form heterodimers with various receptor partners that are important in cellular function and in physiology indicates that the biological activities of bexarotene are more diverse than those of compounds that activate the RARs.

In vitro, bexarotene inhibits the growth of tumour cell lines of haematopoietic and squamous cell origin. In vivo, bexarotene causes tumour regression in some animal models and prevents tumour induction in others. However, the exact mechanism of action of bexarotene in the treatment of cutaneous T-cell lymphoma (CTCL) is unknown.

Absorption

Absorption/dose proportionality

Pharmacokinetics were linear up to a dose of 650 mg/m². Terminal elimination half-life values were generally between one and three hours. Following repeat once daily dose administration at dose levels ≥230 mg/m², C_max and AUC in some patients were less than respective single dose values. No evidence of prolonged accumulation was observed. At the recommended initial daily-dose level (300 mg/m²), single-dose and repeated daily-dose bexarotene pharmacokinetic parameters were similar.

Distribution

Protein binding/distribution

Bexarotene is highly bound (>99%) to plasma proteins. The uptake of bexarotene by organs or tissues has not been evaluated.

Biotransformation

Metabolism

Bexarotene metabolites in plasma include 6- and 7-hydroxy-bexarotene and 6- and 7-oxo-bexarotene. In vitro studies suggest glucuronidation as a metabolic pathway, and that cytochrome P450 3A4 is the major cytochrome P450 isozyme responsible for formation of the oxidative metabolites. Based on the in vitro binding and the retinoid receptor activation profile of the metabolites, and on the relative amounts of individual metabolites in plasma, the metabolites have little impact on the pharmacological profile of retinoid receptor activation by bexarotene.

Elimination

Excretion

Neither bexarotene nor its metabolites are excreted in urine in any appreciable amounts. The estimated renal clearance of bexarotene is less than 1 ml/minute. Renal excretion is not a significant elimination pathway for bexarotene.

Pharmacokinetics in Special Populations

Age

Based on the population pharmacokinetic analysis of data for 232 patients aged ≥65 years and 343 patients aged <65 years, age has no statistically significant effect on bexarotene pharmacokinetics.

Body Weight and Gender

Based on the population pharmacokinetics analysis of data for 614 patients with a weight range of 26 to 145 kg, the bexarotene apparent clearance increases with increasing body weight. Gender has no statistically significant effect on bexarotene pharmacokinetics.

Race

Based on the population pharmacokinetic analysis of data for 540 Caucasian and 44 Black patients, bexarotene pharmacokinetics are similar in Blacks and Caucasians. There are insufficient data to evaluate potential differences in the pharmacokinetics of bexarotene for other races.

Bexarotene is not genotoxic. Carcinogenicity studies have not been conducted. Fertility studies have not been conducted; however, in sexually immature male dogs, reversible aspermatogenesis (28-day study) and testicular degeneration (91-day study) were seen. When bexarotene was administered for six months to sexually mature dogs, no testicular effects were seen. Effects on fertility cannot be excluded. Bexarotene, in common with the majority of retinoids, was teratogenic and embryotoxic in an animal test species at systemic exposures that are achievable clinically in humans. Irreversible cataracts involving the posterior area of the lens occurred in rats and dogs treated with bexarotene at systemic exposures that are achievable clinically in humans. The aetiology of this finding is unknown. An adverse effect of long-term bexarotene treatment on cataract formation in humans has not been excluded.