Chemical formula: C₂₆H₂₉N₃O₃ Molecular mass: 431.536 g/mol
Tirbanibulin disrupts microtubules by direct binding to tubulin, which induces cell cycle arrest and apoptotic death of proliferating cells, and is associated with disruption of Src tyrosine kinase signalling.
Tirbanibulin ointment was minimally absorbed in 18 patients with actinic keratosis after topical application once daily for 5 consecutive days over an area of 25 cm². Tirbanibulin plasma concentrations were low at steady state (mean maximum concentration [Cmax] of 0.258 ng/mL or 0.598 nM and AUC0-24h of 4.09 ng∙h/mL).
The protein binding of tirbanibulin to human plasma proteins is approximately 88%.
In vitro, tirbanibulin is mainly metabolised by CYP3A4, and to a lesser degree by CYP2C8. The main metabolic pathways are N-debenzylation and hydrolysis reactions. The most relevant metabolites were characterised in patients with actinic keratosis in a maximal use pharmacokinetic study and showed minimal systemic exposure.
In vitro studies show that tirbanibulin does not inhibit or induce cytochrome P450 enzymes and it is not an inhibitor of efflux and uptake transporters at maximum clinical exposures.
Elimination of tirbanibulin has not been fully characterized in humans.
No formal studies of tirbanibulin ointment in patients with hepatic or renal impairment have been conducted. Due to the low systemic exposure to tirbanibulin after topical application of tirbanibulin ointment once daily for 5 days, changes in hepatic or renal function are unlikely to have any effect on the elimination of tirbanibulin. Therefore, no dose adjustments are considered needed.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity. Tirbanibulin was a moderate contact sensitiser in animals but this was not confirmed in humans.
Tirbanibulin was not mutagenic but induced chromosomal damage and micronuclei in genotoxicity studies. Detailed testing suggested that tirbanibulin is clastogenic/aneugenic and associated with a threshold, below which there is no induction of genotoxic events. In vivo, genotoxicity occurred at plasma levels >20 times higher than the human exposure in the maximal use pharmacokinetic study. In embryo-foetal development studies in rats and rabbits, embryonic and foetal toxicity, including foetal malformations, occurred at multiples of 22 times and 65 times greater than human exposure in the maximal use pharmacokinetic human study. In a pre- and postnatal development study in rats, reductions in fertility and increased embryo-foetal lethality were seen in the offspring of treated females.
In a fertility and early embryonic development study in rats, decrease in testes weight which correlated with decreased sperm count, decreased sperm motility, increased incidences of abnormal sperm, and increased incidence of degeneration of the seminiferous epithelium, considered indicative of male fertility toxicity, occurred at multiples of 58 times greater than human exposure in the maximal use pharmacokinetic human study. However, there were no changes in male mating or fertility indices.
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