Pharmacokinetics and efficacy of tank water-administered BRAF-inhibitor dabrafenib in a zebrafish melanoma model 

ABSTRACT

Zebrafish models are widely used to study BRAF-mutant melanoma biology. However, long-term treatment of adult fish with small molecule BRAF inhibitors remains challenging, and pharmacokinetic data to inform rational dosing strategies are largely lacking for most small molecules in zebrafish. Here, we assessed the pharmacokinetics, metabolism, and efficacy of continuously tank water-administered BRAF inhibitor dabrafenib in adult zebrafish. Dabrafenib was rapidly absorbed from tank water, reaching efficacious plasma levels within one hour, but also showed fast elimination kinetics with a half-life of 1.0 hours. Most human metabolites of dabrafenib were detected in zebrafish, suggesting conserved metabolic processes. Continuous tank water administration achieved therapeutically relevant steady-state dabrafenib plasma levels that inhibited BRAF-driven signaling and produced robust efficacy in vivo in a genetic zebrafish model of BRAF-mutant melanoma without apparent toxicity. Together, these results demonstrate that continuous tank water administration of dabrafenib is a feasible, efficient, and well-tolerated dosing strategy in zebrafish melanoma models, and may facilitate dosing of other small molecule inhibitors, especially those with a short in vivo half-life in zebrafish.

PMID:42733341 | DOI:10.1242/dmm.052907