Population Pharmacokinetics of Topical Timolol Maleate Gel in Healthy Volunteers and Infants With Superficial Infantile Hemangioma.

Although timolol ophthalmic solutions or hospital-compounded formulations have been used off-label for the treatment of superficial infantile hemangioma (IH), no topical timolol formulation has been developed specifically for this indication. This study was the first to develop a population pharmacokinetic (popPK) model for topical timolol maleate gel and to perform exploratory exposure-safety analyses. Data from Phase I-III clinical trials in healthy adults and infants with proliferative superficial IH were used to develop the popPK model. Potential covariate effects on the pharmacokinetics were investigated, and exploratory relationships between timolol exposure and safety outcomes were assessed. A total of 810 plasma concentration measurements from 138 subjects (24 healthy adults and 114 infants) were included in the popPK analysis. Timolol pharmacokinetics were well described by a one-compartment model with first-order absorption and elimination. No significant covariates influencing clearance were identified. No apparent associations were identified between timolol exposure and the evaluated safety outcomes. Overall, systemic exposure following administration of this topical timolol maleate gel formulation was limited, supporting its favorable safety profile in infants with superficial IH. These quantitative findings may help guide its rational clinical use.