Model-informed drug development: The mechanistic HSK3486 physiologically based pharmacokinetic model informing dose decisions in clinical trials of specific populations.

HSK3486, a central nervous system inhibitor, has demonstrated superior anesthetic properties in comparison with propofol. Owing to the high liver extraction ratio of HSK3486 and the limited susceptibility to the multi-enzyme inducer, rifampicin, the indicated population of HSK3486 is substantial. Nevertheless, in order to expand the population with indications, it is crucial to assess the systemic exposure of HSK3486 in specific populations. Moreover, the main metabolic enzyme of HSK3486 is UGT1A9, which shows a gene polymorphism in the population. Thus, to scientifically design the dose regimen for clinical trials in specific populations, a HSK3486 physiologically based pharmacokinetic model was developed in 2019 to support model-informed drug development (MIDD). Several untested scenarios of HSK3486 administration in specific populations, and the effect of the UGT1A9 gene polymorphism on HSK3486 exposure were estimated as well. The predicted systemic exposure was increased slightly in patients with hepatic impairment and in the elderly, consistent with later clinical trial data. Meanwhile, there was no change in the systemic exposure of patients with severe renal impairment and in neonates. However, under the same dose, the predicted exposure of pediatric patients aged 1 month to 17 years was decreased significantly (about 21%-39%). Although these predicted results in children have not been validated by clinical data, they are comparable to clinical findings for propofol in children. The dose of HSK3486 in pediatrics may need to be increased and can be adjusted according to the predicted results. Moreover, the predicted HSK3486 systemic exposure in the obese population was increased by 28%, and in poor metabolizers of UGT1A9 might increase by about 16%-31% compared with UGT1A9 extensive metabolizers. Combined with the relatively flat exposure-response relationship for efficacy and safety (unpublished), obesity and genetic polymorphisms are unlikely to result in clinically significant changes in the anesthetic effect at the 0.4 mg/kg dose in adults. Therefore, MIDD can indeed provide supportive information for dosing decisions and facilitate the efficient and effective development of HSK3486.