Mechanistic insights into vincristine interactions with azoles and dasatinib: Implications for neurotoxicity in paediatric patients using physiologically based pharmacokinetic modelling

Aims This study aimed to investigate the mechanisms and pharmacokinetic consequences of vincristine (VCR) drug–drug interactions (DDIs) with azole antifungals and dasatinib (DAS). Methods In vitro enzyme and transporter assays were conducted to characterize VCR metabolism and inhibition by posaconazole (POS), voriconazole (VRZ), fluconazole (FLZ) and DAS. Paediatric physiologically based pharmacokinetic (PBPK) models were developed using in vitro parameters and further refined using empirical Bayesian estimates from a VCR population pharmacokinetic model. Cytotoxicity was assessed using dorsal root ganglion (DRG) cell assays. Results POS competitively inhibited CYP3A4 and CYP3A5 ( Kᵢ = 1.62 and 1.35 μM) and P‐gp ( IC 50 = 7.72 μM), whereas VRZ competitively inhibited CYP3A4 and CYP3A5 ( Kᵢ = 8.87 and 4.22 μM) and additionally exhibited mechanism‐based inhibition of CYP3A4 (K I = 16.24 μM, k inact = 0.0263 min −1 ). FLZ showed weak inhibition of CYP3A4 and CYP3A5 (Kᵢ > 60 μM), whereas DAS showed moderate inhibition ( Kᵢ = 1.99–4.42 μM). The simulated VCR clearance was also approximately halved (CL = 0.59 vs . 0.33 L/h/kg) when co‐administrated with POS. Moreover, PBPK modelling indicated that intravenous POS and VRZ increased VCR AUCs by more than twofold. In vitro DRG cell assays demonstrated a concentration‐dependent potentiation of VCR‐induced cytotoxicity by POS. Conclusions Collectively, these PBPK model predictions suggest that POS and VRZ may represent high‐risk perpetrators of VCR DDIs in children and may help guide future dose optimization and toxicity management, pending confirmation in prospective clinical studies.