Tyrosine kinase inhibitors in cancers: Treatment optimization – Part I

AimTo evaluate the effectiveness of a Bayesian adaptive dosing strategy in achieving target busulfan exposure in adult patients undergoing haematopoietic cell transplantation (HCT).MethodsThis study included 71 adult patients scheduled to receive high-dose busulfan. Busulfan was administered to achieve a cumulative area under the curve (AUC) of 66.0 mg/L/h (16 000 μM/min), 82.60 mg/L/h (20 000 μM/min) or 87.6 mg/L/h (21 200 μM/min) depending on the regimen. Individual pharmacokinetic (PK) parameters of busulfan were estimated from three blood samples using a one-compartment model and Bayesian estimation after the first standard dose. Individual PK parameters were used to adjust subsequent doses to achieve the target exposure.ResultsAll patients had their dose adjusted after the first dose administration. The final deviation from the target AUC was significantly improved compared to the initial deviation after standard mg/kg dosing (mean absolute deviation 19.5% vs 11.7%, P < .01). In addition, the proportion of patients with marked deviation from target exposure (ie, >25%) decreased significantly from 31% after standard dosing to 10% after PK-guided dosing (P < .01). Canonical busulfan-related toxicity, specifically veno-occlusive disease, was observed in 5% of patients who achieved successful PK-guided dosing. In contrast, one-third of patients with off-target exposure with poor dosing experienced toxicity.ConclusionThe Bayesian adaptive dosing strategy significantly improves the accuracy of achieving the target busulfan AUC in patients undergoing HCT. This approach not only reduces marked deviations from target exposure, but also reduces the incidence of busulfan-related toxicity, thereby maintaining a favourable toxicity/efficacy ratio.