Determining success rates of the current pharmacokinetically guided dosing approach of topotecan in pediatric oncology patients.

BACKGROUND: Topotecan is a chemotherapeutic agent that is active against many pediatric tumors. Although its effect is related to systemic exposure, the interpatient variability in systemic clearance makes it challenging to achieve desired topotecan targets. This study aims to evaluate the success of the pharmacokinetically (PK) guided dosing process, which was used to achieve a target topotecan area under the concentration-time curve (AUC).
METHODS: Patients received an empiric topotecan dosage on the first day; the topotecan lactone AUC was determined, and based upon these values the topotecan dosage was adjusted. The success rates of both the empiric and PK-guided strategies were calculated. Patient-specific covariates were collected to explain variability observed in the empiric and PK-guided results. A simulation study was performed to assess the differences in cumulative topotecan dosage and systemic exposure between a PK-guided and standard dosing approach.
RESULTS: Data were collected from nine clinical trials open from 1996 to 2016 (n = 232 patients). The empiric dosing success rate was 35.5%, while the PK-guided rate was 64.4%. A difference in mean serum creatinine was observed between successful empiric studies and those above the AUC target. Compared to a standard dosing approach, the PK-guided group had a higher average cumulative dosage and systemic exposure.
CONCLUSION: The low empiric dosing success rate indicates that additional studies are needed to refine the initial topotecan dosage. The role of renal function, measured as serum creatinine, remains to be elucidated. However, the PK-guided targeting success rate highlighted the need to account for variable topotecan systemic clearance.