Population pharmacokinetics of cisplatin in small cell lung cancer patients guided with informative priors

Abstract

Cisplatin-etoposide treatment is recommended as a first line in small cell lung cancer patients (SCLC). However, the prognosis is poor and the dosing is not tailored beyond the body surface area, which is related with indeterminate cisplatin exposure-response relationship. We aimed to evaluate cisplatin pharmacokinetics (PK) and the exposure to unbound cisplatin in SCLC patients using the informative priors, and assess the relationship between the cisplatin exposure and probability of neutropenia. Observational clinical study was performed including 17 cisplatin-treated SCLC patients. External population cisplatin PK models were identified and NONMEM® software and $PRIOR subroutine were used for the model evaluation. The bias and precision of the model-predicted cisplatin concentrations were evaluated. The best models were combined in a final model including several sets of informative priors, which was used to estimate individual cisplatin exposure, analyze the relationship between the exposure and neutropenia and simulate several cisplatin dosing regimens in a virtual patient cohort. The models by Urien with the informative priors best fitted the data. The individual cisplatin exposure ranged between 2430 and 4560μg*h/L. There was a trend of increasing probability of neutropenia and febrile neutropenia with increasing cisplatin exposure. Approximately 50%, 75% and 90% of patients receiving 60mg/m2, 70mg/m2 and 80mg/m2, respectively, achieved the previously identified exposure threshold of 2860μg*h/L. We developed a tool to individualize cisplatin dosing based on the estimated probability of neutropenia. The benefit of more intense dosing regimens in SCLC patients should be further assessed.