Better characterization of vinflunine pharmacokinetics variability and exposure/toxicity relationship to improve its use: Analyses from 18 trials

摘要

Aims Vinflunine is a novel tubulin‐targeted inhibitor indicated as a single agent for the treatment of bladder cancers after failure of prior platinum‐based therapy. Its pharmacokinetics (PK) and pharmacodynamics (PD) have been independently characterized through several phase I and phase II studies. However, no global pharmacometric analysis had been conducted as yet. Methods Vinflunine concentrations and safety data from 18 phase I and phase II studies were used to conduct population PK and PK/PD analysis, using Nonmem. A four‐compartment model was used to describe vinflunine PK and several covariates were tested to explain interindividual variability. In terms of PK/PD relationship, a semiphysiological population PK/PD model was applied to describe time course of absolute neutrophil counts (ANC) after vinflunine administration and logistic regression models were used to test the relationship between vinflunine exposure and toxicities. Results Vinflunine clearance is explained by creatinine clearance, body surface area and combination with PEGylated doxorubicin, leading to a decrease from 28.2 to 25.3% of the interindividual variability. When vinflunine dose is decreased, simulations of ANC time course (via a semiphysiological model) after vinflunine administration show a risk of neutropenia grade 3–4 at cycle 2 always lower than when dose is delayed. As an example, for moderate renal impaired patients, the risk is 42.1% when vinflunine is dosed at 320?mg?m –2 once every 4?weeks vs . 23.3% for 280?mg?m –2 once every 3?weeks. Conclusions We propose for the first time a global comprehensive clinical pharmacological analysis for intravenous vinflunine that may help drive dose adjustment.