Better characterization of vinflunine pharmacokinetics variability and exposure/toxicity relationship to improve its use: analyses from 18 trials
Résumé
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 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 4-compartment model was used to describe vinflunine PK and several covariates were tested in order to explain inter-individual variability. In terms of PK/PD relationship, a semi-physiologic 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, BSA and combination with pegylated doxorubicin, leading to a decrease from 28.2 to 25.3% of the inter-individual variability. When vinflunine dose is decreased, simulations of ANC time course (via a semi-physiological 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/m2 q4w vs. 23.3% for 280 mg/m2 q3w.
Conclusions
We propose for the first time a global comprehensive clinical pharmacological analysis for IV vinflunine that may help drive dose adjustment.