Better characterization of vinflunine pharmacokinetics variability and exposure/toxicity relationship to improve its use: Analyses from 18 trials.
Br J Clin Pharmacol
; 84(5): 900-910, 2018 05.
Article
en En
| MEDLINE
| ID: mdl-29341179
ABSTRACT
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.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Vinblastina
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Ensayos Clínicos Fase II como Asunto
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Ensayos Clínicos Fase I como Asunto
Límite:
Humans
Idioma:
En
Revista:
Br J Clin Pharmacol
Año:
2018
Tipo del documento:
Article
País de afiliación:
Francia