Effect of ethnicity on vinorelbine pharmacokinetics: a population pharmacokinetics analysis

Abstract

Background: Pharmacokinetics of vinorelbine is mainly known from studies conducted in European patients. Interethnic differences in drug disposition may, however, induce interethnic variation in drug exposure. This paper aimed to evaluate the effect of ethnicity on the bioavailability and clearance of oral and intravenous vinorelbine.

Methods: Oral and intravenous vinorelbine pharmacokinetics data in Asian patients were pooled from two-phase II studies of patients with non-small-cell lung cancer or advanced breast cancer in China. Blood vinorelbine and its active metabolite, 4'-O-deacetylvinorelbine, were quantified using liquid chromatography-tandem mass spectrometry. Bayesian pharmacokinetic parameters were calculated and vinorelbine monotherapy results (intravenous 25 mg/m²; oral 60 mg/m²) of the Asian data set were compared to a reference European data set (intravenous 30 mg/m²; oral 80 mg/m²). Subsequently, a population pharmacokinetics analysis was conducted in a combined cohort (Asian data set + historical vinorelbine pharmacokinetics database) to investigate for a potential effect of ethnicity.

Results: Pharmacokinetics data from the Asian data set (oral: n = 47; intravenous: n = 34) was compared to the European reference data set (oral: n = 48; intravenous: n = 48). Mean apparent clearance of oral vinorelbine and mean absolute clearance of intravenous vinorelbine was comparable between the Asian and reference European data set. A population pharmacokinetic analysis (oral: n = 222; intravenous: n = 111) demonstrated no influence of ethnicity on oral and intravenous vinorelbine bioavailability and clearance.

Conclusion: Vinorelbine pharmacokinetics were found to be comparable between Asian and European patients. No relevant influence of ethnicity on vinorelbine bioavailability and clearance for oral and intravenous routes of administration was observed.

Keywords: Breast cancer; China; Non-small-cell lung cancer; Pharmacokinetics; Vinorelbine.

Fig. 1

Comparison of a apparent total clearance (Cl_tot/F) of oral vinorelbine and b absolute total clearance (Cl_tot) of intravenous vinorelbine between Asian and European patients. BSA body surface area, IV intravenous

Fig. 2

Basic goodness of fit of oral model with ethnicity covariate. Concentrations are expressed as ng/ml; time is expressed as hours

Fig. 3

Basic goodness of fit of IV model with ethnicity covariate. Concentrations are expressed as ng/ml; time is expressed as hours

Fig. 4

Visual predictive check (IV model). Dot points represent observed values. Areas are, respectively, confidence interval of P5, median and P95 simulated values

Fig. 5

Visual predictive check (oral model). Dot points represent observed values. Areas are, respectively, confidence interval of median and P95 simulated values. Confidence interval of P5 does not appear because of negative values