Pharmacokinetic profile of vinorelbine, a new semi-synthetic vinca alkaloid, determined by high-performance liquid chromatography

Abstract

1. Vinorelbine (NVB), a new semi-synthetic vinca alkaloid, is currently used in the treatment of advanced non-small-cell lung cancer (NSCLC) and advanced breast cancer. The pharmacokinetic profile of NVB has been redefined with a specific h.p.l.c. method which measures NVB and desacetyl-NVB.

2. In man, the pharmacokinetics of NVB are best characterized by a three-compartment model with a terminal half-life of 42 h and a large volume of distribution (751/kg). The total clearance was 1.261h⁻¹kg⁻¹ and about 11% of the dose was eliminated by the kidneys. Desacetyl-NVB was a minor urinary metabolite.

3. Human pulmonary distribution study showed higher levels of NVB in lung tissue than in serum during the first 3 h after NVB injection; the tumour concentrations were lower than those determined in healthy parenchyma.

4. In the micropig, the 0-48 h biliary excretion of unchanged drug accounted for 25% dose with 21.5% being eliminated during the first 8 h. Desacetyl-NVB concentrations were low and inconsistent.

5. Preliminary results show a better response rate with the combination of cisplatin and NVB than that obtained with NVB alone in the treatment of advanced NSCLC. This increased activity is not the result of a pharmacokinetic interaction since it was shown that cisplatin did not alter the kinetic profile of NVB.

6. This is the first pharmacokinetic investigation of unlabelled vinca alkaloids by a h.p.l.c. procedure. Several aspects of vinorelbine disposition need to be explored, especially the detection of terminal metabolites and the kinetic profile after oral administration.