Pharmacokinetic linearity of i.v. vinorelbine from an intra-patient dose escalation study design

As pharmacokinetics represents a bridge between pharmacological concentrations and clinical regimens, the pharmacokinetic exploration of the therapeutic dose range is a major outcome. This study was aimed at assessing pharmacokinetic linearity of i.v. vinorelbine through an open design with intra-patient dose escalation (3 doses/group). Three groups of six patients received either 20-25-30 mg/m(2); or 25-30-35 mg/m(2); or 30-35-40 mg/m(2). The inclusion criteria were: histologically confirmed tumour with at least one assessable target lesion, age 25-75 years, WHO PS less than or equal to2, normal haematology and biochemistry, life expectancy greater than or equal to3 months. The pharmacokinetics was evaluated in both whole blood and plasma over 120 h. Twenty-six patients were recruited and 18 were evaluable for pharmacokinetics. The toxicity consisted in grade less than or equal to3 leucopenia and neutropenia (<20% of courses) and two grade 4 constipation with rapid recovery (2/54 courses). Compared to blood, plasma was demonstrated to underestimate the pharmacokinetic parameters. In blood, the drug total clearance was about 0.6 l/h/kg, with minor contribution of renal clearance, steady state volume of distribution close to 13 l/h/kg, and elimination half-life at about 40 h. A pharmacokinetic linearity was demonstrated up to 40 mg/m(2), and even up to 45 mg/m(2) when pooling data from another study. A pharmacokinetic-pharmacodynamic relationship was evidenced on leucopenia and neutropenia when pooling the data from the two studies.