Pharmacokinetics of navelbine after oral administration in cancer patients

The pharmacokinetic behavior of navelbine was investigated in 19 patients presenting with advanced cancers (mainly women with breast cancer). Navelbine was given orally at seven dose levels of up to 200 mg/week. For a given dose, patients received four successive weekly treatments. Five subjects also received two different doses. After drug administration, plasma was collected for 48 or 72 h and monitored for navelbine concentration by radioimmunoassay. Absorption of navelbine was very rapid after oral administration: maximal drug concentrations were reached within the first 1 or 2 h (Tmax, 0.9-1.75 h; cmax, 70.9-832.6 ng/ml), with absorption constants ranging from 0.85 to 2.42 l/h. A comparison of dose-normalised plasma concentration profiles revealed significant time dependence in six evaluable patients (P less than 0.001). Only four subjects who received low doses (less than or equal to 100 mg/week) exhibited time-independent kinetics. All of the five patients who were treated at different doses displayed apparent dose dependence (P less than 0.001). No individual profile was characterised by both time- and dose-independent pharmacokinetics. In all, 18 patients presented biphasic plasma concentration-decay patterns, and only 1 subject exhibited monophasic decay kinetics. The navelbine pharmacokinetic parameters obtained following oral administration were similar to those observed after i.v. bolus injection and were characterised by high oral clearance (0.43-1.45 1 h-1 kg-1), a large apparent volume of distribution (27.4-45.9 1/kg), and a long terminal half-life (24.2-56.5 h). Large intra- and inter-individual variations in pharmacokinetic parameters were observed. Moreover, after a high dose of 200 mg, an enterohepatic cycle and/or a delay in navelbine's absorption at a distal intestinal site as evidenced by a marked plasma level rebound was observed.