title: Pharmacokinetic linearity of i.v. vinorelbine from an intra-patient dose escalation study design.
abstract: 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/m2; or 25-30-35 mg/m2; or 30-35-40 mg/m2. The inclusion criteria were: histologically confirmed tumour with at least one assessable target lesion, age 25-75 years, WHO PS < or =2, normal haematology and biochemistry, life expectancy > or =3 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 < or =3 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/m2, and even up to 45 mg/m2 when pooling data from another study. A pharmacokinetic-pharmacodynamic relationship was evidenced on leucopenia and neutropenia when pooling the data from the two studies.
authors.affiliation: Hôpital Pitié-Salpétrière, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Khayat
authors.forename: Olivier
authors.initials: O
authors.lastname: Rixe
authors.forename: René
authors.initials: R
authors.lastname: Brunet
authors.forename: Alain
authors.initials: A
authors.lastname: Goupil
authors.forename: Roland
authors.initials: R
authors.lastname: Bugat
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Harousseau
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.forename: Christian
authors.initials: C
authors.lastname: Puozzo
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D014747:Vinblastine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D000077235:Vinorelbine