NGUYEN L., VARIOL P., PUOZZO C.
Institut de Recherche Pierre Fabre, Castres, France
Vinflunine is a third generation of semisynthetic vinca alkaloids: two flurine atoms were introduced in the molecule thanks to super-acid chemistry. Vinflunine has demonstrated an interesting activity on murine tumors and its clinical development is on going.
The objective of the analysis was to prospectively predict vinflunine (VFL) pharmacokinetic behaviour in patient from animal data, using a population scaling-up strategy. In order to evaluate such an approach, a retrospective analysis on vinorelbine (i.e., a vinca compound widely used for several years) was carried out. Animal data (monkey, dog, rat and mice) were pooled and computed with the NONMEM program (version V.0). A three-compartment open (+ zero order input) pharmacokinetic model (using ADVAN 11 TRANS 4 subroutines) and an exponential error were used to describe basic structural and variability models respectively. Allometric equations were tested on the main pharmacokinetic parameters.
The final equations for clearance along with their respective CI95% parameters ( ) were:
For vinorelbine: TVCL = 1.11 (0.95 – 1.27) . WT exp.[0.929 (0.887 – 0.971)]
For vinflunine: TVCL = 4.65 (1.47 – 7.83) . WT exp.[1.19 (1.07 – 1.31)] . MLP exp.[-0.490 (-0.82 – -0.16)]
(WT = weight in kg and MLP = maximum life span in years).
exp.[ ] = all values in square brackets are exponent.
Vinorelbine clearance predicted for the patient (CI95% = 45 – 83 L/h) was slightly over-estimated compared with the observed clearance (41 – 52 L/h). For vinflunine, the mean predicted clearance was 73 L/h (CI95% = 39 to 108 L/h) and the terminal half-life was around 23 h. The pharmacokinetic analysis on the first recruited patient confirmed the predicted profile by scaling-up approach. The observed terminal half-life (24 h) was the same as predicted and the observed total body clearance (59 L/h) was close to the predicted value. This strategy allowed a secure and rapid determination of the real maximum tolerated dose.
Reference: PAGE 10 (2001) Abstr 229 [www.page-meeting.org/?abstract=229]
Poster: poster