MJ. Garrido(1), JM. Cendrós(2), IF. Trocóniz(1), C. Segura(1), C. Peraire(2), R. Obach(2)
(1) Department of Pharmacy, School of Pharmacy, University of Navarra, Pamplona 31080, Spain; (2) Metabolism and Pharmacokinetic Service, Research Department, Ipsen Pharma S.A., Carretera Laureá Miró, 395, Sant Feliú de Llobregat 088980, Barcelona, Spain.
Purpose: To develop a population pharmacokinetic/pharmacodynamic (pk/pd) model of diflomotecan to assist in the dosing and blood sampling strategies in future Phase II clinical trials.
Study design: Data from two studies were combined. 24 cancer patients were involved in the 001 study. Subjects received diflomotecan as a 20 min i.v. infusion administered every three weeks at doses (mg/m2) of 1 (n=1), 2 (n=2), 4 (n=13), 5 (n=4), 6 (n=3), and 12 (n=1). The number of cycles varied from one to six. Diflomotecan was measured in plasma after the first administration for a period of two days. Neutrophil counts in peripheral blood were followed every 3-4 days for the entire course of the trial. In study 700, 24 cancer patients received the drug in a 20 min i.v. dose of 0.1 (n=6), 0.2 (n=12) or 0.27 (n=6) mg/m2. After a period of two weeks, diflomotecan was given orally once daily for five consecutive days at the following doses: 0.1 (n=3), 0.2 (n=4), 0.27 (n=11), or 0.35 (n=4) mg/m2. Blood samples for pk characterisation were taken during the first two and last cycles. Neutrophil counts were measured every 5-6 days.
Data analysis: The population pk/pd model was derived from a total number of 876 and 1214 plasma levels and neutrophils counts, respectively. The analysis was performed with NONMEM version V. Pk was described with standard absorption and disposition models. Both, inter- and inter-occasion variability were explored in all the parameters. Time course of neutropenia was modelled using a semi-physiological model.[1]
Results: Drug absorption and disposition were best described with a first order and a three compartmental model, respectively. The estimates of plasma clearance and oral bioavailability were 525 L.day-1 and 0.66, respectively. Both parameters showed inter-subject (65 and 26 %) and inter-occasion (23, and 23 %) variability. None of the demographics tested elicited significant covariate effects (P > 0.05). The estimates of the system dependent parameters resembled the ones previously reported, and diflomotecan exerted a linear plasma concentration dependent and reversible inhibition of the rate of synthesis of proliferative cells.
Conclusion: Regarding its pk characteristics diflomotecan behaves linearly with time and over a wide range of doses. The haematological toxicity induced could also be described. Therefore information from this first modelling exercise can be used to explore the outcome of future studies.
References:
[1] Fibreg LE, Henningsson A, Maas H, Nguyen L and Karlsson MO. Model of chemotherapy-induced myelosupression with parameter consistency across drugs. J Clin Oncol 20: 4713-4721; 2002.
Reference: PAGE 12 (2003) Abstr 458 [www.page-meeting.org/?abstract=458]
Poster: poster