Mercier C(1), Vassal G(2), Tranchand B(1), Sicard E(2), Santos A(2), Vernillet L(3), Pein F(2), Doz F(4), Frappaz D(1), Germa MC(5), Ardiet CJ(1)
(1) Centre Léon-Bérard, Lyon, (2) Institut Gustave-Roussy, Villejuif, (3) Aventis Pharma, Antony, (4) Institut Curie, Paris, (5) Laboratoire Aventis, Paris.
Introduction: The main purpose of this study was to determine the pharmacokinetic (PK) models of CPT11 and its 4 main metabolites, in order to build a full PK model including all these molecules.
Patients and method: In a phase I study, 81 children and teenagers (10 months-18 years old) were included in 2 successive cohorts. CPT11 was given as a 2h I.V. infusion (8 dose levels: 200-720 mg/m2). 16 blood samples were collected. CPT11 and its metabolites were assayed by reverse phase high-performance liquid chromatography (HPLC) with fluorescence detection. The limit of quantification was about 10 ng/ml for all components.
PK analysis was made with NONMEM V. We tested 2- and 3-compartment linear models for all molecules and we assumed that a first order absorption model better approached the apparition phase of metabolites. Additive, multiplicative and mixed-error models were tested for the 5 molecules. After this step, we simultaneously modelized CPT11 and its active metabolite SN-38 using differential equations (ADVAN8). We used a 3-compartment model for CPT11 and a 2-compartment model for SN-38.
Results:
1. Individual analysis:
o CPT11: modelized by a 3-compartment model (ADVAN11) and a multiplicative-error model
o SN-38, SN-38G and APC: modelized by a 2-compartment with first order absorption model (ADVAN4) and a mixed-error model
o NPC: modelized by a 2-compartment with first order absorption model (ADVAN4) and a multiplicative-error model
| CL(l.h-1)* | V1(l)* | omega1 | omega2 | sigma1 | sigma2 | |
| CPT11 | 18.2 | 10.7 | 0.619 | 0.681 | 0.126 | |
| SN38 | 920 | 3840 | 0.751 | 0.452 | 0.020 | 7.82.10-5 |
| SN38G | 1040 | 4280 | 8.45 | 0.379 | 0.159 | 9.76.10-5 |
| APC | 102 | 317 | 2.27 | 0.577 | 2.65.10-2 | 1.49.10-3 |
| NPC | 343 | 6300 | 2.06 | 2.95 | 2.39.10-1 |
2. Simultaneous analysis of CPT11 and SN-38 (ADVAN8):
| CL(l.h-1)* | V1(l)* | omega1 | omega2 | sigma1 | sigma2 | |
| CPT11 | 5.75 | 25 | 1.9 | 3.8 | 1.41 | 6.66.10-2 |
Cl* and V* are clearance and Volume taking into account the fraction of the dose metabolized
Discussion: The individual PK models of CPT11 and its 4 metabolites were determined using a 3-compartment model for CPT11 and a 2-compartment-model for the other molecules. In some patients a first order absorption model did not fit well the apparition phase of metabolites. Moreover some patients presented a rebound in their PK. The major parts of these problems were solved using a simultaneous analysis.
Perspectives:
1. Covariables database is currently collected, the subsequent model will be studied.
2. From this study a limited sampling strategy was established for a phase II study. A PK/PD analysis will be performed.
3. We’ll try to modelize simultaneously the 5 molecules after including a sufficient number of patients (phase I and II).
Reference: PAGE 10 (2001) Abstr 190 [www.page-meeting.org/?abstract=190]
Poster: poster