Inflammatory response affects the pharmacokinetics (PK) and pharmacodynamics (PD) of imatinib and CGP 74588 in patients with advanced gastro-intestinal-sarcoma (GIST)

Abstract

2070 Background: PK analyses of Imatinib showed large inter-individual variability in patients with advanced GIST. This study was designed to explore factors affecting PK variability of Imatinib and CGP 74588, along with PK-PD correlations. Methods: Thirty-five patients (26 males; median age 55 yrs, range 28–84 yrs) with advanced GIST, registered in a phase III study, received400 mg/day (d) of Imatinib. Five blood samples were obtained before intake, between 1 and 3 and 6 and 9 hours on d1, prior to next dose on d2 and at steady state on d30 and 60. Imatinib and CGP 74588 plasma levels were quantitated by reverse-phase HPLC coupled with tandem mass spectometry, and analysed by population PK using NONMEM program. We examined the influence of 17 covariates on Imatinib clearance (CL) and apparent CGP 74 588 clearance (CLM/fm, with fm = fraction of Imatinib converted to CGP 74588). These covariates included age, weight, gender, inflammatory proteins, renal, hematological and liver biological values at baseline along with oedema, liver metastasis and occasion (OCC = 0 for PK at d1 or = 1 at d≥ 30). Results: The best regression formulas were: CL = 17.2/(1 + 0.961 * alpha-1-acid glycoprotein [AAG]) and CLM/fm = 164 * (1–0.46 * OCC)/(1 + 1.52 * AAG) (AAG in g/L), showing that both clearances decreased in case of elevated AAG (probably due to higher plasma protein binding). A significant time-dependent decrease in CLM/fm was evidenced with a mean ± SD CGP/Imatinib AUC ratio of 0.25 ± 0.07 at steady state compared to 0.14 ± 0.03 on d1. Hematological toxicity, measured by the relative decrease in absolute neutrophil count (ANC) (Δ ANC = [ANC nadir - ANC on d1]/ANC on d1) and in Δ platelets, was significantly correlated with high exposure to Imatinib (p = 0.0001 and 0.03, respectively). A significant correlation between Δ ANC and AAG was observed on d1 (p < 0.0001). Response and oedema occurrence were not correlated with any PK parameters. Conclusions: Inflammatory response might influence metabolism, disposition and hematological toxicity of Imatinib. (Supported by an IGR, IFR Grant and La Ligue Genevoise contre le Cancer). No significant financial relationships to disclose.