Population pharmacokinetic-pharmacodynamic modeling of efaproxiral in cancer patients receiving radiation therapy

Abstract

Aims Efaproxiral (EFP), a synthetic allosteric modifier of hemoglobin (Hb), reduces O2-binding affinity in blood (p50) and is investigated as a radiation therapy sensitizer. The goal of this work was to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of EFP in cancer (CA) patients. Methods Pooled data from 6 phase I -III trials included: 451 patients, 2582 plasma and 2881 RBC concentrations, and 2483 p50 values. Covariates were age, weight, height, sex, concomitant medications, CA type, Hb, albumin, creatinine clearance, body surface area (BSA) and dose. Data were analyzed using NONMEM. Results A linear, 2-compartment model with RBC:plasma proportionality constant and a linear RBC-p50 model described the PK-PD relationship. Parameters were consistent with previously reported values (%SE): CL=1.88 L/hr (8%), V1=10.5 L (2%), Q=2.58 L/hr (12%), V2=18.1 L (10%), SLPRBC=0.982 (1%), INTp50=26.9 mmHg (~0%), SLPp50=0.0193 mmHg/(μg/mL) (5%). The inclusion of covariates resulted in improvements in goodness of fit and decreases in the estimated inter-individual variances. The final model adequately described the central tendency and population variability for the observed data. Conclusions Differences in PK-PD response due to CA type were small, may have been study-related and were probably not clinically relevant. EFP exposure increased with age, but the clinical relevance of this effect was unknown. BSA was the most important predictor of EFP disposition. Clinical Pharmacology & Therapeutics (2005) 77, P89–P89; doi: 10.1016/j.clpt.2004.12.233