Clinical pharmacokinetics and exposure-toxicity relationship of a folate-Vinca alkaloid conjugate EC145 in cancer patients

Abstract

The clinical pharmacokinetics and exposure-toxicity relationship were determined for EC145, a conjugate of folic acid and the Vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), in cancer patients. EC145 plasma concentration and toxicity data were obtained from a first-in-man phase I study and analyzed by nonlinear mixed effect modeling with NONMEM. EC145 concentration-time profile after intravenous administration was well described by a 2-compartment model with a first-order elimination process from the central compartment. BSA was identified as a significant covariate on EC145 clearance, accounting for 14.6% of interindividual variation on EC145 clearance. Population estimates for the clearance, steady-state volume of distribution, distribution, and elimination half-lives were 56.1 L/h, 26.1 L, 6 minutes, and 26 minutes, respectively. Constipation and peripheral neuropathy were the most common and clinically relevant toxicities. The clearance and area under the concentration-time curve (AUC) were significant predictors for the incidence of EC145-induced constipation but not peripheral neuropathy. In conclusion, EC145 is rapidly distributed and eliminated in cancer patients. BSA is a statistically significant covariate on EC145 clearance, but its clinical relevance remains to be defined. EC145-induced constipation occurs at a higher frequency in the patients with lower EC145 clearance, where the drug exposure tends to be higher.

Figures

Figure 1

The relationships between EC145 dose and Cmax (A and B) and AUC (C and D) following an intravenous bolus injection and a 1-hour infusion. Data are presented as individual patient parameters and mean values.

Figure 2

Basic goodness-of-fit plots from the final 2-compartment model with a first-order elimination process and with BSA being introduced as a significant covariate on CL. Observed and predicted concentrations are shown as log-transformed. The solid lines are linear regression lines, and the dashed lines are lines of identity. DV, observed concentration; PRED, population predicted concentration; IPRE, individual predicted concentration; WRES, weighted residue; IWRES, individual weighted residues.

Figure 3

Correlation between EC145 day-1 AUClast (A), day-3 AUClast (B), and clearance (C) and the incidence of constipation (≥grade 1) in patients receiving intravenous EC145 at the dose ranging from 1.2 to 4.0 mg. The solid and dashed lines represent the logistic regression model predicted probability of no constipation and constipation, respectively. The insertion of observed events of constipation (Δ) and no constipation (○) at probability levels of 1 and 0 is purely for illustration.