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.

• Authors: Jing Li, Edward A Sausville, Patrick J Klein, David Morgenstern, Christopher P Leamon, Richard A Messmann, Patricia LoRusso
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 49 Issue 12 Pg. 1467-76 (Dec 2009) ISSN: 1552-4604 [Electronic] England
• PMID: 19837906 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• EC145
• Folate Receptors, GPI-Anchored
• Receptors, Cell Surface
• Vinca Alkaloids
• 4-desacetylvinblastine hydrazide
• Vinblastine
• Folic Acid

Topics

• Adult
• Aged
• Body Surface Area
• Carrier Proteins (metabolism)
• Constipation (chemically induced)
• Female
• Folate Receptors, GPI-Anchored
• Folic Acid (administration & dosage, adverse effects, analogs & derivatives, blood, pharmacokinetics)
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Neoplasms (metabolism)
• Nonlinear Dynamics
• Peripheral Nervous System Diseases (chemically induced)
• Receptors, Cell Surface (metabolism)
• Vinblastine (analogs & derivatives, blood)
• Vinca Alkaloids (administration & dosage, adverse effects, blood, pharmacokinetics)