title: 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.affiliation: Karmanos Cancer Institute, Wayne State University, 4100 John R, HWCRC/Room 523, Detroit, MI 48201, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Klein
authors.forename: David
authors.initials: D
authors.lastname: Morgenstern
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Leamon
authors.forename: Richard A
authors.initials: RA
authors.lastname: Messmann
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
mesh_terms: D000328:Adult; D000368:Aged; D001830:Body Surface Area; D002352:Carrier Proteins / Q000378:metabolism; D003248:Constipation / Q000139:chemically induced; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D017711:Nonlinear Dynamics; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D011956:Receptors, Cell Surface / Q000378:metabolism; D014747:Vinblastine / Q000031:analogs & derivatives / Q000097:blood; D014748:Vinca Alkaloids / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D002352:Carrier Proteins; C520389:EC145; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; D014748:Vinca Alkaloids; C055170:4-desacetylvinblastine hydrazide; D014747:Vinblastine; D005492:Folic Acid