Population pharmacokinetic model of PI-88, a heparanase inhibitor.

Abstract:

PURPOSE:The aim of this study was to investigate typical population pharmacokinetic (PK) parameters, potential covariates, and interindividual and residual variabilities of PI-88, a heparanase endoglycosidase enzyme inhibitor being developed for the treatment of cancer. METHODS:A population PK model of PI-88 was developed and evaluated using nonlinear mixed effects modeling (NONMEM). Plasma concentration versus time data was obtained from a total of 76 subjects that participated in phase I trials of PI-88 delivered subcutaneously (SC) at doses ranging from 80 to 315 mg. Overall, the PK effects of 12 clinical covariates were evaluated, including weight, age, creatinine clearance, body surface area, body mass index, sex, cancer (vs. healthy subject), docetaxel coadministration, prior chemotherapy, prior investigational therapy, prior radiotherapy and prior surgery. RESULTS:Population PK analysis of the data-set showed that apparent clearance (CL/F) and apparent volume of distribution (V/F) of PI-88 were positively correlated with body surface area and the absorption rate constant (KA) was positively correlated with body mass index. In addition, CL/F was found to be significantly lower in patients with malignancies versus healthy subjects. By incorporating these covariates into the PK parameter equations, the interindividual variability of CL/F was reduced from 30.6 to 20.2% (decrease of 34%), V/F was reduced from 31.4 to 20.7% (decrease of 34.1%) and KA was reduced from 52.6 to 46.2% (decrease of 12.2%). CONCLUSIONS:This population PK model indicates that the PK variability of PI-88 can be significantly reduced by taking BSA into account when dosing this drug SC.

authors

Hudachek SF,Eckhardt SG,Hicks B,Gustafson DL

doi

10.1007/s00280-009-1080-z

subject

Has Abstract

pub_date

2010-03-01 00:00:00

pages

743-53

issue

4

eissn

0344-5704

issn

1432-0843

journal_volume

65

pub_type

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