A population pharmacokinetic meta-analysis of custirsen, an antisense oligonucleotide, in oncology patients and healthy subjects.

Abstract

AIMS:

Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide that reduces clusterin production, is under investigation with chemotherapy in prostate and lung cancer. This meta-analysis evaluated the population pharmacokinetics (PK) of custirsen in cancer patients and healthy subjects.

METHODS:

The population PK analysis used custirsen plasma concentrations from five Phase 1 studies, one Phase 1/2 study, and one Phase 3 study in two stages. Cancer patients received multiple doses of custirsen (40-640 mg intravenously over 120 min) with chemotherapy; healthy subjects received single or multiple doses (320-640 mg). An interim population PK model was developed using a nonlinear mixed-effect approach incorporating data from four Phase 1 or 1/2 studies, followed by model refinement and inclusion of two Phase 1 and one Phase 3 studies.

RESULTS:

The final model was developed with 5588 concentrations from 631 subjects with doses of 160-640 mg. Custirsen PK was adequately described by a three-compartment model with first-order elimination. For a representative 66-year-old individual with body weight 82 kg and serum creatinine level 0.933 mg dl-1 , the estimated typical (95% CI) parameter values were clearance (CL) = 2.36 (2.30-2.42) l h-1 , central volume of distribution (V1 ) = 6.08 (5.93-6.23) l, peripheral volume of distribution (V2 ) = 1.13 (1.01-1.25) l, volume of the second peripheral compartment (V3 ) = 15.8 (14.6-17.0) l, inter-compartmental clearance Q2 = 0.0755 (0.0689-0.0821) l h-1 , and Q3 = 0.0573 (0.0532-0.0614) l h-1 . Age, weight and serum creatinine were predictors of CL; age was a predictor of Q3 .

CONCLUSION:

A population PK model for custirsen was successfully developed in cancer patients and healthy subjects, including covariates contributing to variability in custirsen PK.

• Authors: Alena Y Edwards, Anna Elgart, Colm Farrell, Ofra Barnett-Griness, Laura Rabinovich-Guilatt, Ofer Spiegelstein
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 83 Issue 9 Pg. 1932-1943 (Sep 2017) ISSN: 1365-2125 [Electronic] England
• PMID: 28294391 (Publication Type: Journal Article, Meta-Analysis)
• Copyright: © 2017 The British Pharmacological Society.

Chemical References

• OGX-011
• Oligonucleotides, Antisense
• Thionucleotides

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Clinical Trials as Topic (statistics & numerical data)
• Dose-Response Relationship, Drug
• Female
• Healthy Volunteers
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Neoplasms (blood)
• Nonlinear Dynamics
• Oligonucleotides, Antisense (administration & dosage, blood, pharmacokinetics)
• Thionucleotides (administration & dosage, blood, pharmacokinetics)
• Young Adult