British Journal of Clinical Pharmacology
British Journal of Clinical Pharmacology
5 years ago

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

Colm Farrell, Ofra Barnett-Griness, Anna Elgart, Laura Rabinovich-Guilatt, Ofer Spiegelstein, Alena Y. Edwards
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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bcp.13287

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