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

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.