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Population pharmacokinetic analysis of sorafenib in patients with solid tumours

  1. Author:
    Jain, L.
    Woo, S.
    Gardner, E. R.
    Dahut, W. L.
    Kohn, E. C.
    Kummar, S.
    Mould, D. R.
    Giaccone, G.
    Yarchoan, R.
    Venitz, J.
    Figg, W. D.

  2. Author Address

    [Figg, WD] NCI, Med Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA [Jain, L; Woo, S; Figg, WD] NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA [Gardner, ER] SAIC Frederick Inc, NCI Frederick, Clin Pharmacol Program, Frederick, MD 21702 USA [Mould, DR] Project Res Inc, Phoenixville, PA 19460 USA [Yarchoan, R] NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA [Venitz, J; Figg, WD] Virginia Commonwealth Univ, Sch Pharm, Dept Pharmaceut, Richmond, VA 23298 USA;Figg, WD (reprint author), NCI, Med Oncol Branch, CCR, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA;wdfigg@helix.nih.gov
    1. Year: 2011
    2. Date: Aug
  2. Journal: British Journal of Clinical Pharmacology
    1. 72
    2. 2
    3. Pages: 294-305
  4. Type of Article: Article
  5. ISSN: 0306-5251
  1. Abstract:

    AIMS To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib. METHODS PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis. RESULTS A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h(-1) (3.6-22.3 l h(-1)), volume 213 l (50-1000 l), mean absorption transit time 1.98 h (0.5-13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h. CONCLUSIONS Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.

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  2. DOI: 10.1111/j.1365-2125.2011.03963.x
  3. View record in Web of Science®
  4. WOS: 000292606400013

Library Notes

  1. Fiscal Year: FY2010-2011
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