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Population pharmacokinetic, pharmacodynamic, and pharmacogenomic analysis of CCI‐779 in patients with advanced renal cell cancer
Author(s) -
Boni J. P.,
Leister C.,
Bender G.,
Fitzpatrick V.,
Twine N.,
Stover J.,
Dorner A.,
Immermann F.,
Burczynski M.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.155
Subject(s) - medicine , pharmacodynamics , pharmacokinetics , pharmacogenomics , population , peripheral blood mononuclear cell , adverse effect , pharmacology , oncology , gastroenterology , biology , in vitro , biochemistry , environmental health
CCI‐779 (CCI) is a novel mTOR kinase inhibitor being developed for treatment of various cancers. In this randomized, double‐blind, multicenter trial, 25, 75, or 250 mg IV CCI was given once weekly to 110 patients with renal cancer and was shown to be clinically active (Atkins et al. Proc ASCO 22:201,2003). Herein, the population pharmacokinetics (PPK) of CCI and sirolimus (SIR) were evaluated for dynamic relationship to safety, activity, and pharmacogenomic responses. With correlation analysis, we explored the relationship between gene expression changes in peripheral blood mononuclear cells (PBMC) and cumulative (∑)AUC and AUC sum (CCI+SIR) at 8 and 16 weeks of treatment. Exposures were related to adverse events (AE) and survival. Final PPK models of CCI and SIR included 235 and 305 observations, respectively, from 50 patients. CCI clearance = 1.39*(1+DNUM*0.103)*DOSE 0.551 *BSA 1.28 in which DNUM = 0/1 for single/multiple dose and BSA = body surface area. Age, sex, race, or renal risk factor did not affect disposition. AE severity correlated to AUC sum for thrombocytopenia, pruritis, and hyperlipemia (p < 0.05). Average AUC or AUC sum were not related to survival differences. At 16 weeks, individual ∑AUC sum was significantly correlated with change from baseline gene expression levels for 19 transcripts. Improved survival in the absence of an exposure relationship suggests that test doses are at or near a plateau of maximum response. A transcript subset from PBMCs significantly correlated with ∑AUC sum and may qualify as biomarkers of CCI exposure. Clinical Pharmacology & Therapeutics (2004) 75 , P41–P41; doi: 10.1016/j.clpt.2003.11.155