Population pharmacokinetics of CCI-779: correlations to safety and pharmacogenomic responses in patients with advanced renal cancer.
OBJECTIVE
Our objective was to estimate the pharmacokinetic parameters of CCI-779 and its metabolite, sirolimus, and evaluate associations of exposure parameters with safety and clinical activity. Exposure parameters were also correlated with pharmacogenomic responses in peripheral blood mononuclear cells (PBMCs).


METHODS
In this randomized, double-blind, multicenter trial, once-weekly intravenous doses of 25, 75, or 250 mg CCI-779 were administered to patients with advanced renal cancer. Whole blood for CCI-779 and sirolimus concentrations was drawn. Population pharmacokinetic analyses yielded Bayesian-predicted exposure metrics that were correlated with severity and duration of adverse events and survival. PBMC samples taken before and after treatment were examined for pharmacogenomic responses. Ribonucleic acid samples were converted to labeled probes and hybridized to oligonucleotide arrays containing more than 12,600 human sequences.


RESULTS
The final population pharmacokinetic models of CCI-779 and sirolimus included 235 and 305 observations, respectively, from 50 patients. For CCI-779, dose, single versus multiple dose, and body surface area were significant pharmacokinetic covariates. For sirolimus, dose and hematocrit were significant covariates. Age, sex, or race did not influence drug disposition. CCI-779 area under the curve correlated with adverse event severity for thrombocytopenia (P = .007), pruritus (P = .011), and hyperlipemia (P = .040). Exposure (CCI-779 cumulative area under the curve) correlated with a specific subset of gene transcripts in PBMCs following 16 weeks after therapy (P < .001, Spearman correlation).


CONCLUSIONS
Concentrations of CCI-779 and sirolimus were adequately described with a population model incorporating factors for dose, attenuated exposure of multiple doses, body surface area, and hematocrit. Correlations with adverse event severity and duration profiles were provided to aid in the detection of treatment-emergent effects. Pharmacogenomic profiling of PBMCs identified altered ribonucleic acid transcript expression levels that correlate with exposure. These transcripts represent potential biomarkers of CCI-779 exposure in peripheral blood.
Boni
Joseph P
JP
Department of Clinical Pharmacology, Wyeth Research, Collegeville, PA 19426, USA. bonij@wyeth.com
Leister
Cathie
C
Bender
Gregor
G
Fitzpatrick
Virginia
V
Twine
Natalie
N
Stover
Jennifer
J
Dorner
Andrew
A
Immermann
Fred
F
Burczynski
Michael E
ME
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010597:Pharmacogenetics; D012720:Severity of Illness Index; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000145:classification
C401859:temsirolimus; D020123:Sirolimus