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Pharmacokinetics of a HER2 tyrosine kinase inhibitor CP-724,714 in patients with advanced malignant HER2 positive solid tumors: correlations with clinical characteristics and safety.

AbstractPURPOSE:
CP-724,714 is an orally available, small molecule, potent HER-2 tyrosine kinase inhibitor under development for the treatment of advanced HER2-overexpressing cancers. In this study, the influence of baseline clinical characteristics and pathophysiological variables on the pharmacokinetics (PK) of CP-724,714, and the correlation between PK exposure and safety were examined in patients treated in the First-in-Human trial. PK and safety were also simulated for a Phase 2 trial at the recommended Phase 2 dose (RP2D) to assess if the simulated PK exposures of CP-724,714 covered the preclinically predicted efficacious concentrations, and if the predicted incidence of hepatic toxicities (>or=CTC grade 3) was acceptable.
METHODS:
Patients (n = 30) with advanced malignant HER2 positive solid tumors were enrolled in this open label dose-escalation study, and treated with daily oral dosing of CP-724,714 in 21-day cycles at the following dose levels: 250 mg QD, 250 mg BID, 400 mg BID, and 250 mg TID. PK parameter values were estimated using noncompartmental techniques. PK exposure parameters were correlated with the baseline pathophysiological variables, clinical characteristics, and safety. The simulations of PK exposures and the incidence of >or=grade 3 liver toxicity at the recommended Phase 2 dose were performed by nonparametric bootstrap (n = 1,000).
RESULTS:
C (max) and AUC increased in an approximate dose proportional manner. The terminal t (1/2) was approximately 4.5 h, and was constant across the dose range from 250 to 400 mg. There was some accumulation with BID and TID dosing with a mean AUC accumulation ratio approximately 1.2-1.5, consistent with the t (1/2). Inter-patient variability in PK parameters was 31-65%, resulting in a considerable overlap of systemic exposure parameters (C (max) and AUC) at higher doses (i.e., 250 mg TID and 400 mg BID), as expected for the narrow dose range. Significant correlations were observed for body size and oral clearance (CL/F) (r = 0.574, P = 0.001) and oral steady-state volume of distribution (V (dss)/F) (r = 0.669, P = 0.0001). The most frequently encountered toxicities were elevated ALT and AST, hyperbilirubinemia, rash, asthenia, and nausea/vomiting (N/V). The steady-state AUC0-24 h was significantly correlated with the elevation of total bilirubin (r = 0.670, P = 0.001), ALT (r = 0.548, P = 0.002), and AST (r = 0.461, P = 0.010). The simulation of the Phase 2 trial at 250 mg BID predicted that the 95% confidence interval of the simulated mean concentrations of CP-724,714 were above the preclinically predicted efficacious concentrations throughout the majority of the dosing interval. The probability for >or=33% incidence of grade 3 or greater elevations of liver function test (LFT) was low (1.1%).
CONCLUSIONS:
CP-724,714 demonstrates linear single-dose and multiple-dose PK. Both CL/F and V (dss)/F correlate with body size. Elevations of ALT, AST, and total bilirubin positively correlate with the steady-state AUC0-24 h. The Phase 2 trial simulation suggests that CP-724,714 will be well tolerated and that PK exposures will exceed the preclinically predicted efficacious level at the recommended Phase 2 dose (250 mg BID), supporting further evaluation of CP-724,714 in the Phase 2 trial.
AuthorsFeng Guo, Stephen P Letrent, Pamela N Munster, Carolyn D Britten, Karen Gelmon, Anthony W Tolcher, Amarnath Sharma
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 62 Issue 1 Pg. 97-109 (Jun 2008) ISSN: 0344-5704 [Print] Germany
PMID17805538 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study)
Chemical References
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  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Quinazolines
  • ERBB2 protein, human
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-2
Topics
  • Adult
  • Aged
  • Algorithms
  • Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
  • Area Under Curve
  • Breast Neoplasms (drug therapy)
  • Chemical and Drug Induced Liver Injury (epidemiology, pathology)
  • Chromatography, Liquid
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
  • Female
  • Half-Life
  • Humans
  • Liver Function Tests
  • Middle Aged
  • Neoplasm Metastasis (drug therapy)
  • Neoplasms (drug therapy, genetics)
  • Protein-Tyrosine Kinases (antagonists & inhibitors, genetics)
  • Quinazolines (adverse effects, pharmacokinetics, therapeutic use)
  • Receptor, ErbB-2 (antagonists & inhibitors, genetics)
  • Tandem Mass Spectrometry

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