cp-724714 and Chemical-and-Drug-Induced-Liver-Injury

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.. 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).. 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%).. 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.

Topics: Adult; Aged; Algorithms; Antineoplastic Agents; Area Under Curve; Breast Neoplasms; Chemical and Drug Induced Liver Injury; Chromatography, Liquid; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Half-Life; Humans; Liver Function Tests; Middle Aged; Neoplasm Metastasis; Neoplasms; Protein-Tyrosine Kinases; Quinazolines; Receptor, ErbB-2; Tandem Mass Spectrometry

Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs.. These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Chemical and Drug Induced Liver Injury; Humans; Male; Mitochondria, Liver; Rats; Rats, Sprague-Dawley; Severity of Illness Index

CP-724,714, a potent and selective orally active HER2 tyrosine kinase inhibitor, was discontinued from clinical development due to unexpected hepatotoxicity in cancer patients. Based on the clinical manifestation of the toxicity, CP-724,714 likely exerted its hepatotoxicity via both hepatocellular injury and hepatobiliary cholestatic mechanisms. The direct cytotoxic effect, hepatobiliary disposition of CP-724,714, and its inhibition of active canalicular transport of bile constituents were evaluated in established human hepatocyte models and in vitro transporter systems. CP-724,714 exhibited direct cytotoxicity using human hepatocyte imaging assay technology with mitochondria identified as a candidate organelle for its off-target toxicity. Additionally, CP-724,714 was rapidly taken up into human hepatocytes, partially via an active transport process, with an uptake clearance approximately fourfold higher than efflux clearance. The major human hepatic uptake transporter, OATP1B1, and efflux transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein, were involved in hepatobiliary clearance of CP-724,714. Furthermore, CP-724,714 displayed a concentration-dependent inhibition of cholyl-lysyl fluorescein and taurocholate (TC) efflux into canaliculi in cryopreserved and fresh cultured human hepatocytes, respectively. Likewise, CP-724,714 inhibited TC transport in membrane vesicles expressing human bile salt export pump with an IC(50) of 16 microM. Finally, CP-724,714 inhibited the major efflux transporter in bile canaliculi, MDR1, with an IC(50) of approximately 28 microM. These results suggest that inhibition of hepatic efflux transporters contributed to hepatic accumulation of drug and bile constituents leading to hepatocellular injury and hepatobiliary cholestasis. This study provides likely explanations for clinically observed adverse liver effects of CP-724,714.

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Bile; Bile Acids and Salts; Calcium; Carrier Proteins; Cells, Cultured; Chemical and Drug Induced Liver Injury; Enzyme Inhibitors; Fluoresceins; Hepatocytes; Humans; Liver; Liver-Specific Organic Anion Transporter 1; Membrane Potentials; Mitochondrial Membranes; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Quinazolines; Receptor, ErbB-2