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Purpose: Although several studies have examined tyrosine kinase inhibitor (TKI)-induced hepatotoxicity, the majority of patients in those studies displayed low-grade (grade I–II) hepatotoxicity. The purpose of this study was to investigate factors affecting high-grade (grade III–IV) hepatotoxicity of TKIs. Methods: This multi-center, retrospective study used individual patient data from five studies that examined factors affecting hepatotoxicity by TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib). Odds ratio (OR) and adjusted OR (AOR) were estimated from univariate and multivariate analyses, respectively. Results: Data from 1279 patients treated with TKIs were analyzed. The rate of patients who experienced high-grade hepatotoxicity after TKI administration was 5.5%. In multivariable analysis, H2 blockers and CYP3A4 inducers increased high-grade hepatotoxicity 2.2- (95% CI 1.255–3.944) and 3.3-fold (95% CI 1.260–8.698), respectively. Patients with liver metastasis revealed a 3.4-fold (95% CI 1.561–7.466) higher risk of high-grade hepatotoxicity. Among underlying malignancies, pancreatic cancer and other cancers including acute lymphoblastic leukemia increased the risk of high-grade hepatotoxicity by 2.6- and 24.3-fold, respectively, whereas breast cancer decreased the risk (AOR 0.3, 95% CI 0.106–0.852), compared to non-small cell lung cancer. In patients who administrated TKIs which form reactive metabolites, use of CYP3A4 inducers and liver metastasis increased incidence of high-grade hepatotoxicity by 3.0- and 2.3-fold, respectively. In patients with EGFR mutation, exon 19 deletion and use of proton pump inhibitors were risk factors for high-grade hepatotoxicity in addition to liver metastasis and use of H2 blockers. Conclusion: The use of H2 blockers, presence of liver metastasis, and CYP3A4 inducers were associated with high-grade hepatotoxicity of TKIs. In subgroup analyses, presence of exon 19 deletion, and/or proton pump inhibitors, was additional risk factors for high-grade hepatotoxicity in special patients and use of specific TKIs. Close liver function monitoring is recommended, especially in patients with liver metastasis or using H2 blockers or CYP3A4 inducers. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the effectiveness of pharmacist intervention in reducing and preventing prescribing errors of investigational drugs for cancer patients. Materials and methods: A retrospective study was conducted during two periods: a baseline period from December 2015 to June 2016 and an intervention period from July 2016 to February 2017. The investigational drug service (IDS) pharmacists performed active interventions during the intervention period. Results: Among 12,387 investigational drug orders, 395 (6.1%) prescribing errors were detected in 6477 orders at the baseline period, and 278 errors (4.7%) were detected in 5,910 orders at the intervention period. To identify factors that affect prescribing errors, three models were constructed for the multivariate analysis. Among factors affecting prescribing errors, sponsor initiated trial (SIT) was the strongest factor (AOR: 4.16, 95% CI: 3.31–5.23). Pharmacist intervention reduced prescribing errors by at least 25% in all constructed models after adjusting for confounding variables. Prescribing errors were 1.3 times higher when dealing with intravenous medications than when dealing with oral medications. There were 60% fewer prescribing errors in the blinded study than in the open study. SIT and multi-center/multi-nation studies had 4.2 and 2.4 times more frequent prescribing errors than in investigator-initiated trials (IIT) and single-center/single-nation studies, respectively. Fewer errors occurred in phase 2 and trials covering both phase 1 and phase 2 (phase 1/2) than in phase 3 trials. Conclusions: The IDS pharmacist intervention in cancer clinical trials was associated with significant reductions in prescribing errors and may lead to increased medication safety. [ABSTRACT FROM AUTHOR]