Yi Ling Teo

Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: A meta-analysis

INTRODUCTION Although existing evidence from clinical trials has demonstrated manifestation of hepatic adverse events (AEs) with the use of tyrosine kinase inhibitors (TKIs), overall risks have yet to be reported. Thus we conducted a meta-analysis to determine the risk of hepatotoxicity associated with the use of TKIs, by comparing the occurrence of hepatotoxicity of the TKI arms against that of comparison arms. METHODS A comprehensive literature search of randomized control trials involving TKIs was performed. Only randomized, double-blind and placebo-controlled phase 2 or phase 3 human trials were included. The included studies must involve the comparison of a TKI against placebo, or the comparison of TKI with chemotherapy agent against placebo with the same chemotherapy agent. RESULTS Twelve articles were included in the analysis. There was a significant overall increase in the odds of developing high-grade (grade 3 or above) hepatotoxicity with the use of TKIs compared to the control arms (Pooled OR 4.35, 95% CI 2.96-6.39). The odds of developing all-types all-grades (Pooled OR 2.42, 95% CI 1.52-3.85) and high-grade hepatotoxicity due to elevation in alanine transaminase (Pooled OR 5.22, 95% CI 2.88-9.46), aspartate transaminase (Pooled OR 6.15, 95% CI 3.09-12.25) and total bilirubin (Pooled OR 1.76, 95% CI 0.59-5.24) was higher with the use of TKI than compared to the controls. DISCUSSION This is the first meta-analysis to demonstrate a significantly increased risk of hepatic AEs associated with TKIs use. Clinicians should be aware of this risk and provide close monitoring in patients receiving these therapies.

Metabolism‐related pharmacokinetic drug−drug interactions with tyrosine kinase inhibitors: current understanding, challenges and recommendations

Drug−drug interactions (DDIs) occur when a patients response to the drug is modified by administration or co‐exposure to another drug. The main cytochrome P450 (CYP) enzyme, CYP3A4, is implicated in the metabolism of almost all of the tyrosine kinase inhibitors (TKIs). Therefore, there is a substantial potential for interaction between TKIs and other drugs that modulate the activity of this metabolic pathway. Cancer patients are susceptible to DDIs as they receive many medications, either for supportive care or for treatment of toxicity. Differences in DDI outcomes are generally negligible because of the wide therapeutic window of common drugs. However for anticancer agents, serious clinical consequences may occur from small changes in drug metabolism and pharmacokinetics. Therefore, the objective of this review is to highlight the current understanding of DDIs among TKIs, with a focus on metabolism, as well as to identify challenges in the prediction of DDIs and provide recommendations.

Formation of reactive metabolites and management of tyrosine kinase inhibitor-induced hepatotoxicity: a literature review

Introduction: Existing clinical evidence indicates that many tyrosine kinase inhibitors (TKIs) are associated with idiosyncratic hepatotoxicity. TKIs possess risk factors for developing drug-induced liver injury such as their high daily dose, being substrates of P450 enzyme and being involved in significant hepatic metabolism. Several successful strategies to overcome TKI-induced hepatotoxicity include: switching to an alternative TKI with a similar mechanism of action, using an alternative dose and introduction of corticosteroids for treatment and prevention of hepatotoxicity. Areas covered: This review highlights the formation of reactive metabolites and how this leads to toxicity, as well as the current clinical management of TKI-induced hepatotoxicity. Expert opinion: Numerous events need to occur in an individual patient before converging into an idiosyncratic hepatotoxicity episode. Of these, the formation of a reactive intermediate through metabolism appears to be the prerequisite. This critical event involves an intricate chemico-biological interaction where, on one hand, drug-specific characteristics create the propensity for occurrence and, on the other hand, patient risk factors determine the individuality of response. With improved understanding of the mechanisms leading to adverse events, several strategies are being adopted to prevent and treat TKI-induced hepatotoxicity. However, further evidence is required before they can be recommended to larger populations.

Effect of the CYP3A5 and ABCB1 genotype on exposure, clinical response and manifestation of toxicities from sunitinib in Asian patients

The objective of this study was to determine the effect of the CYP3A5 and ATP binding cassette subfamily B member 1 (ABCB1) single-nucleotide polymorphisms on the disposition of sunitinib and SU12662, on clinical response, and on the manifestation of toxicities in Asian metastatic renal cell carcinoma patients. At week 4 of each treatment cycle, toxicities and plasma steady-state levels were assessed. Clinical response was assessed after two cycles. Genotyping was performed by using the PCR restriction fragment length polymorphism method. The CC genotype for ABCB1 was associated with a higher sunitinib exposure (76.81 vs 56.55 ng ml−1, P=0.03), higher risk of all-grade rash (RR 3.00, 95% CI 1.17–7.67) and mucositis (RR 1.60, 95% CI 1.10–2.34) and disease progression than compared with the CT/TT genotype. There was a lack of association observed between the CYP3A5 polymorphism and exposure, response and toxicities. The polymorphism of ABCB1 (C3435T) has an important role in the manifestation of toxicities and drug exposure, but not polymorphism of CYP3A5.

A systematic review of patient-reported outcome instruments of dermatologic adverse events associated with targeted cancer therapies

PurposeDermatologic adverse events (dAEs) in cancer treatment are frequent with the use of targeted therapies. These dAEs have been shown to have significant impact on health-related quality of life (HRQoL). While standardized assessment tools have been developed for physicians to assess severity of dAEs, there is a discord between objective and subjective measures. The identification of patient-reported outcome (PRO) instruments useful in the context of targeted cancer therapies is therefore important in both the clinical and research settings for the overall evaluation of dAEs and their impact on HRQoL.MethodsA comprehensive, systematic literature search of published articles was conducted by two independent reviewers in order to identify PRO instruments previously utilized in patient populations with dAEs from targeted cancer therapies. The identified PRO instruments were studied to determine which HRQoL issues relevant to dAEs were addressed, as well as the process of development and validation of these instruments.ResultsThirteen articles identifying six PRO instruments met the inclusion criteria. Four instruments were general dermatology (Skindex-16©, Skindex-29©, Dermatology Life Quality Index (DLQI), and DIELH-24) and two were symptom-specific (functional assessment of cancer therapy-epidermal growth factor receptor inhibitor-18 (FACT-EGFRI-18) and hand-foot syndrome 14 (HFS-14)).ConclusionsWhile there are several PRO instruments that have been tested in the context of targeted cancer therapy, additional work is needed to develop new instruments and to further validate the instruments identified in this study in patients receiving targeted therapies.

Association between clinical response and toxicities with drug exposure in an alternative dosing regimen of sunitinib.

439 Background: An alternative dosing (AD) regimen of 37.5mg daily in repeated 4-weeks on, 2-weeks off cycle has been proposed to ameliorate frequent dose modifications due to toxicities as observed with the approved dosing regimen of sunitinib for metastatic renal cell carcinoma (mRCC). This study aims to determine the effect of drug exposure (sunitinib and active metabolite, SU12662) on clinical response and toxicities in patients receiving this AD regimen. Methods: All mRCC patients initiating AD sunitinib were invited to participate in this study. In week 4 of each cycle, toxicities were assessed and plasma steady-state levels (Cmax) were quantified using high-performance liquid chromatography. Clinical response was assessed after 2 treatment cycles; and was used with drug exposure and toxicities data for dose adjustments. Results: 36 patients with a mean age of 59.1 ± 10.1 years were recruited. Majority were males (81%) and Chinese (86%). Among the 24 and 16 analyzable cases for cycle 1 and 2, median...

Supportive Care in Cancer Patients: Current Challenges and Opportunities

According to Multinational Association of Supportive Care in Cancer (MASCC), supportive care in cancer is the prevention and management of the adverse effects of cancer and its treatment [1]. This includes the management of physical and psychological symptoms and side effects across the continuum of the cancer experience from diagnosis through anti-cancer treatment to post-treatment care. With the incorporation of supportive care in contemporary cancer treatment over the past two decades, there is a drastic reduction of occurrence of severe toxicities associated with cancer treatment, as well as improvement of patients’ quality of life. For example, routine prophylaxis with anti-emetics prior to chemotherapy has greatly reduced the occurrence of chemotherapy-induced nausea and vomiting [2]. Nonetheless, a number of chemotherapy-induced toxicities associated with anti-cancer treatment are still poorly managed in today’s clinical practice due to the lack of research in those areas.