Managing Drug Interactions With Oral Anticancer Treatments.

The use of oral anticancer treatments is widespread and vital to modern cancer treatment. Novel oral chemotherapy and targeted therapy treatments continue to receive US Food and Drug Administration approval every year, making knowledge of these agents a necessity for practitioners working in oncology. Many oral anticancer agents are prone to drug interactions that can contribute to adverse effects and decrease therapy efficacy. Potential drug-drug interactions include (1) interactions with CYP3A4 inhibitors and inducers, (2) interactions related to gastric acid suppression, (3) interactions related to prolongation of the cardiac QT interval, (4) interactions related to anticoagulant medications, and (5) drug-food and drug-herb interactions. Identifying potential drug interactions and appropriately managing them is key to preventing adverse effects and ensuring maximum efficacy while on oral anticancer therapy. Management of adverse effects increases patient compliance, ensures medication safety, and allows patients to remain on therapy. This article discusses the mechanisms of interactions and types of interacting medications. Specific recommendations are discussed.

Correction: Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.

[This corrects the article DOI: 10.1371/journal.pone.0164646.].

Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.

The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773.

Improving adherence to oral cancer therapy in clinical practice.

Adherence to oral chemotherapy regimens maximizes their effectiveness and minimizes any potential toxicities. Factors specifically related to the treatment, patient, and health care provider may influence medication adherence. Treatment-related factors include the complexity of the regimen, the cost of therapy, the possibility of side effects, and the delay in treatment benefits. Meanwhile, patients may not have an adequate support system or an understanding of the need for the medication, and providers may not fully succeed in communicating the importance of adherence and the types of side effects that may occur. Nonadherence may lead to an increased risk of toxicity, decreased effectiveness, and increased utilization of health care resources. Although various methods for measuring adherence are available, self-reporting is the most widely used. Studies describing adherence in a broad range of cancers are reviewed. Treatment of chronic myeloid leukemia has been revolutionized by the development of oral tyrosine kinase inhibitors that are highly effective in managing the disease when taken consistently. However, nonadherence is relatively common and can lead to reduced rates of response and increased medical costs. Similar effects of nonadherence on outcome and cost have also been observed in patients with various other hematologic malignancies and solid tumors. Interventions to improve adherence to oral chemotherapy regimens include communication about the importance of adherence and the potential consequences of nonadherence, simplification of the patient's medication schedule (if possible), and inclusion of a caregiver or family member in the conversation. Written materials should always be provided to accompany verbal instructions. This review summarizes factors influencing medication adherence, impact of nonadherence on patient outcomes, methods for measuring adherence, previous studies of nonadherence in patients with cancer, common barriers to access, and interventions to improve adherence in the community setting.

Chemotherapy-induced nausea and vomiting.

Chemotherapy-induced nausea and vomiting (CINV) affects many cancer patients and has a great influence on quality of life. CINV involves coordination of several organs of the gastrointestinal tract, the peripheral and central nervous systems. Many neurotransmitters are involved in this process, and the predominant receptors are serotonin, neurokinin-1 and dopamine receptors. Risk factors for CINV include patient gender and age, past history of CINV, plus the emetogenicity and administration schedule of chemotherapy. Recommended antiemetic regimens for highly emetogenic chemotherapy and moderately emetogenic chemotherapy with a high risk of delayed CINV include a serotonin antagonist, dexamethasone and aprepitant. Other moderately emetogenic chemotherapy requires a serotonin antagonist and dexamethasone. Medications for breakthrough symptoms include dopamine antagonists, lorazepam, metoclopramide, haloperidol, droperidol and other agents. Options for treatment of refractory CINV include olanzapine, dronabinol, nabilone, gabapentin. New evidence from non-controlled studies supports the use of olanzapine, casopitant and gabapentin in controlling the symptoms of CINV.