dihydropyridines and Diarrhea

This is the first clinical study of the MEK1/2 inhibitor AZD8330 (ARRY-424704). This phase I study defined the maximum tolerated dose (MTD) and assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8330 in patients with advanced malignancies.. Patients with refractory cancer or cancer with no standard therapy received either once-daily (OD) or twice-daily (BID) oral AZD8330 on day 1 followed by a 7-day washout period and continuous dosing from day 8. The starting dose was 0.5 mg with dose escalations in subsequent cohorts until a non-tolerated dose was reached.. Eighty-two patients received AZD8330 across 11 cohorts. The most frequent AZD8330-related adverse events were acneiform dermatitis (13/82, 16%), fatigue (11/82, 13%), diarrhoea (11/82, 13%) and vomiting (9/82, 11%). Four patients experienced dose-limiting toxicities: mental status changes (40 mg OD; 2/9 patients and 60 mg OD; 1/3) and rash (20 mg BID; 1/9). The MTD was defined as 20mg BID. AZD8330 exposure increased approximately proportionally with dose across the dose range 0.5-60 mg OD. Dose-dependent modulation of phosphorylated ERK in peripheral blood mononuclear cells (PBMCs) was observed at doses ≥3 mg. One patient had a partial response and thirty-two (39%) had stable disease, with a duration >3 months in 22 patients, assessed by Response Evaluation Criteria in Solid Tumors.. AZD8330 has a manageable toxicity profile at the MTD of 20 mg BID, and target inhibition was confirmed in PBMCs. One patient with malignant melanoma had a partial response.

Topics: Acne Vulgaris; Adolescent; Adult; Area Under Curve; Dermatitis; Diarrhea; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Metabolic Clearance Rate; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Treatment Outcome; Vomiting; Young Adult

Ibrutinib is a recently approved oral anticancer agent with pharmacokinetics that is very sensitive to metabolic inhibition. We report a serious side effect of ibrutinib potentially attributable to interaction with the moderate CYP3A4 inhibitor verapamil.. A patient with mantle cell lymphoma was admitted to our emergency department with severe diarrhoea. During a prescription review, the clinical pharmacist identified a potential drug interaction between ibrutinib and verapamil present in a branded combination product also containing trandolapril. Ibrutinib was discontinued for 5 days, and verapamil was stopped. Lercanidipine 10 mg daily was prescribed as an alternative antihypertensive drug. The patient was discharged after 3 days with symptomatic treatment for his diarrhoea. Three months later, the patient maintained control with ibrutinib and olmesartan, but without verapamil.. This is the first description of a serious side effect of ibrutinib likely due to an interaction with the CYP3A4 inhibitor verapamil. Prescriptions of ibrutinib must be carefully checked to identify possible interactions with CYP3A4 inhibitors and patients monitored accordingly.

Topics: Adenine; Aged; Antihypertensive Agents; Antineoplastic Agents; Cytochrome P-450 CYP3A Inhibitors; Diarrhea; Dihydropyridines; Drug Interactions; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Verapamil

The effects of two dihydropyridine (DHP) calcium channel antagonists, nifedipine and nimodipine, on migrating myoelectric complexes (MMCs) of the small intestine were studied in naive and morphine-dependent rats. In addition, the effects of two other calcium channel antagonists, verapamil and diltiazem, on the MMCs were investigated. Nifedipine (1.0-4.0 mg kg-1 intravenously) or nimodipine (1.0-4.0 mg kg-1 intravenously) had an inhibitory effect on the spontaneously occurring MMCs, whereas verapamil (2.5-5.0 mg kg-1 intravenously) or diltiazem (2.5-5.0 mg kg-1 intravenously) had no effect. Bay K 8644 (0.25 mg kg-1 intravenously), a DHP calcium channel agonist, instantly reversed the inhibition induced by nifedipine or nimodipine. When given alone, Bay K 8644 induced irregular spiking activity. In morphine-dependent rats with regular MMCs naloxone (1.0 mg kg-1 intravenously) induced intense spiking activity and profuse diarrhea. Nifedipine (2.0 and 4.0 mg kg-1 intravenously) and nimodipine (2.0 and 4.0 mg kg-1 intravenously) given before naloxone prevented the intense, abstinence-evoked spiking and associated diarrhea. In healthy volunteers nimodipine at an infusion rate of 2 mg h-1 for 4 h did not inhibit the fasting motility pattern. Our findings indicate that DHP-binding sites are involved in the regulation of MMC in the rat and that drugs acting as antagonists at these sites can be used to suppress morphine withdrawal diarrhea and, tentatively, other functional disorders of the intestine.

Topics: Adult; Animals; Calcium Channel Blockers; Diarrhea; Dihydropyridines; Fasting; Gastrointestinal Motility; Humans; Intestinal Diseases; Intestine, Small; Male; Morphine; Myoelectric Complex, Migrating; Nimodipine; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome