aprepitant and Adenocarcinoma

Our knowledge of the major mechanisms underlying the effect of food on drug absorption allows reliable qualitative prediction based on biopharmaceutical properties, which can be assessed during the pre-clinical phase of drug discovery. Furthermore, several recent examples have shown that physiologically based absorption models incorporating biorelevant drug solubility measurements can provide quite accurate quantitative prediction of food effect. However, many molecules currently in development have distinctly sub-optimal biopharmaceutical properties, making the quantitative prediction of food effect for different formulations from in vitro data very challenging. If such drugs reach clinical development and show undesirable variability when dosed with food, improved formulation can help to reduce the food effect and carefully designed in vivo studies in dogs can be a useful guide to clinical formulation development. Even so, such in vivo studies provide limited throughput for screening, and food effects seen in dog cannot always be directly translated to human. This paper describes how physiologically based absorption modeling can play a role in the prediction of food effect by integrating the data generated during pre-clinical and clinical research and development. Such data include physicochemical and in vitro drug properties, biorelevant solubility and dissolution, and in vivo pre-clinical and clinical pharmacokinetic data. Some background to current physiological absorption models of human and dog is given, and refinements to models of in vivo drug solubility and dissolution are described. These are illustrated with examples using GastroPlus to simulate the food effect in dog and human for different formulations of two marketed drugs.

Topics: Adenocarcinoma; Animals; Aprepitant; Cell Line, Tumor; Chemical Precipitation; Chemistry, Pharmaceutical; Colonic Neoplasms; Computer Simulation; Dogs; Eating; Fasting; Female; Food-Drug Interactions; Gastrointestinal Contents; Gastrointestinal Tract; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Models, Biological; Morpholines; Pharmacokinetics; Solubility; Species Specificity; Theophylline

Polypharmacy of elderly oncology patients and fragmented medication management are well-known risk factors for drug-drug interactions (DDIs). These interactions can occur among antineoplastic, ongoing chronic treatment(s) and chemotherapy-associated treatments, like antiemetics. Clinically relevant interactions based on enzyme- or transporter-inhibition phenomena of active drugs can increase the frequency of their DDIs. We describe a strongly suspected elderly cancer patient's DDI between aprepitant and opium powder in the context of an irinotecan-based regimen manifested by nightmares and visual hallucinations. We discuss this DDI's hypothetical pharmacological mechanisms and management.

Topics: Adenocarcinoma; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Arthralgia; Camptothecin; Dreams; Drug Interactions; Fluorouracil; Hallucinations; Humans; Leucovorin; Male; Nausea; Opium; Polypharmacy; Powders; Sigmoid Neoplasms

Topics: Adenocarcinoma; Aprepitant; Drug Interactions; Drug Therapy, Combination; Erlotinib Hydrochloride; Humans; Lung Neoplasms; Middle Aged; Morpholines; Neurokinin-1 Receptor Antagonists; Off-Label Use; Protein Kinase Inhibitors; Pruritus; Quinazolines

A 50-year-old-woman underwent high anterior resection for sigmoid colon adenocarcinoma. Modified oxaliplatin/l / -LV/ 5-FU(mFOLFOX6)was started as adjuvant treatment due to final-stage III b. Granisetron 3 mg and dexamethasone 8 mg for prophylaxis chemotherapy-induced nausea and vomiting (CINV) were administered intravenously 30 min before oxaliplatin administration. Grade 3 delayed CINV was observed at course 4. CINV could not be controlled by any rescue medications. We adopted a neurokinin-1 receptor antagonist (aprepitant) that alleviated the emetic effects of substance P. The oral aprepitant dose was 125 mg on day 1 and 80 mg on days 2 and 3. Afterward, delayed vomiting was completely controlled and chemotherapy could be continued to course 12. Aprepitant is a very active antiemetic drug for the prevention of delayed nausea and vomiting induced by mFOLFOX6 regimen.

Topics: Adenocarcinoma; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Morpholines; Nausea; Organoplatinum Compounds; Sigmoid Neoplasms; Vomiting