ABSTRACT
Antiemetic treatment compliance is important to prevent chemotherapy-induced nausea and vomiting, a feared chemotherapy side effect. NEPA, a new oral fixed combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron, a second-generation 5-HT3 RA, targets dual antiemetic pathways with a single dose. This study investigated the effect of food intake and age on NEPA pharmacokinetics (PK) and safety. In this open-label, single-center, randomized, phase 1 study, 24 adults (18-45 years) received NEPA in a fed or fasted state during the first treatment period and in the alternative state in the next treatment period. Twelve elderly subjects (≥65 years) received NEPA in a fasted state. Blood samples were taken for netupitant and palonosetron PK analysis. In the fed condition, netupitant plasma exposure increased, whereas palonosetron PK parameters were not affected. Furthermore, elderly subjects showed increased netupitant and palonosetron exposure compared with adults. All adverse events were mild/moderate, with constipation and headache the most common. Although food intake and age altered NEPA PK, dose adjustments were not needed, as netupitant and palonosetron exposure increases did not lead to safety concerns in healthy subjects.
Subject(s)
Antiemetics/administration & dosage , Antiemetics/pharmacokinetics , Food-Drug Interactions , Isoquinolines/administration & dosage , Isoquinolines/pharmacokinetics , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Quinuclidines/administration & dosage , Quinuclidines/pharmacokinetics , Administration, Oral , Adult , Age Factors , Aged , Antiemetics/adverse effects , Antiemetics/blood , Cross-Over Studies , Drug Combinations , Fasting/blood , Female , Germany , Healthy Volunteers , Humans , Isoquinolines/adverse effects , Isoquinolines/blood , Male , Middle Aged , Postprandial Period , Pyridines/adverse effects , Pyridines/blood , Quinuclidines/adverse effects , Quinuclidines/blood , Young AdultABSTRACT
Recent guidelines on bioanalytical method validation have recommended to investigate matrix effects in special matrices such as hemolytic and hyperlipidemic plasma. However, these guidelines were not clear on how to implement these recommendations. The European Bioanalysis Forum has discussed this topic in depth and has asked for feedback from member companies. Those discussions have resulted in more specific guidance on how to define hemolytic and hyperlipidemic plasma, how to validate bioanalytical methods for these matrices and how to deal with hemolytic and hyperlipidemic study samples. These recommendations are presented in this manuscript.
