Complementary Pharmacokinetic Profiles of Netupitant and Palonosetron Support the Rationale for Their Oral Fixed Combination for the Prevention of Chemotherapy‐Induced Nausea and Vomiting

Abstract

NEPA is the first fixed‐combination antiemetic composed of the neurokinin‐1 receptor antagonist netupitant (netupitant; 300 mg) and the 5‐hydroxytryptamine‐3 receptor antagonist palonosetron (palonosetron; 0.50 mg). This study evaluated the pharmacokinetic profiles of netupitant and palonosetron. The pharmacokinetic profiles of both drugs were summarized using data from phase 1‐3 clinical trials. netupitant and palonosetron have high absolute bioavailability (63%‐87% and 97%, respectively). Their overall systemic exposures and maximum plasma concentrations are similar under fed and fasting conditions. netupitant binds to plasma proteins in a high degree (>99%), whereas palonosetron binds to a low extent (62%). Both drugs have large volumes of distribution (cancer patients: 1656‐2257 L and 483‐679 L, respectively). netupitant is metabolized by cytochrome P450 3A4 to 3 major pharmacologically active metabolites (M1, M2, and M3). palonosetron is metabolized by cytochrome P450 2D6 to 2 major substantially inactive metabolites (M4 and M9). Both drugs have similar intermediate‐to‐low systemic clearances and long half‐lives (cancer patients: netupitant, 19.5‐20.8 L/h and 56.0‐93.8 hours; palonosetron: 7.0‐11.3 L/h and 43.8‐65.7 hours, respectively). netupitant and its metabolites are eliminated via the hepatic/biliary route (87% of the administered dose), whereas palonosetron and its metabolites are mainly eliminated via the kidneys (85%‐93%). Altogether, these data explain the lack of pharmacokinetic interactions between netupitant and palonosetron at absorption, binding, metabolic, or excretory level, thus highlighting their compatibility as the oral fixed combination NEPA, with administration convenience that may reduce dosing mistakes and increase treatment compliance.

Discovery of COVID-19 Inhibitors Targeting the SARS-CoV-2 Nsp13 Helicase

“…As expected, the Vina docking scores for ATP in the apo-models were significantly worse (−7.1, −7.8, −8.1, −7.1) than the score for that of the complex-based target (−9.3), indicating that the apo-models were not an ATP-binding competent. The top-scoring hits in these apo-Nsp13 ATP-binding sites ( Figure 3 , Table S5 ) include Cepharanthine, 16 Cefoperazone, 17 Dihydroergotamine, 18 Cefpiramide, 19 Ergoloid (Dihydroergocristine (DHEC)), 20 Ergotamine, 21 Netupitant, 22 Dpnh (NADH), Lifitegrast, 23 Nilotinib, 24 and Tubocurarin. 25 The top-scoring hit Cepharanthine (CEP) is an anti-inflammatory drug used in Japan since the 1950s to treat a number of acute and chronic diseases, including the treatment of leukopenia and alopecia.…”

Discovery of COVID-19 Inhibitors Targeting the SARS-CoV2 Nsp13 Helicase

“…The four models of the apo-Nsp13 helicase provided possible targets of the dynamic helicase. The top-scoring hits in these apo-Nsp13 ATP binding sites ( Figure 3 , Table S3 ) include: Cepharanthine 15 , Cefoperazone, 16 Dihydroergotamine, 17 Cefpiramide, 18 Ergoloid (Dihydroergocristine (DHEC)), 19 Ergotamine, 20 Netupitant, 21 Dpnh (NADH), Lifitegrast, 22 Nilotinib, 23 and Tubocurarin. 24 The top-scoring hit Cepharanthine (CEP) is an anti-inflammatory drug used in Japan since the 1950s to treat a number of acute and chronic diseases, including the treatment of leukopenia and alopecia.…”

Preventing Chemotherapy-Induced Nausea and Vomiting with Netupitant/Palonosetron, the First Fixed Combination Antiemetic: Current and Future Perspective

“…Netupitant & palonosetron -complementary PK/PD profiles Netupitant and palonosetron show no changes in their PK parameters on co-administration as compared with the single agents. Furthermore, both compounds show complementary PK profiles, supporting their combination in NEPA: netupitant and palonosetron present high absolute bioavailability of 63-87% and 97% [79], respectively, suggesting they do not experience clinically significant interactions with intestinal efflux transporters that might affect their absorption or excretion; palonosetron presents low binding affinity to plasma proteins, making it unlikely for palonosetron to displace protein-bound netupitant with potential clinical consequences; the metabolism of netupitant and palonosetron is mediated by different CYP450 enzymes, thus no clinically significant drug-drug interactions should be expected on co-administration. Additionally, their complementary PD properties, such as prolonged occupancy of their respective receptors, and their synergistic effects on NK 1 receptor pathway inhibition [26] provide further support for their combination.…”