In this study, the oseltamivir phosphate for suspension (Oselavir®) produced by Hetero Labs Limited was compared with the originator TAMIFLU® to evaluate the absorption rate and degree of absorption in healthy humans, and to investigate the human bioequivalence of the two drugs. The difference between the test product Oselavir® and the reference product TAMIFLU® under fasting and fed conditio ns in the pharmacokinetic parameters between was not significant, which was similar to the results of previous studies [10, 11]. The Tmax of oseltamivir of reference product and test product in the fasting group were 1.50 h and 1.25 h, respectively, and t1/2 were 3.34 h (65.81% CV) and 3.67 h (58.52% CV), respectively; the Tmax of oseltamivir carboxylate were both 5.00 h, and t1/2 were 7.05 h (16.70% CV) and 6.85 h (14.31% CV), respectively. The Tmax of oseltamivir of reference product and test product in the fed group were both 1.25 h, and t1/2 were 6.18 h (88.47% CV) and 7.23 h (88.69% CV), respectively; the Tmax of oseltamivir carboxylate were 6.00 h and 5.00 h, respectively, and t1/2 were 7.88 h (28.04% CV) and 8.28 h (23.09% CV), respectively. The 90% CIs for the geometrically adjusted mean ratios of Cmax, AUC0 − t, and AUC0−∞ of oseltamivir phosphate under fasting and fed conditions were 92.39–106.50%, 94.26-100.67%, 94.32-100.89%, and 93.61-105.83%, 95.64-100.19%, 96.06-102.66%, respectively, all within the range of 80.00-125.00%, which met the criteria for determining bioequivalence, and both were bioequivalent when administered under fasting and fed conditions. Therefore, food had no effect on the pharmacokinetics and bioequivalence of oseltamivir phosphate for suspension (Oselavir®) and TAMIFLU® in healthy subjects.
Oseltamivir phosphate, an antiviral drug, which used in the treatment of influenza A and B, and early treatment with oseltamivir may be related to enhanced survival in critically ill patients with influenza pneumonia, at the same time, it may decrease the ICU length of stay and duration of mechanical ventilation [12]. During the COVID-19 pandemic, studies have noticed that oseltamivir was invalid for SARS-CoV-2 studied in vitro, it was not improved the patient's signs and symptoms when used oseltamivir for clinical treatment, nor slow down the progression of the disease [13, 14]. However, the combination therapy of oseltamivir has a certain conducive role on the treatment of COVID-19. For example, when it is used in combination with antibiotics, early administration of oseltamivir can reduce the duration of fever in patients with suspected COVID-19 outpatients without hypoxia[15], either when combined use of oseltamivir, lopinavir and ritonavir, was validagainst the SARS CoV-2 protease[16], while a study of drug-pregnancy pharmacokinetic interactions in rhesus monkeys found that pregnancy had little effect on the pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate[17], and oseltamivir had good safety data during pregnancy and was recommended by the CDC as a first-line treatment for pregnant women[18]. In addition, studies have also found that oseltamivir plays a role in affecting platelet function, and oseltamivir can be used as a promising therapy for adjuvant treatment of patients with reduced or defective thrombosis [19]; combination of oseltamivir with dexamethasone may serve as a promising therapy for newly diagnosed primary immune thrombocytopenia, possibly due to the ability of oseltamivir to protect platelets from dealkylation and subsequent phagocytosis [20]. All in all, these are strong evidence of the value of clinical research and application of oseltamivir phosphate. This study confirmed the interchangeability of the test product and TAMIFLU® by verifying their bioequivalence, and that food intake did not affect the pharmacokinetics and bioequivalence of the two products, allowing patients to choose the one at a relatively favorable price and achieve the same therapeutic effect.
In terms of adverse reactions, the most common side effects of oseltamivir phosphate were nausea (incidence 10%), vomiting (2–15%), abdominal pain, diarrhea, headache, insomnia and dizziness. Other side effects included conjunctivitis, rhinorrhagia, allergy, cardiac arrhythmias, gastrointestinal bleeding, erythema multiforme, toxic epidermal necrolysis, confusion, hepatitis, epilepsy, and neuropsychiatric events, but the incidence was < 1%. Oseltamivir is generally well tolerated [21, 22, 23]. In this study, adverse events such as nausea, vomiting, and elevated alanine aminotransferase were mild in severity and were mainly treated by observation.
The limitation of this study is as follows, the study is a bioequivalence trial in healthy Chinese subjects, the pharmacokinetic parameter data express the absorption distribution and elimination in Chinese subjects, and the bioequivalence in other races has not been evaluated yet, so it is not known whether there are differences between different races, which will be further verified in later trials.