Estimation of the value of convenience in taking influenza antivirals in Japanese adult patients between baloxavir marboxil and neuraminidase inhibitors using a conjoint analysis.

AIMS: Estimating the monetary value of the convenience of using influenza antivirals approved in Japan from a patient perspective using a conjoint analysis. METHODS: An online survey (August 2020) was performed on individuals aged 20-64 years living in Japan who had taken oral or inhalant antivirals for influenza treatment in the 2018/19 or 2019/20 seasons. Efficacy and safety were assumed to be equivalent among the antivirals. The attributes for the conjoint analysis included route (oral or inhalant), duration, frequency of administration, and out-of-pocket expenses. A conditional logit model was applied as a baseline model. The monetary value of each attribute was calculated by comparing the same utility of the linearly interpolated level of the out-of-pocket attribute. Another survey to determine the experiences of the latest antiviral intake was also conducted on the same respondents. RESULTS: Of the respondents, 1,550 were men and 1,587 were women. The monetary value for oral antivirals was estimated to be higher, saving JPY 741 (USD 7.06, as of August 2020), compared with inhalant. Regarding the length and frequency of administration, five days corresponds to an increase of JPY 2,072, compared with one day, and twice a day corresponds to a JPY 574 increase compared to once a day. CONCLUSIONS: The results suggest that - among the antivirals approved in Japan - the monetary value of the utility is the highest in the single dose oral antiviral, baloxavir marboxil (baloxavir). Although the drug cost was highest in baloxavir among the brand antivirals, the difference in the value of utility for influenza patient was estimated to be larger than the difference in the drug costs. LIMITATIONS: Although individuals with diverse attributes from all over the country were included in the survey, they are not necessarily a representative population of the Japanese society.

Effect of itraconazole on the pharmacokinetics of everolimus administered by different routes in rats.

The effect of itraconazole on the pharmacokinetics of everolimus was investigated in rats. Ten minutes after an intravenous or intraintestinal administration of itraconazole, everolimus was delivered intravenously (0.2 mg/kg) or intraintestinally (0.5 mg/kg). Blood concentrations of everolimus were measured up to 240 min, and pharmacokinetic parameters were calculated. Intraintestinally administered itraconazole (20 mg/kg) significantly increased the area under the concentration-time curve (AUC) of intraintestinally administered everolimus about 4.5-fold, but even at 50 mg/kg did not affect the AUC of intravenously administered everolimus. However, intravenously administered itraconazole (50 mg/kg) increased the AUC of both intraintestinally and intravenously administered everolimus approximately 2-fold. Using a value for hepatic blood flow from the literature (50 ml/min/kg), the apparent intestinal and hepatic extraction of everolimus without itraconazole was calculated as about 80% and 13%, respectively. Intraintestinally administered itraconazole (20 mg/kg) changed the apparent intestinal extraction by 0.26-fold from 0.829 to 0.215, but the hepatic availability of everolimus was almost unchanged after the intravenous or intraintestinal administration of itraconazole even at a dose of 50 mg/kg from 0.871 to 0.923 or 0.867, respectively. In conclusion, intraintestinally administered itraconazole dramatically increased the AUC of everolimus delivered intraintestinally by inhibiting the intestinal first-pass extraction of this drug.

Effect of intestinal and hepatic first-pass extraction on the pharmacokinetics of everolimus in rats.

The aim of this study was to quantitatively evaluate the effects of intestinal and hepatic extraction on the pharmacokinetics of everolimus in rats. Everolimus was administered intravenously, intraportally or intraintestinally in order to separately evaluate the intestinal and hepatic first-pass extraction. Cyclosporine or tacrolimus was administered into rat intestines, and after 10 min everolimus pharmacokinetics were evaluated. The blood concentrations of everolimus were measured by the high-performance liquid chromatography with tandem mass spectrometry. Total body clearance of everolimus was constant in the dosage from 0.2 to 1.0 mg/kg. The bioavailability after intraportal and intraintestinal administration were 48.0% and 21.2%, respectively. Concomitantly administered cyclosporine (5 mg/kg) , but not tacrolimus (1 mg/kg), significantly decreased the total body clearance of everolimus compared with the control, and also increased the bioavailabilty of everolimus after intraintestinal administration 1.75-fold. Cyclosporine significantly increased the area under the blood concentration-time curve of everolimus after the intraintestinal constant infusion 3-fold, and increased that after the intraportal constant infusion only 1.35-fold. In conclusion, the intestine as well as liver contributes to the first-pass extraction for everolimus in rats. Intestinally administered cyclosporine inhibited the intestinal extraction of everolimus more than its hepatic extraction.