Open-label study of the safety, pharmacokinetics, and effectiveness of a 2 mg/kg dose of baloxavir marboxil 2% granules in children <20 kg with influenza.

INTRODUCTION: Baloxavir marboxil is an oral anti-influenza drug with demonstrated safety and efficacy in pediatric patients when a 2% granules formulation is administered at 1 mg/kg. This study assessed safety, effectiveness, and pharmacokinetics of a higher dose (2 mg/kg) of baloxavir marboxil 2% granules in pediatric patients weighing <20 kg. METHODS: This multicenter, open-label, noncontrolled study was conducted at 15 sites in Japan (January 2019-March 2020; JapicCTI-194577). Patients aged <12 years with confirmed influenza received a single oral dose of baloxavir marboxil at 2 mg/kg if body weight was <10 kg or 20 mg if ≥ 10 to <20 kg. Safety, pharmacokinetics, effectiveness (time to illness alleviation [TTIA] of influenza; time to resolution of fever; virus titer), and polymerase acidic protein (PA) substituted viruses were assessed over 22 days. RESULTS: 45 patients, all aged ≤6 years, were enrolled. Adverse events were reported in 24 (53.3%) patients, most commonly nasopharyngitis, diarrhea, and upper respiratory tract infection. Median (95% confidence interval [CI]) TTIA was 37.8 (27.5-46.7) hours; median (95% CI) time to resolution of fever was 22.0 (20.2-28.6) hours. A >4 log decrease in mean viral titer occurred at day 2 and a subsequent temporary 1-2 log increase in patients with influenza A(H3N2) and B. Treatment-emergent PA/I38X-substituted virus was detected in 16/39 (41.0%) patients, but no prolonged TTIA or time to resolution of fever was associated with its presence. CONCLUSIONS: Baloxavir granules administered at 2 mg/kg in children <20 kg were well tolerated, with symptom alleviation similar to 1 mg/kg.

Population Pharmacokinetics and Exposure-Response Relationships of Baloxavir Marboxil in Influenza Patients at High Risk of Complications.

Baloxavir marboxil, a prodrug of cap-dependent endonuclease inhibitor baloxavir acid, reduces the time to improvement of influenza symptoms in patients infected with type A or B influenza virus. To characterize its pharmacokinetics, a population pharmacokinetic model for baloxavir acid was developed using 11,846 plasma concentration data items from 1,827 subjects, including 2,341 plasma concentration data items from 664 patients at high risk of influenza complications. A three-compartment model with first-order elimination and first-order absorption with lag time well described the plasma concentration data. Body weight and race were found to be the most important factors influencing clearance and volume of distribution. The exposures in high-risk patients were similar to those in otherwise healthy patients, and no pharmacokinetic difference was identified regarding any risk factors for influenza complications. Exposure-response analyses were performed regarding the time to improvement of symptoms and the reduction in the influenza virus titer in high-risk patients. The analyses suggested that body weight-based dosage, 40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg, can shorten the time to improvement of influenza symptoms and reduce virus titer for both type A and B influenza virus regardless of the exposure levels of the high-risk patients as well as for the otherwise healthy influenza patients. The results of our population pharmacokinetic and exposure-response analyses in patients with risk factors of influenza complications should provide useful information on the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil and also for the optimization of dose regimens.

Population Pharmacokinetics of Baloxavir Marboxil in Japanese Pediatric Influenza Patients.

Baloxavir marboxil is a prodrug of baloxavir acid, an inhibitor of cap-dependent endonuclease, and suppresses the replication of influenza virus. The aim of this study was to investigate its pharmacokinetic characteristics in Japanese pediatrics. Population pharmacokinetic analysis was conducted for baloxavir acid with 328 plasma concentration data points in a clinical study of 107 Japanese pediatric influenza patients. The plasma baloxavir acid concentration profiles were well captured by a 2-compartment model including first-order absorption and lag time. Body weight was considered to be the most crucial covariate, which affects clearance and volume of distribution. The body weight-based dose regimen (10 mg for 10 kg to less than 20 kg pediatrics, 20 mg for 20 kg to less than 40 kg pediatrics, and 40 mg for at least 40 kg pediatrics) for Japanese pediatrics can provide comparable exposure to baloxavir acid to that for adults. In conclusion, the population pharmacokinetic model would be useful to comprehend the characteristics of baloxavir acid pharmacokinetics in pediatric patients.

Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza.

Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. Our aim is to characterize its pharmacokinetics and exposure-response relationships. Population pharmacokinetic analysis of the baloxavir acid was performed using 8310 plasma concentration data points from 1109 subjects. Exposure-response analyses were performed regarding the time to alleviation of symptoms and the reduction in the influenza virus titer. A 2-compartment model with first-order absorption and lag time well described the plasma concentration data for baloxavir acid, and body weight and race were found to be the most important factors influencing the clearance and distribution volume. A dose regimen based on the body weight (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg) could provide sufficient exposures for expecting efficacy irrespective of body weight or race; however, the exposures were dependent on the body weight and race. Exposure-response analyses suggested that the reduction in the influenza virus titer was greater in any exposure-based groups in baloxavir marboxil treatment than in the oseltamivir phosphate treatment and placebo groups. In conclusion, the population pharmacokinetic model and exposure-response relationships would be useful for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir acid.

Safety, Tolerability, and Pharmacokinetics of the Novel Anti-influenza Agent Baloxavir Marboxil in Healthy Adults: Phase I Study Findings.

BACKGROUND AND OBJECTIVE: Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. This first-in-human phase I study evaluated the safety, tolerability, and pharmacokinetics of baloxavir marboxil/baloxavir acid in healthy Japanese volunteers (Study 1), while food effects were evaluated in a separate phase I, crossover study in healthy Japanese volunteers (Study 2). METHODS: Study 1 participants were randomized to single-dose oral baloxavir marboxil (6, 20, 40, 60, or 80 mg; n = 6 per dose) or placebo (n = 10), while Study 2 participants (n = 15) received single-dose oral baloxavir marboxil 20 mg in fasted, fed, and before-meal states. RESULTS: Baloxavir marboxil was well tolerated; there were few treatment-emergent adverse events and no serious adverse events/deaths. The mean plasma baloxavir acid concentration 24 h after single-dose (C24) oral baloxavir marboxil 6 mg was 6.92 ng/mL, exceeding the target C24 (6.85 ng/mL) estimated in nonclinical studies. In Study 1, baloxavir acid exposure demonstrated dose-proportional increases in the fasted state, with maximum plasma concentration generally attained within 3.5 h. Terminal elimination half-life ranged from 49 to 91 h. In Study 2, exposure was decreased and apparent clearance increased in the fed and before-meal states versus the fasted state; however, exposure exceeded the target C24 in all states. CONCLUSION: Single-dose oral baloxavir marboxil was well tolerated, had a favorable safety profile, and had favorable pharmacokinetic characteristics, including a long half-life, supporting single oral dosing. The baloxavir acid area under the plasma concentration-time curve decreased with food intake by approximately 40%.

Evaluation of Drug-Drug Interaction Potential between Baloxavir Marboxil and Oseltamivir in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Baloxavir marboxil is a prodrug that is metabolized to baloxavir acid, which suppresses viral replication by inhibiting cap-dependent endonuclease with a single oral administration. As the mode of action of baloxavir marboxil is different from that of neuraminidase inhibitors, such as oseltamivir, combination treatment with these drugs can be a treatment option, particularly for severe influenza infection. The aim of this study was to assess the drug-drug interaction between baloxavir marboxil and oseltamivir. METHODS: Eighteen healthy adult subjects received three treatments in a crossover fashion: single administration of baloxavir marboxil 40 mg alone, repeated twice-daily administration of oseltamivir at 75 mg for 5 days, or single administration of baloxavir marboxil at 40 mg in combination with repeated twice-daily administration of oseltamivir at 75 mg for 5 days. RESULTS: The ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve of baloxavir acid after co-administration compared to baloxavir marboxil alone were 1.03 (0.92-1.15) and 1.01 (0.96-1.06), respectively. The ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve of oseltamivir carboxylate, the active form of oseltamivir, after co-administration compared to oseltamivir alone were 0.96 (0.93-1.00) and 0.99 (0.96-1.01), respectively, at steady state on day 5. Treatment-emergent adverse events reported were mild and not considered to be related to the study drug. CONCLUSION: The lack of a clinically meaningful drug-drug interaction between baloxavir marboxil and oseltamivir has been established.

Contribution of protein binding, lipid partitioning, and asymmetrical transport to drug transfer into milk in mouse versus human.

PURPOSE: Drug transfer into milk is a general concern during lactation. Because data are limited in human subjects, particularly for new drugs, experimental animal models of lactational drug transfer are critical. This study analyzed drug transfer into milk in a mouse model, as well as the contribution of similar and dissimilar host factors. METHODS: Milk/plasma drug concentration ratios (M/P) in humans were obtained from the literature, while those in mice were determined experimentally after intraperitoneal implantation of osmotic pumps containing drugs of interest. Unbound drug fractions in plasma and milk were determined in vitro for both species. RESULTS: M/P values were determined for 27 drugs in mice and compared with those in human. These values were increased in mice for 21 drugs; the geometric mean ratio of M/P between mice and humans was 2.03 (95% CI, 1.42-2.89) for all 27 drugs. These results were reasonably explained by the relatively high protein and lipid content in mouse milk. Moreover, species-specific asymmetrical transport systems were suggested for 9 drugs. CONCLUSIONS: In addition to species-specific differences in milk protein and lipid content, variances in asymmetrical drug transport across the mammary epithelium may yield discordant M/P values in humans and mice.

Analysis and prediction of drug transfer into human milk taking into consideration secretion and reuptake clearances across the mammary epithelia.

Medication use during lactation is a matter of concern due to unnecessary exposure of infants to drugs. Although some studies have predicted the extent of drug transfer into milk from physicochemical parameters, drug concentration-time profiles in milk have not been predicted or even analyzed yet. In the present study, a drug transfer model was constructed by defining secretion and reuptake clearances (CL(sec) and CL(re), respectively) between milk and plasma based on unbound drug concentrations. Through the use of this model, drug concentration-time profiles were analyzed in human milk and plasma based on data collected from the literature. CL(sec) and CL(re) values were obtained successfully for 49 drugs. Because the CL(sec) and CL(re) values were in general similar for each drug, transport across the mammary epithelia was mediated by passive diffusion in most cases. This study demonstrated that the logarithmically transformed values of CL(sec) and CL(re) can be predicted from physicochemical parameters with adjusted R(2) values of 0.705 and 0.472, respectively. Moreover, 66.7 and 77.8% of predicted CL(sec) and CL(re) values were within 3-fold error ranges of the observed values for 45 and 27 drugs, respectively. Finally, time profiles of drug concentrations in milk were simulated from physicochemical parameters. The milk-to-plasma area under the concentration-time curve ratios also were predicted successfully within 3-fold error ranges of the observed values for 71.9% of the drugs analyzed. The method described herein therefore may be useful in predicting drug concentration-time profiles in human milk for newly developed drugs.