A favourable absolute bioavailability in healthy Japanese subjects was seen following a subcutaneous injection of 200 mg belimumab. Considering the intersubject variability, exposures were consistent with those previously observed in healthy non-Japanese subjects. Safety and biomarker data were also consistent with previous non-Japanese clinical studies.

This phase 1 study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of losmapimod and its metabolite GSK198602 following single and repeat doses of oral losmapimod in healthy Japanese volunteers. Subjects (n = 41) received single oral doses of losmapimod (2.5, 7.5, 20 mg) or matching placebo on 3 separate days (n = 20) or losmapimod 7.5 mg or matching placebo twice daily for 14 days (n = 21). Assessments included maximum observed plasma concentration (Cmax ), time to Cmax (Tmax ), apparent terminal-phase half-life (t1/ )2 , area under the curve (AUC), and change in C-reactive protein and phosphorylated heat shock protein 27 levels. No serious adverse events occurred during the study, and there were no safety concerns regarding clinical laboratory parameters, 12-lead electrocardiogram, or vital signs. The losmapimod Tmax was 3-4 hours, and the mean t1/2 was approximately 7.9-9.0 hours, with no appreciable difference in Tmax and apparent clearance following oral dosing between dosing regimens. Single and repeat oral doses of losmapimod were well tolerated in healthy Japanese volunteers. The Tmax of GSK198602 was similar to and t1/2 was slightly longer than those of losmapimod. Approximate dose-proportional increases in exposure to losmapimod and GSK198602 were observed in AUC with single-dose administration. Repeat-dose trough concentrations reached steady state within 2 days, with an observed accumulation ratio of 1.56 and 1.91 for losmapimod and GSK198602, respectively.

ObjectiveFabry disease is a rare X-linked disease caused by mutations to the GLA gene, resulting in a deficiency of the lysosomal enzyme alpha-galactosidase A. This study evaluated the pharmacokinetics, safety, and tolerability of ascending single doses of oral migalastat hydrochloride (HCl), an investigational drug, in healthy Japanese volunteers.MethodsIn this phase I, randomized, placebo-controlled, single-blind, ascending single-dose, cross-over study, migalastat HCl (50 mg, 150 mg, or 450 mg) or placebo was administered orally to 14 fasting male Japanese volunteers (aged 20–55 years) on 4 non-consecutive days. Main plasma and urine pharmacokinetic end-points included maximum observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration–time curve (AUC), apparent terminal-phase half-life (t1/2), urinary recovery of unchanged drug, renal clearance, and percentage of drug excreted in urine. Safety end-points included adverse events, clinical signs and symptoms (e.g., hematology, chemistry, and urinalysis), vital signs (blood pressure and heart rate), and 12-lead electrocardiogram.Clinical trial registration numberClinicalTrials.gov registration identifier is NCT01853852.ResultsMedian tmax of migalastat was 3.0–3.5 h. Migalastat HCl concentrations declined relatively rapidly, with a mean t1/2 of 3.2–4.0 h. The amount of migalastat HCl recovered in the urine and the percentage of migalastat HCl excreted unchanged over 24 h were consistent (∼45–50%) across the dose range. The AUC and Cmax of migalastat HCl were dose proportional from 50–450 mg. Safety results were similar to those observed in non-Japanese populations.ConclusionsThis study demonstrated that ascending single doses of migalastat HCl (50 mg, 150 mg, 450 mg) are absorbed at a moderate rate and eliminated relatively rapidly, with a safety profile consistent with that observed in non-Japanese populations. These results confirm the dose-proportional pharmacokinetics of migalastat HCl from 50–450 mg. This study was limited by a small subject population and a short-term follow-up.

ObjectiveLevocetirizine, the R-enantiomer of cetirizine, is classified as a second generation antihistamine used for the treatment of allergic disorders. This study aimed to compare exposure to levocetirizine when given as levocetirizine oral solution (OS) 5 mg to that when given as cetirizine dry syrup (DS) 10 mg, which contains equal proportions of levocetirizine and dextrocetirizine, in healthy Japanese male subjects.MethodsThe study was conducted in an open-label, single dose, randomized and two-way cross-over design. Eligible subjects were allocated to one of two groups and received either levocetirizine OS 5 mg or cetirizine DS 10 mg under fasting conditions, and the alternate treatment after a 7-days washout period. Serial blood samples were taken after each administration, and plasma levocetirizine concentrations were determined using a validated LC-MS/MS method. Pharmacokinetic parameters were calculated by using non-compartmental analysis. Comparisons of levocetirizine pharmacokinetics were conducted with maximum concentration (Cmax) and the area under the plasma concentration-time curve from dosing until 48 h post-dose (AUC0–48) after each treatment.Clinical Trial registration numberClinicalTrials.gov identifier is NCT01622283ResultsThe mean Cmax and AUC0–48 of levocetirizine after a single dose of levocetirizine OS 5 mg and cetirizine DS 10 mg were 203.3 ± 42.49 ng/mL and 1814.9 ± 304.22 ng.hr/mL, and 196.5 ± 31.31 ng/mL and 1710.5 ± 263.31 ng hr/mL, respectively. The ratios and the 90% CIs of the geometric least squares means ratios of Cmax and AUC0–48 were 1.027 (0.968–1.091) and 1.059 (1.024–1.094), respectively.LimitationThe small sample size and single dose design of this study prevent definitive conclusions regarding the pharmacokinetics and safety of levocetirizine OS in a Japanese patient population being made. Study limitations include conducting the study in adult males, not in children.ConclusionsLevocetirizine exposure in plasma was equivalent when given as levocetirizine OS 5 mg and as cetirizine DS 10 mg. Both preparations were safe and well-tolerated in healthy Japanese male subjects.

Background and Objectives GSK2982772 is an oral small-molecule RIPK1 inhibitor with potential therapeutic efficacy in immune-mediated inflammatory diseases (IMIDs). An inter-ethnic comparison of GSK2982772 pharmacokinetics was conducted based on data from Western (Study 1) and Japanese subjects (Study 2). Methods Both studies were single-centre, randomised, double-blind, placebo-controlled studies with objectives to assess the safety and characterise the pharmacokinetics of GSK2982772. Western subjects in Study 1 (NCT03305419), Part A ( N = 15), were randomly assigned to receive 120 mg three times daily (TID), 240 mg TID, or 360 mg twice daily (BID) doses of GSK2982772, or placebo (TID or BID) for 1 day. Part B subjects ( N = 47) received GSK2982772 120 mg TID, 240 mg TID, or placebo TID for 14 days. Japanese subjects in Study 2 ( N = 13) (NCT03590613) were randomly assigned to receive TID doses of GSK2982772 60, 120, 240 mg TID or placebo TID for 1 day. Results GSK2982772 was well tolerated and adverse events were generally mild. Maximum observed plasma drug concentration ( C max ), time to reach C max ( T max ), area under the plasma drug concentration versus time curve after the first GSK2982772 dose (AUC (0–7) ) of 120 and 240 mg, and (AUC (0–24) ) values for the 120 and 240 mg TID doses over a single day were similar in Japanese and Western subjects. Conclusions The pharmacokinetics and tolerability of GSK2982772 were similar between Western and Japanese subjects, justifying inclusion of Japanese subjects in future global clinical studies to assess the therapeutic potential of RIPK1 inhibition for the treatment of IMIDs. Clinical Trials: NCT03305419 and NCT03590613 available from http://www.clinicaltrials.gov . Electronic supplementary material The online version of this article (10.1007/s13318-020-00652-2) contains supplementary material, which is available to authorized users.