Ethnic evaluation of the pharmacokinetics and safety of new drugs is required in Japan before implementing bridging or joining global studies. As therapeutic monoclonal antibodies (mAbs) show limited ethnic differences, their pharmacokinetics and safety in Japanese individuals could be estimated from prior non-Japanese studies. Therefore, there is potential to re-evaluate the development program for mAbs in Japan. We reviewed the pharmacokinetics of mAbs approved in Japan. Although some differences had been observed in pharmacokinetics of mAbs between Japanese and non-Japanese populations (mainly Caucasians), these differences were attributed to differences of body weight and/or antigen levels. Moreover, the influential factors can be estimated without conducting regional pharmacokinetic/safety studies. The pharmacokinetics of some mAbs is presumably non-linear and show differences between healthy volunteers and patients because of differences in antigen levels. However, for 10/24 mAbs approved in Japan, Japanese healthy volunteer studies were conducted before the patient studies. Additionally, for the mAbs that showed ethnic differences in pharmacokinetics, the doses selected in subsequent patient studies were the same as the doses approved in the United States. In this review, we discuss new drug development strategies in various regions, and assess the need for regional pharmacokinetics/safety studies before joining global studies.

Molnupiravir (MK‐4482) is an oral prodrug of the antiviral ribonucleoside analog, N ‐hydroxycytidine (NHC), which has activity against RNA viruses, including severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). We conducted a phase I safety and pharmacokinetic study of molnupiravir in healthy Japanese adult participants. A sample size larger than typically used in pharmacokinetic studies was implemented to collect additional safety data in the Japanese population to support special approval for emergency use in Japan. Single doses of molnupiravir up to 1600 mg and multiple doses of 400 and 800 mg administered every 12 h (q12h) for 5.5 days were generally well‐tolerated. NHC appeared rapidly in plasma and reached maximum concentration ( C max ), with a median time to C max ( T max ) between 1.00 and 2.00 h. Area under the concentration versus time curve from zero to infinity (AUC 0–inf ), area under the concentration versus time curve from zero to 12 h (AUC 0–12 ), and C max of plasma NHC increased approximately dose proportionally. With q12h dosing, the geometric mean (GM) accumulation ratios for NHC AUC 0–12 and C max were ~1 for 400 and 800 mg. Pharmacokinetics of NHC triphosphate (NHC‐TP), the active metabolite of NHC was assessed in peripheral blood mononuclear cells and also demonstrated roughly dose proportional pharmacokinetics. The GM accumulation ratios for NHC‐TP AUC 0–12 and C max were ~2.5 for 400 and 800 mg. Following administration with food, only a modest reduction (24%) in plasma NHC C max with comparable AUC 0–inf was seen, supporting administration without regard to food.

Pharmacokinetics ( PKs ) in Japanese healthy subjects were simulated for nine compounds using physiologically based PK ( PBPK ) models parameterized with physicochemical properties, preclinical absorption, distribution, metabolism, and excretion ( ADME ) data, and clinical PK data from non‐Japanese subjects. For each dosing regimen, 100 virtual trials were simulated and predicted/observed ratios for peak plasma concentration ( C max ) and area under the curve (AUC) were calculated. As qualification criteria, it was prespecified that >80% of simulated trials should demonstrate ratios to observed data ranging from 0.5–2.0. Across all compounds and dose regimens studied, 93% of simulated C max values in Japanese subjects fulfilled the criteria. Similarly, for AUC , 77% of single‐dosing regimens and 100% of multiple‐dosing regimens fulfilled the criteria. In summary, mechanistically incorporating the appropriate ADME properties into PBPK models, followed by qualification using non‐Japanese clinical data, can predict PKs in the Japanese population and lead to efficient trial design and conduct of Japanese phase I studies.

Letermovir is a human cytomegalovirus terminase inhibitor for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients. The pharmacokinetics, safety, and tolerability of letermovir were assessed in healthy Japanese subjects in 2 phase 1 trials: trial 1—single ascending oral doses (240, 480, and 720 mg) and intravenous (IV) doses (240, 480, and 960 mg), and trial 2—multiple oral doses (240 and 480 mg once daily for 7 days). Following administration of oral single and multiple doses, letermovir was absorbed with a median time to maximum plasma concentration of 2 to 4 hours, and concentrations declined in a biphasic manner with a terminal half‐life of ≈10 to 13 hours. The post absorption plasma concentration–time profile of letermovir following oral administration was similar to the profile observed with IV dosing. There was minimal accumulation with multiple‐dose administration. Letermovir exposure in healthy Japanese subjects was ≈1.5‐ to 2.5‐fold higher than that observed in non‐Japanese subjects. Based on the population pharmacokinetic analysis, weight differences primarily accounted for the higher exposures observed in Asians. Letermovir was generally well tolerated following oral and IV administration to healthy Japanese subjects.

Tazobactam/ceftolozane is a combination of a b-lactamase inhibitor and a cephalosporin antibiotic, with recommended dosage for patients with normal renal function of tazobactam 0.5 g/ceftolozane 1 g administered as a 1-h intravenous infusion every 8 h. The doses in patients with moderate and severe renal impairment are recommended to be reduced by half and 1/4th, respectively. The dose in patients undergoing dialysis is a single loading dose of 750 mg followed after 8 h by a 150 mg maintenance dose. In order to evaluate pharmacokinetics (PK) in Japanese patients, individual Bayes PK parameters were derived using the previously developed population PK models. Furthermore, attainment of PK/pharmacodynamic target in Japanese patients was calculated to confirm the recommended dosage.Based on PK data from 200 Japanese patients in the phase 3 studies, including patients with mild and moderate renal impairment, individual tazobactam/ceftolozane PK parameters were derived. No clinically relevant difference was observed in tazobactam/ceftolozane exposures between Japanese and non-Japanese patients. All Japanese patients achieved a target percent of time that free ceftolozane concentrations are above the minimum inhibitory concentration (MIC) of 30% for MICs of up to 8 mg/mL. Also for tazobactam, all Japanese patients achieved a target percent of time that the free tazobactam concentration exceeds a threshold concentration (1 mg/mL) of 20%. The results suggest that the doses will be efficacious in the Japanese population.The results indicate that the recommended dose in patients with normal renal function or renal impairment is appropriate in Japanese patients.