(M1030-02-12) Investigating Differences in the Pharmacokinetics of Monoclonal Antibodies in Japanese and Non-Japanese Subjects

Purpose: Ethnicity-specific evaluation of the pharmacokinetics (PK) of new drugs is often required in Japan prior to regulatory review and before implementing bridging or joining global clinical efficacy and safety trials [1,2]. As therapeutic monoclonal antibodies (mAbs) show limited ethnic differences, their PK 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 [1,2]. The objective of this work was to examine ethnic similarities and differences in the PK of approved mAbs between Japanese and non-Japanese subjects to evaluate the rationale and potential  necessity of PK studies for mAbs in the Japanese population.

Methods: We constructed a dataset containing PK information on mAbs currently approved in the US and Japan. Our data sources comprised publicly available information from the drug approval packages at the FDA website and published scientific articles. The results obtained from our analysis were categorized into four groups: 1) "Different", mAbs where PK differences were explicitly mentioned for any of the PK parameters or Japanese ethnicity was identified as a significant covariate for any PK parameter in a population pharmacokinetic (PPK) analysis. 2) "Not Different", mAbs where no differences were reported in PK parameters, or exposure metrics (maximum concentration [Cmax] and area under the curve [AUC]) were within the conventional bioequivalence criteria or ethnicity was not deemed a significant covariate for any PK parameter in a PPK analysis.  3) “Insufficient”, this group includes mAbs where PK differences could not be identified with adequate statistical power due to insufficient number of Japanese individuals. 4) “Not Available”, this category includes situations where data regarding ethnicity-related differences in PK were absent.

Results: Our analysis revealed that 64% (76/119) of all reviewed mAbs reported ethnicity-related information about PK. Among these, 62% (47/76) showed “No Differences”, while approximately 33% (25/76) exhibited differences in one or more PK parameters (“Different”). Generally, Japanese subjects demonstrated higher AUC and Cmax than the corresponding non-Japanese subjects, with differences typically falling within the range of 11-71% and 18-70% for the AUC and Cmax, respectively. The higher exposures corresponded to lower clearance (CL ~9-56%) and lower volume of distribution (Vd ~14-29%) in the Japanese compared to the non-Japanese. These differences were mainly attributed to differences in body weight (BW). For instance, Japanese subjects typically have a ~15-20% lower BW compared to Caucasians. However, after adjusting for BW, no significant differences were observed in the PK of most mAbs that would have a clinically relevant impact on the drug's exposure, safety, or efficacy. Exceptions were observed for omalizumab, where CL was 12% faster, and exposure was lower in Japanese patients compared to Caucasian patients. However, the potent target binding in the Japanese (with ~19% lower drug-target binding constant) compared to the Caucasians resulted in the same degree of target suppression (i.e., pharmacodynamic effect) across the two ethnic groups. Therefore, no changes to the dosing regimen was recommended. About 5% (4/76) of the mAbs lacked a sufficient number of Japanese subjects to identify ethnicity-related differences (“Insufficient”) in PK, and for the remaining 36% (43/119), we did not find evidence of clinical trials in Japan or PK was not compared between the Japanese and other ethnic groups (“Not Available”).

Conclusion: Our findings suggest that PK profiles for most mAbs were similar between Japanese and non-Japanese and none of the observed differences were deemed clinically significant, as the proposed dosing recommendations for Japanese and non-Japanese patients remained unchanged. Therefore, the rationale for performing dedicated clinical evaluations on the PK of Japanese individuals appears scientifically unjustified if robust PK data in non-Japanese individuals are available.

References: 1. Chiba, K. et al. Journal of Clinical Pharmacology 54(5) 483–494 (2014).
2. Matsushima, S. et al. Expert Opin. Drug Metab. Toxicol. 11(2):179-191 (2015).