Model-based dose selection and pharmacokinetic bridging of subcutaneous from intravenous pembrolizumab across indicat...

BACKGROUND: A model-based dose selection and pharmacokinetic (PK) bridging approach was applied to support development of pembrolizumab SC (pembrolizumab with berahyaluronidase alfa for subcutaneous administration) from intravenous (IV) administration. METHODS: A combined SC and IV PK model of pembrolizumab was informed by data from participants in the phase 3 study 3475A-D77 (NCT05722015), phase 1 study 3475A-C18 (NCT05017012), and historical IV data. Model-based PK exposures of AUC, Ctrough, and Cmax were derived to enable SC dose selection at Q6W and Q3W regimens, comparable to approved IV doses across indications, and to provide key endpoints of 3475A-D77 confirming the Q6W regimen. The Q3W regimen was confirmed by model-based evaluation validated by observed data from 3475A-C18. RESULTS: For pembrolizumab SC, estimated bioavailability was 60 % and Tmax was 4 days. PK exposures were contained within those of IV administration with comparable AUC, higher Ctrough, and lower Cmax than pembrolizumab IV. Pembrolizumab SC 790 mg Q6W demonstrated noninferior AUC and Ctrough to pembrolizumab IV 400 mg Q6W. Pembrolizumab SC 395 mg Q3W led to exposures consistent with pembrolizumab SC 790 mg Q6W and IV 200 mg Q3W. Participant factors such as age, body weight, tumor type, injection site, and race had no meaningful impact on absorption of pembrolizumab SC. Consistency of PK and exposure-response across tumor types and treatment settings supports applicability of SC dosing regimens across indications. CONCLUSIONS: These findings confirm pembrolizumab SC 790 mg Q6W and 395 Q3W are appropriate to maintain efficacy and safety similar to pembrolizumab IV across approved indications.