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. 2025 Aug 14:115711.
doi: 10.1016/j.ejca.2025.115711. Online ahead of print.

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

Gina Song  1 , Mustafa Erman  2 , Gastón Lucas Martinengo  3 , Judit Kocsis  4 , Gopal Kunta  5 , Mengzhao Wang  6 , Hiroshige Yoshioka  7 , Carolina de Miranda Silva  8 , Mallika Lala  9
Affiliations
Free article

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

Gina Song et al. Eur J Cancer. .
Free article

Abstract

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.

Keywords: Anti–PD-1; Immunotherapy; Modeling; Pembrolizumab; Pharmacokinetic-based bridging; Subcutaneous administration.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Gina Song: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns shares in Merck & Co., Inc., Rahway, NJ, USA. Mustafa Erman: Honoraria through institution for advisory, consulting, or speaking roles: Eczacibasi, Deva, Nobel, Janssen, Abdi Ibrahim, Pfizer, Roche, BMS, Astellas, Novartis, MSD, AstraZeneca. Research funding through institution: MSD, Roche, AstraZeneca, BMS, Incyte, Beigene, Pfizer, Novartis, Regeneron, Biontech. Travel and accommodation: Gen, BMS, MSD, Astellas, Roche, Merck, Novartis, Eczacibasi, Abdi Ibrahim. Gastón Lucas Martinengo: None declared. Judit Kocsis: None declared. Gopal Kunta: None declared. Mengzhao Wang: None declared. Hiroshige Yoshioka: Honoraria for lecture fee from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Kyowa Kirin, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical, and Janssen Pharmaceutical. Consulting fees from Delta Fly Pharmaceutical. Research funding from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Delta Fly Pharmaceutical, Janssen Pharmaceutical, MSD, Novartis, and Regeneron. Carolina de Miranda Silva: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns shares in Merck & Co., Inc., Rahway, NJ, USA. Mallika Lala: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns shares in Merck & Co., Inc., Rahway, NJ, USA.

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