Keytruda
pembrolizumab
Species
Monkey
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“consisted of pivotal 1-month and 6-month repeat-dose chronic toxicity studies both with 4-month recovery periods in Cynomolgus monkey”
Why that species
Comparable binding to human and cynomolgus PD-1 (~2X difference); no binding to rodent or dog PD-1
“Its binding affinities to PD-1 derived from human and cynomolgus monkeys were comparable (~2X difference), however, the antibody did not bind to rodent or dog PD-1.”
Surrogate molecule
No surrogate in toxicology studies; hamster anti-murine PD-1 (J43) used as surrogate for in vivo pharmacology only
“Given the lack of cross-reactivity of MK-3475 with murine PD-1, a commercially available hamster anti-murine PD-1 mAb, J43, was used as surrogate for in vivo pharmacology studies.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“consisted of pivotal 1-month and 6-month repeat-dose chronic toxicity studies both with 4-month recovery periods in Cynomolgus monkey”
Pivotal GLP studies
Pivotal 1-month and 6-month repeat-dose cynomolgus monkey studies, each with 4-month recovery
“consisted of pivotal 1-month and 6-month repeat-dose chronic toxicity studies both with 4-month recovery periods in Cynomolgus monkey”
Route in tox
Intravenous (bolus)
“Route of administration: Bolus IV injection via the saphenous vein”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for pembrolizumab.”
Carcinogenicity
Not conducted; not required for a product to treat advanced cancer; not planned as a post-marketing requirement
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”
Reproductive & developmental
Not conducted; dedicated embryofetal studies not warranted for the intended patient population
“Dedicated nonclinical studies investigating the effects of pembrolizumab on embryofetal development are not warranted at this time to support its use in the intended patient population.”
Safety pharmacology
Evaluated within the 1- and 6-month repeat-dose monkey studies
“safety pharmacology was evaluated as part of the 1-month and 6-months repeat-dose toxicity study in cynomolgus monkeys”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Keytruda don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for monoclonal antibodies
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: Well tolerated; NOAEL was the highest dose tested in both studies (EMA assessment report, p. 30)
NOAEL / key findings
Well tolerated; NOAEL was the highest dose tested in both studies
“Overall, pembrolizumab was well tolerated and the NOAEL in both studies was the highest dose tested.”
Risksopen answer page →
Immune & cytokine safety
No cytokine release (IL-2) from hPBMCs cultured on immobilized pembrolizumab
“Pembrolizumab was evaluated in a cytokine release assay there was no evidence of cytokine release, as assessed by IL-2 production following culture of hPBMCs in pembrolizumab-immobilized (air-dried) plates.”
Biodistribution & persistence
Vss 30.9-54.8 mL/kg in monkeys, similar to plasma volume; limited distribution out of plasma
“the Vss mean value (30.9, 36.8, 54.8 ml/kg) was similar to the plasma volume of monkeys suggesting that pembrolizumab has a limited distribution out of the plasma compartment”
Modality-specific risk
Autoimmune adverse events secondary to the drug's pharmacological action
“In patients that receive pembrolizumab, autoimmune diseases are the most common adverse events, and are likely secondary to the pharmacological actions of the drug.”