Cypsedo
cipepofol
Sources:FDA multi-discipline review ↗
Species
RatDog
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The Applicant conducted 14- and 28-day repeat-dose toxicology studies in rats and dogs with administration of the test article every other day.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Overall, the nonclinical safety studies conducted with cipepofol have characterized the toxicological profile of the drug product.”
Study lengthopen answer page →
Longest pivotal study
4 (rat and dog, dosing every other day)
“No drug accumulation was observed in rats and beagle dogs after 7 or 14 injections given every other day over 2 or 4 consecutive weeks, respectively.”
Pivotal GLP studies
28-day rat and dog studies with every-other-day dosing (plus 14-day studies)
“The Applicant conducted 14- and 28-day repeat-dose toxicology studies in rats and dogs with administration of the test article every other day.”
Route in tox
Intravenous bolus injection
“while all the repeat-dose studies with IV bolus injections reached Cmax levels that were much lower than the human Cmax at the HID”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and mouse bone marrow micronucleus assays
“Cipepofol was not genotoxic in a standard battery of genotoxicity assays, testing negative in an in vitro Ames assay, in the in vitro chromosomal aberration assay, and in the in vivo bone marrow micronucleus test in mice.”
Carcinogenicity
Not conducted
“The carcinogenic potential of cipepofol has not been evaluated.”
Reproductive & developmental
Rat FEED: increased post-implantation loss from resorptions, likely related to maternal hypoxia secondary to anesthesia
“It appears that the significantly increased post-implantation loss was mainly driven by increased resorption. Similar, but not significant and not dose-dependent, effects were observed in the FEED study in rats with every other day IV dosing. The reproductive effects observed in the FEED studies are likely related to maternal hypoxia secondary to anesthesia.”
Safety pharmacology
Dog CV study: transient hypotension and QTcF increase during anesthesia
“Temporary cardiovascular (CV) effects during anesthesia, including reduced blood pressure and ECG changes such as an increase in QTcF, were observed in the cardiovascular safety pharmacology study and a single-dose toxicology study in dogs.”
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 Cypsedo 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Target organs: CNS and cardiovascular system (FDA multi-discipline review, p. 39)
NOAEL / key findings
Target organs: CNS and cardiovascular system
“Target organs of toxicity identified after cipepofol administration were the central nervous system and cardiovascular system.”
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Biodistribution & persistence
Extensive distribution in rats, highest in adrenal, fat, skin, ovary, pancreas and kidney; crosses blood-brain barrier
“Following IV administration of cipepofol injectable emulsion, extensive tissue distribution was observed in Sprague-Dawley rats, with the highest exposures found in the adrenal gland, fat, skin, ovary, pancreas, and kidney. Cipepofol was demonstrated to cross the blood-brain barrier.”
Modality-specific risk
Exaggerated pharmacology (respiratory depression, anesthesia-related mortality) and QTc prolongation
“Several adverse findings were identified from the nonclinical studies but were generally attributed to the pharmacological effects of the active pharmaceutical ingredient (e.g., muscle relaxation, respiratory depression, anesthesia related mortality) or can be clinically monitored (e.g., QTc prolongation, local irritation).”