Cosela
trilaciclib
Species
RatDog
Longest study
1 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Additional oral toxicity studies in rats (up to 28-days) and dogs (up to 14-days) assessed longer term trilaciclib exposures and confirmed similar total drug exposure from repeated oral and iv dosing.”
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
“Dogs were treated for seven days by iv injection followed by a 2-week drug-free recovery period.”
Study lengthopen answer page →
Longest pivotal study
1 (7-day rat and dog iv)
“day iv toxicity studies were considered the pivotal toxicity studies which cover the clinical dosing route and duration.”
Pivotal GLP studies
7-day iv studies plus additional oral rat (up to 28-day) and dog (up to 14-day) studies
“Additional oral toxicity studies in rats (up to 28-days) and dogs (up to 14-days) assessed longer term trilaciclib exposures and confirmed similar total drug exposure from repeated oral and iv dosing. Dose-limiting toxicity in the 14-day and 28-day studies was consistent with exaggerated pharmacology and generally similar to the 7-day iv toxicity study results.”
Route in tox
Intravenous (30-min infusion)
“Seven-day iv (30 min infusion) pilot toxicity in dogs with a two-week drug-free recovery phase.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; negative for clastogenicity in human fibroblasts; increased micronuclei in human lymphocytes in vitro
“Trilaciclib was negative for mutagenic potential in the Ames assays and negative for clastogenic potential in primary human fibroblasts. Trilaciclib increased micronucleus formation in human peripheral blood lymphocytes in vitro, suggesting clastogenic activity.”
Carcinogenicity
Not conducted
“Carcinogenic potential of trilaciclib has not been assessed in animals.”
Reproductive & developmental
Not conducted (no fertility, developmental or reproductive toxicity studies)
“No fertility, developmental, or reproductive toxicity studies were conducted in animals.”
Safety pharmacology
Low-potency hERG inhibition (IC50 ≈20 μM) and increased heart rate in dogs; no QT prolongation in animal studies
“There were signals for potential cardiovascular effects of trilaciclib based on a low potency in vitro signal for hERG inhibition (IC50 ≈ 20 μM) and increased heart rate in dogs. In vitro hERG inhibition is a biological marker of QT prolongation but no QT prolongation was observed in animal studies.”
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 Cosela 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: Rat: non-adverse hematology changes at 10 mg/kg/d; adverse marked neutrophil (↓60%) and lymphocyte (↓77%) reductions at 25 mg/kg/d (FDA pharmacology/toxicology review, p. 50)
NOAEL / key findings
Rat: non-adverse hematology changes at 10 mg/kg/d; adverse marked neutrophil (↓60%) and lymphocyte (↓77%) reductions at 25 mg/kg/d
“Drug-related effects in the low dose were limited to slight hematology changes and hematology changes in the 10 mg/kg/d were considered of insufficient magnitude to be adverse to the animals. Marked reductions in neutrophils (↓ 60%, mean count <600/μL) and lymphocytes ((↓ 77%, mean count <60/μL) at 25 mg/kg/d were considered adverse.”
Risksopen answer page →
Immune & cytokine safety
Failure to clear catheter-related bacterial infections, suggesting compromised immune response from leukocyte suppression
“The bacterial infections likely originated from indwelling catheters but the failure to clear the infections suggest a compromised immune response, consistent with trilaciclib-mediated leukocyte and thrombocyte suppression during treatment.”
Biodistribution & persistence
Highest in thyroid, kidney, harderian, adrenal and lacrimal glands, spleen and liver; eye uveal tract and meninges in pigmented rats
“Highest radioactivity, representing drug or metabolite tissue distribution, was seen in thyroid, kidney, harderian gland, adrenal gland, lacrimal glands, spleen, and liver in non-pigmented rats with additional distribution in eye/eye uveal tract and meninges in pigmented rats.”
Modality-specific risk
Major human metabolite M8 not covered in animals (<1% in rat plasma, absent in dog plasma)
“Negligible levels of M8 (<1%) were detected in rat plasma and none were detected in dog plasma, so animals were not exposed to M8 at expected clinical exposure levels in toxicology studies.”