Truqap
capivasertib
Species
RatDog
Longest study
39 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
“Capivasertib was assessed in GLP-compliant repeat-dose toxicity studies with oral administration in rats for up to 6 months and in dogs for up to 9 months, consistent with the clinical route of administration.”
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
“Capivasertib was assessed in GLP-compliant repeat-dose toxicity studies with oral administration in rats for up to 6 months and in dogs for up to 9 months, consistent with the clinical route of administration.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“Capivasertib was assessed in GLP-compliant repeat-dose toxicity studies with oral administration in rats for up to 6 months and in dogs for up to 9 months, consistent with the clinical route of administration.”
Pivotal GLP studies
Oral GLP studies up to 6 months in rats and 9 months in dogs
“Capivasertib was assessed in GLP-compliant repeat-dose toxicity studies with oral administration in rats for up to 6 months and in dogs for up to 9 months, consistent with the clinical route of administration.”
Route in tox
Oral
“Capivasertib was assessed in GLP-compliant repeat-dose toxicity studies with oral administration in rats for up to 6 months and in dogs for up to 9 months, consistent with the clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and mouse lymphoma assays; positive (aneugenic) in rat bone marrow micronucleus; negative liver comet
“Capivasertib induced a statistically significant increase in the incidence of micronucleated immature erythrocytes at 150 mg/kg in the in vivo rat bone marrow micronucleus assay through an aneugenic mode of action.”
Carcinogenicity
Not conducted (advanced cancer indication)
“Carcinogenicity studies with capivasertib were not warranted to support this NDA, as the proposed indication is for advanced cancer.”
Reproductive & developmental
Rat preliminary EFD: post-implantation loss, minor visceral variations and reduced fetal weights at 150 mg/kg/day
“Administration of capivasertib to rats prior to implantation until Day 16 of gestation resulted in minor fetal visceral variations, an increase in post-implantation loss, and reduced gravid uterine and fetal weights at 150 mg/kg/day.”
Safety pharmacology
Dog: decreased heart rate and blood pressure, sustained QTcR prolongation, raised glucose and insulin
“In safety pharmacology studies, single oral administration of capivasertib at 5, 30 and 40 mg/kg induced decreased heart rate for up to 8 hours, peak decreases in systolic and diastolic blood pressure with recovery within 4 hours, sustained prolongation of QTcR and increases in LVdP/dt+ along with elevation of both glucose and insulin levels 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 Truqap 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 oncology small molecules (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Targets: insulin signaling, cardiovascular system, male reproductive organs, liver, kidney, HPA axis, hematopoietic system (FDA multi-discipline review, p. 47)
NOAEL / key findings
Targets: insulin signaling, cardiovascular system, male reproductive organs, liver, kidney, HPA axis, hematopoietic system
“The major target organs/systems identified in the nonclinical studies comprised insulin signaling, cardiovascular system, male reproductive organs, liver, kidneys, hypothalamic pituitary axis and hematopoietic system.”
Risksopen answer page →
Immune & cytokine safety
Decreased white blood cells and lymphocytes in rats
“Administration of capivasertib to rats resulted in increases in AST, ALT and GLDH, decreases in white blood cells and lymphocytes, increases in TSH”
Biodistribution & persistence
Reversible melanin binding in skin and uveal tract, persisting up to 168 h (skin) and 504 h (eye)
“Capivasertib was reversibly bound to melanin with persistence up to 168 h in the skin and 504 h in the eyes.”
Modality-specific risk
Hyperglycemia and altered insulin signaling from on-target AKT inhibition
“Inhibition of the AKT pathway is expected to alter glucose homeostasis. Increased blood glucose and insulin were seen in rats and dogs treated with capivasertib.”