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.”
Species: general tox
Rat (up to 6 months) and dog (up to 9 months)
“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.”
Species: DART
Rat only (combined preliminary EFD and pre/postnatal study)
“In a GLP-compliant preliminary embryofetal development and pre- and post-natal study, capivasertib was administered at doses of 10, 30 and 150 mg/kg/day to pregnant rats from Day 2 to Day 16 of gestation (Phase 1) or from Day 6 of gestation to at least Day 6 of lactation (Phase 2).”
Species: carcinogenicity
Rat (2-year)
“In a 2-year rat carcinogenicity study, rats received oral doses up to 30 mg/kg/day in males and 75 mg/kg/day in females (approximately 0.2 times and 0.4 times the human exposure at the recommended dose based on AUC, respectively).”
Surrogate used in
No surrogate used; capivasertib tested directly
“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.”
Genotox: Ames
Negative
“Capivasertib was genotoxic in the in vivo rat bone marrow micronucleus assay through an aneugenic mechanism. Capivasertib was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay or mouse lymphoma gene mutation assay.”
Genotox: in vitro mammalian
Mouse lymphoma gene mutation assay: negative
“Capivasertib was genotoxic in the in vivo rat bone marrow micronucleus assay through an aneugenic mechanism. Capivasertib was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay or mouse lymphoma gene mutation assay.”
Genotox: in vivo
Rat bone marrow micronucleus: positive at 150 mg/kg (aneugenic); rat liver Comet: negative
“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. In a Comet assay, capivasertib did not induce DNA damage in the liver of Wistar Han rats at doses up to 150 mg/kg.”
Carcinogenicity model
2-year rat, up to 30 (males) and 75 (females) mg/kg/day, ~0.2x and 0.4x human AUC
“In a 2-year rat carcinogenicity study, rats received oral doses up to 30 mg/kg/day in males and 75 mg/kg/day in females (approximately 0.2 times and 0.4 times the human exposure at the recommended dose based on AUC, respectively).”
Carcinogenicity timing
Not conducted: not warranted for an advanced cancer indication
“Carcinogenicity studies with capivasertib were not warranted to support this NDA, as the proposed indication is for advanced cancer.”
hERG / QT
hERG IC50 73.0 µM (>100-fold unbound clinical Cmax); sustained QT prolongation in dogs at 30 and 40 mg/kg
“Capivasertib exerted concentration-dependent hERG channel activity with the IC50 value of 73.0 μM. This is more than 100-fold of the unbound clinical Cmax. In male Beagle dogs, oral dosing of 30 and 40 mg/kg capivasertib led to a reversible reduction in systolic and diastolic blood pressure and heart rate and caused a sustained statistically significant prolongation of the QT interval.”
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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
- Hyperglycemia
- Diarrhea
- Cutaneous Adverse Reactions
- Embryo-Fetal Toxicity
Metabolic & endocrineGastrointestinalSkin reactionsEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
Repeat-dose tox before first-in-human
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.
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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month dog (oral), no recovery group
“it is acknowledged that cardiac effects were not noticed in the 9-months dog study and no safety signal in clinical studies were observed; however this study did not include a recovery group (similar to the long-term rat study).”
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.”
DART package
Species: DART
Rat only (combined preliminary EFD and pre/postnatal study)
“In a GLP-compliant preliminary embryofetal development and pre- and post-natal study, capivasertib was administered at doses of 10, 30 and 150 mg/kg/day to pregnant rats from Day 2 to Day 16 of gestation (Phase 1) or from Day 6 of gestation to at least Day 6 of lactation (Phase 2).”
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.”
PPND / ePPND: when
Combined preliminary EFD and PPND study in rat completed before the marketing application
“Preliminary studies on embryonic and foetal development in rats and a pre- and postnatal study have been carried out.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year)
“In a 2-year rat carcinogenicity study, rats received oral doses up to 30 mg/kg/day in males and 75 mg/kg/day in females (approximately 0.2 times and 0.4 times the human exposure at the recommended dose based on AUC, respectively).”
Carcinogenicity model
2-year rat, up to 30 (males) and 75 (females) mg/kg/day, ~0.2x and 0.4x human AUC
“In a 2-year rat carcinogenicity study, rats received oral doses up to 30 mg/kg/day in males and 75 mg/kg/day in females (approximately 0.2 times and 0.4 times the human exposure at the recommended dose based on AUC, respectively).”
Carcinogenicity timing
Not conducted: not warranted for an advanced cancer indication
“Carcinogenicity studies with capivasertib were not warranted to support this NDA, as the proposed indication is for advanced cancer.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: toxicities at ≥30 mg/kg in rats and ≥10 mg/kg in dogs, ~0.4x and 0.6x human AUC at 400 mg BID
“Most capivasertib-induced toxicities were dose-dependent and observed in rats at doses ≥ 30 mg/kg and in dogs at doses ≥ 10 mg/kg (approximately 0.4 and 0.6 times the exposure in humans at the recommended dose of 400 mg twice daily based on AUC, respectively).”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human cancer xenografts including ER+ breast cancer models with PIK3CA, AKT1 or PTEN alterations
“Capivasertib demonstrated anti-tumor activity in vivo in human cancer xenograft models including estrogen receptor positive (ER+) breast cancer models with mutations or alterations in PIK3CA, AKT1, and PTEN.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: dose-dependent xenograft efficacy with pharmacodynamic effect at clinically achievable plasma levels
“Oral capivasertib inhibited tumour growth in various mouse xenograft models including patient-derived ER+ breast cancer xenografts in a dose-dependent fashion. This was accompanied by the inhibition of phosphorylation of AKT downstream targets in a time- and dose-dependent manner demonstrating a pharmacodynamic effect at clinically achievable plasma drug levels.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
Only preliminary rat embryo-fetal studies; no definitive or second-species embryo-fetal study
Why: Capivasertib already shown to be embryolethal · Weight of evidence
“The applicant explained that further embryo-foetal development studies were not conducted with capivasertib as it has been shown to be embryolethal.”
“Conclusion on the non-clinical aspects The non-clinical data package evaluating the pharmacology and toxicity of capivasertib is considered acceptable to support the marketing authorisation.”
Impurity or metaboliteAccepted
No dog metabolism study and no toxicokinetic evaluation of the human glucuronide metabolite in animals
Why: Under ICH S9 separate metabolite evaluation generally not warranted for advanced cancer · Within the guideline · Serious disease
“However, it would have been helpful to generate such data in the dog considering that the glucuronide metabolite was formed in dog hepatocytes and in view of the fact that no meaningful margins of safety were found in the appropriate studies.”
“However, it is acknowledged that, according to ICH S9, no need for such evaluation is generally warranted (In some cases, metabolites that have been identified in humans have not been qualified in nonclinical studies. For these metabolites, a separate evaluation is generally not warranted for patients with advanced cancer).”
Safety marginVerdict not stated
Toxicities in rats and dogs at about 0.4 and 0.6 times human AUC at the recommended dose
“Most capivasertib-induced toxicities were dose-dependent and observed in rats at doses ≥ 30 mg/kg and in dogs at doses ≥ 10 mg/kg (approximately 0.4 and 0.6 times the exposure in humans at the recommended dose of 400 mg twice daily based on AUC, respectively).”
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