Piqray
alpelisib
Species
RatDog
Longest study
13 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
“Daily oral administration of alpelisib was assessed in repeat-dose toxicity studies for up to 3 months in rats and dogs, consistent with the clinical route of administration and intended dosing schedule.”
Why that species
Pharmacodynamic target and major human metabolic pathways represented in rat and dog
“The pharmacodynamic target and the major pathways of alpelisib metabolism in humans were all represented in these species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Daily oral administration of alpelisib was assessed in repeat-dose toxicity studies for up to 3 months in rats and dogs, consistent with the clinical route of administration and intended dosing schedule.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“The toxicity of alpelisib after repeated oral administration was studied in rats and dogs with dosing up to 13 weeks.”
Pivotal GLP studies
GLP oral repeat-dose studies up to 3 months in rats and dogs
“Daily oral administration of alpelisib was assessed in repeat-dose toxicity studies for up to 3 months in rats and dogs, consistent with the clinical route of administration and intended dosing schedule. The pivotal repeat-dose toxicology studies were conducted in compliance with Good Laboratory Practice regulations (21 CFR part 58).”
Route in tox
Oral
“Daily oral administration of alpelisib was assessed in repeat-dose toxicity studies for up to 3 months in rats and dogs, consistent with the clinical route of administration and intended dosing schedule.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro micronucleus and chromosome aberration, and in vivo rat micronucleus assays
“Alpelisib did not induce mutations in the bacterial reverse mutation (Ames) assays and was not genotoxic in either the in vitro micronucleus and chromosome aberration tests or the in vivo rat micronucleus assay at 20 mg/kg, the top dose tested (1.7x human exposure based on AUC).”
Carcinogenicity
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Reproductive & developmental
Rat EFD: maternal toxicity and no viable fetuses (post-implantation loss) at 30 mg/kg/day (~3x human AUC)
“In rats, oral administration of alpelisib resulted in maternal toxicity (body weight loss, low food consumption) and no viable fetuses (post-implantation loss) at 30 mg/kg/day (approximately 3 times the exposure in humans at the recommended dose of 300 mg/day based on AUC).”
Safety pharmacology
Dose-independent blood pressure increase in dogs; no adverse ECG, respiratory or neurological effects
“A single oral administration of alpelisib induced a dose-independent increase in systolic and diastolic blood pressure in dogs at all doses tested (5, 15, 30 mg/kg) in the conducted safety pharmacology study. Alpelisib had no adverse effects on ECG, respiration, or neurological behavior in animals.”
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 Piqray 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: GI tract, hemolymphoid system, skin, metabolic (glucose/insulin) and reproductive system (FDA multi-discipline review, p. 38)
NOAEL / key findings
Targets: GI tract, hemolymphoid system, skin, metabolic (glucose/insulin) and reproductive system
“Administration of alpelisib to rats and dogs resulted in adverse effects in the GI tract, hemolymphoid system, skin, metabolic, and reproductive system.”
Risksopen answer page →
Immune & cytokine safety
Inflammation and/or suppression in bone marrow, spleen, thymus and lymph nodes
“The effects in the hemolymphoid system included inflammation and/or suppressive effects in the bone marrow, spleen, thymus, or lymph nodes.”
Biodistribution & persistence
Distribution to hair and eyes of pigmented rats; melanin binding
“Nonclinical ADME studies indicated distribution of radioactivity to hair and eyes of pigmented rats, thus alpelisib and/or its metabolites can bind melanin.”
Modality-specific risk
On-target hyperglycemia and hyperinsulinemia with pancreatic endocrine changes
“Administration of alpelisib to rats and dogs increased blood insulin and glucose levels, which correlated with histopathologic changes in the pancreas (vacuolation or hyperplasia of endocrine cells).”