Jaypirca
pirtobrutinib
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
“Repeat-dose toxicology studies of up to 3 months were conducted in rats and dogs, using an oral route of administration, consistent with the proposed clinical route.”
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
“In this GLP study, pirtobrutinib was administered to Sprague Dawley rats at 0, 50, or 500 mg/kg in males or 0, 60, 300 mg/kg in females BID via oral gavage for 15 weeks.”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and dog)
“Repeat-dose toxicology studies of up to 3 months were conducted in rats and dogs, using an oral route of administration, consistent with the proposed clinical route.”
Pivotal GLP studies
3-month GLP oral repeat-dose studies in rats and dogs
“See additional information provided below for the 3-month repeat-dose toxicity studies in rats and dogs.”
Route in tox
Oral (gavage, twice daily)
“In this GLP study, pirtobrutinib was administered to Sprague Dawley rats at 0, 50, or 500 mg/kg in males or 0, 60, 300 mg/kg in females BID via oral gavage for 15 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; aneugenic in in vitro human lymphocyte micronucleus assays; negative in in vivo rat bone marrow micronucleus assay
“Pirtobrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay. Pirtobrutinib was aneugenic in in vitro micronucleus assays using human peripheral blood lymphocytes. Pirtobrutinib was not genotoxic in an in vivo rat bone marrow micronucleus assay at doses up to 2000 mg/kg.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“No carcinogenicity studies with pirtobrutinib were submitted as these studies are not warranted for advanced cancer indications (ICH S9).”
Reproductive & developmental
EFD: decreased fetal weight and urinary tract, reproductive tract and bone malformations at ≥375 mg/kg BID
“Doses ≥ 375 mg/kg twice daily caused decreased fetal body weights and increased incidence of malformations and variations in the urinary tract (including absent or abnormal ureters and kidneys), reproductive tract (malpositioned ovaries and misshapen uterus), and bone (misshapen sternebrae).”
Safety pharmacology
No CNS, respiratory or cardiovascular toxicities of concern in safety pharmacology studies
“Safety pharmacology studies did not point to any toxicities of concern in the CNS, respiratory, or cardiovascular systems.”
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 Jaypirca 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: Dog: minimal to mild corneal lesions at high dose; NOAEL 2.5 mg/kg BID, limited by adverse eye effects at 5 mg/kg BID (EMA assessment report, p. 33)
NOAEL / key findings
Dog: minimal to mild corneal lesions at high dose; NOAEL 2.5 mg/kg BID, limited by adverse eye effects at 5 mg/kg BID
“Minimal to mild corneal lesions were observed in two high dose dogs at systemic exposure below human exposure at 200 mg QD. In addition, pirtobrutinib caused a decrease in B lymphocytes and a decrease in the TDAR following KLH immunisation. The NOAEL was 2.5 mg/kg BID, due to adverse eye effects at 5 mg/kg BID.”
Risksopen answer page →
Immune & cytokine safety
Decreased B lymphocytes and TDAR response to KLH; adverse only for the anti-KLH TDAR in male rats
“Effects on immune system function consisted of a shift in the balance of T, B, and NK lymphocytes, largely due to a decrease in B lymphocytes, and decreased TDAR response to KLH, a foreign antigen. With the exception of the anti-KLH TDAR in male rats, these effects were not considered adverse due to the lack of effect on the overall well-being of the animals.”
Biodistribution & persistence
Radioactivity persisted in uveal tract and liver at 168 h (t1/2 66.4 and 56.1 h)
“The radioactivity declined over time to below the lower limit of quantitation (< 178 ng-eq) by 168 hours post dose for all tissues but the uveal tract and liver (294 and 262 ng-eq, respectively at 168 hours), with a calculated t1/2 of 66.4 and 56.1 hours, respectively.”
Modality-specific risk
Aneugenicity: in vitro micronucleus induction via chromosome loss
“Pirtobrutinib was positive for the induction of micronuclei under the conditions of this study at concentrations ≥ 12 µg/mL. Based on the high level of centromere-positive staining, the micronuclei were induced via a predominantly aneugenic mechanism (chromosome loss).”