Qinlock
ripretinib
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
“To assess its safety, the Applicant conducted GLP‐compliant toxicology studies of daily oral administration of ripretinib up to 13 weeks in Sprague Dawley rats and Beagle dogs.”
Why that species
Rat and dog form the same metabolites as humans
“The justification for the relevance of these test species includes: in vitro studies of metabolic stability and metabolite identification comparing mouse, rat, dog, monkey, and human, where rat and/or dog were demonstrated to form the same metabolites as humans.”
Surrogate molecule
No surrogate; the clinical compound was tested
“To assess its safety, the Applicant conducted GLP‐compliant toxicology studies of daily oral administration of ripretinib up to 13 weeks in Sprague Dawley rats and Beagle dogs.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“To assess its safety, the Applicant conducted GLP‐compliant toxicology studies of daily oral administration of ripretinib up to 13 weeks in Sprague Dawley rats and Beagle dogs.”
Pivotal GLP studies
4- and 13-week oral studies in rats and dogs, with 4-week recovery
“Ripretinib was evaluated in repeat dose toxicity studies in rats and dogs (14 days, 4 weeks with 4 weeks recovery, 13 weeks with 4 weeks recovery).”
Route in tox
Oral
“The oral route of administration was utilized in all pivotal toxicology studies to match the intended clinical administration route.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration, and in vivo rat micronucleus and comet assays
“Ripretinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in either the in vitro chromosomal aberrations assay in isolated human lymphocytes or the in vivo micronucleus and comet assays in rats.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“The lack of carcinogenicity studies is acceptable and according to the ICH S9 guideline.”
Reproductive & developmental
Rat EFD: cardiovascular and skeletal fetal malformations at 20 mg/kg (~0.4x clinical exposure)
“At the dose of 20 mg/kg daily (approximately 0.4 times the estimated clinical exposure at 150 mg), fetal malformations associated with the cardiovascular and skeletal systems were observed.”
Safety pharmacology
Dog telemetry: heart rate up to +129%, raised diastolic and mean arterial pressure, no QTc effect
“A single dose of ripretinib in beagle dogs resulted in increases in heart rate of up to 129% with secondary decreases in QT and PR intervals, as well as increases in diastolic and mean arterial pressure starting at 7 mg/kg; however, ripretinib did not appear to influence QTc intervals.”
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 Qinlock 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: Skin was the major target in both species; teeth, lung and male reproductive tract also in rats (FDA multi-discipline review, p. 39)
NOAEL / key findings
Skin was the major target in both species; teeth, lung and male reproductive tract also in rats
“The major target organ of toxicity in both species was the skin; in the rat, the teeth, lung, and male reproductive tract were additional target organs.”
Risksopen answer page →
Immune & cytokine safety
Reduced thymus weight with decreased lymphocytes in dogs
“The weight of the thymus was reduced which correlated with the decreased number of lymphocytes observed microscopically.”
Biodistribution & persistence
Extensive, long-lived melanin binding in pigmented eye tissues (rat QWBA)
“Radiolabel associated with [14C]-ripretinib was extensively bound to melanin-containing tissues in pigmented LE rats such as eye ciliary body, eye uveal tract, and eyes, and the radiolabel binding showed a long half-life.”
Modality-specific risk
Phototoxic potential of ripretinib and its active metabolite DP-5439 (positive 3T3 NRU assay)
“Ripretinib and the active metabolite DP-5439 were investigated in the 3T3 NRU assay. Both substances demonstrated phototoxic potential in the assay.”