Retevmo
selpercatinib
Species
RatPig
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and Göttingen minipig
“To assess the safety of selpercatinib, Loxo conducted GLP-compliant toxicology studies of up to 13-weeks in Sprague Dawley rats and Gottingen mini pigs.”
Why that species
Relevant rodent and non-rodent species based on pharmacokinetic and metabolic considerations
“Rats (Sprague-Dawley) and minipig (Göttingen) were chosen as relevant rodent and non-rodent species for toxicology program based on pharmacokinetic and metabolic considerations.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a 13-week study in minipigs, male and female animals received selpercatinib at doses of 2, 5, or 15 mg/kg/day for 13 weeks via oral gavage.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“To assess the safety of selpercatinib, Loxo conducted GLP-compliant toxicology studies of up to 13-weeks in Sprague Dawley rats and Gottingen mini pigs.”
Pivotal GLP studies
13-week GLP oral gavage studies in rats and minipigs, with 4-week recovery
“Due to sex-specific differences in exposure, in the 13-week toxicology study male rats received selpercatinb at doses of 2, 7.5, or 20 mg/kg while females received 7.5, 25, or 75 mg/kg daily via oral gavage, followed by a 4-week recovery.”
Route in tox
Oral gavage
“In a 13-week study in minipigs, male and female animals received selpercatinib at doses of 2, 5, or 15 mg/kg/day for 13 weeks via oral gavage.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and in vitro micronucleus; positive in rat in vivo micronucleus at high doses
“In the standard genotoxicity battery, selpercatinib was negative in both the Ames and the in vitro micronucleus assay regardless of metabolic activation. In the in vivo micronucleus assay in rats, selpercatinib did cause increases in micronuclei at high dose levels”
Carcinogenicity
2-year rat and 6-month rasH2 mouse: not carcinogenic
“not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice”
Reproductive & developmental
Rat EFD: embryolethality and malformations at maternal exposures approximately equal to human exposure
“Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily.”
Safety pharmacology
hERG IC50 1.1 µM; QT prolongation in female minipigs at 5 and 12 mg/kg in 28-day study
“LOXO-292 inhibited the hERG potassium current with IC50 of 1.1 μM in the GLP in vitro hERG assay studies, respectively, suggesting low potential for QTc prolongation. In the 28-day minipig study, statistically significant QT prolongation was observed in females administered 5 and 12 mg/kg LOXO-292 when compared to controls”
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 Retevmo 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: Minipig most sensitive species; major findings at lethal doses with exposures below human therapeutic exposure (FDA multi-discipline review, p. 80)
NOAEL / key findings
Minipig most sensitive species; major findings at lethal doses with exposures below human therapeutic exposure
“Minipigs were exquisitely sensitive to selpercatinib and was the most sensitive species. Major toxicological findings that occurred in the minipig were at doses that induced moribundity/lethality with exposures below therapeutic exposures in human.”
Risksopen answer page →
Immune & cytokine safety
Hematopoietic and lymphoid system changes
“Similar findings included: changes in hematopoietic, lymphoid, and GIT systems, liver and altered inorganic phosphorus levels (hyperphosphatemia).”
Biodistribution & persistence
Rat QWBA: highest in uveal tract, eyes, Harderian gland, meninges and melanin-containing skin
“Tissues from male rats that received 10 mg/kg [14C]-labeled selpercatinib showed the highest levels in uveal tract (24 hours post-dose), eyes (24 hr), Harderian gland (2 hr), meninges (72 hr), and pigmented (melanin-containing) skin (8 hr).”
Modality-specific risk
QTc prolongation (labeled warning)
“The label includes a warning for QTc prolongation.”