Tukysa
tucatinib
Species
MonkeyRat
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 cynomolgus monkey
“Twice daily oral administration of tucatinib was assessed in repeat-dose toxicity studies for up to 3 months in rats and monkeys, consistent with the clinical route of administration and intended dosing schedule.”
Why that species
Sequence homology, historical use (rat) and higher oral tolerability (monkey)
“The pharmacological relevance of the toxicological species was discussed by the applicant and taking sequence homology information as well as a justification based on historical use (rat) and higher oral tolerability (monkey) into account, the chosen species were considered acceptable.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a 90-day cynomolgus monkey study, males and females (6/sex/group) were administered tucatinib at 0, 2.5, 10, or 20 mg/kg/dose twice daily (5, 20, or 40 mg/kg/day) via oral gavage.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Twice daily oral administration of tucatinib was assessed in repeat-dose toxicity studies for up to 3 months in rats and monkeys, consistent with the clinical route of administration and intended dosing schedule.”
Pivotal GLP studies
Twice-daily oral GLP repeat-dose studies up to 3 months in rats and monkeys
“Twice daily oral administration of tucatinib was assessed in repeat-dose toxicity studies for up to 3 months in rats and monkeys, 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 gavage (rats, monkeys); naso-gastric administration in a monkey study
“Repeat dose studies were conducted in rats via oral gavage (Study 1140-028; GLP Study 8369684) and in monkeys via naso-gastric (Study JAY00093; GLP study) and oral gavage (Study 8369685; GLP study).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and mouse bone marrow micronucleus assays
“Tucatinib did not induce mutations in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration test or the in vivo mouse bone marrow micronucleus assay at doses up to the high dose of 2000 mg/kg.”
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 and rabbit EFD: teratogenic in rabbits, embryo-fetal toxicity in rats
“Tucatinib administered to pregnant dams caused teratogenicity in rabbits and embryo-fetal toxicity in rats.”
Safety pharmacology
No adverse ECG, respiratory or neurobehavioral effects in safety pharmacology studies
“Tucatinib had no adverse effect on ECG, respiration, or neurological behavior in safety pharmacology studies.”
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 Tukysa 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 and liver (rat, monkey); hemolymphoid, skeletal muscle and reproductive system (rat) (FDA multi-discipline review, p. 34)
NOAEL / key findings
Targets: GI tract and liver (rat, monkey); hemolymphoid, skeletal muscle and reproductive system (rat)
“Administration of tucatinib to rats and monkeys resulted in body weight loss, reduced food consumption, and adverse effects in the gastrointestinal (GI) system (rat and monkey), liver (rat and monkey), hemolymphoid system (rat), skeletal muscle (rat), and reproductive system (rat).”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion (hemolymphoid system) in rats
“Additional target organs in rats included the hemolymphoid system (lymphoid depletion), male and female reproductive organs, and skeletal muscle (myofiber degeneration/regeneration and hemorrhage) in male rats in the 28-day study.”
Biodistribution & persistence
Rat: highest in uveal tract, eyes, pigmented skin, liver, testes; not detected in CNS
“the highest distribution of tucatinib in rats was in the uveal tract, eyes, pigmented skin, liver, testes, epididymis (male), and thymus (female); tucatinib was not detected in CNS tissues.”
Modality-specific risk
GI and liver toxicity (major toxicities in rats and monkeys)
“Toxicities in the GI system and liver were observed in both rats and monkeys and are considered the major toxicities associated with tucatinib treatment.”