Voquezna
vonoprazan
Sources:FDA integrated review ↗
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“In repeated dose toxicology studies in rats and dogs, the stomach, liver, thyroid, and adrenal glands were identified as target organs of toxicity following oral administration of vonoprazan.”
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 repeated dose toxicology studies in rats and dogs, the stomach, liver, thyroid, and adrenal glands were identified as target organs of toxicity following oral administration of vonoprazan.”
Species: general tox
Rat (up to 26-week) and dog (up to 39-week)
“In repeated dose toxicology studies in rats and dogs, the stomach, liver, thyroid, and adrenal glands were identified as target organs of toxicity following oral administration of vonoprazan.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“In the embryofetal development study in rabbits, no embryo-fetal mortality or toxicity occurred, and there were no external, visceral, or skeletal abnormalities. In the pre- and post-natal developmental study in rats, decreased body weight gain compared to controls was observed in the offspring from dams in the high dose group.”
Species: carcinogenicity
Mouse and rat (2-year)
“In a 2-year carcinogenicity study in mice and rats, hepatocellular adenomas and carcinomas and drug-related increases in benign and malignant neuroendocrine cell tumors in the stomachs were noted.”
Surrogate used in
No surrogate used; vonoprazan tested directly
“In repeated dose toxicology studies in rats and dogs, the stomach, liver, thyroid, and adrenal glands were identified as target organs of toxicity following oral administration of vonoprazan.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“Dose and frequency of dosing: 0, 0.3, 0.6 and 2 mg/kg/day (5 mL/kg), once daily for 39 weeks.”
Pivotal GLP studies
39-week oral gavage study in beagle dogs
“Dose and frequency of dosing: 0, 0.3, 0.6 and 2 mg/kg/day (5 mL/kg), once daily for 39 weeks. Route of administration: Oral gavage Formulation/vehicle: 0.5% methylcellulose solution. Species/strain: Beagle dogs”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, CHL chromosomal aberration and rat bone marrow micronucleus assays
“Vonoprazan was not genotoxic in the bacterial reverse mutation assay, an in vitro chromosomal aberration assay in Chinese Hamster lung cells, and an in vivo rat bone marrow micronucleus test.”
Carcinogenicity
2-year mouse and rat: hepatocellular adenomas/carcinomas and gastric neuroendocrine cell tumors
“In a 2-year carcinogenicity study in mice and rats, hepatocellular adenomas and carcinomas and drug-related increases in benign and malignant neuroendocrine cell tumors in the stomachs were noted.”
Reproductive & developmental
Rat EFD: ventricular septal defect, malpositioned subclavian artery, tail and anal abnormalities only at 300 mg/kg/day
“In the embryofetal development study in rats, fetal abnormalities were limited to the 300 mg/kg/day dose and included ventricular septal defect and mal-positioned subclavian artery in fetuses, as well as tail abnormalities and small anal opening.”
Safety pharmacology
hERG IC50 4.8 mcg/mL (>100-fold human Cmax); no dog cardiovascular effects up to 20 mg/kg
“The IC50 for the inhibitory effect of vonoprazan on human Ether-à-go-go-Related Gene (hERG) current was 4.8 mcg/mL, which is more than 100-fold higher than the mean maximum plasma concentration (Cmax) for the 20 mg dose vonoprazan in humans.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Vonoprazan was not genotoxic in the bacterial reverse mutation assay, an in vitro chromosomal aberration assay in Chinese Hamster lung cells, and an in vivo rat bone marrow micronucleus test.”
Genotox: in vitro mammalian
Chromosomal aberration in Chinese hamster lung cells: negative
“Vonoprazan was not genotoxic in the bacterial reverse mutation assay, an in vitro chromosomal aberration assay in Chinese Hamster lung cells, and an in vivo rat bone marrow micronucleus test.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Vonoprazan was not genotoxic in the bacterial reverse mutation assay, an in vitro chromosomal aberration assay in Chinese Hamster lung cells, and an in vivo rat bone marrow micronucleus test.”
Carcinogenicity model
2-year mouse and 2-year rat
“In a 2-year carcinogenicity study in mice and rats, hepatocellular adenomas and carcinomas and drug-related increases in benign and malignant neuroendocrine cell tumors in the stomachs were noted.”
Carcinogenicity timing
2-year mouse and 2-year rat studies completed before the marketing application
“In a 2-year carcinogenicity study in mice and rats, hepatocellular adenomas and carcinomas and drug-related increases in benign and malignant neuroendocrine cell tumors in the stomachs were noted.”
hERG / QT
hERG IC50 4.8 mcg/mL, >100-fold above human Cmax at 20 mg
“The IC50 for the inhibitory effect of vonoprazan on human Ether-à-go-go-Related Gene (hERG) current was 4.8 mcg/mL, which is more than 100-fold higher than the mean maximum plasma concentration (Cmax) for the 20 mg dose vonoprazan in humans.”
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 Voquezna 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Rat targets: stomach, liver, thyroid, adrenal glands; dog: mainly stomach (FDA integrated review, p. 140)
NOAEL / key findings
Rat targets: stomach, liver, thyroid, adrenal glands; dog: mainly stomach
“In repeated dose toxicology studies in rats, the stomach, liver, thyroid, and adrenal glands were identified as target organs of toxicity. In dogs, the stomach was the main target organ of toxicity.”
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Biodistribution & persistence
Wide distribution in rats, highest in liver, kidney, intestine, lung and stomach wall; low in brain and spinal cord
“In rats, vonoprazan and its metabolites were widely distributed with higher concentration in the liver, kidney, intestine, lung, and stomach wall than in the plasma, and were low in the brain and the spinal cord.”
Modality-specific risk
Carcinogenicity: hepatocellular and gastric neuroendocrine tumors in mice and rats
“In a 2-year carcinogenicity study in mice and rats, hepatocellular adenomas and carcinomas and drug-related increases in benign and malignant neuroendocrine cell tumors in the stomachs were noted.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Warnings and Precautions for VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK
- Additional Warnings and Precautions for VOQUEZNA TRIPLE PAK Due to the Clarithromycin Component
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Voquezna 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Rat targets: stomach, liver, thyroid, adrenal glands; dog: mainly stomach (FDA integrated review, p. 140)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral gavage study in beagle dogs; recovery phase not clearly described
“Dose and frequency of dosing: 0, 0.3, 0.6 and 2 mg/kg/day (5 mL/kg), once daily for 39 weeks.”
Pivotal GLP studies
39-week oral gavage study in beagle dogs
“Dose and frequency of dosing: 0, 0.3, 0.6 and 2 mg/kg/day (5 mL/kg), once daily for 39 weeks. Route of administration: Oral gavage Formulation/vehicle: 0.5% methylcellulose solution. Species/strain: Beagle dogs”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“In the embryofetal development study in rabbits, no embryo-fetal mortality or toxicity occurred, and there were no external, visceral, or skeletal abnormalities. In the pre- and post-natal developmental study in rats, decreased body weight gain compared to controls was observed in the offspring from dams in the high dose group.”
Reproductive & developmental
Rat EFD: ventricular septal defect, malpositioned subclavian artery, tail and anal abnormalities only at 300 mg/kg/day
“In the embryofetal development study in rats, fetal abnormalities were limited to the 300 mg/kg/day dose and included ventricular septal defect and mal-positioned subclavian artery in fetuses, as well as tail abnormalities and small anal opening.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“Study for Effects of TAK-438 on Pre- and Postnatal Development, Including Maternal Functions, in Rats (Study # TAK-438-11215).”
Carcinogenicity
Species: carcinogenicity
Mouse and rat (2-year)
“In a 2-year carcinogenicity study in mice and rats, hepatocellular adenomas and carcinomas and drug-related increases in benign and malignant neuroendocrine cell tumors in the stomachs were noted.”
Carcinogenicity model
2-year mouse and 2-year rat
“In a 2-year carcinogenicity study in mice and rats, hepatocellular adenomas and carcinomas and drug-related increases in benign and malignant neuroendocrine cell tumors in the stomachs were noted.”
Carcinogenicity timing
2-year mouse and 2-year rat studies completed before the marketing application
“In a 2-year carcinogenicity study in mice and rats, hepatocellular adenomas and carcinomas and drug-related increases in benign and malignant neuroendocrine cell tumors in the stomachs were noted.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat EFD NOAEL 100 mg/kg: ~27x clinical exposure
“No treatment-related fetal malformations or variations were reported at the 100 mg/kg dose (27-fold higher exposure than the expected clinical exposure based on exposure data extrapolated from nonpregnant rats).”
NOAEL / key findings
Rat targets: stomach, liver, thyroid, adrenal glands; dog: mainly stomach
“In repeated dose toxicology studies in rats, the stomach, liver, thyroid, and adrenal glands were identified as target organs of toxicity. In dogs, the stomach was the main target organ of toxicity.”
Efficacy evidenceopen answer page →
Efficacy evidence
Rat NSAID-induced gastric lesion and experimental reflux esophagitis models
“Oral administration of vonoprazan inhibited aspirin and indomethacin-induced gastric lesions in rats. Vonoprazan also inhibited experimental reflux esophagitis in rats.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
FDA: nonclinical pharmacology findings support the proposed indications
“Thus, the findings of the nonclinical pharmacology studies conducted with vonoprazan support the proposed indications under the current NDA.”
Flexibilityopen answer page →
Flexibility accepted
No departure named in the public reviews.
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