Accrufer
ferric maltol
Species
Dog
Longest study
4 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Dog
“Twenty-eight-day repeat dose oral administration toxicity studies were conducted in dogs with initial ferric maltol doses of 0, 250, 500, and 1000 mg/kg.”
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
“Twenty-eight-day repeat dose oral administration toxicity studies were conducted in dogs with initial ferric maltol doses of 0, 250, 500, and 1000 mg/kg.”
Study lengthopen answer page →
Longest pivotal study
4 (28-day dog)
“Twenty-eight-day repeat dose oral administration toxicity studies were conducted in dogs with initial ferric maltol doses of 0, 250, 500, and 1000 mg/kg.”
Pivotal GLP studies
GLP 28-day oral (gavage then capsule) dog study with ferric maltol
“Study title/ number: Iron Maltol: 28 Day Oral (Gavage/Capsule) Sub-Chronic Toxicity Study in the Beagle/6148-148/40”
Route in tox
Oral (gavage days 1–5, then capsule)
“Route of administration: Oral gavage on days 1 through 5 then oral capsule from day 6 onward.”
Skipped studiesopen answer page →
Genotoxicity
Ferric maltol positive in Ames; maltol positive in Ames and in vivo mouse micronucleus assay
“Ferric maltol was mutagenic in vitro in bacterial reverse mutation (Ames) assays. Ferric maltol increased revertant frequency in the absence and presence of metabolic activation. Fertility studies have not been conducted with ferric maltol. Maltol was mutagenic in the Ames assay and increased micronuclei in an in vivo clastogenicity assay in mice.”
Carcinogenicity
Maltol (complex component) not carcinogenic in 18-month mouse and 2-year rat studies up to 400 mg/kg
“Maltol was not carcinogenic in a 18-month study in mice at doses up to 400 mg/kg (approximately 5.6 times the human daily dose). Maltol was not carcinogenic in a 2-year study in rats at doses up to 400 mg/kg (approximately 11.2 times the human daily dose).”
Reproductive & developmental
Maltol multigeneration rat study: no effects on mating, fertility or early embryonic development up to 400 mg/kg/day
“In a multi-generation animal reproduction study in male and female rats, there were no effects on mating, fertility, or early embryonic development at doses up to 400 mg/kg/day (approximately 11.2 times the human daily dose).”
Safety pharmacology
Not conducted; justified because the active moiety is iron
“No standalone safety pharmacology studies were conducted for ferric maltol, which is scientifically justified as the active moiety is iron.”
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 Accrufer 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: Dog: reduced food intake; raised platelets, ALP and bilirubin; increased liver, kidney, adrenal and thyroid weights; iron in liver and kidney cells (FDA multi-discipline review, p. 29)
NOAEL / key findings
Dog: reduced food intake; raised platelets, ALP and bilirubin; increased liver, kidney, adrenal and thyroid weights; iron in liver and kidney cells
“Test article-related toxicities included reduced food intake, increased platelet counts, alkaline phosphatase activity, and bilirubin concentrations. Liver, kidney, adrenals, and thyroid weights increased. Liver and kidney cells stained for the presence of iron.”
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
Rat: absorbed iron bound to transferrin; after IV dosing, highest iron levels in liver and bone marrow, protein-bound
“Radiolabeled iron from ferric maltol in the rat intraduodenal administration studies was found bound to transferrin with a time to half maximal concentration (T½) of 133 minutes. Ferric maltol as single 1000 µg or 1 mg IV doses of iron was administered to rats, resulting in highest iron concentrations in the liver and bone marrow, with the iron being bound to proteins.”
Modality-specific risk
Mutagenicity of ferric maltol and maltol in Ames assays
“Ferric maltol was mutagenic in vitro in bacterial reverse mutation (Ames) assays.”