Artesunate
artesunate
Species
RatDog
Longest study
4 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
“No such observations were evident in the 28-day pivotal repeat dose studies in rat and dog up to doses of 30 mg/kg and 40 mg/kg, respectively.”
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
“pivotal repeated-dose toxicity studies in rat and dog were conducted using the to-be-marketed formulation of semi-synthetic artesunate in 0.3 M phosphate buffer.”
Study lengthopen answer page →
Longest pivotal study
4 (28-day rat and dog)
“No such observations were evident in the 28-day pivotal repeat dose studies in rat and dog up to doses of 30 mg/kg and 40 mg/kg, respectively.”
Pivotal GLP studies
28-day rat (up to 30 mg/kg) and dog (up to 40 mg/kg) repeat-dose studies
“No such observations were evident in the 28-day pivotal repeat dose studies in rat and dog up to doses of 30 mg/kg and 40 mg/kg, respectively.”
Route in tox
Intravenous (oral for reproductive and developmental studies)
“IV administration was employed for single and repeat dose studies; oral administration was predominantly used in reproductive and developmental toxicity studies.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, CHO chromosome aberration and in vivo micronucleus assays
“In studies conducted by the Applicant, artesunate was negative in the Ames test, mammalian chromosome aberration assay (CHO), and in vivo micronucleus assay (up to 500 mg/kg, highest concentration tested).”
Carcinogenicity
Not conducted (short treatment duration, up to 7 days)
“No carcinogenicity studies have been conducted with artesunate. Given the short duration of treatment (up to 7 days) carcinogenicity studies are not indicated.”
Reproductive & developmental
Oral EFD in rats, rabbits and monkeys: post-implantation loss at well below clinically relevant doses
“Oral administration of artesunate during organogenesis caused a significant increase in post-implantation loss in pregnant rats, rabbits and cynomolgus monkeys at significantly less than clinically relevant doses based on body surface area comparisons.”
Safety pharmacology
No cardiovascular effects in conscious dogs at IV doses up to 40 mg/kg (~9x clinical dose)
“No adverse effects on cardiovascular function were observed in conscious beagle dogs following single or repeated (up to 27 days) IV dosing up to 40 mg/kg, approximately nine times the clinical dose based on body surface area comparison.”
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 Artesunate 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 NOAEL 3 mg/kg/day (~0.2x clinical dose by BSA); hematologic and histopathologic changes reversible after recovery (FDA multi-discipline review, p. 38)
NOAEL / key findings
Rat NOAEL 3 mg/kg/day (~0.2x clinical dose by BSA); hematologic and histopathologic changes reversible after recovery
“Histopathologic and hematologic changes were comparable to controls at the end of recovery, indicating reversibility of effects. The NOAEL was 3 mg/kg/day, a dose equivalent to 0.2 that of the clinical dose based on body surface area comparisons.”
Risksopen answer page →
Immune & cytokine safety
Increased leukocytes and fibrinogen, indicating an inflammatory response
“In addition to reductions in red blood cells and hemoglobin, animals also had increased leukocytes and fibrinogen, indicating an inflammatory response.”
Biodistribution & persistence
Highest tissue levels at 0.5 h in small intestine, spleen and bone marrow; CNS levels low but persistent
“Highest tissue concentrations were observed 0.5 hr after dosing, in the small intestine, spleen and bone marrow. CNS concentrations were low but persisted until the end of the study, similar to other tissues.”
Modality-specific risk
Embryolethality and fetal malformations without maternal toxicity
“Embryolethality and/or fetal malformations following oral artesunate administration occurred in the absence of maternal toxicity.”