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.”
Species: general tox
Rat and dog (28-day IV)
“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.”
Species: DART
Rat, rabbit and cynomolgus monkey (oral EFD)
“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.”
Species: 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.”
Surrogate used in
No surrogate used; pivotal studies used the to-be-marketed artesunate formulation
“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.”
Genotox: Ames
Negative
“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).”
Genotox: in vitro mammalian
Chromosome aberration assay (CHO): negative
“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).”
Genotox: in vivo
Mouse and rat micronucleus assays: negative
“The potential genotoxicity of artesunate was investigated by the Applicant (bacterial reverse mutagen assay, in vitro chromosome aberration assay and 2 in vivo micronucleus assays (mouse and rat) and was found to be negative for genotoxic or mutagenic potential.”
Carcinogenicity model
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.”
Carcinogenicity timing
Not required: 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.”
hERG / QT
No adverse 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.”
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.
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
28-day IV dog study with 28-day recovery (28-day IV rat study of the same design)
“A 28-day Repeated Intravenous Dose Toxicity and Toxicokinetic Study of Artesunate in Beagle Dogs Followed by a 28-day Recovery Period”
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.”
DART package
Species: DART
Rat, rabbit and cynomolgus monkey (oral EFD)
“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.”
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.”
PPND / ePPND: when
Not conducted: PPND judged uninformative given embryolethality and malformations in oral EFD studies
“The extent of embryolethality and fetal malformations observed in the oral embryo-fetal development studies indicate that pre-and postnatal development study(ies) conducted with artesunate, by any route of administration route, would not yield any clinically meaningful information.”
Carcinogenicity
Species: 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.”
Carcinogenicity model
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.”
Carcinogenicity timing
Not required: 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.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat NOAEL 3 mg/kg/day = 0.2x clinical dose (body surface area)
“The NOAEL was 3 mg/kg/day, a dose equivalent to 0.2 that of the clinical dose based on body surface area comparisons.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Malaria infection models: P. berghei rodents, P. falciparum-infected immunocompromised mice, Plasmodium-infected nonhuman primates
“Overall, the studies support the activity of artesunate and DHA in severe malaria animal models that include rodents infected with the erythrocytic stage parasites of P. berghei, immunocompromised chimeric mice infected with P. falciparum, nonhuman primates infected with P. coatneyi, P. cynomolgi, P. falciparum or P. knowlesi.”
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
Supports activity in severe malaria animal models, but recrudescence occurs after treatment stops
“Overall, the studies support the activity of artesunate and DHA in severe malaria animal models that include rodents infected with the erythrocytic stage parasites of P. berghei, immunocompromised chimeric mice infected with P. falciparum, nonhuman primates infected with P. coatneyi, P. cynomolgi, P. falciparum or P. knowlesi. However, recrudescence occurs after discontinuation of treatment.”
Flexibilityopen answer page →
Flexibility accepted
GenotoxicityAccepted with a conditionBeyond the letter
No adequate in vivo genotoxicity characterisation of IV artesunate at approval; GLP in vivo micronucleus test deferred
Why: Severity of severe malaria and unmet need for treatments · Serious disease · Rare disease / unmet need
“The submitted nonclinical safety information on IV artesunate lacks adequate characterization of the in vivo genotoxic potential and the potential risks on female fertility. However, given the severity of the disease and the unmet need for drugs intended to treat severe malaria the current nonclinical package supports approval for marketing in the U.S.”
“The Applicant will be conducting the following nonclinical studies as postmarketing requirements: a GLP-in vivo micronucleus test and a female fertility study with IV artesunate.”
DARTAccepted with a conditionBeyond the letter
No formal fertility study; female fertility study with IV artesunate deferred to postmarketing
Why: Severity of disease and unmet need; female fertility study required postmarketing · Serious disease · Rare disease / unmet need
“Given the conflicting findings in animals and lack of any formal fertility study(ies), the risk that IV artesunate administration poses to human fertility is uncertain.”
“The Applicant will be conducting the following nonclinical studies as postmarketing requirements: a GLP-in vivo micronucleus test and a female fertility study with IV artesunate.”
DARTAcceptedBeyond the letter
No pre- and postnatal development study; judged uninformative given embryolethality and malformations in oral embryo-fetal studies
Why: Embryolethality and malformations in oral embryo-fetal studies mean a PPND study would add no clinically meaningful information · Weight of evidence
“The extent of embryolethality and fetal malformations observed in the oral embryo-fetal development studies indicate that pre-and postnatal development study(ies) conducted with artesunate, by any route of administration route, would not yield any clinically meaningful information.”
Safety pharmacologyAcceptedBeyond the letter
No GLP hERG study with artesunate
Why: No significant QTc prolongation detected in the clinical QT assessment · Human data
“Artesunate has not been evaluated in GLP studies for effects on human ether-a-go-go-related gene (hERG) tail currents. The Applicant was not requested to conduct a hERG study using artesunate as no significant QTc prolongation of artesunate was detected in the QT assessment (see Section 10.4.9).”
Safety marginVerdict not stated
Rat NOAEL 3 mg/kg/day equals 0.2 times the clinical dose (body surface area)
“The NOAEL was 3 mg/kg/day, a dose equivalent to 0.2 that of the clinical dose based on body surface area comparisons.”
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