Defitelio
defibrotide
Species
RatDog
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 dog
“To support the current application, single-dose and repeat-dose toxicity studies were performed in rats and dogs with intravenous infusion.”
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; defibrotide itself was tested in rats and dogs
“To support the current application, single-dose and repeat-dose toxicity studies were performed in rats and dogs with intravenous infusion.”
Species: general tox
Rat and dog
“To support the current application, single-dose and repeat-dose toxicity studies were performed in rats and dogs with intravenous infusion.”
Species: DART
Rat and rabbit (IV EFD; not evaluable due to maternal mortality, abortion and resorption)
“Embryo-Fetal toxicity assessment was attempted in rats and rabbits, but was not possible because of high maternal mortality, abortion, and fetal resorption at all doses.”
Species: carcinogenicity
Mouse and rat (oral route)
“Two studies in mice and rats were conducted to review the potential long-term/carcinogenicity effects of defibrotide. The studies were performed to GLP standards and used the oral route of administration.”
Surrogate used in
No surrogate used; defibrotide tested directly in rats and dogs
“To support the current application, single-dose and repeat-dose toxicity studies were performed in rats and dogs with intravenous infusion.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“or vehicle was administered as a 2-hour intravenous infusion at a rate of 2.5 mL/kg/hour four times daily for 13 consecutive weeks.”
Pivotal GLP studies
Rat continuous IV infusion for 9 weeks; dog IV infusion of 2 h every 6 hours, 4 times daily, for 13 weeks
“Rats were given defibrotide by continuous iv infusion for 9 weeks. Dogs were given defibrotide by i.v. infusion of 2 h duration every 6 hours 4 times daily for 13 weeks.”
Route in tox
Intravenous infusion
“To support the current application, single-dose and repeat-dose toxicity studies were performed in rats and dogs with intravenous infusion.”
Skipped studiesopen answer page →
Genotoxicity
Negative: Ames assay and in vivo rat bone marrow micronucleus assay
“Defibrotide was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay) nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted by the intravenous route; oral studies inadequate to assess carcinogenic potential
“No carcinogenicity studies have been conducted with defibrotide administered by the intravenous route and the oral studies were inadequate to conduct an assessment of the potential for carcinogenicity.”
Reproductive & developmental
Rabbit embryo-fetal toxicity: fewer implantations and viable fetuses at doses about equal to the clinical dose (mg/m2)
“Exposure to defibrotide was associated with embryo-fetal toxicity (decreased number of implantations and viable fetuses compared to controls) in pregnant rabbits at doses approximately equivalent to the recommended clinical dose on a mg/m2 basis.”
Safety pharmacology
No hERG inhibition up to 500 µg/mL; ECG incorporated into 13-week dog infusion study
“Defibrotide did not reduce hERG tail current at concentrations up to 500 μg/ml. ECG examinations were performed as part of a 13 week intravenous infusion toxicity study in dogs.”
Genotox: Ames
Negative
“Defibrotide sodium was not mutagenic in vitro in a bacterial reverse mutation assay (Ames assay).”
Genotox: in vitro mammalian
Chromosomal aberration in Chinese hamster ovary cells: negative
“Defibrotide sodium was not clastogenic in an in vitro chromosomal aberrations assay in Chinese hamster ovary cells or an in vivo micronucleus assay conducted in bone marrow from rats administered defibrotide sodium by intravenous infusion.”
Genotox: in vivo
Rat bone marrow micronucleus (IV): negative
“Defibrotide sodium was not clastogenic in an in vitro chromosomal aberrations assay in Chinese hamster ovary cells or an in vivo micronucleus assay conducted in bone marrow from rats administered defibrotide sodium by intravenous infusion.”
Carcinogenicity model
No IV carcinogenicity studies; oral studies inadequate for assessment
“No carcinogenicity studies have been conducted with defibrotide administered by the intravenous route and the oral studies were inadequate to conduct an assessment of the potential for carcinogenicity.”
Carcinogenicity timing
Not required: no additional nonclinical studies needed to support approval
“Recommendation: I concur with the pharmacology/toxicology reviewers that from a nonclinical perspective, Defitelio may be approved and that no additional nonclinical studies are needed to support approval”
hERG / QT
Negative: no hERG tail current reduction up to 500 µg/mL
“Defibrotide did not reduce hERG tail current at concentrations up to 500 μg/ml.”
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 Defitelio 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 oligonucleotides 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: 13-week rat: adverse findings in kidneys, liver and lymphoid tissues; prolonged PT (rat) and APTT (rat and dog) (FDA pharmacology/toxicology review, p. 4)
NOAEL / key findings
13-week rat: adverse findings in kidneys, liver and lymphoid tissues; prolonged PT (rat) and APTT (rat and dog)
“Target organs of toxicity were identified in a 13-week rat toxicology study, which included adverse findings in the kidneys, liver and lymphoid tissues. Defibrotide also prolonged prothrombin time (PT) in rats, in addition to activated partial thromboplastin time (APTT) in rats and dogs.”
Risksopen answer page →
Immune & cytokine safety
Mouse 4-week immune function assays (NK activity, anti-SRBC response, macrophage cytotoxicity, lymphocyte proliferation): no clear effect
“Mice were treated orally or i.p. daily (5 days a week) for 4 weeks and a number of functional assays were performed (NK cell activity, anti-SRBC antibody response, macrophage cytotoxicity, lymphocyte proliferation). No clear effect on immune functions was observed.”
Biodistribution & persistence
Radiolabel distributed to kidneys, liver, bone marrow, spleen and small intestine; low levels in brain and fat
“Radio-labelled defibrotide showed preferential distribution into highly perfused tissues: kidneys, liver, bone marrow, spleen and small intestine with lower levels in rat testes and low levels to the brain and to fat.”
Modality-specific risk
Direct effects on coagulation (dose-dependent PT and APTT prolongation)
“Defibrotide may have direct effects on coagulation based on the dose-dependent effects of the drug on PT and APTT.”
Anti-drug antibodies: animals
Anti-drug antibodies assessed in rat and dog 13-week studies; results not reported
“The antigenicity and the potential of defibrotide to elicit anti-drug antibodies was assessed by testing rat and dog plasma samples generated in the repeat dose 13-week toxicity studies.”
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
- Hemorrhage
- Hypersensitivity Reactions
BleedingHypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
13-week rat: adverse findings in kidneys, liver and lymphoid tissues; prolonged PT (rat) and APTT (rat and dog)
“Target organs of toxicity were identified in a 13-week rat toxicology study, which included adverse findings in the kidneys, liver and lymphoid tissues. Defibrotide also prolonged prothrombin time (PT) in rats, in addition to activated partial thromboplastin time (APTT) in rats and dogs.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro studies, primarily in a human microvascular endothelial cell line
“Studies evaluating the pharmacological effects of defibrotide sodium on endothelial cells (ECs) were conducted primarily in the human microvascular endothelial cell line.”
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
EMA: pharmacological rationale not established; no extrapolation to clinical data based on pharmacological plausibility
“Based on the provided data, the CHMP concluded that the pharmacological rationale for the use of defibrotide has not been established; therefore, no extrapolations to clinical data can be made based on”
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