Defencath
taurolidine and heparin
Sources:FDA multi-discipline review ↗
Species
RatMouse
Longest study
2 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat (14-day IV study) and mouse (single-dose IP study)
“A single dose intraperitoneal study conducted with Defencath in mice and a 14-day repeat-dose intravenous study conducted in rats (discussed in additional detail below) did not reveal signs of toxicity.”
Why that species
No pivotal tox species needed: prior clinical experience with taurolidine and heparin in catheter lock solutions judged adequate
“However, the medical reviewers found that previous clinical experience with taurolidine (particularly as a component of CLS) was adequate to support the clinical development of Defencath and the toxicology reviewer deferred to their judgement.”
Surrogate molecule
No surrogate; the clinical product (diluted) was tested
“A diluted solution of Defencath did not cause toxicity in rats when administered intravenously daily for 14 days.”
Study lengthopen answer page →
Longest pivotal study
2 (14-day rat; not considered pivotal)
“Although neither of these studies were considered adequate for a pivotal nonclinical toxicology study to support human drug development (exposure to taurolidine was not sufficient to explore possible toxicity and identify potential target organs)”
Pivotal GLP studies
None required; additional acute or repeat-dose general toxicology testing was not needed
“Thus, additional acute or repeat-dose general toxicology testing in animals was not required for the components of Defencath.”
Route in tox
Intravenous (rat); intraperitoneal (mouse single dose)
“A single dose intraperitoneal study conducted with Defencath in mice and a 14-day repeat-dose intravenous study conducted in rats (discussed in additional detail below) did not reveal signs of toxicity.”
Skipped studiesopen answer page →
Genotoxicity
Taurolidine positive in vitro (mouse lymphoma and Ames) regardless of metabolic activation; negative in vivo
“Although taurolidine is positive for genotoxicity in vitro regardless of metabolic activation (mouse lymphoma and Ames tests), it is negative in vivo.”
Carcinogenicity
Not conducted (not for systemic administration; negligible clinical exposure)
“Carcinogenicity studies were not needed for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Reproductive & developmental
Not conducted; waived because the product is not for systemic administration
“Reproductive and developmental toxicology studies were waived for Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Safety pharmacology
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 doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Defencath 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: No toxicity in rats given diluted product IV daily for 14 days (FDA multi-discipline review, p. 44)
NOAEL / key findings
No toxicity in rats given diluted product IV daily for 14 days
“A diluted solution of Defencath did not cause toxicity in rats when administered intravenously daily for 14 days.”
Risksopen answer page →
Immune & cytokine safety
Not irritating intradermally and nonsensitizing in guinea pigs
“Guinea pig studies with Defencath showed that the product was not irritating when injected intradermally and it was nonsensitizing in these animals.”
Biodistribution & persistence
Not studied; ADME/PK studies not conducted given negligible systemic exposure
“ADME/PK studies were not conducted with Defencath because the product is not intended for systemic administration and clinical exposure to its components is negligible when used as directed.”
Modality-specific risk
In vitro genotoxicity of taurolidine; risk judged low at clinical exposures
“At the levels where taurolidine exposure could be achieved in the clinic during use of the Defencath CLS, the risk of genotoxicity appears low.”