Xdemvy
lotilaner
Species
RatDogRabbit
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rabbit and dog (ocular); rat and dog (systemic)
“The nonclinical safety of Lotilaner and Lotilaner Ophthalmic Solution, 0.25% were evaluated in the rabbit, rat and dog which were considered appropriate.”
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
“1020-7114: Lotilaner: A 6-Month Repeat-Dose Topical Ocular Toxicity Study Followed by a 4-Week Recovery Period in Dutch Belted Rabbits”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog ocular)
“1020-7122: Lotilaner: A 9-Month Repeat-Dose Topical Ocular Toxicity Study Followed by a 4-Week Recovery Period in the Beagle Dog”
Pivotal GLP studies
6-month rabbit and 9-month dog topical ocular GLP studies
“In two ocular GLP toxicity studies with Lotilaner Ophthalmic Solution, 0.25%, in the Dutch Belted rabbit and in the Beagle dog for 6 and 9 months, respectively”
Route in tox
Topical ocular
“In two ocular GLP toxicity studies with Lotilaner Ophthalmic Solution, 0.25%, in the Dutch Belted rabbit and in the Beagle dog for 6 and 9 months, respectively”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (human lymphocytes) and rat micronucleus assays
“AHC 2224920 was negative for genotoxic potential in a complete battery of genotoxicity GLP studies (i.e., Ames test, in vitro chromosome aberration test in cultured human lymphocytes and in vivo micronuclei assay in rats).”
Carcinogenicity
Not conducted; waiver agreed with FDA for the Demodex blepharitis indication
“As agreed with the Sponsor during their pre-NDA interaction with the Division, carcinogenicity studies were not conducted to support the approval of Lotilaner Ophthalmic Solution, 0.25%, for the treatment of Demodex blepharitis.”
Reproductive & developmental
Rat EFD: marked fetal weight reduction and delayed (incomplete) ossification at 50 mg/kg/day
“There was a marked effect on mean fetal weight at 50 mg/kg/day and there was an indication of a developmental delay characterized by an increased number of fetuses with incomplete ossification of individual bones of the skeleton.”
Safety pharmacology
CNS, respiratory and cardiovascular (hERG, dog ECG) assessments: no clinically relevant effects
“The central nervous system, respiratory and cardiovascular assessments of Lotilaner were evaluated in GLP studies in vitro (hERG assay) and in vivo in rats and dogs. No clinically relevant adverse effects were noted in any of the studies.”
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 Xdemvy 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 oral: skin/mucosa, ovary, lung, adrenal, pituitary and thymus findings; mortality at ≥40 mg/kg/day (males) and 60 mg/kg/day (females) (FDA pharmacology/toxicology review, p. 9)
NOAEL / key findings
Rat oral: skin/mucosa, ovary, lung, adrenal, pituitary and thymus findings; mortality at ≥40 mg/kg/day (males) and 60 mg/kg/day (females)
“Test-article related microscopic findings were noted in body weight, skin/mucosa, ovary, lung, adrenal, pituitary (males only) and thymus in rats. Mortality due to early sacrifice of moribund animals occurred at 60 mg/kg/day in female rats and at ≥40 mg/kg/day in male rats.”
Risksopen answer page →
Immune & cytokine safety
Not a skin sensitizer in the mouse local lymph node assay
“In a Local Lymph Node Assay in the mouse, ACH 2224920 did not have the potential to cause skin sensitization.”
Biodistribution & persistence
Accumulates in eyelid margins, with lowest clearance and AUC 10-fold higher than other ocular tissues
“Overall, the data indicated that inferior and superior eyelid margins were prone to drug accumulation, coupled with the lowest clearance in these tissues and an AUC inf 10-fold higher than in all other ocular tissues.”
Modality-specific risk
Local ocular/nasal toxicity: nasal turbinate and nasopharynx not examined histologically in ocular studies
“Nasal turbinate and nasopharynx were not examined under the microscope in any of the ocular studies which was a drawback to the complete evaluation of the potential ocular toxicity of Lotilaner Ophthalmic Solution, 0.25%, but does not influence the decision on approvability of this product.”