Miebo
perfluorohexyloctane
Species
RatRabbit
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rabbit (ocular) and rat (oral)
“based upon the 28-day ocular toxicity study in rabbits (# AB21563), 7-day oral toxicity study in rats (# AB21526)”
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
“In a 28-day oral toxicity study in rats, once daily oral administration of F6H8 at doses up to 2000 mg/kg/ for 28 days were well tolerated and did not produce F6H8 related toxicity.”
Study lengthopen answer page →
Longest pivotal study
26 (26-week rabbit ocular)
“Ocular instillation of F6H8 at the dose of 427.8 mg/animal/day, four times daily bilaterally (~3 hours apart) for up to 26 weeks in NZW rabbit was well tolerated and did not induce any ocular or systemic signs of toxicity.”
Pivotal GLP studies
26-week rabbit topical ocular study (four times daily, bilateral)
“In a 26-week ocular toxicity study in rabbits, ocular instillation of perfluorohexyloctane ophthalmic solution, 100% (code name: F6H8) at the dose of 427.8 mg/day, four times daily bilaterally for up to 26 weeks was well tolerated and did not induce any ocular or systemic signs of toxicity.”
Route in tox
Topical ocular (rabbit); oral gavage (rat)
“Once daily oral administration of F6H8 at doses up to 2000 mg/kg/day to Wistar rats for 28 consecutive days were well tolerated and did not produce F6H8 related toxicity.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosome aberration and in vivo rat bone marrow micronucleus assays
“Perfluorohexyloctane was not mutagenic or clastogenic in a standard battery of genotoxicity tests, including a bacterial mutagenicity assay (Ames assay), an in vitro chromosome aberration assay using human peripheral lymphocytes, and an in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted
“Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of perfluorohexyloctane.”
Reproductive & developmental
Rat and rabbit oral EFD: no effects in rats; maternal toxicity, miscarriages and reduced fetal weight in rabbits at all doses
“no adverse maternal or developmental effects were observed in rats at doses up to 162 times the recommended human ophthalmic dose (RHOD) ( see Data ). Maternal toxicity, miscarriages and reduced fetal weights were observed in rabbits at all doses tested, with the lowest dose as 41 times the RHOD.”
Safety pharmacology
CNS only (Irwin test in 7-day rat oral study): no effects up to 5000 mg/kg/day; no other endpoints assessed
“CNS (Central Nervous System) safety pharmacology was assessed using Irwin test as part of a 7-day oral maximum tolerated dose (MTD) toxicity study in rats at 1 hour after oral dosing of F6H8 at doses up to 5000 mg/kg/day and did not cause CNS effects.”
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 Miebo 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 ocular or systemic toxicity; rabbit systemic NOAEL 427.8 mg/day, ocular NOAEL 213.92 mg/eye/day (3.6x ocular MRHD) (FDA pharmacology/toxicology review, p. 34)
NOAEL / key findings
No ocular or systemic toxicity; rabbit systemic NOAEL 427.8 mg/day, ocular NOAEL 213.92 mg/eye/day (3.6x ocular MRHD)
“The systemic no-observed-adverse-effect level (NOAEL) was 427.8 mg/animal/day whereas the ocular NOAEL was 213.92 mg/eye/day. At the proposed clinical dosing regimen, the ocular exposure margin is 3.6X for the MRHD (60 mg/eye/day), and the systemic exposure margin is 39X for the MRHD (120 mg/day).”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Topical ocular dosing: highest levels in tears, meibomian glands, cornea, conjunctiva and lacrimal glands
“Following the repeated topical ocular dose of 14C-perfluorohexyloctane, rank order of highest mean concentrations (>5000 ng equivalents 14C-F6H8/g) was: tears > meibomian glands > cornea > palpebral conjunctiva > accessory lacrimal gland > main lacrimal gland > bulbar conjunctiva.”
Modality-specific risk
Embryofetal toxicity: rabbit abortions, maternal toxicity and possible malformations at all doses
“Although the findings were within the range of Testing Facility’s HCD (when verified individually), considering the mid and high dose groups have significant increased incidences of these findings (when taken together) compared with the concurrent control group, this reviewer can’t totally exclude the potential test article-related effect”