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.”
Species: general tox
Rabbit (ocular) and rat (oral)
“based upon the 28-day ocular toxicity study in rabbits (# AB21563), 7-day oral toxicity study in rats (# AB21526), and the 28-day oral toxicity study in rats (# AB21563).”
Species: DART
Rat and rabbit (oral, during organogenesis)
“In animal reproduction studies with oral administration of perfluorohexyloctane during the period of organogenesis, no adverse maternal or developmental effects were observed in rats at doses up to 162 times the recommended human ophthalmic dose (RHOD) ( see Data ).”
Species: carcinogenicity
Not conducted
“Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of perfluorohexyloctane.”
Surrogate used in
No surrogate used
“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.”
Genotox: Ames
Negative
“F6H8 was considered not to induce a mutagenic effect with the Ames test or induce structural chromosome aberrations in cultured human lymphocytes.”
Genotox: in vitro mammalian
Chromosome aberration in cultured human lymphocytes: negative
“F6H8 was considered not to induce a mutagenic effect with the Ames test or induce structural chromosome aberrations in cultured human lymphocytes.”
Genotox: in vivo
Rat bone marrow micronucleus: negative up to 2000 mg/kg
“F6H8 was not clastogenic or aneugenic in the bone marrow micronucleus test of male rats up to a dose of 2000 mg/kg.”
Carcinogenicity model
Not conducted
“8 Carcinogenicity No studies were conducted.”
Carcinogenicity timing
Not conducted; no long-term carcinogenicity studies
“Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of perfluorohexyloctane.”
hERG / QT
Not conducted; only CNS (Irwin) safety pharmacology was assessed
“No additional safety pharmacology endpoints were assessed.”
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”
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.
Label warnings
- Use with Contact Lenses
US prescribing information, Warnings and PrecautionsDailyMed ↗
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week rabbit topical ocular (four times daily, bilateral); recovery phase not stated
“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.”
DART package
Species: DART
Rat and rabbit (oral, during organogenesis)
“In animal reproduction studies with oral administration of perfluorohexyloctane during the period of organogenesis, no adverse maternal or developmental effects were observed in rats at doses up to 162 times the recommended human ophthalmic dose (RHOD) ( see Data ).”
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.”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted
“Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of perfluorohexyloctane.”
Carcinogenicity model
Not conducted
“8 Carcinogenicity No studies were conducted.”
Carcinogenicity timing
Not conducted; no long-term carcinogenicity studies
“Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of perfluorohexyloctane.”
Safety marginopen answer page →
Safety margin at NOAEL
26-week rabbit ocular study: ocular NOAEL 3.6X ocular MRHD; systemic NOAEL 39X MRHD (dose-based)
“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).”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Normal NZW rabbits: 7-day ocular dosing showed a trend to increased tear film breakup time (TFBUT)
“Two (2) in vivo non-GLP rabbit studies showed after four times daily ocular instillations of F6H8 into the right eye of NZW rabbits for 7 days, a trend with an increase of TFBUT (tear film breakup time) 15 minutes after the last administration of F6H8”
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
FDA: F6H8 is physically, chemically and physiologically inert, with no known pharmacological activity
“F6H8 is physically, chemically and physiologically inert, and has no known pharmacology activity.”
Flexibilityopen answer page →
Flexibility accepted
Safety pharmacologyVerdict not stated
Safety pharmacology limited to a CNS Irwin test within a short oral rat study; no other endpoints assessed
“No additional safety pharmacology endpoints were assessed.”
CarcinogenicityVerdict not stated
No carcinogenicity studies for a chronically used topical ocular product
“Carcinogenicity No studies were conducted.”
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