Xeglyze
abametapir
Species
RatPig
Longest study
4 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 minipig
“The sponsor has conducted single-dose toxicity studies in rats and repeat-dose toxicity studies in rats and minipigs.”
Why that species
Comparable metabolism data support rat and minipig as suitable models
“These data support the use of the minipig and rat as suitable nonclinical animal models in which to assess the potential toxicity of abametapir.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Once daily dermal administration of abametapir lotion, 0.74% in female minipigs for 28 days was without systemic effects”
Species: general tox
Rat (oral) and minipig (dermal)
“Also the duration of treatment is much greater in the oral rat and dermal minipig studies (i.e., 14 to 28 days) compared to clinical conditions of use (single 10 minute application that is washed off).”
Species: DART
Rat and rabbit (oral)
“Abametapir has been tested for reproductive and developmental toxicology in rats and rabbits after oral administration with no significant findings independent of maternal toxicity.”
Species: carcinogenicity
Not conducted (single-use, non-chronic product)
“No carcinogenicity studies were included in this NDA submission. Abametapir lotion is intended as a single use drug product.”
Surrogate used in
No surrogate used
“Once daily dermal administration of abametapir lotion, 0.74% in female minipigs for 28 days was without systemic effects”
Study lengthopen answer page →
Longest pivotal study
4 (28-day minipig dermal)
“Study title: A 28-day toxicity study of Abametapir Lotion by dermal administration to minipigs with a 16-day recovery”
Pivotal GLP studies
14-day oral rat and 28-day dermal minipig studies
“Also the duration of treatment is much greater in the oral rat and dermal minipig studies (i.e., 14 to 28 days) compared to clinical conditions of use (single 10 minute application that is washed off).”
Route in tox
Oral gavage (rat); dermal (minipig)
“The systemic exposure achieved in the oral rat and dermal minipig studies is greater than obtained under clinical conditions of single application use.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative (parent and COOH metabolite); chromosome aberrations only at cytotoxic concentrations; rat micronucleus negative
“Abametapir and abametapir-COOH, the major human metabolite, were not mutagenic in the Ames test. Abametapir caused increases in chromosome aberrations in Human lymphocytes but only at cytotoxic concentrations and was negative in the in vivo rat micronucleus assay”
Carcinogenicity
Not conducted
“Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of XEGLYZE or abametapir.”
Reproductive & developmental
Rat and rabbit oral reproductive/developmental studies: no significant findings independent of maternal toxicity
“Abametapir has been tested for reproductive and developmental toxicology in rats and rabbits after oral administration with no significant findings independent of maternal toxicity.”
Safety pharmacology
hERG inhibition (IC50 ~56 µM) raised QTc prolongation concern
“Inhibitory effects on the hERG current raised concerns about QTc prolongation (IC50 =~56 µM ).”
Genotox: Ames
Negative (abametapir and abametapir-COOH metabolite)
“Abametapir and abametapir-COOH, the major human metabolite, were not mutagenic in the Ames test.”
Genotox: in vitro mammalian
Chromosomal aberration (human lymphocytes): increases only at cytotoxic concentrations; equivocal
“In the in vitro chromosomal aberration test in Human lymphocytes, chromosomal aberrations were observed, but only at cytotoxic concentrations ( 230.3 µg/mL). This result was considered equivocal.”
Genotox: in vivo
Rat micronucleus (up to 160 mg/kg/day): negative
“Abametapir (<160 mg/kg/day) did not induce micronucleus formation in the in vivo rat micronucleus assay.”
Carcinogenicity model
Not conducted
“Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of XEGLYZE or abametapir.”
Carcinogenicity timing
Not required: single-use product, not intended for chronic use
“No carcinogenicity studies were included in this NDA submission. Abametapir lotion is intended as a single use drug product. Re-infestation would require a second application, but the product is not intended for chronic use.”
hERG / QT
hERG inhibition, IC50 ~56 µM (QTc concern raised)
“Inhibitory effects on the hERG current raised concerns about QTc prolongation (IC50 =~56 µM ).”
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 Xeglyze 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: Repeat-dose target organs: smooth muscle, kidney and red blood cells (FDA pharmacology/toxicology review, p. 56)
NOAEL / key findings
Repeat-dose target organs: smooth muscle, kidney and red blood cells
“In both the rodent and nonrodent models target organs of toxicity after repeat dosing were consistently limited to smooth muscle, kidney and red blood cells.”
Risksopen answer page →
Immune & cytokine safety
Negative for skin sensitization in mouse LLNA
“A SI of 3.8 was recorded for the positive control group and verifies the validity of the conclusion that abametapir is considered as negative for skin sensitization potential under the conditions used in the assay.”
Biodistribution & persistence
Highest radioactivity at dose site, plasma, kidney, uveal tract/retina and pigmented and non-pigmented skin
“The highest radioactive concentrations and areas under the curve (AUCs) were observed at the dose site, plasma, kidney (cortex and medulla), uveal tract/retina, and skin (both pigmented and non-pigmented).”
Modality-specific risk
Systemic smooth-muscle effects: penile protrusion in male minipigs after >10 days of dermal dosing
“In males, extended dosing (>10 days) was associated with penile protrusion and related secondary microscopic findings in the penis and bone marrow.”
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
- Risk of Neonatal Benzyl Alcohol Toxicity
- Risk of Benzyl Alcohol Toxicity from Accidental Ingestion
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 Xeglyze 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: Repeat-dose target organs: smooth muscle, kidney and red blood cells (FDA pharmacology/toxicology review, p. 56)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
8-week oral juvenile rat study starting on PND 7 (with recovery period)
“Abametapir was administered to juvenile rats orally for 8 weeks at oral doses of 0 (vehicle control; ), 5, 12, or 30 mg/kg/day beginning on PND 7 (70658).”
Pivotal GLP studies
14-day oral rat and 28-day dermal minipig studies
“Also the duration of treatment is much greater in the oral rat and dermal minipig studies (i.e., 14 to 28 days) compared to clinical conditions of use (single 10 minute application that is washed off).”
DART package
Species: DART
Rat and rabbit (oral)
“Abametapir has been tested for reproductive and developmental toxicology in rats and rabbits after oral administration with no significant findings independent of maternal toxicity.”
Reproductive & developmental
Rat and rabbit oral reproductive/developmental studies: no significant findings independent of maternal toxicity
“Abametapir has been tested for reproductive and developmental toxicology in rats and rabbits after oral administration with no significant findings independent of maternal toxicity.”
PPND / ePPND: when
Peri- and postnatal development study in rat (oral) completed before the marketing application
“In a perinatal and postnatal development study in rats, oral doses of 10, 25, and 75 mg/kg/day were administered from the beginning of organogenesis (gestation day 6) through the end of lactation (lactation day 20).”
Carcinogenicity
Species: carcinogenicity
Not conducted (single-use, non-chronic product)
“No carcinogenicity studies were included in this NDA submission. Abametapir lotion is intended as a single use drug product.”
Carcinogenicity model
Not conducted
“Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of XEGLYZE or abametapir.”
Carcinogenicity timing
Not required: single-use product, not intended for chronic use
“No carcinogenicity studies were included in this NDA submission. Abametapir lotion is intended as a single use drug product. Re-infestation would require a second application, but the product is not intended for chronic use.”
Safety marginopen answer page →
Safety margin at NOAEL
Rabbit EFD NOAEL (40 mg/kg/day) ~1x MRHD (Cmax)
“No treatment related effects on embryofetal toxicity or malformations were noted at 40 mg/kg/day (~1 times the MRHD based on Cmax comparisons).”
NOAEL / key findings
Repeat-dose target organs: smooth muscle, kidney and red blood cells
“In both the rodent and nonrodent models target organs of toxicity after repeat dosing were consistently limited to smooth muscle, kidney and red blood cells.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro ovicidal assay on resistant head lice eggs (SF-HL strain) with the lotion
“The ovicidal activity of the to-be-marketed formulation, abametapir lotion 0.74%, was investigated using three different developmental stages of a permethrin-and-DDT-resistant strain of head lice eggs”
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
Metalloproteinase inhibition judged sufficient to kill lice based on in vitro and clinical data
“These data are consistent with abametapir being characterized as a broad spectrum metalloproteinase inhibitor of low potency. The extent of metalloproteinase inhibition exhibited by abametapir is sufficient to kill lice based on the in vitro and clinical study data available for abametapir.”
Flexibilityopen answer page →
Flexibility accepted
Safety pharmacologyCriticised but acceptedBeyond the letter
Cardiovascular telemetry study in minipigs too flawed for regulatory use
Why: Studies less than ideal but raise no nonclinical cardiovascular concern · Other reason
“The sponsor subsequently conducted a cardiovascular study in minipigs using telemetry (71456) which was too flawed for regulatory use.”
“These studies are less than ideal, but do not present nonclinical causes for concern for potential cardiovascular effects associated with abametapir.”
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