Wakix
pitolisant
Species
MonkeyRatMouse
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (mouse up to 1 month)
“Single and Repeat dose toxicity studies were conducted in mice, rats, and monkeys up to 1-month, 6-month and 9-month in duration, respectively.”
Why that species
Comparison of in vivo metabolites supported cynomolgus monkey as the non-rodent species
“From the comparison of metabolites formed in vivo in Cynomolgus monkeys and in humans, the applicant did conclude that Cynomolgus monkeys could be used as the non-rodent species for toxicity studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Single and Repeat dose toxicity studies were conducted in mice, rats, and monkeys up to 1-month, 6-month and 9-month in duration, respectively.”
Species: general tox
Rat (6-month) and cynomolgus monkey (9-month); mouse up to 1 month
“Single and Repeat dose toxicity studies were conducted in mice, rats, and monkeys up to 1-month, 6-month and 9-month in duration, respectively.”
Species: DART
Rat and rabbit (embryofoetal, organogenesis dosing)
“Embryofoetal toxicity of pitolisant was evaluated in rats and rabbits following administration during the organogenesis period.”
Species: carcinogenicity
Rat (2-year) and tgRasH2 mouse (6-month)
“A two-year carcinogenicity study of pitolisant was conducted in rats and a 6-month carcinogenicity study was conducted in tgRasH2 mice. The executive carcinogenicity assessment committee concluded that these studies were adequate and that there were no drug-related neoplasms in either study.”
Surrogate used in
No surrogate used; pitolisant tested directly
“Single and Repeat dose toxicity studies were conducted in mice, rats, and monkeys up to 1-month, 6-month and 9-month in duration, respectively.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“Study title: 9 Month Oral (Gavage) Repeat Dose Toxicity Study in the Cynomolgus Monkey with a 4 Week Recovery Period”
Pivotal GLP studies
6-month rat and 9-month monkey chronic studies
“Chronic administration (6 months in rats, 9 months in monkeys) evidenced no significant change on the following parameters: haematology, immune system organ weights and histology, frequency of infections and tumours including in the two carcinogenicity studies.”
Route in tox
Oral gavage
“Study title: 9 Month Oral (Gavage) Repeat Dose Toxicity Study in the Cynomolgus Monkey with a 4 Week Recovery Period”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and in vivo mouse micronucleus assays
“Pitolisant and its metabolites were not mutagenic in the in vitro bacterial reverse mutation assay (Ames), or clastogenic in the in vitro mammalian chromosomal aberration assay. Pitolisant was negative in the in vivo mouse micronucleus assay.”
Carcinogenicity
2-year rat and 6-month tgRasH2 mouse: no drug-related neoplasms
“A two-year carcinogenicity study of pitolisant was conducted in rats and a 6-month carcinogenicity study was conducted in tgRasH2 mice. The executive carcinogenicity assessment committee concluded that these studies were adequate and that there were no drug-related neoplasms in either study.”
Reproductive & developmental
Rat PPND: stillbirths and pup mortality at maternally toxic doses; teratogenic at 22x MRHD (cleft palate, abnormal limb flexure)
“At the maternally toxic doses, fetal toxicity included stillbirths, postnatal pup mortality (due to lack of milk or failure to nurse) and decreased pup length and weight. Pitolisant was teratogenic at 22 times the MRHD based on mg/m2 , causing major malformations including cleft palate and abnormal limb flexure.”
Safety pharmacology
Moderate hERG inhibitor (IC50 1.32 µM); minimal to no QTc effect and no pro-arrhythmic potential in rat, rabbit and dog
“In safety pharmacology studies, pitolisant was a moderate hERG channel inhibitor with an IC50 of 1.32 µM. However, in in vivo studies in rat, rabbit and dog, pitolisant had minimal to no effect on QTc intervals and no pro-arrhythmic potential.”
Genotox: Ames
Negative
“Pitolisant was not genotoxic in an adequate battery of valid genotoxicity studies including bacterial Ames, in vitro mouse lymphoma, and in vivo micronucleus assays.”
Genotox: in vitro mammalian
Negative: in vitro mouse lymphoma assay
“Pitolisant was not genotoxic in an adequate battery of valid genotoxicity studies including bacterial Ames, in vitro mouse lymphoma, and in vivo micronucleus assays.”
Genotox: in vivo
Negative: in vivo micronucleus
“Pitolisant was not genotoxic in an adequate battery of valid genotoxicity studies including bacterial Ames, in vitro mouse lymphoma, and in vivo micronucleus assays.”
Carcinogenicity model
2-year rat and 6-month tgRasH2 mouse; adequate, no drug-related neoplasms
“A two-year carcinogenicity study of pitolisant was conducted in rats and a 6-month carcinogenicity study was conducted in tgRasH2 mice. The executive carcinogenicity assessment committee concluded that these studies were adequate and that there were no drug-related neoplasms in either study.”
Carcinogenicity timing
2-year rat and 6-month tgRasH2 mouse studies completed before the marketing application
“A two-year carcinogenicity study of pitolisant was conducted in rats and a 6-month carcinogenicity study was conducted in tgRasH2 mice. The executive carcinogenicity assessment committee concluded that these studies were adequate and that there were no drug-related neoplasms in either study.”
hERG / QT
Moderate hERG inhibitor (IC50 1.32 µM); minimal to no QTc effect and no pro-arrhythmia in rat, rabbit and dog
“In safety pharmacology studies, pitolisant was a moderate hERG channel inhibitor with an IC50 of 1.32 µM. However, in in vivo studies in rat, rabbit and dog, pitolisant had minimal to no effect on QTc intervals and no pro-arrhythmic potential.”
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 Wakix 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: Oral NOAELs 75, 30 and 12 mg/kg/day in mice, rats and monkeys (EMA assessment report, p. 19)
NOAEL / key findings
Oral NOAELs 75, 30 and 12 mg/kg/day in mice, rats and monkeys
“The NOAEL by oral route were 75, 30 and 12 mg/kg/day in mice, rats and monkeys, respectively”
Risksopen answer page →
Immune & cytokine safety
No changes in haematology, immune organ weights/histology or infections in 6-month rat and 9-month monkey studies; not investigated further
“Chronic administration (6 months in rats, 9 months in monkeys) evidenced no significant change on the following parameters: haematology, immune system organ weights and histology, frequency of infections and tumours including in the two carcinogenicity studies. Therefore, immunotoxicity aspects were not investigated further.”
Biodistribution & persistence
Milk concentrations 1–3x plasma in lactating rats
“Radioactivity was measurable in the milk of lactating rats at concentrations 1 to 3 times higher than measured in plasma.”
Modality-specific risk
CNS toxicity, notably convulsions
“The pharmacology/toxicology reviewer identified CNS-related clinical signs including convulsions as the most prominent toxic effect of pitolisant.”
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
- QT Interval Prolongation
Cardiovascular
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 Wakix 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: Oral NOAELs 75, 30 and 12 mg/kg/day in mice, rats and monkeys (EMA assessment report, p. 19)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week (9-month) oral gavage study in cynomolgus monkeys with 4-week recovery (TK portion non-GLP)
“9 Month Oral (Gavage) Repeat Dose Toxicity Study in the Cynomolgus Monkey with a 4 Week Recovery Period”
Pivotal GLP studies
6-month rat and 9-month monkey chronic studies
“Chronic administration (6 months in rats, 9 months in monkeys) evidenced no significant change on the following parameters: haematology, immune system organ weights and histology, frequency of infections and tumours including in the two carcinogenicity studies.”
DART package
Species: DART
Rat and rabbit (embryofoetal, organogenesis dosing)
“Embryofoetal toxicity of pitolisant was evaluated in rats and rabbits following administration during the organogenesis period.”
Reproductive & developmental
Rat PPND: stillbirths and pup mortality at maternally toxic doses; teratogenic at 22x MRHD (cleft palate, abnormal limb flexure)
“At the maternally toxic doses, fetal toxicity included stillbirths, postnatal pup mortality (due to lack of milk or failure to nurse) and decreased pup length and weight. Pitolisant was teratogenic at 22 times the MRHD based on mg/m2 , causing major malformations including cleft palate and abnormal limb flexure.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“BF-2649. Study for Effects on Pre- and Postnatal Development, Including Maternal Function in Rats by Oral Administration”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and tgRasH2 mouse (6-month)
“A two-year carcinogenicity study of pitolisant was conducted in rats and a 6-month carcinogenicity study was conducted in tgRasH2 mice. The executive carcinogenicity assessment committee concluded that these studies were adequate and that there were no drug-related neoplasms in either study.”
Carcinogenicity model
2-year rat and 6-month tgRasH2 mouse; adequate, no drug-related neoplasms
“A two-year carcinogenicity study of pitolisant was conducted in rats and a 6-month carcinogenicity study was conducted in tgRasH2 mice. The executive carcinogenicity assessment committee concluded that these studies were adequate and that there were no drug-related neoplasms in either study.”
Carcinogenicity timing
2-year rat and 6-month tgRasH2 mouse studies completed before the marketing application
“A two-year carcinogenicity study of pitolisant was conducted in rats and a 6-month carcinogenicity study was conducted in tgRasH2 mice. The executive carcinogenicity assessment committee concluded that these studies were adequate and that there were no drug-related neoplasms in either study.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 12 mg/kg/day: 0.4x human AUC (rat 30 mg/kg/day 1x; mouse 75 mg/kg/day 9x)
“The NOAEL by oral route were 75, 30 and 12 mg/kg/day in mice, rats and monkeys, respectively with safety margins based on AUC for male and female of 9, 1 and 0.4, respectively.”
NOAEL / key findings
Oral NOAELs 75, 30 and 12 mg/kg/day in mice, rats and monkeys
“The NOAEL by oral route were 75, 30 and 12 mg/kg/day in mice, rats and monkeys, respectively”
Efficacy evidenceopen answer page →
Efficacy evidence
Orexin-/- narcolepsy mouse: fewer narcoleptic attacks and shorter total narcolepsy duration
“In addition to enhanced wakefulness, pitolisant decreased the number of narcoleptic attacks and a reduced the total duration of narcolepsy when administered in the narcolepsy mouse model (Orexin-/-).”
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
CHMP: wake-promotion in wild-type and orexin KO mice and cats supports proof-of-concept for narcolepsy
“In vivo studies in wild-type and orexin KO mice, and in cats showed that pitolisant increased the duration of waking at the expense of SWS and PS with corroborating EEG changes at ≥10 mg/kg (p.o.), thereby supporting a proof-of-concept for its use in narcoleptic patients.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No safety margin in the monkey (convulsions) at the NOAEL, whether based on Cmax or AUC
“Nevertheless, the safety margin based upon the Cmax was still 1 for monkey. Whatever based on Cmax or AUC, there was no safety margin in monkey.”
GLPVerdict not stated
Toxicokinetic portion of the 6-month rat toxicity study deemed non-GLP compliant; separate GLP 6-month TK study conducted
Why: A subsequent GLP 6-month toxicokinetic study in rats was conducted
“Therefore, the original toxicokinetic analysis was not adjusted, however, the TK portion of the study was deemed non-GLP compliant. A subsequent GLP 6-month TK study (Study no. HHL5000, GLP) in rats was conducted.”
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