Rapiblyk
landiolol
Species
RatDog
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 dog
“Reports of intravenous bolus and continuous infusion studies in rats and dogs up to 4-week duration were available.”
Why that species
Landiolol is metabolized by the same ester hydrolysis pathway (M-1, then M-2) in all species
“Landiolol is metabolized in all species by hydrolysis of the ester moiety that produces M-1, which undergoes β-oxidation to the M-2 metabolite.”
Surrogate molecule
No surrogate; the clinical compound was tested (published data on the same active, ONO-1101)
“Note that the terms ONO-1101, Onact, and landiolol HCl (LAN) are interchangeably used in this review and represent the same active pharmaceutical.”
Study lengthopen answer page →
Longest pivotal study
4 (4-week rat and dog studies)
“Reports of intravenous bolus and continuous infusion studies in rats and dogs up to 4-week duration were available.”
Pivotal GLP studies
4-week i.v. bolus studies in rats and dogs and a 4-week continuous i.v. infusion study in dogs
“In addition to a single dose 24-hr infusion study conducted by AOP Health, a 4-week i.v. bolus study in rats and dogs and a continuous infusion study of the same duration in dogs with ONO-1101 were cited.”
Route in tox
Intravenous (bolus and continuous infusion)
“Most of the toxicity studies conducted with ONO-1101 that the applicant cited were conducted with daily intravenous bolus doses, while intravenous infusion is recommended for the clinical use.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro mouse lymphoma TK and in vivo rat micronucleus assays
“Landiolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK +/- , and in vivo micronucleus test in rats).”
Carcinogenicity
Not conducted (short-term use, ICH M3(R2))
“The sponsor has not conducted carcinogenicity studies citing ICH M3 (R2) since the product is intended for short-term use.”
Reproductive & developmental
Rat: low pup viability at 50-100 mg/kg/day and lower male fetal weight at 100 mg/kg/day; no malformations
“Viability was low for rat pups in the 50 or 100 mg/kg/day groups, and body weight of male fetuses were decreased in the 100 mg/kg/day group, but there were no malformations.”
Safety pharmacology
hERG IC50 >300 µM for landiolol (~5-fold Cmax at MRHD) and >1,000 µM for metabolites M-1 and M-2
“IC50 of >300 µM (>21µM free) was predicted for LAN, representing 5-fold the Cmax at MRHD. IC50 of >1,000 µM was predicted for the metabolites M-1 and M-2.”
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 Rapiblyk 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: 4-week continuous i.v. infusion study NOAEL 1 mg/kg/min (~136-fold MRHD AUC) (FDA pharmacology/toxicology review, p. 22)
NOAEL / key findings
4-week continuous i.v. infusion study NOAEL 1 mg/kg/min (~136-fold MRHD AUC)
“Steady state was reached within 1 hr and constant changes occurred over time until 4-weeks. The NOAEL was 1 mg/kg/min, with the average AUC0-96h of 281.2 µg.h/mL providing ~136-fold margin to the MRHD based on AUC.”
Risksopen answer page →
Immune & cytokine safety
Decreased thymus weight at the high dose in the rat fertility study
“Absolute and relative thymus weight was decreased at the high dose.”
Biodistribution & persistence
Rat radiolabel: brain and fetal levels much lower than plasma; no brain radioactivity after repeat dosing
“Radioactivity levels in the brain and fetuses were much lower than that of plasma; drug-related radioactivity was not observed in the brain after repeat dosing.”
Modality-specific risk
Potential carcinogenic impurity identified in drug product batches
“a potential carcinogenic impurity, was identified in drug product batches tested at the request of the Agency’s quality review team.”