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.”
Species: general tox
Rat and dog (i.v. bolus and infusion, up to 4 weeks)
“Reports of intravenous bolus and continuous infusion studies in rats and dogs up to 4-week duration were available.”
Species: DART
Rat and rabbit (EFD; rat also fertility and pre/postnatal), published ONO-1101 studies
“The same doses of ONO-1101 were administered intravenously to pregnant rats and rabbits during the time of organogenesis (Nishimura et al, 1997b).”
Species: carcinogenicity
Not conducted (short-term use)
“The sponsor has not conducted carcinogenicity studies citing ICH M3 (R2) since the product is intended for short-term use.”
Surrogate used in
No surrogate used; published studies used 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.”
Genotox: Ames
Negative
“Landiolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK +/- , and in vivo micronucleus test in rats).”
Genotox: in vitro mammalian
Mouse lymphoma TK assay: negative
“Landiolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK +/- , and in vivo micronucleus test in rats).”
Genotox: in vivo
Rat micronucleus test: negative
“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 model
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.”
Carcinogenicity timing
Not required for short-term use
“The applicant has not conducted carcinogenicity study because of short-term clinical use (consistent with the reference drug) nor juvenile studies.”
hERG / QT
hERG IC50 >300 µM (>21 µM free), 5-fold Cmax at MRHD; metabolites >1,000 µM
“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.”
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
- Hypotension
- Bradycardia
- Cardiac Failure
- Reactive Airways Disease
- Use in Patients with Diabetes Mellitus and Hypoglycemia
- Infusion Site Reactions
- Use in Patients with Prinzmetal’s Angina
- Use in Patients with Pheochromocytoma
- Use in Patients with Peripheral Circulatory Disorders
- Abrupt Discontinuation of RAPIBLYK Injection
- Hyperkalemia
- Use in Patients with Metabolic Acidosis
- Use in Patients with Hyperthyroidism
- Use in Patients at Risk of Severe Acute Hypersensitivity Reactions
CardiovascularMetabolic & endocrineHypersensitivity & infusion reactions
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week IV bolus rat and dog studies (published), each with 4-week recovery; also 4-week continuous infusion in dogs
“Reports of intravenous bolus and continuous infusion studies in rats and dogs up to 4-week duration were available. Four-week i.v. bolus study in rats with 4-week recovery period (Yamaguchi 1997c)”
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.”
DART package
Species: DART
Rat and rabbit (EFD; rat also fertility and pre/postnatal), published ONO-1101 studies
“The same doses of ONO-1101 were administered intravenously to pregnant rats and rabbits during the time of organogenesis (Nishimura et al, 1997b).”
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.”
PPND / ePPND: when
Published rat pre/postnatal study (reference drug ONO-1101) available before the marketing application
“The same doses that were tested in rat fertility and EFT studies were tested in the rat pre/postnatal developmental study (Nishimura, 1997d).”
Carcinogenicity
Species: carcinogenicity
Not conducted (short-term use)
“The sponsor has not conducted carcinogenicity studies citing ICH M3 (R2) since the product is intended for short-term use.”
Carcinogenicity model
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.”
Carcinogenicity timing
Not required for short-term use
“The applicant has not conducted carcinogenicity study because of short-term clinical use (consistent with the reference drug) nor juvenile studies.”
Safety marginopen answer page →
Safety margin at NOAEL
4-week dog continuous infusion NOAEL (1 mg/kg/min) ~136-fold human AUC at MRHD
“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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Dog halothane-epinephrine, electrical stimulation and aconitine-induced arrhythmia/tachycardia models
“The results in halothane-epinephrine, electrical stimulation, and aconitine-induced-arrhythmia and tachycardia models indicated that ONO-1101 has a potential to improve experimental tachycardic atrial flutter and fibrillation and increased sympathetic nerve activity.”
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: halothane-epinephrine and aconitine models emulate clinical tachyarrhythmia and pathophysiology
“The halothane-epinephrine and aconitine models emulate clinical tachyarrhythmia and clinical pathophysiology.”
Flexibilityopen answer page →
Flexibility accepted
OtherAcceptedBeyond the letter
Core nonclinical package taken from published literature on the Japanese landiolol product ONO-1101 (Onoact) rather than new studies
Why: Same active salt, pharmaceutically equivalent, same IV use and comparable human PK · Human data · Pharmacology or kinetics
“It is concluded in this review that the reliance on ONO-1101 literature for nonclinical support is justifiable since both products share the same active salt and appear to be pharmaceutically equivalent. Both products are administered intravenously for the same medical condition and comparable PK parameters were obtained for the LAN and Onact in healthy volunteers at the same doses.”
CarcinogenicityAccepted
No carcinogenicity studies
Why: Short-term use, per ICH M3(R2) and ICH S1A · Within the guideline
“The sponsor has not conducted carcinogenicity studies citing ICH M3 (R2) since the product is intended for short-term use. ICH S1A may be also relevant, and the issue of carcinogenicity study was not raised by the Division during the Pre-NDA meeting.”
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