Olinvyk
oliceridine
Species
MonkeyRat
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 monkey
“The nonclinical program supporting clinical development of Oliceridine included a pharmacology, ADME, general toxicology studies (28 days duration in rats and 14 days duration in monkeys), genetic toxicology, and reproductive toxicity studies.”
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
“The gastric lesions were not observed after continuous IV infusion of oliceridine for 14 or 28 days in rats or in monkeys as long as the animals were sacrificed within 45 minutes after the termination of infusion.”
Study lengthopen answer page →
Longest pivotal study
4 (28-day rat)
“The nonclinical program supporting clinical development of Oliceridine included a pharmacology, ADME, general toxicology studies (28 days duration in rats and 14 days duration in monkeys), genetic toxicology, and reproductive toxicity studies.”
Pivotal GLP studies
28-day rat and 14-day monkey general toxicity studies
“The nonclinical program supporting clinical development of Oliceridine included a pharmacology, ADME, general toxicology studies (28 days duration in rats and 14 days duration in monkeys), genetic toxicology, and reproductive toxicity studies.”
Route in tox
Continuous intravenous infusion
“Intravenous bolus administration is the intended clinical route of administration; however, continuous infusion was selected to maximize daily exposure in the toxicology studies.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration and rat micronucleus assays
“Oliceridine was negative in an in vitro Ames bacterial reverse mutation assay, the in vitro chromosomal aberration assay using human peripheral blood lymphocytes, and the in vivo rat micronucleus assay.”
Carcinogenicity
Not conducted
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of oliceridine.”
Reproductive & developmental
Rat female fertility effects and reduced postnatal pup survival; no male fertility or rat/rabbit EFD effects
“A battery of reproductive toxicity studies identified effects on female fertility (longer estrous cycle, reduced number of implantation sites, increased preimplantation loss, and reduced viable embryos) and postnatal development (reduced live litter size, postnatal survival, and body weight). No effects on male fertility or EFD were observed.”
Safety pharmacology
Weak hERG inhibitor (IC50 2.2 µM, 43x unbound Cmax at MRHD); no consistent QTc effects in vivo
“oliceridine is a weak hERG inhibitor with an IC50 of 2.2 mcM which is 367 times its binding affinity of 6 nM at the MOR and 43 times the estimated Cmax of the unbound drug at the proposed maximum recommended human dose (MRHD) of 40 mg/day. No consistent effects on QTc interval have been observed in nonclinical studies.”
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 Olinvyk 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: Dose-dependent infusion-site inflammation in 28-day rat study; NOAEL 0.5 mg/kg/h (FDA multi-discipline review, p. 164)
NOAEL / key findings
Dose-dependent infusion-site inflammation in 28-day rat study; NOAEL 0.5 mg/kg/h
“dose-dependent increases in inflammation were observed at infusion sites in the 28-day rat general toxicity study with a no observed adverse effect level (NOAEL) of 0.5 mg/kg/h at a concentration of 0.5 mg/mL”
Risksopen answer page →
Immune & cytokine safety
Stress-related reductions in white blood cells and lymphocytes; minimal thymus atrophy
“Stress- or dehydration-related changes in clinical chemistry, hematology (such as reduced white blood cells and lymphocytes), and histopathology (such as increased hypertrophy of adrenal cortex corresponding to increased adrenal weight as well as minimal thymus atrophy) were observed across nonclinical studies”
Biodistribution & persistence
Wide distribution in rats to liver, kidney, skin and skeletal muscle
“Total radioactivity (parent and metabolites) is distributed widely after IV dosing of oliceridine in rats, with 14C-concentrations found in well-perfused (liver, kidney) and poorly-perfused (skin, skeletal muscle) tissues.”
Modality-specific risk
Disproportionate human metabolite TRV0109662 not adequately qualified; embryo-fetal effects not characterized (MIST)
“Specifically, it is not clear that the disproportionate major human metabolite, TRV0109662, has been adequately qualified for safety, because the exposure data for this metabolite from rat intravenous toxicity studies could not be reproduced. As such, it is not clear that effects of TRV0109662 on embryofetal development have been adequately characterized by the existing studies.”