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.”
Species: general tox
Rat and monkey
“Potential systemic safety/toxicity of the drug product was evaluated in safety pharmacology, repeat-dose toxicity studies in rats and monkeys, reproductive toxicity studies in rats and rabbits.”
Species: DART
Rat and rabbit
“Potential systemic safety/toxicity of the drug product was evaluated in safety pharmacology, repeat-dose toxicity studies in rats and monkeys, reproductive toxicity studies in rats and rabbits.”
Species: carcinogenicity
Not conducted
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of oliceridine.”
Surrogate used in
No surrogate used; the drug product itself was tested
“Potential systemic safety/toxicity of the drug product was evaluated in safety pharmacology, repeat-dose toxicity studies in rats and monkeys, reproductive toxicity studies in rats and rabbits.”
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.”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
Chromosomal aberration (human peripheral blood lymphocytes): negative
“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.”
Genotox: in vivo
Rat micronucleus: negative
“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 model
Not conducted; long-term studies not completed
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of oliceridine.”
Carcinogenicity timing
Long-term carcinogenicity studies not completed; no requirement, waiver or reason stated
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of oliceridine.”
hERG / QT
Weak hERG inhibitor, IC50 2.2 µM (43x unbound Cmax at 40 mg/day MRHD); no consistent nonclinical QTc effects
“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.”
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
Boxed warning: Serious and life-threatening risks from use of olinvyk
- Addiction, Abuse, and Misuse
- Life-Threatening Respiratory Depression
- Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants
- Neonatal Opioid Withdrawal Syndrome
- Potential for QT prolongation with Daily Doses exceeding 27 mg
- Risk of Use in Patients with Decreased Cytochrome P450 2D6 Function or Concomitant Use or Discontinuation with Cytochrome P450 3A4 Inhibitors and Inducers
- Opioid-Induced Hyperalgesia and Allodynia
- Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
- Adrenal Insufficiency
- Severe Hypotension
- Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness
- Risks of Gastrointestinal Complications
- Increased Risk of Seizures in Patients with Seizure Disorders
- Withdrawal
- Risks of Driving and Operating Machinery
- Patient-Controlled Analgesia (PCA)
PsychiatricPulmonary toxicityCardiovascularNephrotoxicityMetabolic & endocrineSecondary malignancyGastrointestinalNeurotoxicity
US prescribing information, Boxed Warning and 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
28-day rat continuous IV infusion; recovery phase not stated (monkey 14 days)
“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.”
DART package
Species: DART
Rat and rabbit
“Potential systemic safety/toxicity of the drug product was evaluated in safety pharmacology, repeat-dose toxicity studies in rats and monkeys, reproductive toxicity studies in rats and rabbits.”
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.”
PPND / ePPND: when
PPND in rat completed and reviewed with the NDA
“In a pre- and post-natal development study in rats, maternal dosing of oliceridine between Gestation Day 6 (GD 6) and Lactation Day 21 (LD 21) resulted in an overall increase in pups found dead or sacrificed moribund from birth to weaning.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of oliceridine.”
Carcinogenicity model
Not conducted; long-term studies not completed
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of oliceridine.”
Carcinogenicity timing
Long-term carcinogenicity studies not completed; no requirement, waiver or reason stated
“Long-term animal studies have not been completed to evaluate the carcinogenic potential of oliceridine.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat and rabbit EFD: no effect at 7x and 8x MRHD AUC (no repeat-dose NOAEL margin stated)
“Oliceridine had no effect on embryo-fetal development in rats and rabbits when administered intravenously during organogenesis at doses producing plasma exposures 7 and 8 times the estimated plasma exposure at the maximum recommended human dose (MRHD) on an AUC basis, respectively (see Data)”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Rodent (mouse, rat) spinal reflexive and supraspinal affective nociceptive pain models
“In mice and rats, oliceridine elicits antinociception in multiple models of spinal reflexive and supraspinal affective nociceptive pain (potency reported to be 3 to 10 times that of morphine) with less respiratory depression and constipation in rodents compared to “equianalgesic” doses of morphine.”
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: pharmacology and toxicology adequately characterized; approval recommended from nonclinical perspective
“These studies have adequately characterized the pharmacology and toxicology of oliceridine.”
Flexibilityopen answer page →
Flexibility accepted
Impurity or metaboliteAcceptedBeyond the letter
Major human metabolite TRV0109662 not shown qualified in EFD studies (failed ISR); no dedicated metabolite study, original EFD samples reanalysed instead
Why: Revalidated assay showed rat and rabbit EFD exposures exceeded projected human exposure at the revised 27 mg/day maximum dose · Pharmacology or kinetics
“Thus, we were unable to conclude that TRV0109662 had been adequately qualified with respect to an impact on embryo-fetal development.”
“As noted in Dr. Zhang’s review, these data confirmed that the original EFD studies adequately characterized the safety of this major human metabolite for the revised maximum daily dose of 27 mg/day.”
Juvenile toxAccepted with a conditionBeyond the letter
Juvenile and neonatal rat toxicity studies deferred to postmarketing requirements under the pediatric study plan
Why: Agreed initial Pediatric Study Plan · Other reason
“If the drug product is approved in this review cycle, the following additional studies are recommended as post-marketing requirements as outlined in the agreed initial Pediatric Study Plan:”
Safety marginVerdict not stated
Reproductive and developmental toxicity margins low relative to the maximum human daily dose
“The exposure margins in these studies suggest the potential for adverse effects on reproduction and development at clinically relevant doses compared to the currently proposed maximum human daily dose of 27 mg.”
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