Cipepofol

The mechanism of action of cipepofol for induction of general anesthesia in adults undergoing surgery is poorly understood. However, cipepofol is thought to produce anesthetic effects by the positive modulation of the inhibitory function of the neurotransmitter GABA through ligand-gated GABAA receptors.

The anesthetic effects of cipepofol were assessed using the MOAA/S and BIS in a randomized, dose-escalation, open-label, two-way crossover clinical pharmacology trial that evaluated the pharmacodynamics and pharmacokinetics of cipepofol compared with propofol at different doses in healthy male subjects. An MOAA/S score of 0 indicates that the patient is unresponsive and score 5 indicates that the patient is fully alert; a BIS score of 0 indicates that there is no detectable brain activity, and a score of 100 indicates that the patient is fully conscious and alert. A total of 19 subjects were enrolled in the trial and were randomized to 1 of 3 treatment sequences. For the 0.4 mg/kg cipepofol dose (administered over 1 minute) in 6 subjects, the:

• MOAA/S score decreased after cipepofol administration, and all subjects reached a MOAA/S ≤1 within 2 minutes after dosing. The mean (standard deviation [SD]) time to complete alertness after dosing was 13.3 (6.2) minutes after dosing.
• The BIS decreased to the minimum after cipepofol administration with a mean (SD) BIS nadir of 42.5 (5.5) at median time of 2.3 minutes.

MOAA/S and BIS parameters in geriatric patients, patients with HI, and patients with RI were comparable to healthy adults.

Cardiac Electrophysiology

At the recommended initial cipepofol dose for patients with ASA-PS I or II, <65 years old, and BMI ≤40 kg/m² of 0.4 mg/kg intravenously over 30 seconds, clinically significant QTc interval prolongation was not observed.

Pharmacokinetic parameters were evaluated in 48 healthy adult patients, who received a single intravenous bolus of cipepofol 0.4 mg/kg administered over 30 seconds. The mean (SD) venous maximum plasma concentration (C_max) of cipepofol (administered over 30 seconds) was 2,790 (1,890) ng/mL and mean (SD) area under the plasma concentration time curve from 0 to infinity (AUC_0-inf) was 256 (54.9) ng.h/mL. In dose ranging studies, pharmacokinetics were linear and dose proportional over the dose range of 0.128 to 0.81 mg/kg.

Distribution

Cipepofol has a large volume of distribution of 4.19±1.10 L/kg. Cipepofol is highly protein bound (approximately 99%) and protein binding was unaffected by mild or moderate RI or HI.

Elimination

After a single intravenous bolus of cipepofol 0.4 mg/kg, the mean (SD) clearance was 1.63 (0.357) L/h/kg, and the mean (SD) half-life was 1.81 (0.431) hours.

Metabolism

Cipepofol is extensively metabolized by UGT enzymes (predominantly UGT1A9) and CYP2B6, and to a minor extent, CYP1A2 and CYP2C19.

Following a single intravenous dose of 0.8 μCi/0.4 mg/kg [¹⁴C]-cipepofol (radiolabeled cipepofol), cipepofol represented approximately 1.1% of total plasma radioactivity, with the major metabolite M4, a pharmacologically inactive O-glucuronide metabolite, accounting for 71% of total plasma radioactivity.

Excretion

While cipepofol is not excreted in the urine, renal excretion is the primary route of elimination for the metabolites. In a mass balance study, approximately 85% of the administered cipepofol dose was excreted in urine, with glucuronide metabolites M4 and M5-1 accounting for 51.6% and 19.3% of the administered dose, respectively.

Specific Populations

Population pharmacokinetics analysis indicated that weight, sex, race, and age were covariates on cipepofol clearance or volume. Neither sex nor race had a clinically meaningful impact on cipepofol exposure.

Geriatric Patients

Cipepofol exposures following intravenous administration of a cipepofol 0.4 mg/kg dose were similar in adults 65 years of age and older and those less than 65 years of age, indicating that age did not have a significant effect on plasma cipepofol exposure. With regard to PD effects, adult patients 65 years of age or older who received a cipepofol dose of 0.3 mg/kg had similar pharmacodynamic (MOAA/S and BIS) results compared with adult patients less than 65 years of age who received a dose of 0.4 mg/kg.

Patients with Renal Impairment

In a clinical pharmacology study of cipepofol in patients with chronic mild and moderate RI and patients without RI, mean C_max was slightly decreased in those with worse renal function, but AUC_0-last and AUC_0-inf values showed no clear trend with worse renal function:

• Mild RI (i.e., estimated GFR [eGFR]: 60 to 89 mL/minute/1.73 m²): geometric mean AUC values were increased by approximately 12% to 13%, and C_max was decreased by approximately 32% compared with those without RI.
• Moderate RI (i.e., eGFR: 30 to 59 mL/minute/1.73 m²): geometric mean AUC values were similar, and C_max was decreased by approximately 19% compared with those without RI.
• Severe RI (i.e., eGFR: less than 30 mL/minute/1.73 m² with or without dialysis): pharmacokinetics was not assessed and is not known.

MOAA/S and BIS parameters were similar across patients with mild RI, moderate RI, and without RI groups.

Patients with Hepatic Impairment

In a clinical pharmacology study, mean cipepofol C_max showed no clear trend when comparing patients with normal hepatic function and patients with mild HI (Child-Pugh A) or moderate HI (Child-Pugh B), while AUC_0-last and AUC_0-inf increased slightly with worse HI:

• Mild HI: geometric mean AUC values were increased by approximately 10% to 12%, and C_max was increased by 14% compared with those without HI.
• Moderate HI: geometric mean AUC values were increased by approximately 22% to 30% while C_max was not changed compared with those without HI.
• Severe HI: pharmacokinetics was not assessed and is not known.

Sedation assessed by MOAA/S and BIS nadir showed similar trends in patients with mild HI, moderate HI, and without HI, indicating that there were no effects of mild and moderate HI on sedation.

Patients with BMI >40 kg/m²

In population pharmacokinetics analyses, there was increased cipepofol exposure with increasing lean body weight. Specifically, simulated cipepofol doses of 0.2 mg/kg to 0.25 mg/kg in patients with BMI >40 kg/m² were predicted to have similar exposure to a dose of 0.4 mg/kg in patients with BMI ≤40 kg/m²; therefore, in Trials 1, 2, and 3, patients with BMI >40 kg/m² received a lower cipepofol dose than those with a BMI ≤40 kg/m².

Drug Interaction Studies

Clinical Studies

There was no significant pharmacokinetic/pharmacodynamic drug interaction of cipepofol with rifampicin (CYP2B6 inducer, UGT1A9 inducer), voriconazole (CYP2B6 inhibitor), mefenamic acid (UGT1A9 inhibitor), or divalproex.

In vitro Studies

Metabolizing enzymes:

Cipepofol inhibited CYP2B6 and CYP2C19 in vitro, while its major metabolite, M4, did not inhibit any CYP enzymes. Cipepofol also inhibited UGT1A9 metabolism in vitro. Based on the rapid decline in cipepofol concentrations following administration of a 0.4 mg/kg cipepofol dose, there are not anticipated to be any clinically relevant drug interactions affecting CYP2B6, CYP2C19, and UGT1A9 substrates.

Cipepofol and its major metabolite, M4, did not induce CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations.

Drug transporters:

Cipepofol and M4 are not substrates of P-gp, BCRP, OAT1, OCT2, MATE1, and MATE2K. Cipepofol was not a substrate of OAT3, OATP1BI, and OATP1B3, while M4 was possibly a substrate of these transporters. Cipepofol was not an inhibitor of P-gp, BCRP, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1, and MATE2K. M4 was not an inhibitor of P-gp, BCRP, OCT2 and MATE2K, but at high concentrations showed inhibitory activity for OAT1, OAT3, OATP1B1, OATP1B3, and MATE1. Based on in vitro studies, cipepofol and M4 are not expected to show clinically relevant inhibition of any drug transporters.

There was no evidence of local vascular irritation following single intravenous or repeated daily (7 days) intra-arterial dosing of cipepofol to rabbits. Minimal local irritation was observed in rabbits following repeated daily (7 days) subcutaneous dosing of cipepofol.

Effects on the Use of Anesthetic Drugs in Animals

Published studies in animals demonstrate that the use of anesthetic drugs during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester through the first several months of life but may extend out to approximately 3 years of age in humans. In primates, exposure to 3 hours of an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, anesthetic treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but prolonged cognitive deficits in learning and memory.