Oveporexton

The mechanism of action of oveporexton in the treatment of narcolepsy type 1 (NT1) is through agonism of the orexin receptor 2 (OX2R). NT1 is associated with the loss of orexin neuropeptide signaling.

Cardiac Electrophysiology

Based on a comprehensive concentration-QTc analysis, there was no clinically relevant effect of oveporexton (i.e., >10 ms) on the QTc interval up to 11 times the mean steady state C_max at the maximum recommended dose.

Oveporexton showed dose proportional increase in exposures (C_max and AUC_0-t) at steady state over the dosage range of 1 mg twice daily to 2 mg twice daily. With two times daily administration, steady state was reached within 5 days, with an accumulation ratio of approximately 1.6 after a oveporexton dosage of 1 mg twice daily to 2 mg twice daily.

Absorption

Oveporexton median (min, max) time to maximum plasma concentration (T_max) is 1.5 hours (1 to 4 hours) at steady state.

Effect of Food: No clinically significant differences in the pharmacokinetics of oveporexton were observed following administration with a high-fat high-calorie meal.

Distribution

The apparent steady state volume of distribution of oveporexton is approximately 325 L. Protein binding is high (>96%) and concentration-independent in human plasma. The whole blood to plasma concentration ratio ranged from 0.61 to 0.90.

Elimination

The mean terminal elimination half-life of oveporexton is approximately 23.2 hours.

Metabolism: Oveporexton is primarily eliminated by hepatic metabolism. CYP3A4 is the predominant CYP enzyme involved in oveporexton metabolism with no major metabolites identified in circulation.

Excretion: After a single 25 mg radiolabeled oral dose of oveporexton, 80.5% of the total dose was recovered in feces and 11.0% was recovered in urine. Renal elimination of unchanged drug accounts for <1% of the total clearance of oveporexton.

Specific Populations

Patients with Hepatic Impairment

Exposure of oveporexton in patients with mild hepatic impairment (HI) (Child-Pugh A) or moderate HI (Child-Pugh B) compared to patients with normal hepatic function is summarized in Figure 1. Changes in oveporexton exposures (AUC_inf) due to HI did not exceed 2-fold compared to patients with normal hepatic function.

Patients with severe HI (Child-Pugh C) were not evaluated in clinical trials.

Patients with Renal Impairment

Exposures of oveporexton in patients with severe renal impairment (RI) (eGFR<15 mL/min; not on dialysis) compared to patients with normal renal function is summarized in Figure 1. Changes in oveporexton exposures (AUC_inf) due to RI did not exceed 2-fold compared to patients with normal renal function.

Patients with ESRD (eGFR <15 mL/minute or dialysis patients) were not evaluated in clinical trials.

Figure 1. Effects of Hepatic and Renal Impairment on Oveporexton Pharmacokinetics:

Other Specific Populations

Based on population pharmacokinetic analysis, age, sex, race/ethnicity, and body weight did not have clinically meaningful effects on the pharmacokinetics of oveporexton.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Effects of Other Drugs on Oveporexton:

• Strong and Moderate CYP3A Inhibitors: Concomitant use of oveporexton with itraconazole (a strong CYP3A inhibitor) resulted in increases in oveporexton AUC_inf (7.4-fold increase) and C_max (1.7-fold increase), compared to the use of oveporexton alone. The half-life of oveporexton was approximately 5-fold longer in the presence of itraconazole. Concomitant use of oveporexton with fluconazole (a moderate CYP3A inhibitor) resulted in increases in oveporexton AUC_inf (2.9-fold increase) and C_max (1.5-fold increase), compared to the use of oveporexton alone. The half-life of oveporexton was approximately 2-fold longer in the presence of fluconazole.
• Weak CYP3A Inhibitors: Based on physiologically-based pharmacokinetic (PBPK) modeling, no clinically meaningful interaction is expected during concomitant use of oveporexton with weak CYP3A inhibitors.
• Strong and Moderate CYP3A Inducers: Concomitant use of oveporexton with phenytoin (a strong CYP3A inducer) resulted in decreases in oveporexton AUC_inf and C_max by 81% and 56%, respectively, compared to use of oveporexton alone. Based on PBPK modeling, concomitant use of oveporexton with a moderate CYP3A inducer is predicted to decrease AUC_inf and C_max by 73% and 55%, respectively, compared to use of oveporexton alone.
• Weak CYP3A Inducers: Based on PBPK modeling, no clinically meaningful interaction is expected during concomitant use of oveporexton with weak CYP3A inducers.

Effects of Oveporexton on Other Drugs:

Based on a clinical evaluation of the effect of oveporexton on CYP3A activity assessed by 4β-hydroxycholesterol to cholesterol ratios and PBPK modeling, oveporexton is not expected to affect CYP3A activity or alter systemic exposure of CYP3A substrates at the maximum recommended oveporexton dose.

Based on a clinical evaluation of the effects of oveporexton on OATP1B1/B3 activity assessed by Coproporphyrin I (CPI) and Coproporphyrin III (CPIII), there was no apparent risk of inhibition of these transporters at the maximum recommended oveporexton dose.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes:

In vitro, oveporexton exposures at the maximum recommended oveporexton dose is not expected to directly inhibit or induce CYP enzymes (CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6).

Drug Transporter Systems

• Transporter Inhibition: In vitro, oveporexton did not inhibit P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2K, or MRP2.
• In vitro, oveporexton was an inhibitor of efflux transporters BSEP, MRP3, MRP4, and MDR3. However, inhibition of these transporters by oveporexton is not expected at the maximum recommended oveporexton dose.
• Transporter Substrate: In vitro, oveporexton was not a substrate of P-gp, BCRP, OATP1B1, or OATP1B3.