Clinical Assessment of the Drug-Drug Interaction Potential of Omaveloxolone in Healthy Adult Participants

Abstract

Omaveloxolone is approved in the United States and the European Union for the treatment of patients with Friedreich ataxia aged ≥16 years. It is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro. Two drug-drug interaction studies (NCT04008186 and NCT05909644) were performed to evaluate (1) the effect of drug-metabolizing enzymes (DMEs) and drug transporter (DT) modulators on the pharmacokinetics of omaveloxolone and (2) the effect of omaveloxolone on the pharmacokinetics of DME and DT substrates. Additionally, the safety of coadministering these drugs with omaveloxolone was assessed. Coadministration of the strong CYP3A4 inhibitor itraconazole significantly increased omaveloxolone maximum plasma concentration (C_max) and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC_0-∞) by approximately 3- and 4-fold, respectively. Conversely, coadministration with the moderate CYP3A4 inducer efavirenz decreased C_max and AUC_0-∞ of omaveloxolone by 38.0% and 48.5%, respectively. Omaveloxolone exposure was also increased following coadministration with verapamil, a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor, but it was unaffected by the strong CYP2C8 inhibitor gemfibrozil. Coadministration of omaveloxolone reduced systemic exposure of the substrates of CYP3A4, CYP2C8, breast cancer resistance protein, and organic anion transporting polypeptide 1B1 but had no effect on those of P-gp and organic cation transporter 1. Omaveloxolone was well tolerated when administered alone and in combination with the DME and DT modulators or substrates. These findings support concomitant medication precautions and dosing recommendations for omaveloxolone when coadministered with a moderate or strong CYP3A4 inhibitor or inducer, as well as the substrates of certain CYP450 enzymes or transporters.

Keywords: CYP3A4; Friedreich ataxia; drug–drug interaction; omaveloxolone; pharmacokinetics.

Figure 1

Schematic of study 1806 (a) part 1 and (b) parts 2, 3, and 4. Probe drugs refer to drug‐metabolizing enzyme and drug transporter substrates in part 1 and drug‐metabolizing enzyme and drug transporter modulators in parts 2‐4. ^aPK blood samples for omaveloxolone were collected predose on Days 17‐24. ^bPK sampling time points for probe drugs: midazolam (predose on Days 1 and 18, and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 h postdose); repaglinide (predose on Days 2 and 19, and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 h postdose); metformin (predose on Days 3 and 20, and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h postdose); rosuvastatin (predose on Days 5 and 22, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, and 48 h postdose); and digoxin (predose on Days 5 and 22, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 120, and 144 h postdose). ^cPK blood samples for omaveloxolone were collected predose on Days 1 and 13, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 h postdose. ^dPK blood samples for probe drugs were collected predose on Days 11‐17. BID, twice daily; CRU, clinical research unit; PK, pharmacokinetics; QD, once daily.

Figure 2

Schematic of study 2202. ^aPK blood samples for omaveloxolone were collected predose (within 60 min before omaveloxolone dosing) on Days 1 and 29, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 288, and 336 h postdose. The 336‐h postdose sample of Period 1 and the predose sample of Period 2 are the same sample. CRU, clinical research unit; PK, pharmacokinetics; QD, once daily.

Figure 3

Mean plasma omaveloxolone concentrations versus time (semilog scale) following administration of a single dose of omaveloxolone 150 mg alone or coadministration with drug‐metabolizing enzyme and drug transporter modulators: (a) gemfibrozil 600 mg BID (strong CYP2C8 inhibitor), (b) itraconazole 200 mg QD (strong CYP3A4 inhibitor), (c) verapamil 120 mg QD (P‐gp inhibitor and moderate CYP3A4 inhibitor), and (d) efavirenz 600 mg QD (moderate CYP3A4 inducer). The lower limit of quantification was 0.0750 ng/mL for all analytes as shown by the horizontal dashed lines (not shown in panel d). BID, twice daily; CYP, cytochrome P450; P‐gp; P‐glycoprotein; QD, once daily.

Figure 4

Forest plots displaying the effect of coadministered drug‐metabolizing enzyme and drug transporter modulators on omaveloxolone pharmacokinetic parameters (primary endpoints). AUC_0‐∞, area under the plasma concentration–time curve from time 0 extrapolated to infinity; AUC_0‐tlast, area under the plasma concentration–time curve from time 0 to time of the last measurable concentration. C_max, maximum plasma concentration; GLSM, geometric least squares mean.

Figure 5

Mean plasma concentrations of drug‐metabolizing enzyme and drug transporter substrates versus time (semilog scale) following single‐dose administration alone or coadministration with omaveloxolone 150 mg once daily: (a) midazolam 2 mg (CYP3A4 substrate), (b) repaglinide 1 mg (CYP2C8 substrate), (c) metformin (OCT1 substrate), (d) rosuvastatin 10 mg (BCRP and OATP1B1 substrate), and (e) digoxin 0.25 mg (P‐gp substrate). BCRP, breast cancer resistance protein; CYP, cytochrome P450; OATP1B1, organic anion transporting polypeptide 1B1; OCT1, organic cation transporter 1; P‐gp; P‐glycoprotein.

Figure 6

Forest plots displaying the effect of omaveloxolone on the pharmacokinetic parameters of drug‐metabolizing enzymes and drug transporter substrates. AUC_0‐∞, area under the plasma concentration–time curve from time 0 extrapolated to infinity; C_max, maximum plasma concentration; GLSM, geometric least squares mean.

Figure 7

Summary of drug interactions with omaveloxolone and implications on concomitant medication precautions. AUC, area under the plasma concentration–time curve; BCRP, breast cancer resistance protein; C_max, maximum plasma concentration; CYP, cytochrome P450; DME, drug‐metabolizing enzyme; DT, drug transporter; OATP1B1, organic anion transporting polypeptide 1B1; OCT1, organic cation transporter 1; P‐gp, P‐glycoprotein; PI, prescribing information.