Lurasidone drug-drug interaction studies: a comprehensive review

Abstract

Background: To evaluate potential drug-drug interactions with the atypical antipsychotic lurasidone. Methods: Seven phase I studies were conducted to investigate the effects of repeated dosing of ketoconazole, diltiazem, rifampin, or lithium on the pharmacokinetics (PK) of single oral doses of lurasidone, or the effects of repeated dosing of lurasidone on the PK of digoxin, midazolam, or the oral contraceptive norgestimate/ethinyl estradiol. Two 6-week, phase III studies included evaluation of the potential for interaction between lurasidone and lithium or valproate. Maximum serum or plasma concentration (C max ) and area under the concentration-time curve (AUC) were calculated. Results: Concomitant ketoconazole administration resulted in a 6.8-fold increase in lurasidone C max and a 9.3-fold increase in lurasidone AUC; concomitant diltiazem administration resulted in 2.1-and 2.2-fold increases, respectively. Rifampin decreased lurasidone C max and AUC (one-seventh and onefifth of lurasidone alone, respectively). Steady-state dosing with lurasidone increased C max and AUC 0-24 (AUC from time 0 to 24 h postdose) of digoxin by 9% and 13%, respectively, and of midazolam by 21% and 44%, respectively. There were no significant interactions between lurasidone and lithium, valproate, ethinyl estradiol, or norelgestromin (the major active metabolite of norgestimate). Conclusions: Lurasidone PK is altered by strong cytochrome P450 (CYP) 3A4 inhibitors or inducers, and coadministration is contraindicated; whereas moderate CYP3A4 inhibitors have less effect, and lurasidone dosage restrictions are recommended. No dose adjustment

Lurasidone: A Review of Its Use in Adult Patients with Bipolar I Depression

“…Lurasidone C max and AUC values were increased significantly (by seven-and nine-fold, respectively) when the drug was administered with ketoconazole (a strong CYP3A4 inhibitor), whereas these values were reduced significantly when lurasidone was coadministered with rifampicin (rifampin; a strong CYP3A4 inducer) [11]. Therefore, lurasidone should not be administered with strong CYP3A4 inhibitors (e.g.…”

“…Similarly, coadministration of lurasidone with the following drugs had no clinically important effects on the systemic exposure to the coadministered drug: lithium, digoxin (a substrate of P-glycoprotein transporter), midazolam (a CYP3A4 substrate), and ethinyl estradiol or norelgestromin (contraceptives) [11].…”

Lurasidone in the Treatment of Bipolar Depression: Systematic Review of Systematic Reviews

“…According to the US package insert, rifampin, a potent CYP3A4-inducer, decreased lurasidone area under the curve fivefold [68]. There are no published studies of potent antiepileptic drugs CYP3A4 inducers that are expected to dramatically increase lurasidone metabolism, including those seldom prescribed to BD patients too [69].…”

Lurasidone in the treatment of schizophrenia: a critical evaluation

“…Lower doses are recommended in the presence of hepatic impairment, with the maximum daily dose not to exceed 80 mg in the presence of moderate impairment or 40 mg in the presence of severe impairment. Lurasidone is not found to affect the pharmacokinetics of lithium, valproate, digoxin (a glycoprotein substrate), midazolam or oral contraceptives (CYP3A4 substrates) [9]. No consistent Box 1.…”