Lurasidone drug-drug interaction studies: a comprehensive review.
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 (Cmax) and area under the concentration-time curve (AUC) were calculated.


RESULTS
Concomitant ketoconazole administration resulted in a 6.8-fold increase in lurasidone Cmax 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 Cmax and AUC (one-seventh and one-fifth of lurasidone alone, respectively). Steady-state dosing with lurasidone increased Cmax and AUC0-24 (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 for lurasidone is needed when administered with lithium or valproate. Dose adjustment is not required for lithium, valproate, digoxin (a P-glycoprotein substrate), or midazolam or oral contraceptives (CYP3A4 substrates) when coadministered with lurasidone.
Yu-Yuan
YY
Chiu
Larry
L
Ereshefsky
Sheldon H
SH
Preskorn
Nagaraju
N
Poola
Antony
A
Loebel
D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D017321:Clinical Trials, Phase I as Topic; D051544:Cytochrome P-450 CYP3A / Q000494:pharmacology; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D054833:Isoindoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000494:pharmacology; D018020:Lithium Compounds / Q000494:pharmacology; D000069056:Lurasidone Hydrochloride; D012293:Rifampin / Q000494:pharmacology; D013844:Thiazoles / Q000009:adverse effects / Q000493:pharmacokinetics*
D014150:Antipsychotic Agents; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D054833:Isoindoles; D018020:Lithium Compounds; D013844:Thiazoles; D051544:Cytochrome P-450 CYP3A; D004110:Diltiazem; D000069056:Lurasidone Hydrochloride; D007654:Ketoconazole; D012293:Rifampin