This poster was presented at the 30th annual Psych Congress, held Sept. 16-19, 2017, in New Orleans, Louisiana.
Background: Potential pharmacokinetic interactions between valbenazine (INGREZZA; FDA-approved for tardive dyskinesia) and concomitant medications were assessed in Phase 1 studies and using standard in vitro methods.
Methods: In vitro studies assessed valbenazine effects on CYP enzymes and drug transporters. Two single-dose studies were conducted with (Test) or without (Reference) valbenazine as the perpetrator: Study 1 (N=24), digoxin 0.5mg (P-glycoprotein substrate) with/without valbenazine 80mg; Study 2 (N=12), midazolam 2mg (CYP3A4 substrate) with/without valbenazine 80mg. Two studies were conducted with valbenazine alone (Reference) or with (Test) concomitant perpetrator: Study 3 (N=24), single-dose valbenazine 50mg alone/during twice-daily ketoconazole 200mg (CYP3A4 inhibitor); Study 4 (N=12), single-dose valbenazine 80mg alone/during once-daily rifampin 600mg (CYP3A4 inducer). Non-compartmental pharmacokinetic parameters were determined. Point estimate and two-sided 90% CI for Test-to-Reference (T/R) differences of log-normalized pharmacokinetic parameters were determined.
Results: Valbenazine as perpetrator: T/R ratios [90%CI] of digoxin Cmax and AUCinf were 192% [166-221%] and 136% [126-148%], respectively; T/R ratios of midazolam Cmax and AUCinf were 102% [86-121%] and 107% [100-114%]. Ketoconazole as perpetrator: T/R ratios of valbenazine Cmax and AUCinf were 151% [141-162%] and 214% [204-224%], respectively. Rifampin as perpetrator: T/R ratios of valbenazine Cmax and AUCinf were 68.2% [57.9-80.3%] and 27.7% [25.5-30.1%].
Conclusions: Co-administration with potent CYP3A4 inhibitors may require adjusting valbenazine dose in clinical practice (80mg to 40mg), and CYP3A4 inducers may lower valbenazine exposure and effect. Apart from potential increased absorption of P-glycoprotein substrates, valbenazine showed minimal potential to affect CYP-mediated metabolism of co-medications and low potential to affect pharmacokinetics of drug transporter substrates.