Once-Daily MeltDose Tacrolimus (Envarsus) Offers Dosing Flexibility and Maintains Therapeutic Activity When Make-Up Dose Is Taken Outside of Schedule.

Abstract

Tacrolimus (Tac) is considered a Narrow Therapeutic Index drug and non-adherence may be an issue in transplant patients. Missed or delayed doses may result in subtherapeutic drug levels resulting in rejection-associated morbidity/mortality. Missed dose guidance is important to helping patients maintain therapeutic Tac levels. Envarsus is a novel once-daily, MeltDose formulation of Tac with greater bioavailability, less peak and trough-to-peak fluctuations, and similar efficacy and safety vs. twice-daily Tac (Prograf). Envarsus' pharmacokinetic (PK) profile is similar whether dosed morning or evening (Nigro V., et al. Flexible Dosing Of Once-daily LCP-Tacro Tablets: Morning Vs. Evening Chronopharmacokinetic Study, AST/ESOT Joint Meeting 2012). We evaluated the impact of non-adherence on PK of Envarsus vs. Prograf using a System Dynamics model inspired by physiologically based PK models and data from kidney transplant recipients (KTR). A “what if” analysis of various non-adherence simulated scenarios, based on varying trough levels from 12ng/ml to 6ng/ml in the presence of perfect adherence, no make-up dose, missed dose, double-dose, and makeup doses at 21, 18 and 15hrs after missed dose was conducted. (Figure) Results showed: a double dose 24h after missed dose results in higher blood concentration vs. perfect adherence; the concentration peak is highest when the Envarsus make-up dose is taken 18 or 21 hours after the missed dose (vs. 15); and taking an Envarsus make-up dose never results in peak blood concentration that exceeds Prograf normal peak. Based on the observations, it is recommended that if KTR miss a dose, a make-up dose be taken as soon as possible, followed by the next regularly scheduled dose; a double dose can be taken although it is not recommended. In addition to the lack of diurnal variation, Envarsus maintains Tac levels and offers dosing flexibility beyond a 24 hour dosing window.Figure: No Caption available.DISCLOSURES:Nachtrieb, R.: Other, Veloxis Pharmaceuticals, Paid consultant. Nigro, V.: Employee, Veloxis Pharmaceuticals.