Emilie HENIN, Mirco GOVONI, Giovanni PIOTTI, Massimo CELLA, Christian LAVEILLE
Calvagone, Liergues, France; Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy; Department of Nephrology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
Objectives:
Tacrolimus is a pivotal immunosuppressant agent used in solid-organ transplantation necessitating therapeutic drug monitoring (TDM), due to its narrow therapeutic window. Its original formulation, Prograf®, is an immediate-release capsule to be administered twice daily. Envarsus® has been developed recently to be administered once daily: the Meltdose® drug delivery technology enables a broader absorption throughout the gastro-intestinal tract and a sustained consistent tacrolimus concentration.
The objectives of this study was to develop a population PK model for tacrolimus concentrations after Envarsus administration, in de novo renal transplant recipients, and to explore by simulation the performance of TDM strategies.
Methods:
Thirty-three de novo renal transplant recipients, receiving Envarsus once daily, were monitored for 28 days. A total of 1951 tacrolimus concentration measurements were collected over 0-24 hour period, on day 1, 3 7 and 14, and at trough on day 2, 3, 4, 5, 6, 7, 8, 14, 15, 21 and 28. Envarsus treatment was initiated on transplantation day, at 0.17 mg/kg; dose was then adjusted based the basis of tacrolimus trough level (TTL) in order to target 5-15 ng/mL from day 4 to 8 and 5-10 ng/mL from day 15 to 22.
Population PK model development was guided by parsimony principles, quality of estimations, model diagnostics and predictive performance.
Several TDM strategies, evaluating both a priori adaptation to covariates and a posteriori schedule for TDM based on TTL, were simulated and compared in terms of Envarsus dose and number of patients reaching the TTL target.
Model development, parameter estimation and simulations were performed using NONMEM 7.3.
Results:
Envarsus pharmacokinetics were adequately described by a 1-compartment disposition model with first-order elimination; absorption was characterised by three parallel chains composed respectively of 3, 6 and 9 compartments, allowing a 3-phase absorption profile. 13.3% of the dose had a fast absorption (mean transit time, MTT of 1.06h), 61.2% had a medium absorption (MTT of 4.81h) and 25.5% had slow absorption (MTT of 26.1h). Inter-individual variability was accounted on clearance, volume, repartition among transit chains and fast and medium MTTs. Eta-shrinkage was lower than 11% on all parameters. Inter-occasion variability was accounted on relative bioavailability, no trend was found between occasions. Residual error was additive on the log scale, with a separate magnitude for 24-hour profiles (26.9%) and TTL (34.9%).
Parameter-covariate relationships were identified for Envarsus PK: bodyweight at inclusion had an allometric impact on clearance (+0.75 FIX) and on volume (+1 FIX); and CYP3A5 polymorphism resulted in a 67% increase in *1/*3 compared to *3/*3 patients.
Simulations of the TDM strategy implemented in the original study (0.170 mg/kg up to day 3, dose adaptation based on TTL on days 4, 7, 15 and 22) were in accordance with the observed TTL profiles. The median TTL profile was in accordance with the specified target ranges. The proportion of patients reaching the specified target was below 40% on day 3, and rose above 70% from day 7.
An alternative TDM strategy allowed maintaining concentrations within the specified target. On day 1, the dose was a priori adapted to covariates, in median 0.160 mg/kg and 0.272 mg/kg for *3/*3 and *1/*3 patients respectively. Subsequently, doses were adapted based on TTL: on day 2, median doses were 0.061 mg/kg and 0.094 mg/kg for *3/*3 and *1/*3 patients respectively; on day 3, median doses were 0.085 mg/kg and 0.137 mg/kg; on day 4 and onwards, median doses were 0.0759 mg/kg and 0.147 mg/kg. The proportion of patients reaching the specified target was maintained over 70% from day 2 and onwards.
This model-based approach allowed a better exploration of dose adaptation strategies to maintain tacrolimus concentrations within specified range after Envarsus administration in de novo renal transplant patients.
Reference: PAGE 28 (2019) Abstr 8872 [www.page-meeting.org/?abstract=8872]
Poster: Clinical Applications