LCPTonce‐daily extended‐release tacrolimus tablets versus twice‐daily capsules: a pooled analysis of two phase 3 trials in importantde novoand stable kidney transplant recipient subgroups

Abstract

SUMMARYAfrican-American and elderly kidney transplant recipients (KTR) have increased risk for poor clinical outcomes post-transplant. Management of immunosuppression may be challenging in these patients and contribute to worse outcomes. A novel once-daily formulation of tacrolimus (LCPT) has demonstrated noninferiority, similar safety, improved bioavailability, a consistent concentration time profile, and less peak and peak-trough fluctuations vs. tacrolimus twice-daily (Tac BID). This pooled analysis of two phase 3 randomized, controlled trials, including 861 (LCPT N = 428; Tac BID N = 433; 38% of patients were stable KTR, and 62% were de novo KTR) patients, examined the efficacy of LCPT in KTR subgroups (blacks, females, and age ≥65). Overall, treatment failure [death, graft failure, centrally read biopsy-proven acute rejection (BPAR), or lost to follow-up] at 12 months was as follows: LCPT: 11.9%, BID Tac: 13.4% [À1.48% (À5.95%, 2.99%)]. BPAR rates were as follows: LCPT: 8.2%, Tac BID: 9.5% [À1.29% (À5.14%, 2.55%)]. Numerically, fewer treatment failure events with LCPT were found in the majority of subgroups, with significantly less treatment failure associated with LCPT among black KTR [À13.82% (À27.22%, À0.31%)] and KTR ≥65 [À13.46% (À25.27%, À0.78%)]. This pooled analysis suggests numerically lower efficacy failure rates associated with LCPT among high-risk subgroups, in particular black KTR and KTR ≥65 years old.

Pharmacokinetics of Once‐Daily Extended‐Release Tacrolimus Tablets Versus Twice‐Daily Capsules in De Novo Liver Transplant

“…As demonstrated in other studies, the increased bioavailability associated with LCPT allows for utilization of a lower dose to achieve similar systemic exposure. 12,13,15,16 On days 1, 7, and 14, t max was significantly prolonged with LCPT, which is consistent with a controlledrelease formulation. Additionally, there was a robust correlation between AUC 0-24h and C min with LCPT, demonstrating that the current practice of therapeutic drug monitoring of C min as a measure of tacrolimus exposure can be applied to LCPT in liver transplant patients.…”

“…While bioavailability was not specifically assessed in this PK study, dose‐adjusted AUC can be used as a surrogate for bioavailability. As demonstrated in other studies, the increased bioavailability associated with LCPT allows for utilization of a lower dose to achieve similar systemic exposure …”

“…Results of this 1-year study, in addition to those of previous kidney de novo and conversion trials, a liver conversion trial, and PK comparisons among LCPT, IR-Tac, and Tac-XL support further investigation of LCPT for de novo liver transplant patients. 12,13,[15][16][17]23 Future studies are warranted to examine whether oncedaily dosing and the unique PK parameters provided by LCPT are associated with safety or efficacy differences in liver transplant recipients.…”

“…This extended‐release once‐daily tablet (LCPT) increases the bioavailability of tacrolimus by the creation of a solid dispersion, or a solid solution, of the drug substance through a physical process called “controlled agglomeration.” Prior randomized trials in renal transplant recipients comparing LCPT with IR‐Tac have shown that LCPT has greater bioavailability, a steadier and more consistent concentration time profile over 24 hours, and reduced fluctuation (the peak‐to‐trough change in drug concentrations around the average concentration) and swing (the peak‐to‐trough change in drug concentrations relative to the minimum concentration) compared to IR‐Tac . In addition, LCPT has demonstrated comparable efficacy, improved tolerability in regard to hand tremors, and robust correlations between area under the concentration‐time curve (AUC) and minimum whole blood concentration (C min ) in trials evaluating the product in renal transplantation …”

Comparative pharmacokinetic characteristics of tacrolimus following application of its different pharmaceutical formulations in humans

“…Међутим, показано је да 50% паци-јената након конверзије захтева промену дозе у смислу повећања или смањења оне која је иницијална након конверзије [25][26][27][28][29][30][31] . Због тога, тренутно су у току клиничке студије у којима је иницијална доза при конверзији 70% од дозе пре конверзије 32 . Тако су Ogura и сарадници недавно пока-зали да је код пацијената са трансплантира-ном јетром, код којих је урађена конверзија, просечна концентрација такролимуса сма-њена за 30,4% током 14 дана након пре-вођења на формулацију са продуженим осло-бађањем у односу 1:1 33 .…”