Tacrolimus Capsules Research Articles

Changes in drug crystallinity in a commercial tacrolimus amorphous formulation result in variable pharmacokinetics

Tacrolimus capsules contain the drug as the amorphous form. It is well known that drug crystallinity is a risk factor for the performance of amorphous formulations. This study investigated the impact of varying levels of crystalline drug on the pharmacokinetics of tacrolimus following oral dosing of a 5 mg capsule under fasting conditions. Two treatments with percent crystallinity of 20% and 50% were achieved by exposing a marketed generic tacrolimus product to open dish storage conditions of 35 °C and 75% relative humidity (RH) for up to 20 days. Crystallinity was monitored with X-ray powder diffraction. Prograf®, the reference listed drug (RLD), an amorphous generic drug product, and generic drug products containing 20% and 50% crystalline tacrolimus were evaluated. All four treatments were administered to healthy participants in a randomized, single-dose, four-treatment, four-period, four-way crossover study. Blood sampling occurred over 24 h. The amorphous generic tacrolimus product was determined not to be bioequivalent to the RLD. The capsules containing both 20% and 50% crystalline tacrolimus also failed the bioequivalence recommendations when compared to the amorphous generic or to the RLD. Both levels of crystalline tacrolimus resulted in BE failure for both Cmax and AUC parameters. The impact of tacrolimus crystallization was greater for maximum blood concentration (Cmax) values relative to the area-under-the-curve (AUC) values. This study demonstrates that crystalline tacrolimus formed in a marketed generic product and these changes resulted in variable pharmacokinetics which could be of significant clinical concern.

Efficacy of tacrolimus capsules in patients undergoing high-risk keratoplasty

Purpose: To evaluate the efficacy of tacrolimus capsules in patients undergoing high-risk keratoplasty.
 Methods: 40 high-risk patients who underwent penetrating keratoplasty at The Third Hospital of Hebei Medical University, China between January 2016 and December 2021 were included in this study. These patients were divided into two groups based on the specific immunosuppressant administered post-surgery. Twenty patients were administered oral tacrolimus capsules in conjunction with 0.1 % tacrolimus eye drops, constituting the combination with systemic treatment group (group 1), while another twenty patients were solely administered 0.1 % tacrolimus eye drops, forming the topical treatment group (group 2). The occurrence of rejection, corneal neovascularization, corneal graft edema and visual acuity were documented in both groups.
 Results: In comparison to patients in group 2, patients in group 1 exhibited a significant reduction in rejection rate (p < 0.05). Additionally, the average time of neovascularization in group 1 was delayed and the number of cases was lower (p < 0.05). Furthermore, a smaller proportion of patients in group 1 experienced corneal graft edema (25 vs 60 %, p < 0.05), while a higher percentage of patients in group 1 demonstrated improved visual acuity (90 vs 60 %, p < 0.05).
 Conclusion: Concurrent administration of tacrolimus eye drops and capsules orally effectively mitigates anti-rejection reactions, regulation of neovascularization, management of graft edema and enhancement of visual acuity in high-risk keratoplasty patients when compared to the use of tacrolimus eye drops as a standalone treatment. These results have the potential to stimulate novel avenues of investigation in future clinical research.

Comparison of the Prolonged- and Immediate-Release Tacrolimus Capsule Formulation: The Patient's View and Medication Satisfaction of Patients After Pediatric Heart Transplantation

Medication adherence is essential for long-term success after pediatric organ transplantation. Causes of reduced adherence should be detected early to improve the consequent medication intake. We describe the influence of switching from tacrolimus twice daily (tacrolimus-BID) to tacrolimus once daily (tacrolimus-QD) on medication satisfaction and medication adherence in patients after pediatric heart transplantation. A retrospective analysis was conducted regarding patient satisfaction and adherence to the immunosuppressant tacrolimus after pediatric heart transplantation, before and after conversion from tacrolimus-BID to tacrolimus-QD, using questionnaires. Thirty-eight patients were enrolled (tacrolimus-BID: n=35, mean age 15.7 ± 5.2 years; tacrolimus-QD: n=38, mean age 16.2 ± 5.6 years). The amount of unadministered medication in the last 3 months did not differ between the 2 pharmaceutical forms. However, 17% (n=6) reported unstable tacrolimus trough levels when taking tacrolimus-BID, vs 8% (n=3) under tacrolimus-QD (P=.453). However, there was no statistically significant difference in the stability of the last 6 trough levels of each patient (P=.074). A total of 57% (n=20) of patients had subjective side effects before conversion, compared to only 29% (n=11) after conversion (P=.013). Regarding the intensity of the side effects, 6 patients reported strong/very strong side effects when taking tacrolimus-BID vs 1 patient when taking tacrolimus-QD (P=.250). In addition, the overall satisfaction with the immunosuppressant was higher under tacrolimus-QD (92% vs 83%; P=.508). However, this improvement was statistically not significant and may not be clinically relevant. The amount of forgotten medication was not reduced after conversion from tacrolimus-BID to tacrolimus-QD. However, subjective side effects as well as patient satisfaction improved under tacrolimus-QD.

Evaluation of the efficacy and safety of conversion from the tacrolimus capsule to tablet in stable liver transplant recipients with maintenance therapy: a 24-week, open-label, single-center, phase IV exploratory clinical study.

The tablet form of tacrolimus is more convenient for drug ingestion than the capsule form. We examined the efficacy and safety of tacrolimus tablets and a satisfaction survey after formula conversion in liver transplant (LT) recipients. This study was an open-label, prospective clinical trial for tacrolimus formula 1:1 conversion from capsule to tablet in 41 adult LT recipients with tacrolimus maintenance therapy of more than 1 month. The primary endpoint was incidence of biopsy-proven acute rejection (BPAR) within 24 weeks. Surveys 1 week before and 4 weeks after formula conversion were conducted for total daily dose of medication, number, scale of discomfort and satisfaction. The overall incidence of BPAR was 0% and there was no graft loss or patient death. The incidence of adverse effects was 34.1% (n = 14) after formula conversion. The most common severe adverse effect was abnormal liver function test (n = 5): biliary complications (n = 4) and alcoholic recidivism (n = 1). Total daily dose and number of tacrolimus doses were significantly lower after formula conversion (P < 0.05) without changes in trough level. According to survey analysis, there was no significant difference in discomfort and satisfaction scales from capsule to tablet conversion (P < 0.05). The present study suggests that the new tablet formula can be a useful treatment option to maintain a consistent level of tacrolimus with a lower total daily dose and number in adult LT recipients.

Outcomes in kidney transplant recipients treated with immediate-release tacrolimus capsules versus extended-release tacrolimus capsules: A cohort study.

Prior randomized trials and observational studies have generally reported similar outcomes in kidney transplant recipients (KTRs) treated with immediate-release tacrolimus (IR-TAC) versus extended-release tacrolimus (ER-TAC). However, many of these previous studies focused on patients with low immunological risks, had small sample sizes and brief follow-up periods, and excluded outcomes associated with graft loss, such as chronic rejection. To address these limitations, we conducted a cohort study of 848 KTRs at a single transplantation center who had generally high immunological risks and were treated with either IR-TAC capsules (589 patients, 65.9%) or ER-TAC capsules (289 patients, 34.1%). All patients received their designated maintenance immunosuppressive regimen for at least 3months post-transplantation. Afterwards, tacrolimus formulation was at the discretion of each patient's transplant nephrologist. For the two treatment groups, we compared the hazards of experiencing a composite outcome of acute or chronic antibody-mediated rejection (AMR), acute or chronic T-cell-mediated rejection, de novo DSA, and/or graft loss over a 3-year period starting at 3 months post-transplantation. In a multivariable Cox proportional hazards regression model, KTRs treated with IR-TAC capsules had an increased hazard of experiencing the composite outcome when compared to patients treated with ER-TAC capsules; however, this result was not significant (adj HR 1.24, 95% CI .92-1.68, p=.163). Similar results were obtained with inverse probability of treatment weighting (IPTW) using a propensity score (adj HR 1.25, 95% CI .93-1.68, p=.146). These findings suggest that when compared to IR-TAC capsules, ER-TAC capsules do not reduce the hazard of poor outcomes in KTRs with generally high immunological risks.

Health System Encounters in Kidney Transplant Recipients Converted from Immediate-Release Tacrolimus Capsules to Extended-Release Tacrolimus Tablets

Health System Encounters in Kidney Transplant Recipients Converted from Immediate-Release Tacrolimus Capsules to Extended-Release Tacrolimus Tablets

Clinical observation on the effect of Wuzhi soft capsule on FK506 concentration in membranous nephropathy patients.

The current research aimed to investigate the correlation between the effect of Wuzhi soft capsule (WZC) on FK506 concentration and CYP3A5 gene polymorphism in patients with membranous nephropathy (MN).Seventy-five patients with idiopathic MN were enrolled and divided according to the expression of CYP3A5 gene metabolic enzyme into group A (CP3A5 metabolic enzyme function expression types CYP3A5∗1/∗1 type and CYP3A5∗1/∗3 type), and group B (non-expression type CYP3A5∗3/∗3 type). All patients were given oral administration of tacrolimus capsule at the initial dose of 1 mg for twice a day 1 hour before breakfast and dinner. Afterwards, the oral administration of WZC was added at the dose of 0.5 g for 3 times a day within half an hour after 3 meals.The blood concentrations of FK506 in groups A and B were significantly higher than those before administration. Compared with that before administration, the FK506 blood concentration was increased by 3.051 ± 0.774 ng/ml after adding the WZC. Besides, the blood concentrations of FK506 in group A were lower than those in group B before and after administration; meanwhile, the 24 hours total urine protein and the biochemical indexes in both groups displayed no statistically significant difference. Only 1 case of diarrhea was observed, which was relieved after the reduction of tacrolimus.Wuzhi soft capsule can significantly increase the blood concentration of FK506 in MN patients. Moreover, the CYP3A5 genotyping should be considered when WZC is used to increase the blood concentration of FK506.

A Prospective, Observational Study of Conversion From Immediate- to Prolonged-Release Tacrolimus in Renal Transplant Recipients in France: The OPALE Study.

BackgroundPotential benefits of once-daily, prolonged-release tacrolimus over the immediate-release formulation include improved adherence to immunosuppressives post transplantation. An observational study was performed to characterize real-world practice surrounding conversion from immediate- to prolonged-release tacrolimus in kidney transplant recipients.Material/MethodsWe performed a prospective, observational study of renal transplant recipients converted from immediate- to prolonged-release tacrolimus capsules. Conversion took place at the baseline visit, within the first 6 months of transplantation (early conversion group) or between 6 and 12 months of transplantation (late conversion group). Data collection was performed at routine follow-up at 6 and 12 months. Endpoints included conversion ratio from immediate- to prolonged-release tacrolimus, reasons for conversion, additional visits due to conversion, safety, and tolerability.ResultsThe analysis population comprised 591 patients. Baseline characteristics were similar between the 2 groups. The mean conversion ratio of the daily dose of tacrolimus was 0.98±0.17 in the early group and 0.99±0.09 in the late group. Time from conversion (mean ±SD) to first measurement of trough tacrolimus blood concentration was 12.1±11.6 and 27.6±26.7 days in the early and late groups, respectively. The highest number of additional visits required was 6 in the early conversion group, in 3 patients (0.7%), and 3 in the late conversion group, in 2 patients (1.6%). Conversion from immediate- to prolonged-release tacrolimus was associated with a very low rate of graft rejection.ConclusionsFavorable clinical outcomes and safety profiles were observed with conversion from immediate- to prolonged-release tacrolimus over 1 year following renal transplantation, with no marked differences between the early and late conversion groups.

Prolonged-Release vs Immediate-Release Tacrolimus Capsules in Black vs White Kidney Transplant Patients: A Post Hoc Analysis of Phase III Data

BackgroundBlack kidney transplant patients experience inferior outcomes compared with other ethnicities. Because scrutiny is required when immunosuppressant drugs are used in such at-risk populations, we report the first large-scale clinical efficacy data assessing prolonged-release tacrolimus (PR-T) in black de novo kidney transplant patients. Methods and materialsWe used logistic regression and proportionate hazards to compare a composite outcome measure (biopsy-proven acute rejection, graft loss, mortality, and loss to follow-up) in black and white patients in treatment groups longer than 24 weeks, from 3 large Phase III randomized controlled trials. Secondary endpoints included tacrolimus trough concentration, dose, and estimated glomerular filtration rate. ResultsThe study included 2162 patients whose treatments belonged to two categories (immediate-release tacrolimus: 77 black patients, 721 white patients; and PR-T: 87 black patients, 1277 white patients). Despite demographic factors generally predictive of worse outcomes, efficacy failure among black patients who received PR-T was non-inferior to that among white patients who received either therapy. Compared with immediate-release tacrolimus, black patients who received PR-T achieved stable tacrolimus concentrations 2.5 times faster (21 vs 56 days, P = .04), and more achieved stable target concentrations (76.7% vs 69.3%). Treatment-emergent adverse events were consistent with those reported separately in pivotal trials. ConclusionsOverall, black patients who received PR-T achieved non-inferior outcomes compared to white patients, despite higher pretransplant risk among black patients. Moreover, PR-T improved the time to achieve, and the likelihood of reaching, stable therapeutic concentrations among black patients, suggesting that PR-T could improve the consistency of tacrolimus exposure in this patient population.

Tacrolimus - Pharmacokinetic Considerations for Clinicians.

The calcineurin inhibitor tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, clinical management of Tac therapy can be challenging because of its narrow therapeutic window and because many factors interfere with its metabolism. Therefore, therapeutic drug monitoring is used to adjust the dosage. Recently, we were able to classify patients receiving tacrolimus into two major metabolism groups by simple calculation of the C/D ratio (expressed as the blood concentration normalized by the dose). We showed that the C/D ratio is significantly associated with the (renal) outcome of recipients after kidney and liver transplantation. These findings are interesting and relevant to transplant physicians and physicians interested in immunosuppressive therapy. We therefore review current state of the art aspects of tacrolimus pharmacokinetics including genetics or different tacrolimus formulations (twice-daily immediate-release tacrolimus capsules, once-daily extended- release tacrolimus capsules; novel once-daily tacrolimus tablets) and their possible clinical impact including practical considerations for clinicians.

Investigating the Impact of Drug Crystallinity in Amorphous Tacrolimus Capsules on Pharmacokinetics and Bioequivalence Using Discriminatory In Vitro Dissolution Testing and Physiologically Based Pharmacokinetic Modeling and Simulation

Delivering a drug in amorphous form in a formulated product is a strategy used to enhance the apparent solubility of a drug substance and its oral bioavailability. Drug crystallization in such products may occur during the manufacturing process or on storage, reducing the solubility advantage of the amorphous drug. However, the impact of partial drug crystallization in the drug product on the resulting bioavailability and pharmacokinetics is unknown. In this study, dissolution testing of commercial tacrolimus capsules (which are formulated to contain amorphous drug), both fresh and those containing different amounts of crystalline drug, was conducted using both United States Pharmacopeia and noncompendial dissolution tests with different dissolution media and volumes. A physiologically based pharmacokinetic (PBPK) absorption model was developed to predict the impact of crystallinity extent on the oral absorption of the products and to evaluate the discriminatory ability of the different dissolution methods. Virtual bioequivalence simulations between partially crystallized tacrolimus capsules versus fresh Prograf or generic tacrolimus capsules were performed using the PBPK model and in vitro dissolution data of the various fresh and partially crystallized capsules under United States Pharmacopeia and noncompendial dissolution conditions. The results suggest that compendial dissolution tests may not be sufficiently discriminatory with respect to the presence of crystallinity in an amorphous formulation. Nonsink dissolution tests using lower dissolution volumes generate more discriminatory profiles that predict different pharmacokinetics of tacrolimus capsules containing different extents of drug crystallinity. In conclusion, the PBPK modeling approach can be used to assess the impact of partial drug crystallinity in the formulated product and to guide the development of appropriate dissolution methods.

A Steady-State Head-to-Head Pharmacokinetic Comparison of All FK-506 (Tacrolimus) Formulations (ASTCOFF): An Open-Label, Prospective, Randomized, Two-Arm, Three-Period Crossover Study.

This two‐sequence, three‐period crossover study is the first pharmacokinetic (PK) study to compare all three innovator formulations of tacrolimus (twice‐daily immediate‐release tacrolimus capsules [IR‐Tac]; once‐daily extended‐release tacrolimus capsules [ER‐Tac]; novel once‐daily tacrolimus tablets [LCPT]). Stable renal transplant patients were dosed with each drug for 7 days, and blood samples were obtained over 24 h. Thirty subjects were included in the PK analysis set. A conversion factor of 1:1:0.80 for IR‐Tac:ER‐Tac:LCPT was used; no dose adjustments were permitted during the study. The median (interquartile range) total daily dose was 6.0 (4.0–8.0) mg for IR‐Tac and ER‐Tac and 4.8 (3.3–6.3) for LCPT. Significantly higher exposure on a per milligram basis, lower intraday fluctuation and prolonged time (Tmax) to peak concentration (Cmax) were found for LCPT versus IR‐Tac or ER‐Tac. ER‐Tac showed no differences versus IR‐Tac in exposure, Cmax, Tmax or fluctuation. The observed exposure of IR‐Tac was used to normalize exposure for LCPT and ER‐Tac, resulting in the following recommended total daily dose conversion rates: IR‐Tac:ER‐Tac, +8%; IR‐Tac:LCPT, −30%; ER‐Tac:LCPT, −36%. After exposure normalization, Cmax was ~17% lower for LCPT than for IR‐Tac or ER‐Tac; Cmin was ~6% lower for LCPT compared with IR‐Tac and 3% higher compared with ER‐Tac.

Rectal and sublingual administration of tacrolimus: a single-dose pharmacokinetic study in healthy volunteers.

The immunosuppressant tacrolimus is usually administered orally. When this is not feasible, other routes of administration may be useful. Previous research suggested that tacrolimus may be applied sublingually or rectally. Pharmacokinetic data are sparse. The aim of this study was to investigate and compare the pharmacokinetics of these alternative formulations with orally administered tacrolimus. Three single, fixed-dose formulations of tacrolimus were administered in a random sequence in 18 healthy subjects, using a cross-over study design. For sublingual administration, 3 mg of powder obtained from oral capsules was applied under the tongue for a period of 15 min without swallowing, with mouth rinsing afterwards. For rectal administration, a suppository containing 15 mg of the oral powder was used. Oral administration consisted of 7 mg of instant-release tacrolimus capsules (Prograf). Main pharmacokinetic outcome parameters were compared by anova. Sublingual administration showed no clinically significant exposure, contrary to rectal administration, where all subjects had clinically relevant exposure, with a lower relative bioavailability (78%), a lower maximal blood concentration and a later time of maximal blood concentration compared with oral administration. Sublingual administration of a single dose of tacrolimus does not result in systemic exposure if care is taken not to swallow saliva and to rinse the oral cavity afterwards. Rectal administration of tacrolimus results in clinically relevant systemic exposure and might represent an alternative formulation in case oral administration is not feasible. When used as a topical agent, systemic side-effects should be considered.

Two-Year Results of Envarsus (Once-Daily MeltDose Tacrolimus Tablets) vs Prograf (Twice-Daily Tacrolimus Capsules): A Phase 3, Double-Blind, Double-Dummy, Multi-Center, Prospective, Randomized Study.

In this Phase 3, double-blind, double-dummy, multi-center, prospective, randomized study, 543 kidney transplant recipients (KTR) (Mean age 56 yrs; 65% male; 77% White, 5% Black; 51% deceased donor) were randomly assigned to Envarsus (N=268 patients [pts]) or Prograf (N=275). 517 pts (95%) completed 1 year followup; to date, 83% of patients (451) have completed the 2 year visit. For the entire two year study only 12 (2%) pts were lost to followup; only 3 pts between year 1 and 2. One year results showed noninferiority to Prograf based on the composite treatment failure primary endpoint (Envarsus 18%, Prograf 20%). Three month failure rates were 10% and 14% respectively. One year analyses of adverse events showed no statistically significant differences. Envarsus patients attained targeted troughs within 1 day of first dose; Prograf levels were achieved within 4 to 7 days. From month 3 onward, Envarsus KTR required a lower daily dose vs. Prograf KTR with similar trough levels, suggesting Envarsus' improved bioavailability. Two year data on estimated glomerular filtration rate of Envarsus and Prograf pts show a steady improvement in renal function over the two year study. Database lock will be in March 2014 and full two year efficacy and safety data on all unblinded pts will be available April 2014. Patient retention was excellent in this large, well-controlled, 2 year trial. Data to date show excellent efficacy and safety with both tacrolimus formulations and a gradual improvement in renal function over the course of two years. Pending the imminent completion of the study, the full two-year followup efficacy and safety results will be available for presentation.Figure: No Caption available.DISCLOSURES:Rostaing, L.: Other, Chiesi, Advisory Board. Bunnapradist, S.: Grant/Research Support, Veloxis, Genentech, Novartis, Speaker's Bureau, Novartis, Other, Veloxis, Advisory Board. Budde, K.: Grant/Research Support, AiCuris, Astellas, BmT GmbH, Bristol-Myers Squibb, speaker's fees, honoraria, travel expenses, Chiesi, Hexal, Novartis, Roche, Pfizer, Siemens, speaker's fees, honoraria, travel expenses, Veloxis, speaker's fees, honoraria, travel expenses, Other, Bristol-Myers Squibb,, Consultant, Chiesi, Effimune, Hexal, Veloxis, Novartis, Consultant.

Conversion from twice daily tacrolimus capsules to once daily extended‐release tacrolimus (LCP‐Tacro): Phase 2 trial of stable liver transplant recipients

LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Studies in renal transplantation demonstrate greater bioavailability with similar safety and efficacy vs. twice-daily tacrolimus capsules. In this phase 2 study, adult stable liver transplant patients on tacrolimus capsules (Prograf) twice-daily were converted to tacrolimus tablets (LCP-Tacro) once-daily; patients continued on LCP-Tacro once-daily for days 8-21; target trough levels were 5-15 ng/mL; 24-hour pharmacokinetic (PK) assessments were done on days 7 (baseline pre-switch), 14, and 21. A 6 month extension study phase evaluated PK and safety following a total of 52 weeks of LCP-Tacro. Fifty-seven patients completed LCP-Tacro dosing in the core study; 43 completed the extension phase. The mean conversion ratio was 0.71 (Prograf:LCP-Tacro). PK data demonstrated consistent exposure (AUC) at the lower conversion dose. Cmax , Cmax /Cmin ratio, percent fluctuation and swing were significantly (P<0.001) lower and Tmax significantly (P<0.001) longer for LCP-Tacro vs. Prograf. AUC24 and Cmin correlation coefficients after 7 and 14 days of therapy were ≥0.93. There were no significant differences in PK parameters at week 26 vs. 14. One patient experienced an unrelated serious adverse event (SAE) during the core study and discontinued. There were six unrelated SAEs in the extension and 1 possibly related (rejection) that resolved; there were 3 discontinuations due to AEs during the extension. In this study, patients were safely converted from Prograf twice-daily to LCP-Tacro. The greater bioavailability of LCP-Tacro allowed for once-daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP-Tacro displayed significantly lower peak and peak-trough fluctuations. LCP-Tacro administered over one year was well tolerated with no new safety concerns.

Analyses of marketplace tacrolimus drug product quality: Bioactivity, NMR and LC–MS

Tacrolimus (FK506) is a potent, narrow therapeutic index, immunosuppressive drug used to avoid organ rejection in patients that have undergone organ transplantation. Recent clinical reports suggested a significant reduction in the tacrolimus concentration/dose ratio in the plasma of liver and kidney recipients when the reference listed drug was substituted with a generic drug. In response to these concerns about switching between tacrolimus from different approved manufacturers during treatment, the FDA initiated purity, potency and quality studies of the innovator and generic tacrolimus products available in the US marketplace. A combination of analytical methods, including mass spectrometry (LC–MS), nuclear magnetic resonance (NMR) and bioactivity assay were developed and validated to assess the quality of tacrolimus. These tests measured the identity, impurities and activity of tacrolimus from active pharmaceutical ingredient (API) sources and with formulated drug product from five different approved manufactures. In addition, some testing was performed on tacrolimus capsules obtained from a non US approved Indian source. The data obtained showed no discernible difference in the impurity profiles and potency between the generic and innovator tacrolimus products.

Once– versus twice–daily tacrolimus: are the formulations equivalent?

Tacrolimus is one of the most often used immunosuppressive drugs in organ transplantation. It was first approved in 1994 for use in liver transplantation, replacing cyclosporine A, due to better absorption properties regardless of bile secretion. Then it use was extended to other organs and nowadays more that 90% of kidney graft recipient in the United States receive tacrolimus as a basic immunosuppressant [1]. The use of tacrolimus is complicated by its narrow therapeutic index and wide intra– and interpatient pharmacokinetics variability, thus it dosage should be based on monitoring trough drug blood concentration. The main complications of drug overdosage are nephro– and neurotoxicity and metabolic disturbances like posttransplant diabetes mellitus and hyperlipidemia. On the other hand low, non–therapeutic drug blood level can lead to graft rejection and loss. Patients’ noncompliance is the main cause of fluctuating tacrolimus blood concentration and in many cases could be the reason of acute graft rejection episodes. It is an important problem both in young, active but also in older kidney graft recipients and reduction of immunosuppressive drugs daily doses is one method to overcome this problem [2]. The once–daily (OD) extended–release formulation of tacrolimus (Advagraf, Astellas) was launched in 2007 in 0.5, 1, 3, and 5 mg doses. This drug formulation allows most of liver transplant and some kidney transplant recipients (on tacrolimus monotherapy or in dual therapy with prednisone) to use only one morning dose of immunosuppressants. Such therapy simplifies treatment protocol and increases patient compliance. Converting patients from twice daily (BID) to OD tacrolimus was proposed on equivalent daily dose but there was a concern of adequate blood levels after treatment switch. We observed in our center that OD tacrolimus doses had to be 10–15% higher than BID formulation to get the same trough blood drug concentration after conversion. In a multicenter, open–label, phase III study in stable adult liver transplant recipients converted from tacrolimus BID to OD (1:1 [mg:mg] total daily dose basis). Following conversion, mean tacrolimus trough levels were reduced by approximately 15% (7.5 ng/ml vs. 6.5 ng/ml; P <0.0001) but were more consistent, showing reduction between– and within–patient variability in trough levels [3]. However, in our retrospective analysis of 60 kidney graft recipients converted from tacrolimus BID to OD formulation in identical (1:1) daily doses in late posttransplant period trough blood drug concentration did not significantly differ pre and after conversion. OD tacrolimus doses were increased in 11 patients and decreased in 13 patients based on trough blood concentration during consecutive patient visits (unpublished data). OD tacrolimus is non inferior to BID formulation in long term effect in kidney transplant recipients. A systematic review of 6 randomized controlled trials and 15 observational studies revealed no significant differences in biopsy–proven acute rejection, patient and graft survival between the two formulations at 12 months [4]. However, there are some disadvantages of OD tacrolimus therapy. First, risk of overdose–related side effects is very high in first postransplant days and with BID tacrolimus formulation dose correction can be made with the evening dose. Secondly, only 1 mg OD tacrolimus capsules are reimbursed in Poland, making treatment rather difficult in case of higher daily doses. In the present paper authors describe their experience with kidney transplant recipients from living donors who received OD tacrolimus [5]. They investigated tacrolimus pharmacokinetics and compared the dose of OD tacrolimus OD TAC to BD drug formulation. The study group is relatively small and there are some demographic differences between the groups that could affect pharmacokinetic parameters of the study drug: patients on OD tacrolimus were younger and were shorter time on dialysis. The authors compare daily doses and minimal concentration (Cmin) of both formulations, what is most important in clinical practice. However, detailed pharmacokinetic parameters are presented only for OD tacrolimus. In conclusions OD tacrolimus appears to have efficacy and safety equivalent to that of BD formulation but a larger dose of OD tacrolimus compared to that of BD drug form may be required during the early period after kidney transplantation [5].

Postoperative Transplant Immunosuppression in the Critical Care Unit

Postoperative Transplant Immunosuppression in the Critical Care Unit

A Phase III Randomized Trial of Conversion to Once-Daily Extended Release Meltdose® Tacrolimus Tablets (LCP-Tacro™) from Twice-Daily Tacrolimus Capsules (Prograf®): Efficacy Results from an Analysis of Specific Patient Sub-Populations

Introduction: Enhanced pharmacokinetics, optimized dosing, and noninferior efficacy have been demonstrated for extended-release tacrolimus (TAC) once-daily (qd) tablets (LCP-Tacro; Veloxis Pharma) vs. TAC twice-daily (bid) capsules (Prograf; Astellas Pharma). This sub-analysis evaluated whether LCP-Tacro was equally efficacious when considering ethnicity, presence of diabetes, and time post-transplant at time of conversion from Prograf to LCP-Tacro. Methods: Stable adult (mean age: 50 years; 67% male) renal transplant recipients (RTRs) (3-60 months post Tx) on Prograf (mean daily dose 2 mg/day) and TAC trough levels within the predefined therapeutic range of 4 to 15 ng/mL were randomized to either remain on Prograf bid or convert to LCP-Tacro tablets qd. By protocol, initial LCP-Tacro dose was 15% lower than the pre-conversion Prograf total daily dose; subsequent doses of both drugs were adjusted to maintain whole blood TAC trough levels of 4-15 ng/mL. Efficacy/safety monitoring of this phase III study was through 12 months. Results: The modified intent-to-treat population included 162 patients on LCP-Tacro and 162 on Prograf. Mean TAC dose (mg/day) over the 12 month period was similar in the LCP-Tacro (4.7) and Prograf (4.9) groups; mean TAC trough levels were within the target range and similar between the drug groups throughout the study. Patient survival was LCP-Tacro: 98.8% and Prograf: 99.4%; graft survival was 100.0% for both treatments. Biopsy proven acute rejection (BPAR) was infrequent in both groups (Table) and tended to be more frequent in the Prograf vs. LCP-Tacro group among African Americans (P=0.11), patients with no diabetes pre-transplantation (P=0.37), and patients who were >2 years post-transplant at time of study (P=0.23); however, no significant differences in BPAR were found between LCP-Tacro and Prograf for any of the subgroups examined.Table: [Percent of Patients with BPAR by Subgroup]Conclusion: Previously, we reported that the efficacy of LCP-Tacro was noninferior to Prograf in RTRs converted to LCP-Tacro from Prograf. These results further demonstrate the efficacy of LCP-Tacro in specific RTR populations. LCP-Tacro is efficacious both in RTRs who are in the early or long term maintenance phase post-transplantation; RTRs with or without pre-transplant diabetes, and in both African Americans and non-African Americans.

Effect of aminoalkyl methacrylate copolymer E/ HCl on in vivo absorption of poorly water-soluble drug

This study aimed to investigate in vivo absorption of tacrolimus formulated as a solid dispersion using Eudragit E®/HCl (E-SD). E-SD is an aminoalkyl methacrylate copolymer that can be dissolved under neutral pH conditions. E-SD was used alone as a solid dispersion carrier and/or was mixed with tacrolimus primarily dispersed with hydroxypropylmethylcellulose (HPMC). Tacrolimus was formulated with E-SD at several different ratios. Formulations with tacrolimus/E-SD ratio of 1/3 showed higher in vivo absorption, compared to tacrolimus dispersed in the excipients (primarily HPMC) found in commercially available tacrolimus capsules, using a rat in situ closed loop method. Good correlation was observed between in vitro drug solubility and in vivo drug absorption. In vitro solubility tests and rat oral absorption studies of tacrolimus/HPMC solid dispersion formulations were also conducted after mixing the HPMC dispersion with several ratios of E-SD. E-SD/tacrolimus/HPMC formulations yielded high in vitro drug solubility but comparatively low in vivo absorption. Dog oral absorption studies were conducted using capsules containing a formulation of tacrolimus/E-SD at a ratio of 1/5. The E-SD formulation-containing capsule showed higher in vivo drug absorption than tacrolimus dispersed in the standard HPMC capsule. These studies report enhancement of the in vivo absorption of a poorly water-soluble drug following dispersion with E-SD when compared to formulation in HPMC.