Twice-daily Tacrolimus Formulation Research Articles

Modelling changes in the pharmacokinetics of tacrolimus during pregnancy after kidney transplantation: A retrospective cohort study.

Pregnancy after kidney transplantation is realistic but immunosuppressants should be continued to prevent rejection. Tacrolimus is safe during pregnancy and is routinely dosed based on whole-blood predose concentrations. However, maintaining these concentrations is complicated as physiological changes during pregnancy affect tacrolimus pharmacokinetics. The aim of this study was to describe tacrolimus pharmacokinetics throughout pregnancy and explain the changes by investigating covariates in a population pharmacokinetic model. Data of pregnant women using a twice-daily tacrolimus formulation following kidney transplantation were retrospectively collected from 6 months before conception, throughout gestation and up to 6 months postpartum. Pharmacokinetic analysis was performed using nonlinear mixed effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. The final model was evaluated using goodness-of-fit plots, visual predictive checks and a bootstrap analysis. A total of 260 whole-blood tacrolimus predose concentrations from 14 pregnant kidney transplant recipients were included. Clearance increased during pregnancy from 34.5 to 41.7L/h, by 15, 19 and 21% in the first, second and third trimester, respectively, compared to prior to pregnancy. This indicates a required increase in the tacrolimus dose by the same percentage to maintain the prepregnancy concentration. Haematocrit and gestational age were negatively correlated with tacrolimus clearance (P≤ 0.01), explaining 18% of interindividual and 85% of interoccasion variability in oral clearance. Tacrolimus clearance increases during pregnancy, resulting in decreased exposure to tacrolimus, which is explained by gestational age and haematocrit. To maintain prepregnancy target whole-blood tacrolimus predose concentrations during pregnancy, increasing the dose is required.

Tremor Induced by Cyclosporine, Tacrolimus, Sirolimus, or Everolimus: A Review of the Literature.

Calcineurin inhibitors such as cyclosporine and tacrolimus are immunosuppressant drugs that are known to induce tremors. Non-calcineurin inhibitors such as sirolimus and everolimus have also reportedly been accompanied by tremors, albeit less likely. However, the prevalence rates reported in the literature are notably wide, and the risk profiles for these drug-induced tremors are less understood. We searched PubMed to extract data on the risk of tremors with these drugs when prescribed for various transplant and non-transplant indications. We ascertained whether the risk of drug-induced tremor is influenced by the underlying diagnosis, dosing formulations, drug concentrations, and blood monitoring. We extracted data on treatment strategies and outcomes for tremors. Articles were primarily screened based on English language publications, abstracts, and studies with n ≥ 5, which included case series, retrospective studies, case-controlled studies, and prospective studies. We found 81 eligible studies comprising 33 cyclosporine, 43 tacrolimus, 6 sirolimus, and 1 everolimus that discussed tremor as an adverse event. In the pooled analysis of studies with n > 100, the incidence of tremor was 17% with cyclosporine, 21.5% with tacrolimus, and 7.8% with sirolimus and everolimus together. Regarding the underlying diagnosis, tremor was more frequently reported in kidney transplant (cyclosporine 28%, tacrolimus 30.1%) and bone marrow transplant (cyclosporine 40%, tacrolimus 41.9%) patients compared with liver transplant (cyclosporine 9%, tacrolimus 11.5%) and nontransplant indications (cyclosporine 21.5%, tacrolimus 11.3%). Most studies did not report whether the risk of tremors correlated with drug concentrations in the blood. The prevalence of tremors when using the twice-daily formulation of tacrolimus was nearly the same as the once-daily formulation (17% vs 18%). Data on individual-level risk factors for tremors were lacking. Except for three studies that found some benefit to maintaining magnesium levels, there were minimal data on treatments and outcomes. A large body of data supports a substantive and wide prevalence of tremor resulting from tacrolimus use followed by cyclosporine, especially in patients receiving a kidney transplant. However, there is little reporting on the patient-related risk factors for tremor, risk relationship with drug concentrations, treatment strategies, and outcomes.

Influence of the Circadian Timing System on Tacrolimus Pharmacokinetics and Pharmacodynamics After Kidney Transplantation.

Introduction: Tacrolimus is the backbone immunosuppressant after solid organ transplantation. Tacrolimus has a narrow therapeutic window with large intra- and inter-patient pharmacokinetic variability leading to frequent over- and under-immunosuppression. While routine therapeutic drug monitoring (TDM) remains the standard of care, tacrolimus pharmacokinetic variability may be influenced by circadian rhythms. Our aim was to analyze tacrolimus pharmacokinetic/pharmacodynamic profiles on circadian rhythms comparing morning and night doses of a twice-daily tacrolimus formulation. Methods: This is a post-hoc analysis from a clinical trial to study the area under curve (AUC) and the area under effect (AUE) profiles of calcineurin inhibition after tacrolimus administration in twenty-five renal transplant patients. Over a period of 24 h, an intensive sampling (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 20, and 24 h) was carried out. Whole blood and intracellular tacrolimus concentrations and calcineurin activity were measured by UHPLC-MS/MS. Results: Whole blood and intracellular AUC12–24 h and Cmax achieved after tacrolimus night dose was significantly lower than after morning dose administration (AUC0–12 h) (p < 0.001 for both compartments). AUE0–12 h and AUE12–24 h were not statistically different after morning and night doses. Total tacrolimus daily exposure (AUC0–24 h), in whole blood and intracellular compartments, was over-estimated when assessed by doubling the morning AUC0–12 h data. Conclusion: The lower whole blood and intracellular tacrolimus concentrations after night dose might be influenced by a distinct circadian clock. This significantly lower tacrolimus exposure after night dose was not translated into a significant reduction of the pharmacodynamic effect. Our study may provide conceptual bases for better understanding the TDM of twice-daily tacrolimus formulation.

Ten-Year Efficacy and Safety of Once-Daily Tacrolimus in Kidney Transplant: A Prospective Cohort Study

Tacrolimus is a cornerstone in the immunosuppressive therapy of kidney transplantation. The once-daily formulation of tacrolimus has been shown to improve adherence of patients without affecting short-term efficacy. However, long-term proof of once-daily tacrolimus efficacy and safety is still lacking. From January 2009 to November 2013, 170 clinically stable kidney transplant patients were offered to change from the ongoing twice-daily tacrolimus (TDT) formulation to a once-daily tacrolimus (ODT) regimen. Kidney transplant recipients agreeing to the change to be treated with an ODT regimen (n = 105, estimated glomerular filtration rate [eGFR] 57.1 ± 1.6 mL/min/1.73 m2) and patients continuing on a TDT formulation (n = 65, eGFR 52.0 ± 2.2 mL/min/1.73 m2) were prospectively followed (median follow-up time 10.4 and 12.6 years in the ODT and TDT groups, respectively, P = not significant). At the end of the follow-up, patients in both groups experienced similar eGFR (50.4 ± 2.2 vs 48.0 ± 2.7 mL/min/1.73 m2 in the ODT and TDT groups, respectively, P = not significant). No differences were observed in biopsy-proven acute rejection, overall graft survival, doubling of serum creatinine, and new onset of proteinuria. The 2 groups also had a comparable rate of death, sepsis, and neoplasia.In conclusion, ODT appears safe and effective in stable kidney graft recipients even 10 years after transplantation. These findings support the use of ODT as a primary tacrolimus formulation in patients with kidney transplantation.

A comparative analysis of once-daily and twice-daily formulation of tacrolimus in de novo kidney transplant recipients

Objectives:We aimed to compare the once-daily and twice-daily formulation of tacrolimus concerning the efficiency and effects on graft function in de novo kidney transplant patients.Methods:Twenty once-daily (TAC-OD) and twenty twice-daily (TAC-BID) tacrolimus administrated de novo kidney recipients who had received initial immunosuppressive therapy according to protocols at our institution (0.2 mg/kg of tacrolimus combined with 1000 milligrams of steroid taper plus 720 mg of mycophenolate and with 2.5mg/kg anti-thymocyte globulin) assessed concerning demographics, drug doses and blood concentration, and graft function.Results:The mean tacrolimus blood concentration measurements were higher in the TAC-OD group in the first sixty days after transplantation, and the TAC-OD group showed more blood concentration overshoots/fluctuations in the first 30 days of the treatment. The initial drug dose was significantly higher in the TAC-OD group than the TAC-BID group (p=0.04). There was no meaningful difference among groups according to graft function (creatinine measurements) (p>0.05).Conclusion:Between de novo kidney recipients, the new TAC-OD formulation presents a similar short-term efficacy profile as TAC-BID. However, a higher daily dosage of TAC-OD is needed to achieve similar blood concentrations in the early postoperative period.

Conversion From Twice-Daily to Once-Daily Tacrolimus Among Egyptian Living-Donor Kidney Allograft Recipients: A Single-Center Experience.

Adherence to immunosuppression and minimization of drug exposure are important con-siderations in preventing rejection and maximizing transplant outcomes. The once-daily tacrolimus protocol confers potential benefit by simplifying immunosuppressive regimens, thereby improving adherence among transplant recipients. Studies of stable transplant recipients have suggested that once-daily tacrolimus is bioequivalent to twice-daily tacrolimus and is noninferior to twice-daily tacrolimus with a concentration-dependent rejection risk. Our aim was to evaluate the safety and efficacy of conversion from twice-daily tacrolimus formulation to a once-daily formulation among a cohort of adult living related-donor renal transplant patients as a single-center experience. This prospective, one arm, single-center study included 238 patients with at least 12 months posttransplant follow-up and no rejection episodes in the last 3 months. Conversion from twice-daily to once-daily formulation was based on a 1:1 ratio. The mean tacrolimus dose was 4.7 ± 2.7 mg/day preconversion versus 4.9 ± 3.2 mg/day postconversion (P = .8). The mean tacrolimus level was 7.4 ± 3.4 versus 6.1 ± 2.8 ng/mL (P = .75). Of total patients, 45% were maintained on a tacrolimus dose of less than 2 ng/dL. Renal function was comparable before and after conversion (mean serum creatinine was 1.25 ± 0.88 vs 1.23 ± 0.78 mg/dL; P = .9). The incidence of biopsy-proven acute rejection was 19.7% preconversion versus 4.2% postconversion. Graft and patient survival rates were comparable between the 2 tacrolimus formulations. Once-daily tacrolimus also had favorable effects on blood pressure, lipid profile, and glucose tolerance. Conversion from conventional tacrolimus (twice daily) to once-daily tacrolimus may be a valuable option with comparable patient and graft survival and may lead to improved adherence that may be reflective of better long-term results. It should be considered for de novo immunosuppression among living-donor renal allotransplant recipients.

Lower Variability in 24-Hour Exposure During Once-Daily Compared to Twice-Daily Tacrolimus Formulation in Kidney Transplantation

Tacrolimus has originally been registered as a twice-daily formulation (Prograf, Tac BID), although a once-daily formulation (Advagraf, Tac QD) is also available. A reduced intrapatient variability of Tac Cmin, a surrogate marker for 24-hour drug exposure (AUC0-24), has been suggested. The variability of AUC0-24 has never been studied prospectively yet. The purpose of this study was to investigate the change in intrapatient variability of Tac AUC0-24 after converting from Tac BID to Tac QD. Forty renal transplant patients on Tac BID were converted on a 1:1 (mg/mg) basis to Tac QD in an investigator-driven comparative pharmacokinetic (PK) study. AUC0-24 was determined five times before and after conversion. Duplicate samples were collected by the patients themselves using the dried blood spot method. The main outcome measure is the change in intrapatient variability of AUC0-24 expressed as coefficient of variation (CV). Moreover, the influence of Cyp3A5 genotype polymorphism on the change in CV was studied. In total, 400 AUC0-24 profiles were available for analysis. Conversion to Tac QD resulted in a significant improvement in intra-patient CV from 14.1% to 10.9% (P=0.012). Patients with the Cyp3A5*1/*3 genotype (n=11) had a numerically larger improvement in CV than patients with the CYP3A5*3/*3 genotype. Intrapatient CV of Tac AUC0-24 improved after converting from Tac BID to Tac QD in stable renal transplant patients, especially in patients with the CYP3A5*1/3 genotype. Given the very strict protocol of this PK study, this improvement is most likely due to the different intrinsic PK properties of Tac QD and Tac BID.

Budget impact of switching from an immediate-release to a prolonged-release formulation of tacrolimus in renal transplant recipients in the UK based on differences in adherence.

Background and aimsAdvagraf is a once-daily prolonged-release formulation of tacrolimus with proven noninferiority to Prograf, a twice-daily immediate-release formulation of tacroli-mus, in biopsy-proven acute rejection, graft survival and patient survival in renal transplant recipients. Advagraf is associated with improved adherence compared with Prograf, which may ultimately improve long-term outcomes. The present study assessed the budget impact of switching patients from Prograf to Advagraf in the UK.Materials and methodsA budget-impact model was constructed based on published data on acute rejection, graft failure, and mortality in the UK setting. Patients were assumed to convert from Prograf to Advagraf on a 1:1 milligram:milligram basis. In a study comparing the adherence rates between once-daily versus twice-daily formulations of tacrolimus, the proportion of patients taking the prescribed number of daily doses was 88.2% in Advagraf patients and 78.8% in Prograf patients. The model applied a relative risk of graft failure of 3.47 to nonadherent patients based on data from a 2004 meta-analysis (based on graft-failure rates of 1.3%–40.0% in adherent patients, compared with 6.1%–100% in nonadherent patients). Cost data were taken from the March 2013 British National Formulary and 2012–2013 National Health Service tariff information. The analysis was performed over a 5-year time horizon and future costs were not discounted, in line with International Society for Pharmacoeconomics and Outcomes Research guidelines.ResultsOver a 5-year time horizon, the mean cost per patient (including tacrolimus, concomitant immunosuppressive medications, dialysis after graft failure, and treatment for acute rejection) was £29,328 (standard deviation [SD] £2,844) for Advagraf versus £33,061 (SD £3,178) for Prograf. The total cost saving of £3,733 (SD £530) was driven primarily by reduced dialysis costs arising from the lower incidence of graft failure (21.6% with Prograf versus 18.3% with Advagraf) in the larger proportion of adherent patients in the Advagraf arm. In a hypothetical transplant centre of 100 kidney-transplant recipients, this would result in cost savings approaching £375,000 over 5 years.ConclusionConversion of renal transplant recipients from Prograf to Advagraf was associated with lower pharmacy and dialysis costs, with the reduction in dialysis costs being driven by improved adherence to Advagraf regimen and the consequent improvement in graft survival.

Conversion to prolonged release tacrolimus formulation in stable kidney transplant recipients

The once-daily tacrolimus formulation (Advagraf®), with the potential for improving medical adherence, has been advocated to improve long-term kidney allograft outcomes. However, experience with late conversion from the twice-daily tacrolimus formulation (Prograf®) to Advagraf in the daily care of stable kidney transplant recipients has been limited. The aim of this study was to observe the efficacy and safety of conversion from Prograf to Advagraf in chronic stable kidney transplant recipients in routine clinical practice. The recruited patients had postconversion follow-up at least once monthly for a total of six months, unless they had discontinued the use of Advagraf, had been lost the follow-up or had lost the graft. The mean age of the 199 patients was 51.5 ± 10.4 years (60.8% male). The mean time from transplantation to the conversion to Advagraf was 8.3 ± 3.2 years and the mean tacrolimus trough level at conversion was 4.2 ± 1.4 ng/ml. After conversion, 147 patients (73.8 %) had a reduced trough level at one month and the mean change in trough level postconversion was -13.5%. The mean serum creatinine level between conversion and six months postconversion was not significantly different (1.12 ± 0.36 vs 1.10 ± 0.42 mg/dl). Thirty-four patients (17%) discontinued the treatment with Advagraf and two (1%) developed biopsy-proved acute rejection. In conclusion, frequent conversion caused by a high discontinuation rate may further raise the potential risk of allograft rejection and increase unnecessary cost. In view of this, the policy of converting to Advagraf with the purpose of improving medical adherence should be individualised in routine clinical practice.

Conversion of Twice-Daily Tacrolimus to Once-Daily Tacrolimus Formulation in Stable Pediatric Kidney Transplant Recipients: Pharmacokinetics and Efficacy

The pharmacokinetics, efficacy and safety of once-daily tacrolimus formulation (Tac-OD) were assessed in 34 stable pediatric kidney transplant recipients. Enrolled patients received their dose of twice-daily tacrolimus formulation (Tac-BID) on study Days 0 through 7. On the morning of study Day 8, the total daily doses for patients were converted to Tac-OD on a 1:1 basis and maintained on a once-daily morning dosing regimen. Tacrolimus pharmacokinetic profiles were obtained on study Days 7, 14 and 28 (after dose adjustment). Although the mean C0 concentrations (4.10 ± 1.16–3.53 ± 1.10 ng/mL, p = 0.004), and AUC0–24 (151.8 ± 41.6–129.8 ± 39.3 ng h/mL, p < 0.001) were decreased significantly after a 1:1 based conversion, there was high interindividual variability. The dose of Tac-OD was decreased in 26.5% and increased in 44.1% of patients. The resultant tacrolimus dose and pharmacokinetic profiles on study Day 28 were comparable to those on Day 7. There were no serious adverse events. In conclusion, Tac-BID can be safely converted to Tac-OD in stable pediatric kidney transplant patients with the heightened therapeutic drug monitoring. Effects of drug conversion on the cardiovascular risk factors, neurological side effects and adherence should be further evaluated.

Once-Daily Extended-Release Versus Twice-Daily Standard-Release Tacrolimus in Kidney Transplant Recipients

A simplified dosing regimen may improve drug compliance in kidney transplant recipients and long-term graft outcomes. We aimed to identify, appraise, and synthesize the current evidence comparing the relative safety and efficacy of the recently introduced daily versus standard twice-daily tacrolimus administration. We systematically reviewed all randomized controlled trials and observational studies that compared the outcomes of daily versus twice-daily tacrolimus formulation in kidney transplant recipients. Medline (from 1948 to July week 4 2011), Embase (1980 to 2011 week 31), the Cochrane Library (1991 to June 2011), and conference proceedings were searched without language restriction. Six randomized controlled trials (n=2499) and 15 observational studies (n=2886) were included in the review. There were no significant differences in biopsy-proven acute rejection (two trials, n=1093; risk ratio [RR; confidence interval (CI)], 1.24 [0.93-1.65]; P=0.15; I=0%), patient survival (three trials, n=1156; RR [CI], 0.99 [0.97-1.02]; P=0.55; I=32%), and graft survival (three trials, n=1156; RR [CI], 0.99 [0.97-1.02]; P=0.67; I=0%) between the two formulations at 12 months. Similar results for acute rejection (five studies, n=391; RR [CI], 0.99 [0.93-1.06]; P=0.84; I=0%) and overall patient survival (two studies, n=218; RR [CI], 1.02 [0.94-1.10]; P=0.62; I=0%) were observed in observational studies. Once-daily tacrolimus appears to be as effective as twice-daily tacrolimus up to 12 months after kidney transplantation.

The psychosocial impact of presenting adolescent transplant recipients with the possibility of a simplified regimen : implications for patient education during transition to self-managed care

Introduction: As they transition from parentally controlled care to self-managed care, and from paediatric care to adult care, chronically ill adolescents are facing many challenges, one of them being to find their own ways of fitting their medication intake schedule into their daily liferoutines. The complexity and frequency of medication regimens is a well-documented risk factor of non-adherence in patients with a chronic disease. We hypothesized that a possible benefit of the conversion from a twice-daily formulation of tacrolimus (Prograf®) to once daily prolonged release tacrolimus (Advagraf®) in adolescent transplant patients might be a decrease of non-intentional non-adherence due to forgetfulness. The aim of our study was to assess the subjective experience of such change, including the impact on adherence to treatment. Methods: As a prerequisite to our study, the medical safety of such switch was assessed in 32 patients. At 8-week post-switch, a sub-sample of 11 patients underwent a semi-directed interview by an independent researcher, to assess the subjective impact of the switch. Results: The results of our study illustrate that the switch improved the young patients' self-efficacy and self-determination regarding self-managed care. The relevance of our hypothesis that a simplified regimen might be associated with increased adherence in this population is confirmed. Conclusions: We discuss strategies to support self-management and enhance adherence during the healthcare transition process of adolescents toward adult-oriented care. © 2012 EDP Sciences, SETE.

Pharmacokinetic properties of a once-daily formulation of tacrolimus in patients with renal transplantation

The present study was designed to determine the pharmacokinetic profiles of a once-daily formulation of tacrolimus (CAS 104987-11-3; TAC-once) in patients before and after introduction of renal transplantation. Pharmacokinetic parameters for tacrolimus were almost comparable among patients receiving TAConce before, 2 weeks after and 3 weeks after renal transplantation. Among various parameters, C(trough) correlated most closely with the area under the concentration-time curve during 24 h (AUCo-24) (R2 = 0.82, P < 0.001), while no consistent correlation was observed between AUCo_24 and concentrations at 2 h or 4 h, or the dose of TAC-once. The clinical outcomes such as the incidence of acute re-jection, renal tissue injury and cytomegalovirus infection were evaluated during the first 3 weeks and 3 months after transplantation, and the data were compared with the historical data obtained from patients who had received the conventional twice-daily formulation of tacrolimus (TAC-twice). There were no significant differences in the incidence of such clinical outcomes between the two groups. These findings suggest that C(trough) is useful for therapeutic monitoring of tacrolimus in patients receiving TAC-once. In addition, pharmacokinetics and clinical outcomes were comparable between TAC-once and TAC-twice formulations.

A Prospective, Multicenter Study of Once-Daily Extended-Release Tacrolimus in De Novo Liver Transplant Recipients

To minimize noncompliance in organ transplantation, a new formulation was developed of once-daily extended-release (EXTD) tacrolimus. To analyze the efficacy and safety of this new drug formulation in de novo liver transplant recipients, a prospective, multicenter study was performed in six centers in Spain. The primary objective of the study was to evaluate the incidence of biopsy-proven acute rejection episodes (BPAR) according to the BANFF criteria during the first 3 months of immunosuppression with the EXTD formulation of tacrolimus. Fifty-two patients received a mean initial dose of 10.0 ± 3.8 mg that was gradually reduced to 7.1 ± 4.0 mg, achieving stable mean blood levels of 8.6 ± 3.7 ng/mL at 3 months. BPAR was reported in seven (13%) patients, but patient and graft survivals were 100%. After transplantation liver function improved and was stably maintained throughout the study. At 3 months, mean bilirubin levels were 2.1 ± 5.5 mg/dL and mean alanine aminotransferase and aspartate aminotransferase were 61.6 ± 75.2 U/L and 55.2 ± 76.9 U/L, respectively. Mean serum creatinine of 0.8 ± 0.3 mg/dL pretransplant increased to 1.1 ± 0.4 mg/dL after 3 months ( P < .0001). There was no significant increase in the rate of hypertension from pretransplant levels: 30% at baseline versus 31% at 3 months. Mean glucose levels did not change significantly throughout the study. There were no cases of hepatitis C virus relapse. EXTD tacrolimus demonstrated excellent stability in blood trough levels with a good efficacy and safety profile in de novo liver transplant recipients that was similar to the well-described properties of standard-release twice-daily formulation of tacrolimus.

Reduced C0 Concentrations and Increased Dose Requirements in Renal Allograft Recipients Converted to the Novel Once-Daily Tacrolimus Formulation

Recently, a once-daily prolonged release formulation of tacrolimus (TacOD) has been approved for the prevention of renal allograft rejection. Studies reported equivalent area under the concentration-time curve0-24 and predose trough (C0) concentrations when compared with the standard twice-daily tacrolimus (Tac) formulation. Hence, the package insert advices a 1:1 mg conversion. Here, we report our independent experience with conversion to TacOD according to the manufacturer's instructions. Retrospective single-center study evaluating the evolution of C0 concentrations and dose requirements after conversion to TacOD in 284 renal allograft recipients. Potential clinical, biochemical, and genetic determinants of changes in C0 concentrations and dose requirements after conversion were explored in univariate and multivariate analyses. After conversion, C0 concentrations decreased significantly (-1.36+/-2.51 microg/L or -12.66%+/-24.36%, P<0.0001). In 38.3% of patients, this decrease exceeded 20%. TacOD dose was increased in 52.5% of patients. Average dose requirements increased to 0.71+/-1.78 mg/day or 14.68%+/-28.87% (P<0.0001). In 28.0% of patients, dose requirements increased more than 20%. Dose changes were more profound in patients converted within 1 year after transplantation, and in this subgroup (n=78), higher creatinine and lower hemoglobin levels were associated with a larger increase in dose requirements in multivariate analysis (r=0.35, P<0.0001). Despite dose adjustments, average C0 concentrations remained 9.09%+/-28.85% lower after conversion (P<0.0001). Conversion from standard twice-daily tacrolimus formulation to TacOD on a 1:1 mg basis results in reduced Tac C0 concentrations and increased dose requirements. Thus, conversion is not as straightforward as suggested by the manufacturer, and converted patients should be monitored strictly until stable C0 concentrations are achieved.