For more than 20 years, immunosuppression (IS) regimens after liver transplantation (LT) have been based on a calcineurin inhibitor (CNI): cyclosporine A or tacrolimus (TAC). TAC is available as an immediate-release formulation administered twice daily (bid) for the prevention and treatment of allograft rejection in liver, kidney, and heart transplantation (Prograf, Astellas Pharma Europe, Ltd., Middlesex, United Kingdom). A prolonged-release formulation of TAC has recently been developed (Advagraf, Astellas Pharma Europe) to provide more consistent exposure and convenient once daily (qd) dosing.
In a large multicenter study, TAC qd was shown to be therapeutically equivalent to TAC bid in de novo LT recipients. Moreover, the conversion of stable LT recipients from TAC bid to TAC qd on a 1 mg to 1 mg total daily dose basis was investigated in an open-label, multicenter study with a single sequence and a 4-period crossover design.[3, 4] The purpose of that pharmacokinetic study, which included 70 stable renal transplant and LT recipients, was to evaluate TAC exposure in stable transplant recipients converted from TAC bid to TAC qd. The steady-state exposure of TAC qd was equivalent to that of TAC bid.
Because few data are available to date, the aim of the present study was to analyze the safety of a 1:1 dose conversion from TAC bid to prolonged-release TAC qd in daily practice in a large cohort of stable LT recipients.
PATIENTS AND METHODS
This was a single-center study conducted with adult LT patients. We performed a retrospective analysis of our cohort of patients on the basis of prospectively recorded clinical charts. The inclusion criteria were as follows: at least 6 months' posttransplant follow-up and no acute rejection episodes in the last 3 months. The conversion from TAC bid to TAC qd was based on a 1:1 ratio and was then modified on the basis of serum levels or adverse effects. TAC was taken in the morning 1 hour before or 2 hours after breakfast, as recommended by the manufacturer. Doses and serum levels of TAC and liver and renal function were recorded on the day of conversion, 1, 6, and 12 months after conversion, and every 6 months thereafter. In addition, rejection episodes, arterial hypertension, diabetes mellitus, and dyslipidemia were assessed during routine follow-up. Adverse effects were also recorded.
Renal function was measured as the glomerular filtration rate, which was evaluated with the Cockroft-Gault formula [calculated glomerular filtration rate (cGFR)]. Arterial hypertension was defined as a blood pressure > 140/90 mm Hg at 2 follow-up visits or as the use of an antihypertensive treatment. Diabetes mellitus was defined as a fasting plasma glucose level > 126 mg/dL at 2 follow-up visits or as the use of a hypoglycemic treatment. Dyslipidemia was defined as hypercholesterolemia > 220 mg/dL and hypertriglyceridemia > 200 mg/dL at 2 follow-up visits or as the use of a hypolipidemic treatment. Rejection was defined according to the Banff criteria on liver biopsy.
Quantitative variables were described with means, ranges, and standard deviations. Categorical values were tabulated, and percentages were calculated. Variables were compared with the Student t test (for repeated measures) and the χ2 test and were considered significant at P < 0.05.
Characteristics of the Study Population
From January 2008 to November 2010, 394 patients [259 males and 135 females with a mean age of 53 years (range = 18-72 years)] were enrolled in this study at a mean of 74 months (range = 6-218 months) after LT. Alcoholic cirrhosis was the main indication for LT. IS therapy at the time of conversion consisted of TAC alone in 45% of patients; TAC and mycophenolate mofetil (MMF) or azathioprine in 35%; TAC, MMF or azathioprine, and steroids in 10%; and TAC and steroids in 10%. The mean TAC trough level before conversion was 6.1 ± 5.6 ng/mL with a daily dose of 3.2 ± 1.9 mg. The mean follow-up after conversion was 24 ± 11 months. The patient characteristics are summarized in Table 1. To the best of our knowledge, the patients were not taking drugs that could interact with TAC.
Table 1. Patient Characteristics at the Time of Conversion
The mean serum TAC trough level had decreased by 1 month after conversion (6.1 ± 5.6 ng/mL before conversion versus 4.9 ± 2.5 ng/mL after conversion, P < 0.05) with the same daily dose (3.2 ± 1.9 mg). At the end of follow-up, the mean TAC trough level was 4.4 ± 2.4 ng/mL with a daily dose of 2.6 ± 2.3 mg (Fig. 1).
When we considered patients with less than 5 years of follow-up after LT (n = 185) or more (n = 209), similar decreases in the mean trough level were observed: from 6.5 ± 2.9 to 5.5 ± 2.6 ng/mL (P < 0.05) and from 5.6 ± 7.5 to 4.2 ± 2.4 ng/mL (P < 0.05), respectively.
At the end of follow-up, 6 patients had converted from TAC qd to cyclosporine A (because of diabetes mellitus), 14 patients had stopped all CNIs and had been converted to an everolimus-based IS regimen (because of CNI-related side effects or post-LT cancer), 16 patients had returned to TAC bid, and 358 patients were still on TAC qd. The switch back from TAC qd to TAC bid was due to tremor (n = 3), diarrhea (n = 2), cutaneous eruption (n = 2), oral drought (n = 2), headaches (n = 2), insomnia (n = 1), arterial hypertension (n = 1), diabetes mellitus (n = 1), asthenia (n = 1), or erectile dysfunction (n = 1). For these 16 patients, the mean TAC trough level was 4.5 ± 2.9 ng/mL, and this did not significantly differ from the level for the entire population (4.4 ± 2.4 ng/mL, P = 0.73). After the switch back, symptoms (except for erectile dysfunction) improved in all patients.
Between the time of conversion and the end of follow-up, aspartate aminotransferase (31 ± 64 versus 30 ± 49 IU/L, P = 0.57), alanine aminotransferase (41 ± 98 versus 37 ± 74 IU/L, P = 0.75), gamma-glutamyltransferase (37 ± 52 versus 36 ± 48 IU/L, P = 0.60), and alkaline phosphatase levels (129 ± 38 versus 134 ± 38 IU/L, P = 0.52) remained stable.
Between the time of conversion and the end of follow-up, the mean serum creatinine level (113 ± 62 versus 110 ± 67 μmol/L, P = 0.71) and cGFR (73 ± 32 versus 75 ± 41 mL/minute/1.73 m2, P = 0.69) remained stable; these values include patients who were converted to an everolimus-based IS regimen. Similarly, after the exclusion of patients who were converted to an everolimus-based IS regimen, the mean serum creatinine level (102 ± 48 versus 100 ± 47 μmol/L, P = 0.68) and cGFR (76 ± 30 versus 79 ± 35 mL/minute/1.73 m2, P = 0.67) remained stable between the time of conversion and the end of follow-up.
Liver biopsy samples were available for 42 patients during follow-up. They consisted of 32 protocol liver biopsy samples obtained 1, 5, 10, 15, and 20 years after LT and 10 clinically indicated liver biopsy samples. Biopsy-proven acute rejection occurred in 7 patients (1.8%) after the conversion to TAC qd (mild in 5 patients and moderate in 2 patients according to the Banff criteria). The mean TAC trough level at the time of rejection was 4.3 ± 2.0 ng/mL. In those 7 patients, the IS regimen consisted of TAC alone (n = 2), TAC with MMF (n = 4), and TAC with MMF and steroids (n = 1). IS was increased with increased doses of TAC (n = 7), the introduction of MMF (n = 1), and the use of steroid boluses (n = 2).
At the end of follow-up, no difference (P > 0.99) was observed in the prevalence of arterial hypertension (n = 177 or 45%). Two or more different antihypertensive drugs were required for 21% of these patients.
The prevalence of diabetes mellitus had increased slightly at the end of follow-up (n = 77 or 19.5% before conversion and n = 96 or 24.4% after conversion) but without statistical significance (P = 0.10). The proportions of patients treated with insulin were similar before and after conversion (34% versus 35%).
As for dyslipidemia, the prevalence of hypercholesterolemia remained unchanged (P > 0.99) after conversion (n = 43 or 11%).
In 2005, Florman et al. reported the first conversion pharmacokinetics for stable LT recipients who were converted from TAC bid to TAC qd. An equivalence of exposure in the steady state was demonstrated in that study. Seventy LT recipients were enrolled: 69 received at least 1 dose of TAC qd, and 56 completed at least 2 years of treatment. We report here our experience with conversion from TAC bid to TAC qd in the largest cohort to date (394 LT recipients). The present report confirms that stable LT patients can be safely converted from standard TAC bid to TAC qd, but it also provides additional and comprehensive information on this conversion.
Reports on de novo LT have demonstrated that systemic exposure to TAC qd is 50% lower than exposure to TAC bid during the first week after LT, and significant dose adjustments are required to achieve similar TAC exposure.[2, 7] Interestingly, it has been reported that the difference progressively diminishes over a 12-month period. We observed in our cohort a significant 20% decrease in the TAC trough level after a 1:1 conversion, even though we included stable LT patients after a mean delay of more than 5 years after LT. Similarly, in a prospective, observational, multicenter study including 187 LT patients with a median conversion time of 55 months, Dopazo et al. reported that TAC levels had decreased approximately 20% 1 month after conversion. In that study, the TAC trough levels reached initial values 6 and 12 months after conversion despite no modification in the dosage during follow-up in the majority of patients (88%). In addition, in the multicenter, open-label, phase 3 study reported by Sańko-Resmer et al., which included 112 stable LT recipients converted from TAC bid to TAC qd (on a 1:1 total daily dose basis), the mean TAC trough levels were reduced by 15% (approximately 1 ng/mL) without any cases of acute rejection, and they remained stable during the remainder of the study (74.5% of the patients required no dose adjustment on conversion). In our study, the mean TAC level remained lower in comparison with inclusion, but the daily dose of TAC was progressively reduced according to our usual practice of CNI minimization (from 3.2 ± 1.9 to 2.6 ± 2.3 mg). We suggest that close initial monitoring could be helpful in identifying patients who do require dose adjustments (we propose that an early trough level should be obtained 2 weeks after conversion). Despite this lower exposure to TAC, we did not observe significant renal function improvement, but the mean cGFR slightly increased during follow-up from 76 to 79 mL/minute/1.73 m2. This is consistent with the study of Sańko-Resmer et al. The patient and graft survival rates were 100%. The incidence of adverse events was low during both treatment phases. In addition, we did not find a significantly increased risk of arterial hypertension, hypercholesterolemia, or diabetes mellitus in our cohort. These findings are consistent with those previously reported, except that Dopazo et al. observed an increased incidence of dyslipidemia 1 year after conversion (30% versus 21% before conversion).
We report here 7 cases of biopsy-proven acute rejection among our 394 patients (1.8%). This ratio can be compared to the 1% rate of Dopazo et al. during a 1-year follow-up and to the 5% rate reported by Florman during a 2-year follow-up. Nevertheless, it can be hypothesized that the prevalence of rejection in all these studies, including ours, may have been underestimated in the absence of protocol liver biopsy.
Because all available data strongly support the idea that TAC qd is therapeutically equivalent to TAC bid without a beneficial effect on renal function or the usual adverse effects of TAC, the question of its role in daily practice remains. The most relevant question is whether taking IS drugs only 1 time a day could improve adherence and quality of life. Poor adherence to IS drugs has been clearly identified as a major risk factor for graft rejection and, therefore, as a significant cause of posttransplant complications in LT recipients, including death.[10-13] Four major categories of risk factors for nonadherence to long-term therapies have been identified: socioeconomic variables, patient-related variables, disease- and treatment-related variables, and environment-related variables. For all these factors, simplifying the doses of IS medications is an important way of improving adherence. In a recent large French observational study including LT and kidney transplant patients, good adherence was significantly dependent on sex, age at transplantation, retransplantation, and time since transplantation, and the rate of good adherence was significantly higher in patients taking fewer IS drugs (45% for 1 immunosuppressant versus 24% for 3 immunosuppressants). The Multivisceral Transplant Unit of Padua University Hospital reported 68 LT patients who were switched from TAC bid to TAC qd after a mean post-LT follow-up of 82 months. The rate of patients who reported being late in taking their IS drugs dramatically decreased after conversion (50% versus 6.3%), and so did the percentage of patients who reported forgetting to take their IS medication at least once a month (46.9% versus 15.6%). These results need to be confirmed from larger series but are very encouraging. In addition to improving adherence, reducing the frequency of dosing may also have a positive impact on patients' health-related quality of life. In a literature review of 7 studies including patients with angina, asthma, chronic obstructive pulmonary disease, Parkinson's disease, and seizure disorders, reducing the number of doses per day was associated with the maintenance of or an improvement in patients' health-related quality of life. In addition, patients also report preferring qd dosing regimens as long as these regimens remain efficacious. In the field of LT, data are strongly missing. In the experience of Padua University Hospital, among the 68 LT patients who were switched from TAC bid to TAC qd, nearly 80% were satisfied with the conversion and judged the avoidance of a second dose (79.7%) and the convenient mode of intake (42.2%) to be the most important advantages.
In conclusion, our results from the largest available cohort strongly confirm that the conversion of stable maintenance LT recipients from TAC bid to TAC qd on a 1:1 daily dose basis is associated with lower systemic exposure but is safe and effective. The reduced frequency of dosing with TAC qd may help to optimize adherence and quality of life, and this needs to be investigated in the near future. We, however, would advise caution when conversion is being considered for patients believed to require higher levels of IS (eg, patients with previous rejection episodes or autoimmune disease). This is particularly true when TAC is being used as the sole IS agent.
The authors are very indebted to Mr. Ahmed Arkhis for his help in collecting the data.