Objectives: Sustained-release once-daily tacrolimus pharmacokinetics have not yet been characterized in de novo living-donor liver transplant recipients. Here, a 12-week, phase IV, single center, open-label, pros­pective pilot study was conducted to investigate the pharmacokinetics of this formulation in these patients.

Materials and Methods: Patients received continuous intravenous infusion of tacrolimus on days 0 to 5 after transplant, which was followed by oral once-daily sustained-release tacrolimus. Two 24-hour pharma­cokinetics profiles were generated for 10 patients on days 6 and 14. Secondary endpoints were minimum (trough level) and maximum whole blood concent­rations, time to maximum concentration, and incidences of acute rejection, patient and graft survival, and adverse events.

Results: Mean doses (± standard deviation) of sustained-release tacrolimus on days 6 and 14 were 0.14 ± 0.03 and 0.17 ± 0.04 mg/kg. Levels were within the recommended range throughout the study. When the actual dose was examined, area under the curve from 0 to 24 hours on day 14 was 1.8-fold higher than that on day 6 (423.9 vs 235.7 ng × h/mL). When tacrolimus was normalized to 0.1 mg/kg, area under the curve from 0 to 24 hours on day 14 was 1.5-fold higher than on day 6 (279.3 vs 183.4 ng × h/mL). When we used the actual dose, we found the correlation coefficient between area under the curve from 0 to 24 hours and trough level to be higher on day 6 (r = 0.87) than on day 14 (r = 0.691). No acute rejections, graft losses, patient deaths, or drug-related adverse events were reported.

Conclusions: Initial intravenous followed by sustained-release tacrolimus was safe and efficacious in living-donor liver transplant recipients. The mean area under the curve from 0 to 24 hours on day 14 was higher than previously reported; this difference may reflect cautious dosing regimens.

Key words : Drug-level monitoring, Immunosuppression, Prolonged release

Introduction

Tacrolimus is the most widely used calcineurin inhibitor for the prevention of allograft rejection. The drug exhibits a narrow therapeutic index,^1,2 and its oral bioavailability varies substantially between individuals.³ By monitoring the minimum (Cmin; trough level) and maximum (C_max) whole blood concentrations of tacrolimus as surrogate markers of systemic exposure, clinicians can tailor treatment to optimize efficacy and minimize toxicity.

A once-daily sustained-release formulation of tacrolimus (once-daily tacrolimus) was developed recently and is already widely used for immuno­suppressive therapy in liver transplant recipients. The pharmacokinetics properties of the once-daily tacrolimus and twice-daily tacrolimus formulations have been investigated in previous clinical studies. In stable kidney transplant and liver transplant recipients, the area under the curve from 0 to 24 h (AUC0-24h), the C_min, and the correlation of AUC0-24h to C_min were comparable for both formu­lations.^4,5 These results suggest that the same drug-level monitoring concept can be applied to both formulations of tacrolimus.

Pharmacokinetics data from a phase II study in stable liver transplant recipients, in which the once-daily and twice-daily tacrolimus formulations were converted on a 1:1 (mg:mg) total daily dose basis, showed that the AUC0-24h of once-daily tacrolimus measured at steady state (14 days after conversion) was approximately 10% lower than that of twice-daily tacrolimus.6 However, clinical evidence from liver, kidney, and heart transplant recipients during clinical trials indicated that there were no marked differences between the efficacy and safety profiles of the 2 formulations.^7-9 The pharmacokinetics characteristics of once-daily tacrolimus in living-donor liver transplant (LDLT) recipients have not yet been assessed; therefore, the objective of this study was to examine the pharmacokinetics properties of once-daily tacrolimus, both after the first oral dose and under steady-state conditions (before the 10th oral dose), in patients undergoing de novo LDLT.

Materials and Methods

Patients
In this pilot investigation, a 12-week, open-label, prospective, nonrandomized, phase IV, single-arm study of LDLT recipients administered once-daily tacrolimus was performed (ClinicalTrials.gov identi­fier NCT00909571). Eight scheduled visits took place during the study. All patients were recruited from a single clinical center in Korea, and patient data were collected between May 2009 and February 2010. All patients enrolled in the study were older than 18 years, were undergoing primary partial liver graft from a living donor, had provided written informed consent, had received the first intravenous dose of tacrolimus after transplant, and were expected to be maintained on tacrolimus throughout the duration of the study. Patients were excluded if they had malignancy (except hepatic cell carcinoma fulfilling the Milan criteria) or a history of malignancy within the last 5 years, systemic infections requiring treatment, serum creatinine levels ≥ 2.0 mg/dL, received an ABO-incompatible graft, previously received or were receiving an organ transplant other than liver, or were likely to be nonadherent to the study protocol. Patients could be withdrawn due to withdrawal of consent, an intolerable adverse event, retransplant, noncompliance with the study protocol, loss during follow-up, pregnancy, or the initiation of prohibited concomitant medication known to affect the pharmacokinetics of tacrolimus (including ketoconazole, fluconazole, itraconazole, clotrimazole, nifedipine, nicardipine, erythromycin, clarithro­mycin, josamycin, danazol, ethinyl estradiol, and omeprazole; and calcium antagonists such as diltiazem, nefazodone, pheno­barbital, phenytoin, and rifampicin).

Administration of tacrolimus
Starting on day 0 (the day of transplant), tacrolimus was administered at a dose of 0.025 to 0.05 mg/kg/­day by continuous intravenous infusion. On the morning of day 5, this treatment was discontinued and patients were administered once-daily tacrolimus orally at an initial dose of 0.15 to 0.3 mg/kg/day, which was 6 times the tacrolimus intravenous dose administered on days 0 to 4. There was no washout period between ending intravenous tacrolimus administration and commencing once-daily tacrolimus treatment. The once-daily tacrolimus doses were taken orally in the morning. The attending physician was permitted to adjust the daily dose of once-daily tacrolimus and to modify the dosing regimen as deemed necessary to minimize adverse events and maintain effective immuno­suppression. Steroids, mycophenolate mofetil, azathioprine, and basiliximab were permitted as adjunct immunosuppressive agents.

Monitoring tacrolimus levels and pharmaco­kinetics analyses
Whole blood samples were collected on day 4; at weeks 4, 8, and 12; and whenever clinically indicated. Concentrations of tacrolimus were determined locally using a microparticle enzyme immunoassay. The recommended trough level (C_min) of tacrolimus in whole blood on days 1 to 5 was 10 to 20 ng/mL. After conversion to once-daily tacrolimus, the recommended trough levels were 10 to 20 ng/mL on days 5 to 30 and 5 to 15 ng/mL from day 30 to week 12. Two 24-hour pharmacokinetics profiles were generated during the study: the first profile was generated after administration of the second dose of once-daily tacrolimus (day 6), and the second profile was generated after the tenth dose (day 14). The pharmacokinetics parameters measured on day 14 were obtained under steady-state conditions (ie, the tacrolimus dose had not been adjusted in the previous 3 days). To generate the pharmacokinetics profiles, 10 timed blood samples were collected over a 24-hour period. The first sample was drawn immediately before tacrolimus administration (0 h), and then subsequent samples were drawn at 1, 2, 3, 4, 6, 8, 12, and 24 hours after dose administration. All blood samples (2-mL aliquots) were drawn into polystyrene tubes/Vacutainers (Becton Dickinson, Franklin Lakes, NJ, USA) containing ethylenedi­aminetetraacetic acid, which were gently inverted to ensure thorough mixing of the blood and antico­agulant. Pharmacokinetics parameters were calculated from concentration-time profiles of tacrolimus in whole blood. The tacrolimus concentrations were determined using a validated high-performance liquid chromatography tandem mass spectroscopy assay, based on the method developed by Alak and associates.¹⁰ Tacrolimus levels were measured at the investigational site. All procedures were performed in compliance with the principles of Good Laboratory Practice.

Primary and secondary endpoints
The primary endpoint was the systemic exposure (AUC0-24h) to once-daily tacrolimus on days 6 and 14. The secondary pharmacokinetics endpoints were C_max, time to maximum concentration, and C_min at 24 hours. The secondary efficacy endpoints determined at 12 weeks were the incidence of, time to, and severity of biopsy-proven acute rejection; the incidence of and time to corticosteroid-resistant acute rejection; and patient and graft survival. Safety evaluations included adverse event reporting and clinical laboratory tests. Acute rejection episodes were classified as biopsy-proven episodes or suspected acute rejection episodes, the latter of which were further classified as spontaneously resolving, corticosteroid-sensitive, or corticosteroid-resistant acute rejections. The incidence of graft loss (defined as retransplant or death) and the duration of patient survival were also recorded. Patients were evaluated for adverse events at each assessment visit. Abnormal hematologic and biochemical laboratory measurements (performed at baseline and at each assessment visit) were also recorded.

Data and statistical analyses
Because of the descriptive design of this study, power calculations and estimations of sample size were not performed. The enrollment of a minimum of 10 patients was considered appropriate. Efficacy and safety analyses were performed on the full analysis set (n = 11), which was defined as all patients with results attributed to the study treatment. The incidence of biopsy-proven rejection was assessed with a chi-squared test. The incidence of and time to the first biopsy-proven rejection episode was calculated with Kaplan-Meier survival estimates. Patient and graft survival were also analyzed with Kaplan-Meier estimates. Pharmacokinetics analyses were con­ducted in the pharmacokinetics evaluable set (n = 10), which included all patients in the full analysis set who provided complete data for both pharmaco­kinetics profiles. The pharmacokinetics parameters were calculated from the complete 24-hour concentration-time profiles of tacrolimus in whole blood. The AUC0-24 was estimated using the linear trapezoidal rule method. The C_max, time to maximum concentration, and Cmin were obtained directly from the 24-hour concentration-time profiles. The correlation between C_min and AUC0-24 also was determined for both pharmacokinetics profiles.

Ethical considerations
Each LDLT procedure was approved by the ethics committee of the local authority and by the Korean Network for Organ Sharing, which is affiliated with the Korean Ministry of Health. Informed consent was obtained from all enrolled patients. The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki. The protocol was reviewed and approved by the relevant Ethics Committee before implementation.

Results

Study population
Eleven patients were enrolled and included in the full analysis set. Nine patients completed the study; 1 patient had a major pharmacokinetics-relevant protocol violation and withdrew prematurely from the study, and 1 patient withdrew prematurely but did provide blood samples on days 6 and 14. Therefore, valid pharmacokinetics data were available for 10 patients. The mean age (± standard deviation) of the patients was 51.6 ± 5.8 years. All patients were of Asian ethnicity, and 2 were female. Ten patients had a primary diagnosis of posthepatic cirrhosis caused by hepatitis B, and 1 patient had a primary diagnosis of alcoholic cirrhosis. Four patients had hepatocellular carcinoma. All patients tested negative at baseline for Cytomegalovirus and hepatitis C virus. The mean age of the living donors was 26.2 years.

Drug administration and exposure
After being treated with intravenous tacrolimus on days 0 to 4, all patients were administered once-daily tacrolimus starting 5 days after transplant. The protocol instructed the clinician to administer once-daily tacrolimus on day 5 at a dose level that was 6 times higher than the intravenous dose of tacrolimus administered on day 4. The actual converted doses of once-daily tacrolimus ranged from 5.4 to 6.7 times the intravenous dose (median, 6.1 times). Table 1 shows the mean daily dose of intravenous tacrolimus on day 4 and the mean daily doses of once-daily tacrolimus on days 6 and 14 and weeks 4, 8, and 12. The daily dose of once-daily tacrolimus remained fairly constant over the 12-week duration of the study (Table 1); however, the whole blood concentration of the drug fluctuated. Trough levels of tacrolimus dropped on day 6 immediately after conversion from continuous intravenous to the oral once-daily tacrolimus formulation but increased by 1.7-fold on day 14 (Table 1 patients receiving maintenance corticosteroids at week 12.

Pharmacokinetics analyses
Pharmacokinetics profiles were generated using 10 timed whole blood samples collected over a 24-hour period on days 6 and 14. The actual sampling times differed only slightly from the scheduled times listed in the protocol. The AUC0-24, C_max, C_min, and time to maximum concentration are shown in Table 2. When the actual once-daily tacrolimus dose was considered, the mean AUC0-24h and C_max values at day 14 were 1.80-fold and 2.00-fold higher than those at day 6. When the tacrolimus dose was normalized to 0.1 mg/kg, the mean AUC0-24h and C_max values at day 14 were 1.52-fold and 1.49-fold higher than those at day 6. One extreme outlying AUC0-24h value at day 14 (415.8 ng/mL) contributed to the nonnormal distribution of the data.

Tacrolimus exposure, measured as Cmin, was within the recommended range at days 6 and 14 (Table 2). When we calculated using either the actual tacrolimus dose or the tacrolimus dose normalized to 0.1 mg/kg, we found the Cmin values at day 14 to be highly variable across individuals (Table 2). The time to maximum concentration occurred earlier on day 6 than on day 14 (Table 2), reflecting the prolonged release characteristics of once-daily tacrolimus that result in extended absorption of the drug. Two patients had exceptionally delayed time to maximum concentration on day 14 (12.0 and 16.1 h).

When we used the actual tacrolimus dose, we found the correlation between AUC0-24 and C_min to be stron­ger on day 6 (r = 0.87) than on day 14 (r = 0.69) (Figure 1). In contrast, when the daily dose of once-daily tacrolimus was normalized to 0.1 mg/kg, there was a very strong correlation between AUC0-24 and C_min on both day 6 (r = 0.96) and day 14 (r = 0.97) (Figure 2).

Secondary endpoints
No incidences of acute rejection, graft loss, or death occurred during the study.

Adverse events
A few adverse events were identified by the investigator and deemed to be causally related to the once-daily tacrolimus treatment. The causally related adverse events (defined as per the preferred term classification in the Medical Dictionary for Regulatory Activities) reported in ≥ 20% of patients were increased blood creatinine levels (6 of 11 patients), hyperkalemia (5 of 11 patients), and hypomagnesemia (3 of 11 patients). However, we observed no significant differences in the incidence of adverse events according to the administration route (intravenous form vs oral form). None of the patients required renal replacement therapy, and all patients showed recovery of renal dysfunction either spontaneously or after clinician-directed adjustment of once-daily tacrolimus dose. One patient withdrew from the study prematurely due to uncontrolled hypertension, which was reported as an adverse event.

Biochemical analyses of blood alanine amino­transferase, aspartate aminotransferase, glucose, and serum creatinine levels indicated that liver function was improved after transplant (Table 3). Slight increases in blood glucose and serum creatinine levels were observed during the 12-week study (Table 3). There were no clinically significant findings for other laboratory variables, including body weight, blood pressure, and pulse rate.

Discussion

Twice-daily tacrolimus is a well-established immuno­­suppressive therapy for the effective prevention or treatment of allograft rejection in solid-organ trans­plant. Most experts in the transplantation field believe that tacrolimus is one of the most powerful factors contributing to improvements in transplant outcome over the past few decades.^11,12 Lifelong immuno­suppression is crucial for the maintenance of graft function; however, the daily intake of medications required to sustain immunosuppression can be a substantial burden on the quality of life of transplant recipients.¹³ Simpler dosing regimens facilitate better adherence behavior, reducing graft rejection and loss on longer-term follow-up.^14,15

Previous studies in healthy volunteers showed that twice-daily and once-daily tacrolimus regimens that maintain equivalent total daily doses result in similar exposures to the drug. Furthermore, clinical trials in transplant recipients that substituted one formulation for the other but retained the same total daily dose demonstrated equivalent exposure and similar ratios of C_min to AUC0-24 for twice-daily and once-daily tacrolimus.^16-18 Therefore, the decision was made to apply the same therapeutic drug monitoring strategy (measurement of C_min) and target concentration range to stable organ transplant recipients irrespective of the formulation used in clinical practice. However, the information required to guide the appropriate tacrolimus dose in de novo LDLT recipients is currently lacking.

This pilot study investigated the pharmacokinetics of once-daily tacrolimus administered to LDLT recipients. The initial use of intravenous tacrolimus was selected to prevent the occurrence of under­exposure attributable to reduced gastrointestinal function during the first few days after LDLT.¹⁹ On the morning of day 5 (after restoration of gastrointestinal motility and initiation of oral intake), intravenous tacrolimus was discontinued and oral once-daily tacrolimus was administered at an initial dose of 0.15 to 0.3 mg/kg/day; the peroral dose administered on day 5 was 6 times higher than the intravenous tac­rolimus dose administered on day 4. The intravenous administration of tacrolimus is not routine clinical practice due to high rates of nephrotoxicity, neurotoxicity, or anaphylactic reactions, although those adverse events are rare.^20,21 Oral tacrolimus admi­nistration is the common route of drug adminis­tration. However, gut and hepatic metabolism by cytochrome P450 microsomal enzymes and P-glyco­protein efflux at the gut result in low tacrolimus bioavailability after oral administration of tac­rolimus.²² Therefore, sublingual forms of tacrolimus, bypassing gut processes, may provide comparable drug bioavailability and might be an alternate route, considering the usual clinical situation prohibiting the oral administration of tacrolimus such as endotracheal intubation or postoperative ileus.²³ However, the sublingual form was not considered the route of administration in this study because it was not available in Korea.

The primary objective of this study was to evaluate systemic exposure (AUC0-24h) to tacro­limus after the second dose of oral once-daily tacrolimus on day 6 and under steady-state conditions on day 14. The use of whole blood trough level monitoring as a surrogate marker of tacrolimus exposure is indicated in the clinical setting because of the narrow therapeutic index for tacrolimus; a good correlation between area under the curve and trough levels indicates the efficacy and safety of tacrolimus. The degree of correlation between the AUC0-24h and Cmin was higher after the second dose of once-daily tacrolimus than at steady-state conditions. However, the AUC0-24h was 1.8-fold higher on day 14 than on day 6. Daily doses of once-daily tacrolimus were also higher on day 14 than on day 6. Most previous pharmacokinetics studies comparing twice-daily and once-daily tacrolimus in de novo transplant recipients have reported that, after once-daily tacrolimus administration, Cmin values are reduced in the immediate posttransplant period and higher doses of the drug are required to maintain target concentrations.^9,24,25 A previous multicenter com­parison of the safety and efficacy of tacrolimus administered once- versus twice-daily to de novo LDLT recipients also demonstrated lower Cmin values and a higher dose requirement for once daily tacrolimus than for twice-daily tacrolimus when normalized to mr doses of tacrolimus (unpublished data). Here, a higher dose of once-daily tacrolimus was required to maintain target concentrations during the posttransplant period, especially immediately after the conversion from intravenous to oral administration of the drug. The repeated increases in the daily dose of tacrolimus may have resulted in a cumulative effect and higher drug exposure on day 14. This finding highlights the need to modulate the once-daily tacrolimus dose to avoid unnecessary toxic effects, which will be helpful for future large-scale studies.

Because this study was a pilot investigation, its main limitations are the small study cohort and lack of a comparative arm. In addition, over 90% of the patients enrolled had hepatitis B-related liver disease. Despite these limitations, the results presented here provide some evidence of the efficacy and safety of an immunosuppressive regimen consisting of initial intravenous tacrolimus and subsequent once-daily tacrolimus in de novo LDLT patients and contribute to an understanding of how treatment of transplant patients may be managed in daily clinical practice. Although this study was not designed to absolutely prove the efficacy of once-daily tacrolimus in LDLT recipients, no cases of acute rejection were reported and there were no patient deaths or loss of liver allografts during the 12-week follow-up. The adverse events reported during the study are in accordance with the known risks and safety profile of tacrolimus. Furthermore, there was no abnormal clinical laboratory finding of relevance.

In conclusion, a dosing regimen comprising initial intravenous tacrolimus and subsequent conversion to oral once-daily tacrolimus may be safe and efficacious in de novo LDLT patients. However, because the steady-state drug exposure was higher than expected in this study, a randomized, com­parative study with a larger cohort is warranted. Additional studies will aid the development of an adequate once-daily tacrolimus dosing regimen for de novo LDLT recipients.

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