Conversion From Twice-Daily to Once-Daily Tacrolimus in Simultaneous Pancreas-Kidney Transplant Patients S.J. Falconer, C. Jansen, and G.C. Oniscu* Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
ABSTRACT Background. Data on the effectiveness of once-daily tacrolimus (Tac-QD) in simultaneous pancreas-kidney (SPK) transplant patients are limited, which is of particular concern because diabetic gastroparesis may affect absorption. The aim of this study was to evaluate the clinical impact of converting SPK patients from twice-daily (Tac-BD) to Tac-QD. Methods. From November 2008 to August 2011, 27 SPK recipients (out of 130) were converted from Tac-BD to Tac-QD. Demographics, prescribed doses, trough levels, and creatinine, glucose, and HbA1c values were collected prospectively at the time of conversion and at 1, 2, 3, 6, and 12 months after conversion. Results. The mean time from transplantation to conversion was 35.81 27.31 months, with 20 patients (74.07%) converted to Tac-QD >12 months after transplantation. There were no significant differences in the tacrolimus dose and trough levels before and after conversion and at all points during the follow-up. Creatinine, glucos,e and HbA1c levels remained stable throughout. Eight patients (29.63%) with gastroparesis had clinical outcomes, drug doses, and trough levels similar to all other patients. Conclusions. Stable SPK recipients can safely be converted from Tac-BD to Tac-QD, with no clinical impact on the transplant function. Gastroparesis does not appear to influence tacrolimus dose requirements or trough levels.
T
ACROLIMUS in its twice-daily formulation (Tac-BD; Prograf), along with mycophenolate mofetil (MMF), has been the mainstay of immunosuppression for solid organ transplantation for more than a decade [1]. A oncedaily oral preparation of tacrolimus (Tac-QD; Advagraf) has been introduced in clinical practice in recent years, and published reports suggest that it is as safe and effective as Tac-BD for renal as well as liver transplant recipients [2e4]. However, there is a paucity of data for simultaneous pancreas-kidney (SPK) transplant recipients, with only 1 small study suggesting that Tac-QD could be used in this patient group [5]. The perceived benefits of Tac-QD are a reduction in pill burden, which may translate into better patient compliance [6], thus minimizing the risk of graft dysfunction. There have been concerns, however, that converting stable patients on an mg:mg basis, as recommended in the manufacturer’s guidance, may lead to reduced tacrolimus exposure, placing SPK transplant patients at risk of inadequate immunosuppression [7]. Patients who
undergo SPK transplantation have a higher incidence of gastroparesis and gut motility dysfunction secondary to diabetic autonomic neuropathy. This may be particularly relevant with Tac-QD, which is absorbed more distally in the gut than the Tac-BD preparation. The diabetogenic effects of immunosuppressive drugs are also important, particularly in pancreatic transplantation, and the influence of Tac-BD on insulin production and diabetes are well recognized [8]. The effect of Tac-QD, however, is less well described.
Disclosure: Stuart Falconer’s salary through the University of Edinburgh is met by an unrestricted research grant from Astellas Pharma. *Address correspondence to Mr Gabriel C. Oniscu, Consultant Transplant Surgeon, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, United Kingdom. E-mail: [email protected]
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.12.056
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1458
Transplantation Proceedings, 46, 1458e1462 (2014)
ONCE-DAILY TACROLIMUS IN PANCREAS-KIDNEY TRANSPLANTATION
The aim of the present study was to evaluate the clinical impact of converting stable SPK transplant patients from Tac-BD to Tac-QD and the effect this had on their glucose homeostasis and outcome. PATIENTS AND METHODS Twenty-seven SPK recipients, out of the 130 transplantations performed from 2002 to 2010, were converted from Tac-BD to Tac-QD from November 2008 to August 2011 and followed for 1 year after conversion. Conversion was at physician’s latitude or if requested by the patients. Ethical approval for this study was obtained from the local Research Ethics Committee. Data on tacrolimus dose, tacrolimus trough level (C0), creatinine, serum glucose and HbA1c, episodes of biopsy-proven acute rejection before and after conversion to Tac-QD, and patient and graft survivals were collected prospectively as part of routine clinical care and analyzed retrospectively. For the purpose of this study, these data were recorded just before conversion and then at 1, 2, 3, 6, and 12 months after conversion to Tac-QD. Tacrolimus C0 was measured with the use of a tandem mass spectrometry method. Data are expressed as mean SD unless otherwise stated and analyzed with the use of IBM SPSS version 19.
Transplant Technique and Immunosuppression Pancreatic transplantation was performed via a right paramedian incision with intraperitoneal implantation, with the use of a donor iliac Y-graft to the splenic and superior mesenteric arteries and anastomosis to the recipient’s common iliac artery. Venous outflow was achieved by systemic drainage into the inferior vena cava and exocrine drainage was achieved via a side-to-side loop enteroduodenostomy. The renal grafts were placed extraperitoneally in the left iliac fossa with the renal artery and vein anastomosed to the iliac artery and vein, respectively. The ureter was anastomosed to the bladder with the use of a 2-layer technique over a double J stent. Standard immunosuppression consisted of induction with 20 mg basiliximab (days 0 and 4), 0.1 mg/kg/d Tac-BD (Prograf), 1 g MMF (Cellcept) twice daily, and 20 mg prednisolone once daily, tapered to 5 mg at 3 months. The target range for tacrolimus trough level was 10e14 mg/L in the 1st month after transplantation and 8e12 mg/ L from 2e8 months. Thereafter, the maintenance target trough range was 5e10 mg/L.
RESULTS
Twenty-seven SPK recipients (14 male and 13 female) were converted from Tac-BD to Tac-QD. The demographic data are presented in Table 1. The mean time from transplantation to conversion was 35.81 27.31 months (range, 0e101 mo), and the mean follow-up time after conversion was 27.70 8.31 months (range, 16e49 mo). Twenty patients (74.07%) were converted >12 months after transplantation, and 7 patients were converted in the early post-transplantation follow-up (3 patients [11.11%] in the 1st 3 months, 2 patients [7.41%] in 4e6 months, and 2 patients [7.41%] in 7e12 months). One patient experienced delayed pancreatic graft function, and all of the remaining patients had immediate pancreatic graft function. All patients were insulin independent at the time of discharge from hospital from the index admission.
1459 Table 1. Patient Demographics
Age, y, mean SD (range) Sex Female Male BMI, kg/m2, mean SD (range) Renal replacement therapy Preemptive Transplant Hemodialysis Peritoneal dialysis Gastroparesis Yes No Cold ischemia time, h:min, mean SD (range) Kidney Pancreas Rejection episodes Before conversion After conversion Time to conversion, mo, mean SD (range) Converted back to Prograf Days until converted back, mean SD (range) Donor age, y, mean SD (range) HLA mismatch A/B/DR, mean Donor sex Male Female Donor cause of death Intracranial hemorrhage Head trauma Meningitis Hypoxic brain injury Unknown Delayed graft function, n (%) Kidney Pancreas
44.07 9.02 (25e61) 13 14 24.31 3.73 (18.51e30.83) 8 7 12 8 19
14:06 02:31 (07:06e17:53) 12:37 01:56 (10:14e16:51) 4 2 35.81 27.31 (0e101) 8 192.50 231.173 (29e742) 35.92 13.66 (9e54) 1.08/1.5/1.42 11 15 13 11 1 1 1 10 (37.04%) 1 (3.70%)
Ten patients experienced delayed renal graft function after SPK transplantation. Eight patients (29.63%) had documented gastroparesis, based on clinical symptoms and preoperative investigations. Eleven patients (40.74%) were converted on an mg:mg basis, and 11 patients were converted within 1 mg of their preceding Tac-BD dose. Four patients (14.82%) had their dose changed by >1 mg when converted to Tac-QD. Ten patients (37.0%) had no dose adjustments in the 12 months after conversion. Three patients (11.11%) had >3 dose changes in the 1st 12 months after conversion. Patients converted early to Tac-QD required more dose changes than those who were converted late (2.29 2.36 vs 0.95 1.10), although this was not statistically significant (P ¼ .054; 1-way analysis of variance [ANOVA]). A total of 8 patients (29.63%) were converted back to Tac-BD at a mean time of 192.50 231.17 days after the initial conversion to Tac-QD. The reasons for conversion
1460
back to Tac-BD varied and included tacrolimus neurotoxicity, acute rejection, and diarrhea. There was no significant difference in the number of patients who were converted back to Tac-BD in the gastroparesis group versus the no gastroparesis group (6/19 [31.6%] vs 2/8 [25.0%]; P ¼ .558; chi-square test). There were similar numbers of patients converted back to Tac-BD in the early conversion group compared with the late conversion group (2/7 [28.6%] vs 6/20 [30.0%]; P ¼ .943; chi-square test). There was no significant difference between the mean dose of Tac-BD before conversion (6.46 3.08 mg [range, 2e13 mg]), the mean initial dose of Tac-QD (7.26 4.83 mg [range, 1e25 mg]), and the doses at all time points up to 12 months after conversion, as shown in Fig 1A (P ¼ .9719; 1-way ANOVA). Similarly, the mean tacrolimus C0 at the time of conversion (8.85 4.52 mg/L [range, 3.3e24.5 mg/L]) was similar at 1 month (8.07 5.25 mg/L [range, 2.4e19.8]) and all other time points up to 12 months after conversion (P ¼ .47; 1-way ANOVA; Fig 1B). Conversion to Tac-QD did not affect renal function, with similar creatinine levels at the point of conversion (114.30 35.55 mmol/L), 1 month after conversion (119.80 28.23 mmol/L), and all other time points up to 12 months, as shown in Fig 2A (P ¼ .91; 1-way ANOVA). Pancreas function remained stable, with mean serum glucose levels of 5.28 0.93 mmol/L (range, 3.5e7.4 mmol/ L) at the time of conversion and 5.33 0.66 mmol/L (range, 4.5e6.6 mmol/L) 1 month after conversion. The glucose level was similar at all other time points during the 12 months of follow-up (P ¼ .82; 1-way ANOVA). Similarly, HbA1c levels remained stable throughout the 1st yea, as shown in Fig 2B. There was no difference in tacrolimus dose (either Tac-BD or Tac-QD), tacrolimus C0, or creatinine, glucose, or HbA1c levels between patients with gastroparesis and those without gastroparesis (C0 shown in Fig 3). There were 6 episodes of biopsy-proven acute rejection during the follow-up, 4 of which occurred before conversion to Tac-QD and 2 after conversion to Tac-QD. There was no difference in the biopsy-proven acute rejection between patients with gastroparesis (1/8, 12.5%) and those without gastroparesis (3/19, 15.8%; P ¼ .663; chi-square test). Patient survival, pancreatic graft survival, and renal graft survival were 100% at the end of the follow-up period. One patient was noted to have significant deterioration in renal graft function after an antibody-mediated rejection episode but had not required dialysis by the end of the study follow-up.
DISCUSSION
Tac-QD appears to have found a niche in kidney and liver transplantation with an apparent improvement in the compliance rates [6]. However, the use in simultaneous pancreas-kidney remains rare, primarily owing to concerns regarding the drug metabolism in the presence of gastrointestinal diabetic complications.
FALCONER, JANSEN, AND ONISCU
Fig 1. Tacrolimus dose (A) and tacrolimus level (B) before and after conversion.
The present study has shown that stable SPK transplant patients can be converted from Tac-BD to Tac-QD (without any significant impact on dosing requirements or tacrolimus C0 in the 12 months following conversion. This mirrors the results from renal transplantation studies showing that conversion is safe and effective. Furthermore, the majority of patients in this study (81.5%) were converted either on a 1 mgetoe1 mg basis or within 1 mg of their previous Tac-BD dose. Most patients had relatively few dose changes after conversion. This seems to suggest that gastrointestinal tract drug handling is not greatly different from kidney transplant patients. However, we did not perform a comparison of SPK recipients and diabetic patients receiving a kidney transplant alone to confirm this specific point. Conversion to Tac-QD had no deleterious effect on glycemic control. This is particularly relevant because patients with diabetes often have autonomic dysfunction of their gastrointestinal tract [9]. We found that patients with gastroparesis had Tac-QD doses similar to patients without gastroparesis. This translated into equivalent glycemic control and creatinine levels. The vast majority of patients in this study were converted >12 months after transplantation, and it is conceivable that the gastrointestinal diabetic complications may have improved within the 1st year with a functioning transplant [10]. The patients in the present study had no significant change in renal function in the 12 months following
ONCE-DAILY TACROLIMUS IN PANCREAS-KIDNEY TRANSPLANTATION
1461
Fig 3. Effect of gastroparesis on tacrolimus levels after conversion to once-daily preparation.
was not part of a protocol and was performed at the latitude of the treating physician as indicated by the clinical situation or if the patients requested it. Furthermore, 8 patients were converted back to Tac-BD after varying periods of time. There were clearly documented reasons for converting some, but not all, of these patients back to Tac-BD. Therefore, it is difficult to draw a definitive conclusion about when and why SPK patients should be converted back to Tac-BD. A combination of factors, including side effects, tacrolimus C0 variability, patient preference, or a lack of experience using Tac-QD for recent transplant patients, is likely to have played a role in the decision to convert these patients back to Tac-BD during this study. In summary, stable SPK patients can be converted from a twice-daily to a once-daily preparation of tacrolimus with no detrimental clinical impact. However, a randomized study and larger observational studies are required to fully evaluate the place of this tacrolimus formulation in SPK transplant patients. REFERENCES
Fig 2. Creatinine (A) and HBA1c (B) levels before and after conversion.
conversion, which is in keeping with earlier studies in renal transplantation alone [4]. This suggests that the immunosuppressive efficacy as well as the nephrotoxic burden of Tac-QD is similar to that of Tac-BD in this group of patients. Patient and graft survival of both organs remained at 100% to the end of the study period, although a direct correlation with the type of tacrolimus preparation in SPK transplantation requires evaluation in an adequately powered clinical trial comparing the 2 products. Although we conclude that SPK transplant patients can be safely converted from Tac-BD to Tac-QD without a negative clinical impact, we acknowledge that conversion
[1] Gruessner AC. 2011 update on pancreas transplantation: comprehensive trend analysis of 25,000 cases followed up over the course of twenty-four years at the International Pancreas Transplant Registry (IPTR). Rev Diabet Stud 2011;8:6e16. [2] Alloway R, Steinberg S, Khalil K, Gourishankar S, Miller J, Norman D, et al. Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc 2005;37:867e70. [3] Trunecka P, Boillot O, Seehofer D, Pinna AD, Fischer L, Ericzon BG, et al. Once-daily prolonged-release tacrolimus (Advagraf) versus twice-daily tacrolimus (Prograf) in liver transplantation. Am J Transplant 2010;10:2313e23. [4] Kramer BK, Charpentier B, Backman L, Silva Jr HT, Mondragon-Ramirez G, Cassuto-Viguier E, et al. Tacrolimus once daily (Advagraf) versus twice daily (Prograf) in de novo renal transplantation: a randomized phase III study. Am J Transplant 2010;10:2632e43. [5] Schenker P, Klein T, Kruger B, Claas S, Wunsch A, Traska T, et al. Modified release tacrolimus in de novo immunosuppression after simultaneous pancreas-kidney transplantationda first singlecenter experience. Transplant Proc 2009;41:2573e5. [6] Kuypers DR, Peeters PC, Sennesael JJ, Kianda MN, Vrijens B, Kristanto P, et al. Improved adherence to tacrolimus
1462 once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Transplantation 2013;95:333e40. [7] Barraclough KA, Isbel NM, Johnson DW, Campbell SB, Staatz CE. Once- versus twice-daily tacrolimus: are the formulations truly equivalent? Drugs 2011;71:1561e77. [8] Vincenti F, Friman S, Scheuermann E, Rostaing L, Jenssen T, Campistol JM, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant 2007;7:1506e14.
FALCONER, JANSEN, AND ONISCU [9] Parkman HP, Yates K, Hasler WL, Nguyen L, Pasricha PJ, Snape WJ, et al. Similarities and differences between diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol 2011;9: 1056e64. [10] Hathaway DK, Abell T, Cardoso S, Hartwig MS, el Gebely S, Gaber AO. Improvement in autonomic and gastric function following pancreas-kidney versus kidney-alone transplantation and the correlation with quality of life. Transplantation 1994;57:816e22.
ABSTRACT Background. Data on the effectiveness of once-daily tacrolimus (Tac-QD) in simultaneous pancreas-kidney (SPK) transplant patients are limited, which is of particular concern because diabetic gastroparesis may affect absorption. The aim of this study was to evaluate the clinical impact of converting SPK patients from twice-daily (Tac-BD) to Tac-QD. Methods. From November 2008 to August 2011, 27 SPK recipients (out of 130) were converted from Tac-BD to Tac-QD. Demographics, prescribed doses, trough levels, and creatinine, glucose, and HbA1c values were collected prospectively at the time of conversion and at 1, 2, 3, 6, and 12 months after conversion. Results. The mean time from transplantation to conversion was 35.81 27.31 months, with 20 patients (74.07%) converted to Tac-QD >12 months after transplantation. There were no significant differences in the tacrolimus dose and trough levels before and after conversion and at all points during the follow-up. Creatinine, glucos,e and HbA1c levels remained stable throughout. Eight patients (29.63%) with gastroparesis had clinical outcomes, drug doses, and trough levels similar to all other patients. Conclusions. Stable SPK recipients can safely be converted from Tac-BD to Tac-QD, with no clinical impact on the transplant function. Gastroparesis does not appear to influence tacrolimus dose requirements or trough levels.
T
ACROLIMUS in its twice-daily formulation (Tac-BD; Prograf), along with mycophenolate mofetil (MMF), has been the mainstay of immunosuppression for solid organ transplantation for more than a decade [1]. A oncedaily oral preparation of tacrolimus (Tac-QD; Advagraf) has been introduced in clinical practice in recent years, and published reports suggest that it is as safe and effective as Tac-BD for renal as well as liver transplant recipients [2e4]. However, there is a paucity of data for simultaneous pancreas-kidney (SPK) transplant recipients, with only 1 small study suggesting that Tac-QD could be used in this patient group [5]. The perceived benefits of Tac-QD are a reduction in pill burden, which may translate into better patient compliance [6], thus minimizing the risk of graft dysfunction. There have been concerns, however, that converting stable patients on an mg:mg basis, as recommended in the manufacturer’s guidance, may lead to reduced tacrolimus exposure, placing SPK transplant patients at risk of inadequate immunosuppression [7]. Patients who
undergo SPK transplantation have a higher incidence of gastroparesis and gut motility dysfunction secondary to diabetic autonomic neuropathy. This may be particularly relevant with Tac-QD, which is absorbed more distally in the gut than the Tac-BD preparation. The diabetogenic effects of immunosuppressive drugs are also important, particularly in pancreatic transplantation, and the influence of Tac-BD on insulin production and diabetes are well recognized [8]. The effect of Tac-QD, however, is less well described.
Disclosure: Stuart Falconer’s salary through the University of Edinburgh is met by an unrestricted research grant from Astellas Pharma. *Address correspondence to Mr Gabriel C. Oniscu, Consultant Transplant Surgeon, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, United Kingdom. E-mail: [email protected]
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.12.056
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1458
Transplantation Proceedings, 46, 1458e1462 (2014)
ONCE-DAILY TACROLIMUS IN PANCREAS-KIDNEY TRANSPLANTATION
The aim of the present study was to evaluate the clinical impact of converting stable SPK transplant patients from Tac-BD to Tac-QD and the effect this had on their glucose homeostasis and outcome. PATIENTS AND METHODS Twenty-seven SPK recipients, out of the 130 transplantations performed from 2002 to 2010, were converted from Tac-BD to Tac-QD from November 2008 to August 2011 and followed for 1 year after conversion. Conversion was at physician’s latitude or if requested by the patients. Ethical approval for this study was obtained from the local Research Ethics Committee. Data on tacrolimus dose, tacrolimus trough level (C0), creatinine, serum glucose and HbA1c, episodes of biopsy-proven acute rejection before and after conversion to Tac-QD, and patient and graft survivals were collected prospectively as part of routine clinical care and analyzed retrospectively. For the purpose of this study, these data were recorded just before conversion and then at 1, 2, 3, 6, and 12 months after conversion to Tac-QD. Tacrolimus C0 was measured with the use of a tandem mass spectrometry method. Data are expressed as mean SD unless otherwise stated and analyzed with the use of IBM SPSS version 19.
Transplant Technique and Immunosuppression Pancreatic transplantation was performed via a right paramedian incision with intraperitoneal implantation, with the use of a donor iliac Y-graft to the splenic and superior mesenteric arteries and anastomosis to the recipient’s common iliac artery. Venous outflow was achieved by systemic drainage into the inferior vena cava and exocrine drainage was achieved via a side-to-side loop enteroduodenostomy. The renal grafts were placed extraperitoneally in the left iliac fossa with the renal artery and vein anastomosed to the iliac artery and vein, respectively. The ureter was anastomosed to the bladder with the use of a 2-layer technique over a double J stent. Standard immunosuppression consisted of induction with 20 mg basiliximab (days 0 and 4), 0.1 mg/kg/d Tac-BD (Prograf), 1 g MMF (Cellcept) twice daily, and 20 mg prednisolone once daily, tapered to 5 mg at 3 months. The target range for tacrolimus trough level was 10e14 mg/L in the 1st month after transplantation and 8e12 mg/ L from 2e8 months. Thereafter, the maintenance target trough range was 5e10 mg/L.
RESULTS
Twenty-seven SPK recipients (14 male and 13 female) were converted from Tac-BD to Tac-QD. The demographic data are presented in Table 1. The mean time from transplantation to conversion was 35.81 27.31 months (range, 0e101 mo), and the mean follow-up time after conversion was 27.70 8.31 months (range, 16e49 mo). Twenty patients (74.07%) were converted >12 months after transplantation, and 7 patients were converted in the early post-transplantation follow-up (3 patients [11.11%] in the 1st 3 months, 2 patients [7.41%] in 4e6 months, and 2 patients [7.41%] in 7e12 months). One patient experienced delayed pancreatic graft function, and all of the remaining patients had immediate pancreatic graft function. All patients were insulin independent at the time of discharge from hospital from the index admission.
1459 Table 1. Patient Demographics
Age, y, mean SD (range) Sex Female Male BMI, kg/m2, mean SD (range) Renal replacement therapy Preemptive Transplant Hemodialysis Peritoneal dialysis Gastroparesis Yes No Cold ischemia time, h:min, mean SD (range) Kidney Pancreas Rejection episodes Before conversion After conversion Time to conversion, mo, mean SD (range) Converted back to Prograf Days until converted back, mean SD (range) Donor age, y, mean SD (range) HLA mismatch A/B/DR, mean Donor sex Male Female Donor cause of death Intracranial hemorrhage Head trauma Meningitis Hypoxic brain injury Unknown Delayed graft function, n (%) Kidney Pancreas
44.07 9.02 (25e61) 13 14 24.31 3.73 (18.51e30.83) 8 7 12 8 19
14:06 02:31 (07:06e17:53) 12:37 01:56 (10:14e16:51) 4 2 35.81 27.31 (0e101) 8 192.50 231.173 (29e742) 35.92 13.66 (9e54) 1.08/1.5/1.42 11 15 13 11 1 1 1 10 (37.04%) 1 (3.70%)
Ten patients experienced delayed renal graft function after SPK transplantation. Eight patients (29.63%) had documented gastroparesis, based on clinical symptoms and preoperative investigations. Eleven patients (40.74%) were converted on an mg:mg basis, and 11 patients were converted within 1 mg of their preceding Tac-BD dose. Four patients (14.82%) had their dose changed by >1 mg when converted to Tac-QD. Ten patients (37.0%) had no dose adjustments in the 12 months after conversion. Three patients (11.11%) had >3 dose changes in the 1st 12 months after conversion. Patients converted early to Tac-QD required more dose changes than those who were converted late (2.29 2.36 vs 0.95 1.10), although this was not statistically significant (P ¼ .054; 1-way analysis of variance [ANOVA]). A total of 8 patients (29.63%) were converted back to Tac-BD at a mean time of 192.50 231.17 days after the initial conversion to Tac-QD. The reasons for conversion
1460
back to Tac-BD varied and included tacrolimus neurotoxicity, acute rejection, and diarrhea. There was no significant difference in the number of patients who were converted back to Tac-BD in the gastroparesis group versus the no gastroparesis group (6/19 [31.6%] vs 2/8 [25.0%]; P ¼ .558; chi-square test). There were similar numbers of patients converted back to Tac-BD in the early conversion group compared with the late conversion group (2/7 [28.6%] vs 6/20 [30.0%]; P ¼ .943; chi-square test). There was no significant difference between the mean dose of Tac-BD before conversion (6.46 3.08 mg [range, 2e13 mg]), the mean initial dose of Tac-QD (7.26 4.83 mg [range, 1e25 mg]), and the doses at all time points up to 12 months after conversion, as shown in Fig 1A (P ¼ .9719; 1-way ANOVA). Similarly, the mean tacrolimus C0 at the time of conversion (8.85 4.52 mg/L [range, 3.3e24.5 mg/L]) was similar at 1 month (8.07 5.25 mg/L [range, 2.4e19.8]) and all other time points up to 12 months after conversion (P ¼ .47; 1-way ANOVA; Fig 1B). Conversion to Tac-QD did not affect renal function, with similar creatinine levels at the point of conversion (114.30 35.55 mmol/L), 1 month after conversion (119.80 28.23 mmol/L), and all other time points up to 12 months, as shown in Fig 2A (P ¼ .91; 1-way ANOVA). Pancreas function remained stable, with mean serum glucose levels of 5.28 0.93 mmol/L (range, 3.5e7.4 mmol/ L) at the time of conversion and 5.33 0.66 mmol/L (range, 4.5e6.6 mmol/L) 1 month after conversion. The glucose level was similar at all other time points during the 12 months of follow-up (P ¼ .82; 1-way ANOVA). Similarly, HbA1c levels remained stable throughout the 1st yea, as shown in Fig 2B. There was no difference in tacrolimus dose (either Tac-BD or Tac-QD), tacrolimus C0, or creatinine, glucose, or HbA1c levels between patients with gastroparesis and those without gastroparesis (C0 shown in Fig 3). There were 6 episodes of biopsy-proven acute rejection during the follow-up, 4 of which occurred before conversion to Tac-QD and 2 after conversion to Tac-QD. There was no difference in the biopsy-proven acute rejection between patients with gastroparesis (1/8, 12.5%) and those without gastroparesis (3/19, 15.8%; P ¼ .663; chi-square test). Patient survival, pancreatic graft survival, and renal graft survival were 100% at the end of the follow-up period. One patient was noted to have significant deterioration in renal graft function after an antibody-mediated rejection episode but had not required dialysis by the end of the study follow-up.
DISCUSSION
Tac-QD appears to have found a niche in kidney and liver transplantation with an apparent improvement in the compliance rates [6]. However, the use in simultaneous pancreas-kidney remains rare, primarily owing to concerns regarding the drug metabolism in the presence of gastrointestinal diabetic complications.
FALCONER, JANSEN, AND ONISCU
Fig 1. Tacrolimus dose (A) and tacrolimus level (B) before and after conversion.
The present study has shown that stable SPK transplant patients can be converted from Tac-BD to Tac-QD (without any significant impact on dosing requirements or tacrolimus C0 in the 12 months following conversion. This mirrors the results from renal transplantation studies showing that conversion is safe and effective. Furthermore, the majority of patients in this study (81.5%) were converted either on a 1 mgetoe1 mg basis or within 1 mg of their previous Tac-BD dose. Most patients had relatively few dose changes after conversion. This seems to suggest that gastrointestinal tract drug handling is not greatly different from kidney transplant patients. However, we did not perform a comparison of SPK recipients and diabetic patients receiving a kidney transplant alone to confirm this specific point. Conversion to Tac-QD had no deleterious effect on glycemic control. This is particularly relevant because patients with diabetes often have autonomic dysfunction of their gastrointestinal tract [9]. We found that patients with gastroparesis had Tac-QD doses similar to patients without gastroparesis. This translated into equivalent glycemic control and creatinine levels. The vast majority of patients in this study were converted >12 months after transplantation, and it is conceivable that the gastrointestinal diabetic complications may have improved within the 1st year with a functioning transplant [10]. The patients in the present study had no significant change in renal function in the 12 months following
ONCE-DAILY TACROLIMUS IN PANCREAS-KIDNEY TRANSPLANTATION
1461
Fig 3. Effect of gastroparesis on tacrolimus levels after conversion to once-daily preparation.
was not part of a protocol and was performed at the latitude of the treating physician as indicated by the clinical situation or if the patients requested it. Furthermore, 8 patients were converted back to Tac-BD after varying periods of time. There were clearly documented reasons for converting some, but not all, of these patients back to Tac-BD. Therefore, it is difficult to draw a definitive conclusion about when and why SPK patients should be converted back to Tac-BD. A combination of factors, including side effects, tacrolimus C0 variability, patient preference, or a lack of experience using Tac-QD for recent transplant patients, is likely to have played a role in the decision to convert these patients back to Tac-BD during this study. In summary, stable SPK patients can be converted from a twice-daily to a once-daily preparation of tacrolimus with no detrimental clinical impact. However, a randomized study and larger observational studies are required to fully evaluate the place of this tacrolimus formulation in SPK transplant patients. REFERENCES
Fig 2. Creatinine (A) and HBA1c (B) levels before and after conversion.
conversion, which is in keeping with earlier studies in renal transplantation alone [4]. This suggests that the immunosuppressive efficacy as well as the nephrotoxic burden of Tac-QD is similar to that of Tac-BD in this group of patients. Patient and graft survival of both organs remained at 100% to the end of the study period, although a direct correlation with the type of tacrolimus preparation in SPK transplantation requires evaluation in an adequately powered clinical trial comparing the 2 products. Although we conclude that SPK transplant patients can be safely converted from Tac-BD to Tac-QD without a negative clinical impact, we acknowledge that conversion
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