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Modigraf Administration Through Jejunostomy in Liver Transplant Recipient: Case Report
Modigraf Administration Through Jejunostomy in Liver Transplant Recipient: Case Report V. Camacho Marente, L.M. Marin Gomez, J. Gracia Martinez, C. Bernal-Bellido, G. Suárez-Artacho, J.M. Álamo-Martínez, L. Barrera-Pulido, J. Serrano-Díaz-Canedo, F.J. Padillo-Ruiz, and M.A. Gómez-Bravo ABSTRACT We report our experience with a 61-year-old patient with alcoholic and hepatitis C cirrhosis who underwent liver transplantation. On the 3rd postoperative day he presented a mediastinitis secondary to esophageal perforation produced by a Linton tube. An esophagectomy with jejunostomy was performed. Tacrolimus granules for oral suspension (Modigraf) were administered through the jejunostomy. This case report highlights the use of Modigraf and the absence of secondary effects. We observed biochemical parameters during the jejunostomy period. We discuss the administration strategy applied and whether tacrolimus granules for oral suspension by jejunostomy affect the bioavailability and its side effects.
T
HE ABSOLUTE bioavailability and a large variability in the rate of absorption of orally administered tacrolimus (FK506) has been previously reported.1 It is absorbed mainly from the duodenum through the upper jejunum.2 The rate of absorption of tacrolimus is variable, with peak blood or plasma concentrations being reached in 0.5-6 hours; w25% of the oral dose is bioavailable. There are 3 oral presentations: Prograf oral for 12 hours, Advagraf long-acting tablets, and Modigraf granules for oral suspension, which is the presentation given in children or patients with swallowing problems.
during the stay. The dose and blood level of tacrolimus were analyzed at different time points after liver transplantation. The creatinine ranges were monitored, with an isolated incident of an increase in creatinine levels (1.26 mg/dL) in blood drug levels of 8.3 ng/mL, without clinical relevance. Liver enzyme levels were
CASE REPORT We report the case of a 61-year-old man, with alcoholic cirrhosis and hepatocellular carcinoma, engrafted in segment 3 (4 cm). Transplantation was indicated. During implantation, he had massive hematemesis requiring placement of a Linton tube which satisfactorily controlled the bleeding. On the 3rd postoperative day the patient experienced a worsening general condition, with fever and dyspnea. An esophageal perforation was diagnosed (Fig. 1). Emergency esophagectomy, jejunostomy, and esophagostomy were performed. There were no postoperative complications. After the transplantation, immunosuppression was begun, with tacrolimus in triple therapy (with mycophenolate mofetil and prednisone). We chose Modigraf (tacrolimus monohydrate oral suspension; Astellas Pharma, United Kingdom) delivered through the jejunostomy. Our strategy for antirejection treatment was to adjust the dose of triple therapy to maintain the optimum levels if the trough level was low. Initially, we prescribed Modigraf at 4 mg/12 h through the jejunostomy. Plasma levels of tacrolimus (7e10 ng/mL) were constant
Fig 1. Distal esophageal perforation and mediastinitis.
From the Hepatobiliopancreatic Surgery Unit, General and Digestive Surgery, Virgen del Rocío University Hospitals, Seville, Spain. Address reprint requests to Violeta Camacho Marente, C/Bami 14 B2 5 B, 41013, Sevilla, España. E-mail: violeta. [email protected]
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.09.018
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3670
Transplantation Proceedings, 45, 3670e3671 (2013)
MODIGRAF ADMINISTRATION THROUGH JEJUNOSTOMY also monitored to detect a possible graft rejection, with no episode of rejection and enzymes levels remaining constant. We can therefore state that Modigraf by jejunostomy is a safe alternative in such a patient. In the following 11 months there were no featured incidents, except for requiring progressively decreasing dosages to 2.6 mg/12 h to keep levels at 3e5 ng/mL. Corticosteroids were withdrawn at 6 months after transplantation. He underwent surgery 1 year later for digestive tract reconstruction by retrosternal gastroplasty and esophageal-gastric sleeve anastomosis. During the postoperative period he developed a cervical fistula. We retained the jejunostomy.
DISCUSSION
Analysis of previously published animal studies3 and human case reports4e6 suggests that administration through a jejunostomy may be more appropriate and cost effective. Preuss et al showed that the administration of tacrolimus by the oral route in a patient with jejunostomy necessitates increasing the doses by 2- or 4-fold over those administered before.7 Hasewaga et al. in a similar case, observed a decrease in the bioavailability in the presence of a jejunostomy, and the dose required before the closure was 2.3e2.7 times the dose required after the closure.8 We maintained the initial doses, making the 1:1 conversion, without increasing subsequent doses. In our case, the direct administration of tacrolimus formulation into the intestinal lumen through a jejunostomy
3671
had no impact on kidney or liver biochemistry, and drug levels were constant. In conclusion, the administration of Modigraf in the jejunal lumen directly through a jejunostomy can be an effective and safe alternative in liver transplant patients. REFERENCES 1. Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995;29: 404e430. 2. Wallemacq PE, Furlan V, Mollet A, et al. Pharmacokinetics of tacrolimus (FK 506) in paediatric liver transplant recipients. Eur J Drug Metab Pharmacokinet. 1998;23:367e370. 3. Kagayama A, Tanimoto S, Fujisaki J, et al. Oral absorption of FK506 in rats. Pharmacol Res. 1993;10:1446e1450. 4. Busuttil RW, Klintmalm CBG, Lake JR, et al. General guidelines for the use of tacrolimus in adult liver transplant patients. Transplantation. 1996;61:845e847. 5. Thielke J, Martin J, Eeber FL, et al. Pharmacokinetics of tacrolimus and cyclosporine in short- bowel syndrome. Liver Transpl Surg. 1998;4:432e434. 6. Novelli M, Muiesan P, Mieli Vergani G, et al. Oral absorption of tacrolimus in children with intestinal failure due to short or absent small bowel. Transplant Int. 1999;12:463e465. 7. Preuss J, Gazon M, Mabrut J-Y, et al. Tacrolimus trough levels before, during and after jejunostomy in a liver transplant patient: a case report. Clin Res Hepatol Gastroenterol. 2012;36: 126e130. 8. Hasewaga T, Nara K, Kimura T, et al. Oral administration of tacrolimus in the presence of jejunostomy after liver transplantation. Pediatr Transplant. 2001;5:204e209.
T
HE ABSOLUTE bioavailability and a large variability in the rate of absorption of orally administered tacrolimus (FK506) has been previously reported.1 It is absorbed mainly from the duodenum through the upper jejunum.2 The rate of absorption of tacrolimus is variable, with peak blood or plasma concentrations being reached in 0.5-6 hours; w25% of the oral dose is bioavailable. There are 3 oral presentations: Prograf oral for 12 hours, Advagraf long-acting tablets, and Modigraf granules for oral suspension, which is the presentation given in children or patients with swallowing problems.
during the stay. The dose and blood level of tacrolimus were analyzed at different time points after liver transplantation. The creatinine ranges were monitored, with an isolated incident of an increase in creatinine levels (1.26 mg/dL) in blood drug levels of 8.3 ng/mL, without clinical relevance. Liver enzyme levels were
CASE REPORT We report the case of a 61-year-old man, with alcoholic cirrhosis and hepatocellular carcinoma, engrafted in segment 3 (4 cm). Transplantation was indicated. During implantation, he had massive hematemesis requiring placement of a Linton tube which satisfactorily controlled the bleeding. On the 3rd postoperative day the patient experienced a worsening general condition, with fever and dyspnea. An esophageal perforation was diagnosed (Fig. 1). Emergency esophagectomy, jejunostomy, and esophagostomy were performed. There were no postoperative complications. After the transplantation, immunosuppression was begun, with tacrolimus in triple therapy (with mycophenolate mofetil and prednisone). We chose Modigraf (tacrolimus monohydrate oral suspension; Astellas Pharma, United Kingdom) delivered through the jejunostomy. Our strategy for antirejection treatment was to adjust the dose of triple therapy to maintain the optimum levels if the trough level was low. Initially, we prescribed Modigraf at 4 mg/12 h through the jejunostomy. Plasma levels of tacrolimus (7e10 ng/mL) were constant
Fig 1. Distal esophageal perforation and mediastinitis.
From the Hepatobiliopancreatic Surgery Unit, General and Digestive Surgery, Virgen del Rocío University Hospitals, Seville, Spain. Address reprint requests to Violeta Camacho Marente, C/Bami 14 B2 5 B, 41013, Sevilla, España. E-mail: violeta. [email protected]
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.09.018
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3670
Transplantation Proceedings, 45, 3670e3671 (2013)
MODIGRAF ADMINISTRATION THROUGH JEJUNOSTOMY also monitored to detect a possible graft rejection, with no episode of rejection and enzymes levels remaining constant. We can therefore state that Modigraf by jejunostomy is a safe alternative in such a patient. In the following 11 months there were no featured incidents, except for requiring progressively decreasing dosages to 2.6 mg/12 h to keep levels at 3e5 ng/mL. Corticosteroids were withdrawn at 6 months after transplantation. He underwent surgery 1 year later for digestive tract reconstruction by retrosternal gastroplasty and esophageal-gastric sleeve anastomosis. During the postoperative period he developed a cervical fistula. We retained the jejunostomy.
DISCUSSION
Analysis of previously published animal studies3 and human case reports4e6 suggests that administration through a jejunostomy may be more appropriate and cost effective. Preuss et al showed that the administration of tacrolimus by the oral route in a patient with jejunostomy necessitates increasing the doses by 2- or 4-fold over those administered before.7 Hasewaga et al. in a similar case, observed a decrease in the bioavailability in the presence of a jejunostomy, and the dose required before the closure was 2.3e2.7 times the dose required after the closure.8 We maintained the initial doses, making the 1:1 conversion, without increasing subsequent doses. In our case, the direct administration of tacrolimus formulation into the intestinal lumen through a jejunostomy
3671
had no impact on kidney or liver biochemistry, and drug levels were constant. In conclusion, the administration of Modigraf in the jejunal lumen directly through a jejunostomy can be an effective and safe alternative in liver transplant patients. REFERENCES 1. Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995;29: 404e430. 2. Wallemacq PE, Furlan V, Mollet A, et al. Pharmacokinetics of tacrolimus (FK 506) in paediatric liver transplant recipients. Eur J Drug Metab Pharmacokinet. 1998;23:367e370. 3. Kagayama A, Tanimoto S, Fujisaki J, et al. Oral absorption of FK506 in rats. Pharmacol Res. 1993;10:1446e1450. 4. Busuttil RW, Klintmalm CBG, Lake JR, et al. General guidelines for the use of tacrolimus in adult liver transplant patients. Transplantation. 1996;61:845e847. 5. Thielke J, Martin J, Eeber FL, et al. Pharmacokinetics of tacrolimus and cyclosporine in short- bowel syndrome. Liver Transpl Surg. 1998;4:432e434. 6. Novelli M, Muiesan P, Mieli Vergani G, et al. Oral absorption of tacrolimus in children with intestinal failure due to short or absent small bowel. Transplant Int. 1999;12:463e465. 7. Preuss J, Gazon M, Mabrut J-Y, et al. Tacrolimus trough levels before, during and after jejunostomy in a liver transplant patient: a case report. Clin Res Hepatol Gastroenterol. 2012;36: 126e130. 8. Hasewaga T, Nara K, Kimura T, et al. Oral administration of tacrolimus in the presence of jejunostomy after liver transplantation. Pediatr Transplant. 2001;5:204e209.