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Proliferation Signal Inhibitors After Lung Transplantation


Steven Ivulich, PharmD
Alfred Hospital, Melbourne, Australia

Jennifer Iuppa, PharmD
Barnes-Jewish Hospital, St Louis, Missouri, USA

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The proliferation signal inhibitors (PSIs) or mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are two of the most recent immunosuppressants introduced for use in lung transplantation.1

The mechanism of action of PSIs is distinct from calcineurin inhibitors (CNIs), and complementary when utilized together.2,3 PSIs bind to the cytoplasmic protein FKBP-122, inhibiting a protein kinase, the mammalian target of rapamycin (mTOR). The mTOR is a key regulatory pathway for several biologic processes.4 Inhibition of mTOR results in blockade of T and B cell proliferation in response to cytokine signals.2

Sirolimus was the first PSI available for use, while everolimus was later introduced with improved bioavailability and a distinct pharmacokinetic profile. The half-life of everolimus is 28 hours, considerably shorter than sirolimus (62 hours), which allows for steady state to be achieved more rapidly (4 vs. 6 days).5 PSIs are oxidized by the hepatic CYP3A isoenzyme6,7 and are substrates of P-glycoprotein (p-gp), an intestinal efflux pump.8 Thus, significant drug interactions result with inhibitors or inducers of CYP3A and p-gp, such as azole antifungals.

Similar to CNIs, PSIs display a narrow therapeutic index.8,9 Target concentrations are dependent on many factors including time since transplant, number and severity of rejection and infection episodes, and concomitant immunosuppressants.7 When combined with CNIs, a trough should be targeted in the lower range of the therapeutic window.1 In the absence of a CNI, trough levels up to 12 ng/mL have been evaluated; however, higher troughs are associated with increased adverse effects with little incremental gain in efficacy.10

Major adverse effects that have limited the use of PSIs after lung transplantation include impaired wound healing, particularly of the bronchial anastomosis, and pneumonitis. PSIs are known to cause delayed wound healing as a result of their antiproliferative effects, and sirolimus has been associated with cases of bronchial anastomotic dehiscence.11,12,13 Historically, PSIs have not routinely been introduced before the third post-operative month unless the endobronchial anastomoses have healed. Sirolimus, and, less commonly, everolimus,14 have been associated with a non-infective pneumonitis in lung transplant recipients. This is characterized by bilateral alveolo-interstitial lung infiltrates.15 Treatment consists of drug discontinuation, and symptom resolution typically occurs within three months.16

Although PSIs do not directly affect glomerular filtration, they may cause histologic changes consistent with tubular toxicity.17 In acute renal failure, PSIs can inhibit full recovery of renal function by slowing glomerular healing. PSIs can also cause or worsen proteinuria; this effect may be explained by loss of the antiproteinuric effect of CNIs, interference with albumin reabsorption, or inhibitory effects on vascular endothelial growth factor.18 Other commonly reported side effects include dose-dependent reversible dyslipidemia (38-57%) and myelosuppression.19

Increasing data have supported the use of PSIs in kidney and heart transplantation, but there remains a lack of strong clinical data in lung transplantation. Early reports suggested that the antiproliferative effects of PSIs might be protective against the development of BOS20;21,22,23 however, this has not been borne out by definitive studies comparing rates of BOS in patients receiving everolimus compared to azathioprine (AZA) or mycophenolate mofetil (MMF).24,25 Today, PSIs are utilized in lung transplantation in patients with renal impairment attributed to CNIs or when other immunosuppressants are ineffective or contraindicated.6

PSI use in patients with renal impairment has evolved over time. Initially, PSIs were combined with CNIs to allow lower CNI exposure and to stabilize CNI-induced renal damage. Many trials, however, have shown no improvement in renal function after reduction of CNI exposure and have revealed additive nephrotoxicity with the combination.26 Today, many patients with CNI nephropathy are switched to a PSI alone or in combination with an antiproliferative agent.

Neurotoxicity attributed to CNIs is problematic, the manifestations of which range from simple tremors or headaches to encephalopathy and seizures. The PSIs are an alternative option when adverse effects persist despite CNI substitution or dose modification. Both PSIs cross the blood brain barrier27; however, neurotoxicity has not yet been reported with their use.

The incidence of cytomegalovirus (CMV) infection is significantly less in patients treated with PSIs as compared to MMF or AZA.4,28,29,30 Given the detrimental effects of CMV infection on morbidity and long term outcomes in lung transplantation, this is a distinct advantage for PSIs.

The role of PSIs in lung transplantation has yet to be specifically defined. Compared to CNIs, the PSIs offer therapeutic advantages that can be useful in some recipients - relatively less nephrotoxicity, neurotoxicity, and a lower predilection to CMV infection. Their use, however, has not demonstrated improved survival and further evaluation is required to define their role in therapy.31

Disclosure Statement: The authors have no conflicts of interest to disclose.

References:

  1. Parada MT, Alba A, Sepulveda C, et al. Long-term use of everolimus in lung transplant patients. Transplant Proc 2011; 43(6):2313-15.
  2. Monchaud C, Marguet P. Pharmacokinetic optimization of immunosuppressive therapy in thoracic transplantation: part II. Clin Pharmacokinet 2009; 48(8):489-516.
  3. McAlister VC, Peltekian KM, Malatjalian DA, et al. Orthotopic liver transplantation using low-dose tacrolimus and sirolimus. Liver Transpl 2001; 7(8):701-8.
  4. Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005; 17(6):596-603.
  5. Koch M. Everolimus in liver and lung transplantation. Drugs Today (Barc) 2009; 45(1):11-20.
  6. Kahan BD, Keown P, Levy GA et al. Therapeutic drug monitoring of immunosuppressant drugs in clinical practice. Clin Ther 2002 Mar; 24 (3): 330-50.
  7. Briffa N, Morris RE. New immunosuppressive regimens in lung transplantation. Eur Respir J 1997; 10(11):2630-7.
  8. Kirchner GI, Meier-Wiedenbach I, Manns MP. Clinical pharmacokinetics of everolimus. Clin Pharmacokinet 2004; 43(2):83-95.
  9. Mabasa VH, Ensom MH. The role of therapeutic drug monitoring of everolimus in solid organ transplantation. Ther Drug Monit 2005; 27(5):666-76.
  10. Kovarik JM, Snell GI, Valentine V, et al. Everolimus in pulmonary transplantation: pharmacokinetics and exposure-response relationships. J Heart Lung Transplant 2006; 25(4):440-6.
  11. King-Biggs MB, Dunitz JM, Park SJ, et al. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation 2003; 75(9):1437-43.
  12. Groetzner J, Kur F, Spelsberg F, et al. Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression. J Heart Lung Transplant 2004; 23(5):632-8.
  13. Zuckermann A, Manito N, Epailly E, et al. Multidisciplinary insights on clinical guidance for the use of proliferation signal inhibitors in heart transplantation. J Heart Lung Transplant 2008; 27(2):141-9.
  14. Bouvier G, Cellerin L, Henry B, et al. Everolimus associated interstitial pneumonitis: 3 case reports. Respiratory Medicine CME 2009; 2(4):181-4.
  15. Pham PT, Pham PC, Danovitch GM, et al. Sirolimus-associated pulmonary toxicity. Transplantation 2004; 77(8):1215-20.
  16. McWilliams TJ, Levvey BJ, Russell PA, et al. Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation. J Heart Lung Transplant 2003; 22:210-3.
  17. Thliveris JA, Yatscoff RW. Effect of rapamycin on morphological and functional parameters in the kidney of the rabbit. Transplantation 1995; 59(3):427-9.
  18. Vogelbacher R, Wittman S, Braun A, et al. The mTOR inhibitor everolimus induces proteinuria and renal deterioration in the remnant kidney model in the rat. Transplantation 2007; 84(11):1492-9.
  19. Hoogeveen RC, Ballantyne CM, Pownall HJ, et al. Effect of sirolimus on the metabolism of apoB100-containing lipoproteins in renal transplant patients. Transplantation 2001; 72(7):1244-50.
  20. Snell GI, Levvey BJ, Chin W, et al. Rescue therapy: a role for sirolimus in lung and heart transplant recipients. Transplant Proc 2001; 33(1-2):1084-5.
  21. Cahill BC, Somerville KT, Cromptonn JA, et al. Early experience with sirolimus in lung transplant recipients with chronic allograft rejection. J Heart Lung Transplant 2003; 22(2):169-76.
  22. Hernandez RL, Gil PU, Gallo CG, et al. Rapamycin in lung transplantation. Transplant Proc 2005; 37(9):3999-4000.
  23. Villanueva J, Boukhamseen A, Bhorade SM. Successful use in lung transplantation of an immunosuppressive regimen aimed at reducing target blood levels of sirolimus and tacrolimus. J Heart and Lung Transplant 2005; 24(4):421-5.
  24. Snell GI, Valentine VG, Vitulo P, et al. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. Am J Transplant 2006; 6(1):169-77.
  25. Glanville AR, Aboyoun CL, Klepetko W, et al. 1-year results of the CeMyLungs study, a 3-year randomized, open label, multi-centre investigator driven study comparing de novo enteric coated mycophenolate sodium with delayed onset everolimus, both arms in combination with cyclosporine (using C2 monitoring) and corticosteroids for the prevention of the bronchiolitis obliterans syndrome in heart-lung, bilateral lung and single lung transplant recipients. J Heart and Lung Transplant 2010; 29(2):S94.
  26. Podder H, Stepkowski SM, Napoli KL, et al. Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations. J Am Soc Nephrol 2001; 12(5):1059-71.
  27. Schwartz RB, Bravo SM, Klufas RA, et al. Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. AJR Am J Roentgenol 1995; 165(3):627-31.
  28. Bhorade S, Ahya VN, Baz MA, et al. Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation. Am J Respir Crit Care Med 2001;183(3):379-87.
  29. Lorber MI, Mulgaonkar S, Butt KM, et al. Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study. Transplantation 2005; 80(2):244-52.
  30. Vigano M, Tuzco M, Benza R, et al. Prevention of acute rejection and allograft vasculopathy by everolimus in cardiac transplant recipients: a 24-month analysis. J Heart Lung Transplant 2007; 26(6):584-92.
  31. Snell GI, Westall GP. Immunosuppression for lung transplantation: evidence to date. Drugs 2007; 67(11):1531-9.