Immunosuppression Dosing in Obese Solid Organ Transplant Recipients

B. Andrew Mardis, Caitlin R. Mardis, and Nicole A. Pilch

Introduction

As with the general population, the rates of obesity among transplant recipients continue to increase, and some patients continue to gain weight following transplantation.^1-11 Across organ transplantation, the contraindicated body mass index (BMI) limits are being increased.^12-15 Armstrong and colleagues describe a multifactorial etiology of obesity following kidney transplant due to a sedentary lifestyle during recovery from chronic renal failure and the transplant event, negative metabolic effects of high dose steroids, and baseline obesity prior to transplantation.¹⁶ In addition to the effects of obesity on the pharmacokinetics and dynamics of immunosuppressant medications, obesity has significant effects on the management and outcomes of this critical population.

The impact of obesity and its sequelae have been well documented in kidney transplantation. In 1999 and 2002, Meier-Kriesche and colleagues described the impact of increased BMI on the relative risk of death-censored graft loss and chronic allograft nephropathy.^17,18 Post-transplant hypertension, dyslipidemia, insulin resistance, and diabetes are all prevalent among obese kidney transplant recipients, and these various components of the metabolic syndrome have made cardiovascular disease the primary cause of death with a functioning graft for this patient population.^16,19 Obese kidney transplant patients are also at a risk for surgical site infections, wound complications, delayed graft function, and decreased graft survival, while patients who are extremely obese may even be at risk for decreased overall survival.^17,20-24

With the increase in prevalence of transplantation for nonalcoholic fatty liver disease, liver transplant recipients may become, on average, the most obese of all transplant recipients. However, it should be noted that obesity as determined by standard measures such as BMI can complicate the study of the prevalence and risk of obesity in this patient population, as BMI may overestimate obesity given significant levels of ascites.^11,25 The impact of obesity on graft and patient survival outcomes following liver transplantation remains unclear. An evaluation of over 18,000 liver transplant recipients in the United Network of Organ Sharing (UNOS) database in 2002 showed that morbidly obese patients had higher rates of primary graft nonfunction—30-day, 1-year, and 2-year mortality—while both severely and morbidly obese patients had significantly higher 5-year mortality.²⁶ Leonard and colleagues at the Mayo Clinic reported no differences in survival based on BMI if a corrected BMI was used following ascites removal.¹¹ More recently, a meta-analysis performed by Saab and colleagues demonstrated that there was no difference in mortality between control and increased weight patients even when stratified by BMI and accounting for ascites.²⁷ However, they did see worse survival in obese patients when pooling studies evaluating similar causes of liver disease. Both pre- and post-transplant obesity have been tied to increased cardiovascular risks for those receiving a liver transplant.^25,26,28 Also, obesity in the liver transplant population has been associated with increased perioperative complications, increased wound infections, and increased hospital length of stay as well as costs at the time of transplantation.^26,29

The most recent listing criteria published by the International Society of Heart and Lung Transplantation (ISHLT) for heart transplant candidates recommend candidates achieve a BMI <30 kg/m² or weigh <140% of their ideal body weight (IBW) before being listed for cardiac transplantation to limit the poor outcomes previously reported.^30-32 Subsequently, Russo and colleagues evaluated nearly 20,000 heart transplant recipients through the UNOS database. They found similar risk-adjusted median survival when comparing underweight, normal weight, overweight, obesity I, and obesity II/III patients; however, BMI in the underweight and obesity II/III groups was associated with decreased survival in multivariate Cox proportional hazard regression analysis, as was similarly seen by Grady and colleagues.^33,34 These results potentially suggest that obese I patients are acceptable candidates for transplantation, although another UNOS database review in 2012 showed increased mortality for patients with a BMI 30 kg/m² or greater.³⁵ Nonetheless, obese patients wait for donor organs longer and are less likely to receive an organ as compared to nonobese patients waiting for heart transplantation.⁹ Following transplantation, obesity continues to be common and is linked to cardiovascular disease in the graft and possible chronic allograft vasculopathy, which can lead to both fatal and nonfatal cardiac events.^36,37

ISHLT recommends a BMI >30 kg/m² as a relative contraindication for lung transplantation, although many transplant centers make this an absolute contraindication due to reports suggesting up to a three-fold increase in post-transplant mortality in obese patients.^12,15,38 To assess the effect of obesity at the time of transplantation, Allen and colleagues performed an analysis of the UNOS database including over 11,000 patients who received a lung transplant between 1987 to 2008. Overweight and obese patients had lower survival than did normal-weight patients, and BMI strata continued to be predictive of mortality after risk adjustment in multivariate analysis. When first-year deaths were removed, this difference was no longer present suggesting that overweight and obese patients have a higher degree of early mortality.⁷ However, a similar analysis of lung transplants in the United States between 2005 and 2011 after the implementation of the lung allocation score/based organ allocation system demonstrated that mortality nearly doubles at 1 year in patients with a BMI >35 kg/m². Notably, a BMI between 30 and 34.99 kg/m² was not associated with an increased risk in 1-year mortality, potentially suggesting the relative success of transplanting obese I patients.¹² Furthermore, obesity at the time of transplant can increase the risk of primary graft dysfunction and early post-transplant death.³⁹ Clinicians can potentially reverse the negative effects of obesity by promoting weight loss to lung transplant candidates, because data from the Mayo Clinic suggest obese patients who decrease their BMI by one unit reduce their risk of death by over 10%.⁴⁰

Polyclonal and Monoclonal Antibodies

Rabbit Anti-thymocyte Globulin (Thymoglobulin)

Rabbit anti-thymocyte globulin (rATG) is a purified, pasteurized, and polyclonal gamma immunoglobulin created through immunizing rabbits with human lymphocytes. The preparation of cytotoxic antibodies produces profound immunosuppression through direct action against a host of surface antigens of T-lymphocytes, which subsequently leads to opsonization, phagocytosis, cell lysis, and reticuloendothelial removal. rATG is FDA approved for the treatment of renal transplant acute rejection when used with concomitant immunosuppression; however, it is the most common agent used for induction immunosuppression in kidney transplantation and is used in approximately 10% to 20% of liver, heart, and lung transplantations.^10,41-44 The labeled dosage for rATG in the treatment of acute renal graft rejection is 1.5 mg/kg of body weight administered daily for 7 to 14 days with dosage reductions or omissions for severe leukopenia and/or thrombocytopenia.⁴⁴ When used off-label for induction immunosuppression, there is no globally accepted dosing regimen, but dosing for this indication can range from 1 to 4 mg/kg/day for 3 to 10 days.⁴⁵ Often in practice, doses are rounded to the nearest 25 mg given the commercially available vial sizes. The manufacturer uses total body weight (TBW) for dosing recommendations.⁴⁴

Tsapepas and colleagues hypothesized that small rATG dose changes due to dose rounding and/or capping doses at 150 mg would negatively affect rejection-free graft survival in a patient population that included high-immunologic-risk kidney recipients.⁴⁶ They evaluated patients receiving rATG induction therapy (1.5 mg/kg of TBW × four doses with a cumulative dose target of 6 mg/kg with each dose rounded to the nearest 25 mg and limited to 150 mg), rapid steroid withdrawal, and modern maintenance immunosuppression. Patients were grouped based on cumulative rATG dose: 5 to 6 mg/kg or 6 mg/kg or more. Additionally, a cumulative dose of 6 mg/kg or more was protective of acute rejection in multivariate logistic regression when controlling for known risk factors for rejection. They concluded that doses should be rounded up to the nearest 25 mg, and larger patients should receive additional doses if necessary to achieve target center protocol doses.

Outside of solid organ transplantation, the American Society for Blood and Marrow Transplantation Practice Guideline Committee recommends dosing based on TBW because no data support deviating from the manufacturer’s recommendations.⁴⁷

Helpful Tips

•Center-specific protocols and patient-specific characteristics generally dictate dosing for induction immunosuppression or treatment of rejection.

•Infusion-related reactions, including anaphylaxis, regarding cytokine release are possible. Patients should be premedicated with acetaminophen and antihistamines.

Summary

•rATG should be dosed using TBW per the manufacturer’s recommendations.

Basiliximab

Basiliximab is a chimeric (70% human/30% murine) monoclonal antibody that antagonistically binds with high affinity to the alpha subunit of the IL-2 receptor (CD25) on activated T-lymphocytes to prevent T-cell activation and proliferation.⁴⁸ Basiliximab is FDA approved for the prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of an immunosuppressive regimen that includes cyclosporine (modified) and corticosteroids.⁴⁸ Although consensus recommendations do not yet exist, the off-label use of basiliximab in heart, lung, and liver transplantation for induction immunosuppression has been described.^49-56 Of note, the labeling states that no clinically relevant impact from body weight or gender on volume of distribution (V_d) or clearance (Cl) has been observed for this hydrophilic agent.⁴⁸

Helpful Tips

•The optimal role of basiliximab is not known across all organ types, and the specifics of its use are mostly center specific.

Summary

•Dosing should be based on TBW and whether the patient is greater than or less than 35 kg according to the manufacturer’s labeling.

Calcineurin Inhibitors

Cyclosporine

Cyclosporine inhibits calcineurin phosphatase by creating a complex with the cytoplasmic protein cyclophilin, which ultimately inhibits T-cell activation and expansion. Cyclosporine is FDA approved for prophylaxis of organ rejection in kidney, liver, and heart allogenic transplantation, rheumatoid arthritis, and psoriasis, and is commercially available as three products: Sandimmune, Neoral (modified), and Gengraf (modified).^57-59

Cyclosporine is notorious for its pharmacokinetic and pharmacodynamics properties. With oral administration, there is incomplete absorption of cyclosporine with the true bioavailability dependent on multiple patient- and drug-specific factors. It is metabolized extensively by the liver without a specific major pathway. The parent drug is responsible for the majority of its immunosuppressive effects. Its primary elimination occurs through the biliary system and follows a generally biphasic pattern.^57-60

Sandimmune is a nonmodified, oil-based preparation of cyclosporine with incomplete and variable bile-dependent absorption resulting in an absolute bioavailability of 30% for the oral solution and capsules with a range from <10% in liver transplant recipients up to 89% in kidney transplant recipients.^58,59 To improve the consistency of the pharmacokinetic profile, the modified microemulsion product Neoral was subsequently developed followed by the branded generic Gengraf.⁶⁰ For the modified products, a mean cyclosporine area under the concentration curve (AUC) increase of 20% to 50% and peak blood concentration (C_max) of 40% to 106% has been seen over Sandimmune.⁵⁹

This high level of intra- and interpatient variability highlights the need for therapeutic drug monitoring via trough level or AUC.^61-63 There are many factors besides obesity to consider—such as whether trough or C₂ serum levels are used for monitoring, the type of organ transplanted, the immunologic risk of the specific patient, subsequent additional immunosuppression, and the method to measure blood levels—and these patients should be monitored in association with a provider specialized in systemic immunosuppressive therapy.

The impact of body weight on cyclosporine dosing in organ transplantation was first described in 1989 by Flechner and colleagues who showed through pharmacokinetic analysis that there is no difference in bioavailability, elimination half-life, Cl, or steady-state V_d between obese (>125% IBW) and nonobese patients.⁶⁴ They recommended that IBW be used for dosing to obtain comparable early transplant drug concentrations. Others subsequently confirmed their hypothesis by demonstrating that overweight and obese patients required lower daily doses reaching comparable whole blood levels.^65,66 In 1998, Flechner’s group extended their conclusion to include morbidly obese patients when they reported the case of a 511-pound kidney transplant recipient who required relatively very low doses of cyclosporine to maintain therapeutic levels.⁶⁷

Outside of solid organ transplantation, Shibata and colleagues have reported that obesity in patients receiving cyclosporine for psoriasis should be considered when determining dosing regimens due to an increase in trough levels seen with the same mg/kg dosage as obesity index increases.⁶⁸ Additionally, Wu and Furlanut reported the use of intravenous (IV) cyclosporine in hematologic patients and found that the use of TBW was a better predictor of steady-state and poststeady-state blood concentrations, while lean body weight was suggested as a better presteady-state predictor for dosing.⁶⁹

Helpful Tips

•Dosing should be individualized based on center protocols taking patient, drug, and lab specifics into consideration.

•Cyclosporine products are not bioequivalent and should not be used interchangeably.

Summary

•IBW should be used to dose cyclosporine based on multiple small studies and case reports.

Tacrolimus

Tacrolimus binds to FK-binding protein 12, a different cytoplasmic protein from cyclosporine, to create a complex that inhibits translocation of nuclear factor of activated T-cells and the subsequent production of cytokines and T-cell activation and proliferation.^60,70,71 Tacrolimus is used for the prophylaxis of organ rejection following kidney, liver, and heart transplantation as well as prevention of graft-versus-host disease in allogeneic stem cell transplant recipients in combination with other medications. Similar to cyclosporine, tacrolimus dosing is complicated by significant inter- and intrapatient pharmacokinetic variability. Tacrolimus oral dosing recommendations are based on the organ transplanted, concomitant immunosuppressive agents, and whole blood trough concentrations.

As with cyclosporine, body weight has the potential to influence tacrolimus pharmacokinetics and subsequent dosing. A retrospective review of Japanese kidney transplant recipients demonstrated that 17 overweight and obese patients (BMI ≥25 kg/m²) required a statistically significant 33% lower weight-adjusted tacrolimus dose to obtain goal trough concentrations than did patients with normal weight.⁷² Based on subsequent animal modeling, the authors hypothesized that the V_d at steady state in obese individuals may be reduced due to increased lipoprotein concentrations that increase the plasma protein binding opportunities of tacrolimus and decrease its unbound free fraction. Additionally, they suggested an increase in tacrolimus bioavailability given decreased P-glycoprotein activity in the small intestines of the obese animals. The grouping of overweight and obese patients into one category, however, does limit the applicability of this data.

Rodrigo and colleagues reported a single-center experience of patients with higher BMIs having an increased risk for elevated first tacrolimus trough concentrations in spite of receiving the same weight-adjusted tacrolimus dosing.⁷³ BMI was shown to be a significant risk factor for elevated initial tacrolimus blood levels, so the authors recommended lower initial tacrolimus dosing in overweight transplant recipients or estimating tacrolimus doses based on IBW.

In an analysis to examine factors affecting tacrolimus dosing requirements, Stratta and colleagues divided a cohort of kidney transplant patients into four groups based on their concentration/dose (C/D) ratio ranging from very slow to very fast tacrolimus metabolizers.⁷⁴ Patients with higher BMIs were most frequently associated with the subgroup of very slow metabolizers and had a higher C/D ratio. These results may be interpreted to suggest that patients with higher BMIs would be more likely to achieve appropriate tacrolimus trough concentrations if they received dosing less than the recommended mg/kg dose or if they were dosed based on their IBW or adjusted body weight.

Although not specifically noted in the literature as cyclosporine, there may be benefit to dosing tacrolimus based on either an IBW or adjusted body weight in overweight or obese patients. Regardless of which body weight is used, tacrolimus therapeutic drug monitoring should be employed to achieve appropriate trough concentrations as determined by patient-specific factors and center protocols.

Helpful Tips

•Similar to cyclosporine, tacrolimus should be dose adjusted to achieve therapeutic trough concentrations as determined by patient-specific factors such as immunologic risk and concomitant immunosuppression as well as center-specific protocols.

Summary

•No definitive evidence and consensus exist regarding which body weight to use when dosing tacrolimus; however, several reports suggest that overweight and obese patients may not need full mg/kg doses at their TBW.

Antiproliferative Agents

Mycophenolate Mofetil and Mycophenolate Sodium

Mycophenolic acid (MPA) is a selective, reversible, noncompetitive inhibitor of inosine monophosphate dehydrogenase that inhibits the proliferation of monocytes and lymphocytes. Furthermore, MPA impairs the proliferation of B- and T-lymphocytes as well as the humoral immune response of B-lymphocytes. Mycophenolate mofetil is a prodrug of MPA, which is rapidly hydrolyzed to the active MPA, and was developed to improve bioavailability.^60,71,75-78 Subsequently, mycophenolate sodium, an enteric-coated sodium salt of MPA, was created with the aim of minimizing the gastrointestinal side effects of mycophenolate mofetil.⁷⁹ Mycophenolate products have largely replaced azathioprine as the antiproliferative agent of choice in post-transplant immunosuppression regimens across all organs given a decreased risk of malignancy and superior protection from acute rejection, although some conflicting data exist.^10,60,80-82

Both mycophenolate products have a recommendation for a fixed-dose dosing strategy rather than weight-based in adult patients and dosing based on body surface area doses for pediatric patients.^75,76 Higher doses of mycophenolate mofetil were shown in clinical trials to be safe and effective in kidney transplant recipients, although there was no benefit in efficacy, and a daily dose of 2 g was found safer than 3 g.^75,83-85

Nonetheless, the correlation of MPA concentrations to safety and efficacy of mycophenolate mofetil—a complex pharmacokinetic profile—and the high levels of interpatient variability of MPA exposure call into question this fixed-dose model for mycophenolate mofetil and mycophenolate sodium, and some data suggest that extremes in body weight contribute to this variability.^80,86-90 Yau and colleagues sought to determine the optimal mycophenolate mofetil dose in an Asian kidney transplant population with widely varying body weights up to 108 kg who were concomitantly receiving cyclosporine and corticosteroids. MPA exposure expressed as AUC demonstrated a weak correlation with TBW-adjusted mycophenolate mofetil dose, and this correlation became stronger when outlying data points were removed. The authors estimated through their regression analysis that a dose of 5 to 15 mg/kg TBW twice daily attained the recommended MPA AUC₂₄ (30 to 60 mg × hr/L).^89,91

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