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Paradoxical Cyclosporine A Requirements in Pediatric Renal Transplants Receiving High-Dose Steroids

From the Department of Pediatrics, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia (Dr Crocker, Ms McLellan, Dr Goralski, Dr Acott); Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia (Dr Goralski, Dr Renton, Dr Acott); and Queen's University School of Medicine, Kingston, Ontario (Ms Hardy).

Address for reprints: Dr Philip D. Acott, Department of Pediatrics, IWK Health Centre, Halifax, 5850/5980 University Avenue, P.O. Box 3070, Halifax, Nova Scotia, B3J 3G9, Canada.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
The potent immunosuppressant cyclosporine A (CyA) is a mainstay of treatment in the renal transplant population. During episodes of acute allograft rejection, therapy also includes the pulse administration of high-dose steroids such as prednisone or methylprednisolone. Both steroids and CyA are metabolized by the CYP3A4 isoenzyme of the cytochrome P450 catalytic system. On a theoretical basis, high steroid concentrations during a rejection episode could competitively inhibit CyA metabolism, increasing its systemic concentration and decreasing its dose requirements. A database was compiled consisting of pediatric patients who had undergone an acute renal rejection event during the years 1993 to 2003. The severity of rejection events, as well as the CyA and prednisone dosing regimens used during rejection, were assessed using a comprehensive chart analysis. The presence or absence of additional medications that could potentially interact with CyA was also examined. Although some patients responded in the predicted manner, the authors also found that a subgroup of pediatric patients placed on highdose pulse steroid therapy for acute graft rejection required increased amounts of CyA to maintain therapeutic concentrations. The authors recommend monitoring of patients on high-dose steroids for paradoxical CyA requirements intermittently during high-dose steroid treatment to individualize CyA therapy appropriately during renal allograft rejection and thereby maximize efficacy while minimizing potential toxic side effects of CyA such as under-immunosuppression and organ rejection.

Key Words: CyA • corticosteroid • pediatric • kidney • transplantation

Cyclosporine A has a narrow therapeutic index (TI) requiring therapeutic drug monitoring at regular intervals throughout treatment. Target trough therapeutic concentrations depend on the time since transplantation, ranging from 100 to 350 µg/L.³ Concentrations above the therapeutic range place the patient at an increased risk of toxicities, including hepatic and renal damage, whereas subtherapeutic concentrations are associated with under-immunosuppression and organ rejection.² Although there is significant variability in the immunosuppressive protocol used before rejection, treatment of acute rejection episodes has traditionally involved a high-dose pulse intravenous or oral corticosteroid administration⁴ in conjunction with maintenance CyA therapy.

Concurrent administration of potent medications such as steroids and CyA has the potential to increase the risk of adverse drug interactions as both corticosteroids and CyA are metabolized by cytochrome P450 3A4 (CYP3A4).^5,6 In addition, P-glycoprotein (PGP), ⁷ a multispecific drug efflux transporter protein located in the liver, blood-brain barrier, kidney, placenta, and intestine, ⁸ contributes to the overall pharmacokinetic behavior of the drug. P-glycoprotein is important in regulating the bioavailability of many therapeutic agents⁹ and has been predominantly examined in the modulation of chemotherapeutic regimens.¹⁰ For drugs with a narrow TI such as CyA, the potential for dangerous drug interactions is exacerbated if determinants of absorption/elimination (PGP) or metabolism (CYP3A4) are altered. Some studies have found that when CyA and steroids are coadministered, CyA concentrations increase, presumably the result of CYP3A4 competitive inhibition, ¹¹ whereas another study has found that high-dose methylprednisolone administration decreases CyA concentration, possibly by induction of CYP3A4 and increased hepatic metabolism.¹² The observations in our center were inconsistent, although the majority of patients' CyA levels decreased during high-dose steroid administration, necessitating a compensatory increase in dosing to maintain therapeutic concentrations, as measured by immunoassay. The purpose of this study was to investigate and characterize changes in CyA concentrations and dosing regimens in pediatric patients treated with high-dose steroids during acute allograft rejection. The role of patient characteristics, such as age, gender, and the presence of other medications in predicting altered CyA pharmacokinetics, was also examined.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Patient Population
Retrospective data on all pediatric renal transplant patients admitted to our center for acute rejection events from June 1993 until June 2003 were included in the study population. Fifty-seven episodes of acute rejection occurred in 32 individual patients; only the first acute rejection episode was used for assessment (n = 32). Acute allograft rejection was confirmed by renal biopsy and classified according to the Banff criteria.¹³ All patients received an oral formulation of CyA (Neoral; Novartis Pharmaceutical Ltd, Basel, Switzerland) and prednisone at the time of rejection. Patients receiving other formulations of CyA (eg, Sandimmune) or other calcineurin inhibitors (eg, FK-506) were excluded (n = 5). Patients who received high-dose steroids but not in a 3- or 4-day tapering cycle were not included in the analysis (n = 3). Table I summarizes the characteristics of the pediatric population examined (n = 24). Study protocols were based on a summary clinical review of patients in our care and were not part of any studies requiring investigational review board approval.

Immunosuppressive Protocol
At the time of rejection, all patients were receiving an oral maintenance formulation of CyA and were compliant with their medications prior to admission, as indicated by blood level monitoring. Prior to the acute rejection episode, whole-blood samples were obtained from patients at regular intervals to monitor cyclosporine levels. The interval between samples was shortest immediately posttransplant and progressively increased with time. In the immediate posttransplant period, CyA trough concentrations were assessed daily and maintained between 250 and 350 µg/L. After 6 months, the targeted trough levels of CyA were between 150 and 250 µg/L. During acute rejection episodes, daily blood samples were obtained in the morning before the first dose of CyA. Only trough CyA concentrations were assessed to ensure that the nadir of CyA levels fell within the therapeutic range. All patients in our center are initiated on tid daily dosing of Neoral, which is not changed to bid dosing until full pharmacokinetic profiles to assess drug clearance are obtained several months after transplantation, when they are stable on baseline drug therapy and alternate-day steroids. CyA concentrations were assessed using a specific monoclonal antibody radioimmunoassay (DiaSorin CYCLO-Trac SP-Whole Blood; DiaSorin, Stillwater, Minn).

High-dose pulse corticosteroids (prednisone or methylprenisolone) were used in conjunction with CyA maintenance therapy to treat acute rejection episodes. Initial steroid dosing of 500 mg/m²/d was administered intravenously (IV) or orally (PO), to a maximum of 500 mg per day. All results are presented as oral prednisone equivalent dosage, based on methylprednisolone being 80% the mg/mg potency of prednisone. Twenty-one patients were placed on an oral prednisone regimen, and 3 patients received IV methylprednisolone.

Statistical Analysis
The data presented in Figure 1 are shown as mean ± standard error. All other data, including Tables I, II, III, are presented as mean ± standard deviation. Multiple groups were compared using a straight regression multivariate analysis (GB-STAT v8.0; Dynamic Microsystems, Inc, Silver Spring, MD). The Kolmogorov-Smirnov test within GB-STAT was used for assessing normal distribution. Time of rejection was assigned as early (0-6 months after transplant) or late (>6 months after transplant). Nonparametric tests were used for all categories except age and CyA dosing. Statistical significance was defined as P < .05.

View larger version (30K): [in this window] [in a new window]   Figure 1. (a) Pulse steroid administration over time. Prednisone administration was increased to treat acute renal rejection within 24 to 36 hours of biopsy-proven rejection. Dosing was subsequently halved in 3- to 4-day increments over the course of 14 to 16 days to reach pretherapeutic levels. (b) CyA dose changes over time. CyA dosing routines were adjusted based on the daily trough concentration of CyA. Dose changes were analyzed as the percent change from the starting dose. (c) CyA dose changes. Patients were analyzed according to the pattern of CyA dose change exhibited during the course of the rejection episode. Patients who required increased doses of CyA during rejection were grouped together. The change in CyA dose on each day after biopsy was averaged (bold circles) and a line of best fit applied. Patients who did not require any changes in their CyA dosage and patients who required decreased dosages were also grouped together. The decrease in CyA dose daily postbiopsy was averaged (bold diamonds) and a line of best fit applied. Both lines were linear and approximately equal. The individual patient response to dosing is represented using dotted black lines. (d) Trough CyA concentration changes over time. The therapeutic concentration of CyA was maintained within the appropriate therapeutic range (250-350 µg/mL; solid lines), indicating that the adjustments in CyA dosing did not alter appropriate immunosuppression.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
This study reviewed 24 pediatric patients at the IWK Health Centre who had undergone renal transplantation and a subsequent acute allograft rejection episode during the years 1993 to 2003. Only first rejection episodes were assessed to avoid overrepresenting children who had had multiple rejection events or who had progressive organ damage. Patient characteristics are summarized in Table I. The patients ranged in age from 2 to 18 years (mean = 11.64, median = 12.49) and included comparable numbers of males and females. The timing of their first rejection episode after transplantation ranged from 10 days to 3 years (range, 10-1171 days; mean = 189 days, median = 58 days), and most allograft rejections were Banff grade I or mild (79.2%), with only 1 episode classified as severe (4.2%). At the time of rejection, all patients received CyA doses that sustained blood concentrations in a therapeutic range (based on the time since transplantation), with average daily doses of approximately 5 mg/kg given orally 3 times a day (5.36 ± 3.31 mg/kg/d PO tid). Patients were also receiving chronic oral prednisone therapy, with the concentration and choice of daily or alternate-day administration dependant on the time since transplantation and encouragement of optimal growth. Alternate-day steroids are preferred for optimal growth, except in the immediate 3 to 4 weeks post-transplant. Children who receive steroids on alternate days have been shown to grow better without any compromise in graft survival.¹⁴ Patients who were within 45 days of transplantation received daily prednisone (n = 4), and patients who were more than 45 days post-transplantation were placed on alternate-day prednisone (n = 20). The average prednisone dosage before rejection was 11.22 ± 8.56 mg/m² orally on alternate days.

Within 24 to 36 hours of biopsy-proven rejection, patients were given high-dose PO (n = 21) or IV (n = 3) pulse corticosteroids in addition to maintenance CyA therapy. The dose of steroid given over the acute rejection period (mg/m²) is shown in Figure 1a. After the initial high-dose period, the amount of prednisone given was halved in either 3- or 4-day increments such that by the end of 2 weeks, prednisone dosages were approaching prerejection values. CyA doses were altered daily to maintain levels within the therapeutic range. The average dose of CyA required to maintain therapeutic levels increased within 72 hours of initiating pulse steroid therapy (Figure 1b), although this was associated with a large standard error. This increase in CyA dosage was maintained for approximately 9 days before returning to the initial dosing regimen (days 12-14). The standard error associated with each dose also increased over the course of therapy, indicating that variable interpatient changes in CyA requirements occurred following pulse steroid therapy.

The administered measured CyA doses increased in 12 patients (50.0%), decreased in 7 (29.2%), and were unchanged in 5 (20.8%). Increases in CyA dose ranged from 10% to almost 50% of prerejection values (Figure 1c). Trend lines fitted to the average of the increase (solid) and decrease (dashed line) in CyA dosing were linear and had similar magnitudes of change. This suggested that 2 different populations of CyA response to high-dose systemic steroids exist.

A multivariate analysis was undertaken to assess correlations between dose changes and a variety of patient characteristics. Patients were placed into 2 groups: those who required increased CyA dosing (n = 12) and those who required either decreased or no change in dosing (n = 12) during the acute rejection episode. There were no significant differences between groups in terms of gender, age, time from transplantation, rejection grade, starting CyA dose, or starting prednisone dose (Table II). There were also no significant associations between CyA dosing alterations and age, gender, time since transplantation, or route of steroid administration (IV vs PO; Table III). There was no correlation between rejection severity and CyA dosing changes (Table III). Also included in the analysis was the presence of medications known to interact with CYP3A4 and/or PGP, such as verapamil, fluconazole, and norfloxacin. The presence of these medications did not correlate with increases or decreases in individual CyA dosing (Table III) whether they were present alone or in combination (data not shown). None of the patients were on other drugs known to affect 3A4, including statin drugs, macrolide antibiotics, antiarrythmics, benzodiazepines, antihistamines, or HIV antiviral medications.

The concentration of CyA in the blood changed minimally during therapy, indicating that all patients received appropriate immunosuppression during the acute rejection event (Figure 1d). Stability of CyA concentrations 1 week, 48 hours, and immediately before renal biopsy demonstrates patient compliance with the TI of 250 to 300 µg/L for 0 to 6 months after transplantation.³ This time frame correlates with the highest incidence of acute allograft rejection episodes.¹⁵

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Corticosteroids, usually prednisone, are the most commonly used immunosuppressants in pediatric renal transplant patients.¹⁶ CyA is another essential and commonly used immunosuppressant used to treat pediatric transplant patients.^16,17 CyA and steroids exhibit significant pharmacokinetic overlap in both absorption and metabolism. An adenosine triphosphate (ATP)–dependent P-glycoprotein in the small intestine and liver⁹ eliminates both, and both are metabolized by CYP3A4 in the liver.⁵ Basedonthiscommonmetabolic pathway of CyA and steroids, high doses of prednisone or solumedrol should competitively inhibit CyA metabolism, thereby increasing the therapeutic concentrations of a given dosage, although a reduction of therapeutic concentrations would be noted if high doses of prednisone were to induce CyA metabolism. Indeed, the literature suggests that corticosteroids increase serum concentration of CyA through corticosteroid inhibition of CyA metabolism.¹¹ In contrast, however, other studies have found increased clearance of CyA following high-dose methylprednisolone administration, suggesting that corticosteroids increase hepatic metabolism of CyA.¹² Variations in CyA bioavailability and pharmacokinetics have been shown to correlate with transplant rejection, ¹⁸ and hence it is relevant that clinicians be aware of the alteration of CyA pharmacokinetics when there are changes in synthetic corticosteroid dosage.

In the current study, analysis of 10 years of pediatric renal rejection episode data suggests that in a significant percentage of patients, systemic CyA concentrations decrease during pulse steroid therapy. We were able to identify that half of the patients (n = 12) exhibited decreased concentrations of systemic CyA during pulse steroid administration, which required increased CyA doses to maintain therapeutic levels (Figure 1c). About one third of the subjects (n = 7) required decreased CyA dosing to maintain therapeutic levels (Figure 1c). The 2 groups of patients examined were not significantly different in terms of gender or age. There was a wide variability in the timing of the rejection episode, with some patients exhibiting pathological changes within weeks of transplant and others developing signs more than a year later. This most likely reflects the variability and unpredictability associated with acute rejection episodes.¹⁵ Most patients (80.8%) had histologically defined grade I, or mild, rejection. Multivariate analysis showed that the presence of other drugs was not responsible for the changes in CyA requirements that were observed during acute renal rejection episodes (Table III).

The precise determinants of steroid and CyA interaction have yet to be elucidated and may relate to pharmacokinetic interactions altering CyA absorption distribution and metabolism. A number of studies have suggested that steroids, particularly dexamethasone, induce CYP3A4 activity in rats, ¹⁹ leading to lower levels of CyA. Ptachcinski and colleagues¹² showed that patients undergoing rejection episodes while on steroids and CyA had lower trough levels of CyA, requiring significantly higher CyA doses to achieve therapeutic levels. An induction of CyA metabolism and subsequent clearance could therefore account for its decreased systemic concentrations. Another explanation for increased CyA requirements is the possible involvement of PGP, which limits drug absorption in the small intestine, ²⁰ and therefore bioavailability, by exporting drugs from the epithelial cells into the intestinal lumen. Dexamethasone has been shown to increase PGP expression in rat cell lines in a time- and concentration-dependent manner.²¹ PGP expression is induced by steroids, resulting in decreased absorption of CyA, which could therefore explain increased CyA requirements in some patients. Recent studies have shown that, in fact, both CYP3A4 and PGP may be relevant in pharmacokinetic interactions with steroids.^19,22 When dexamethasone and the HIV protease inhibitor indinavir were concurrently administered, dexamethasone decreased the bioavailability (due to increased first-pass metabolism) of indinavir through CYP3A4 induction and induced PGP in the intestine and liver of rats, increasing the intestinal metabolism of indinavir.²¹ There are 2 potential mechanisms by which high-dose steroids could decrease the effective concentration of CyA: by increasing CyA metabolism by induction of CYP3A4 or by limiting absorption by induction of PGP.

Explanations based on simple pharmacokinetic interactions between CyA and corticosteroids are confounded by the presence of different populations of responders in our study. Although most patients required more CyA to compensate for decreased systemic levels, others actually displayed increased systemic concentrations of CyA, requiring lower doses (Figure 1c). Competitive inhibition of CYP3A4 by prednisone cannot be solely responsible, as we would have expected more than 29% of patients to display increased CyA levels. There may be a role for genetic PGP polymorphism expression, as mutations in PGP have been shown to alter drug bioavailability in renal transplant patients, ²³ although other studies have been unable to find any changes in PGP activity in the presence of mutations.²⁴ Verapamil is a PGP substrate and inhibitor and can induce PGP expression in colonic epithelial cells.²⁵ Fluconazole is not transported by PGP and does not inhibit MDR1 or mdr1a.²⁶ Neither drug appeared to influence the CyA distribution in our population to suggest a PGP effect.

	CONCLUSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Cyclosporine A concentrations are altered by the concomitant administration of high-dose synthetic corticosteroids during acute renal transplant rejection events in pediatric patients. In the current study, 79% of our cohort showed altered pharmacokinetics during treatment of acute renal rejection episodes with CyA and prednisone. Although half of the study population required increased administration of CyA to compensate for decreased systemic concentrations, another 29% had the opposite clinical situation, requiring less CyA to maintain therapeutic concentrations. Variable CyA pharmacokinetics could lead to toxic effects if CyA concentrations increased during pulse steroid administration, or it could lead to insufficient immunosuppression and immune-mediated organ damage if CyA levels decreased. Periodic therapeutic CyA monitoring is recommended in all pediatric patients undergoing acute renal rejection episodes to ensure that CyA concentrations are maintained within therapeutic limits.

	FOOTNOTES

 
Dr Goralski was the recipient of funding from the IWK Research Foundation.

DOI: 10.1177/0091270004271403

Submitted for publication June 9, 2004; Revised version accepted September 23, 2004.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hardy, K. W. Articles by Acott, P. D. Search for Related Content PubMed PubMed Citation Articles by Hardy, K. W. Articles by Acott, P. D. Social Bookmarking                   What's this?