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Methylprednisolone Exposure, Rather than Dose, Predicts Adrenal Suppression and Growth Inhibition in Children with Liver and Renal Transplants¹

Children’s Hospital (S.S., K.H., J.L., C.H.) and Department of Clinical Pharmacology (P.J.N.), University of Helsinki, Helsinki, Finland

Address all correspondence and requests for reprints to: Samu Sarna, Children’s Hospital, University of Helsinki, Stenbäckinkatu 11, FIN-00290, Helsinki, Finland.

	Abstract

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Some patients receiving glucocorticoids develop adverse effects even with very low doses, whereas others fail to achieve the desired effects with the usual therapeutic doses. We hypothesized that glucocorticoid exposure, rather than the dose, would predict the development of adverse effects in children receiving long-term glucocorticoid treatment.

Sixteen liver and 10 renal transplant recipients on triple immunosuppression were studied. Serum total methylprednisolone (MP) and cortisol were determined before and up to 10 h after peroral MP administration. Heights were recorded 6 months before and after the study day.

The MP dose (in milligrams per kilogram) was not correlated with the serum cortisol concentration or with the change in height SD score. The area under the serum MP time vs. concentration curve was inversely related to the serum cortisol concentration and to the height SD score, and was the best predictor of both adrenal function and growth. Dosing according to area under the serum MP time vs. concentration curve in children receiving long-term glucocorticoid treatment may substantially reduce the incidence of adverse effects without affecting therapeutic efficacy.

	Introduction

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GLUCOCORTICOIDS are widely used as immunosuppressants in various autoimmune disorders and after organ transplantation (Tx). Without glucocorticoid administration, up to 50% of all children with transplants can be expected to reject their grafts (1). Unfortunately, prolonged treatment often causes adverse effects, such as osteoporosis, suppression of adrenal cortisol production, and Cushingoid features. In children, the main problem is inhibition of longitudinal growth, which may cause long-term psychosocial problems.

Adrenal suppression and growth retardation are often seen in children after liver and renal Tx, and the factor mainly responsible is believed to be glucocorticoid treatment (2, 3). We have previously shown that growth inhibition in children with liver transplants can be predicted by the extent of adrenal suppression rather than by the absolute or cumulative glucocorticoid dose (2, 3). We concluded that individual pharmacokinetic differences could account for the variable expression of adverse effects, and that these adverse effects were closely related to each other.

We hypothesized that glucocorticoid exposure, rather than the dose, predicts the extent of adrenal suppression and growth inhibition in children receiving long-term glucocorticoid treatment after Tx. We studied the relation of the methylprednisolone (MP) dose and the drug concentrations to adrenal function and growth in children with liver and renal transplants.

	Materials and Methods

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Sixteen liver and 10 renal Tx recipients admitted to our hospital for a regular post-Tx follow-up visit between May 1994 and May 1995 were studied. The median age was 7.9 yr (range, 2.6–15.8 yr) for liver Tx and 4.6 yr (range, 2.8–8.8 yr) for renal Tx patients. The median time elapsed after Tx was 2.8 yr (range, 0.5–6.9 yr) for liver Tx and 3.0 yr (range, 1.6–6.2 yr) for renal Tx recipients. Triple immunosuppression with alternate-day MP was used (3).

The study protocol was approved by the Medical Ethics Committee of the Children’s Hospital, and the study was performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patients and/or their parents or guardians.

Patients received their usual MP dose orally in the morning after an overnight fast. At least 20 h had elapsed since the preceding MP dose. Blood samples were drawn from an iv cannula before and 1, 2, 3, 4, 6, 8, and 10 h after MP administration.

Serum concentrations of total MP and cortisol were determined using high-performance liquid chromatography (4). The sensitivity of the method was 10 µg/L for MP and cortisol. The coefficient of variation (day to day) for MP was 4.8% at 99 µg/L (n = 18) and for cortisol 4.5% at 99 µg/L (n = 18). The area under the serum MP time vs. concentration curve (AUC) was calculated using the trapezoidal method with extrapolation to infinity (5). The extrapolated area was 5.5–46.9% of the total AUC in the children with liver Tx and 3.6–25.3% in those with renal Tx.

Heights were recorded 6 months before and after the study day. Height measurements were performed at 1200 h by the same trained observers, using a Harpenden stadiometer (Holtain LTD., Crymych, Dyfed, U.K.). Height SD score (hSDS) was calculated according to the following equation: hSDS = (observed value - mean value)/SD for normal. The change in hSDS (hSDS) was calculated from height measurements performed 6 months before and after the study. Six of the 26 patients were >9 yr old. In 4 of these children, pubertal development had been normal. Four patients with liver Tx were excluded from the growth analysis because of concomitant recombinant human GH (rhGH) treatment. These 4 patients included 2 patients who were not found suitable for growth evaluation also because of delayed pubertal development. Thus, growth data were available for 12 liver and 10 renal Tx recipients.

Most of the children with liver transplants received their graft from an older donor. The catabolic capacity of the liver is known to decrease with age. Thus, catabolism of MP may be different between liver and renal transplant recipients. Therefore, liver and renal transplant patients were analyzed together and separately.

The Mann-Whitney U test and simple and multiple linear regression analysis were used in the statistical analysis. Statistical association was considered significant at P < 0.05.

	Results

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The serum bilirubin levels were normal (<20 µmol/L) in all children with liver transplants, and serum alanine aminotransferase levels were normal (<50 IU/L) in all except two patients during the study. All except two renal transplant recipients had a glomerular filtration rate >60 mL·min·1.73 m² (EDTA clearance). The median MP dose was similar in the children with liver Tx (0.25 mg/kg, range 0.14–0.32 mg/kg) and those with renal Tx (0.26 mg/kg, range 0.19–0.36 mg/kg; P = NS).

The median morning cortisol concentration was significantly lower in the children with liver Tx (46.1 µg/L, range 0–143 µg/L) than in those with renal Tx (114 µg/L, range 32.7–237 µg/L; P = 0.0024). During the 1-yr follow-up the median hSDS was -0.1 (range, -0.4-0.6) in the children with liver Tx and 0.1 (range, -0.5-0.5) in those with renal Tx (P = NS).

The MP dose (in milligrams per kilogram) had a linear relationship to the maximum binding concentration C_max (r = 0.58, P = 0.0015) but not to the AUC of MP, the serum cortisol concentration, or to the hSDS. The C_max of MP did not relate significantly to the serum cortisol concentration or the hSDS when all the patients were considered. However, when only the children with liver Tx were considered, the C_max of MP related significantly to the cortisol concentration (r = -0.50, P = 0.048) and the hSDS (r = -0.66, P = 0.018).

The best predictor of both adrenal function and growth was the AUC of MP, which was inversely related to the serum cortisol concentration (r = -0.47, P = 0.014; Fig. 1). The relation was even more significant (r = -0.70, P = 0.0018) when only the children with liver Tx were considered. A serum cortisol concentration below the median (68.3 µg/L) was observed in 12/16 patients with AUC of MP above 650 µg/L.

View larger version (16K): [in this window] [in a new window]   Figure 1. Relation between AUC and morning cortisol in 16 children with liver (•) transplants and 10 with renal () transplants.

View larger version (14K): [in this window] [in a new window]   Figure 2. Relation between AUC and hSDS in 12 children with liver (•) transplants and 10 with renal () transplants.

	Discussion

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For clinical purposes, it would be of great benefit to be able to predict individual sensitivity to glucocorticoid treatment. This would allow the use of an optimal therapeutic dose, which would have minimal adverse effects. In clinical settings, determination of individual sensitivity to the adverse and beneficial effects of glucocorticoids have been approached in two ways: by monitoring the more easily observed glucocorticoid effects, such as the cutaneous vasoconstrictor response (6) or adrenal suppression (7), and by determining glucocorticoid pharmacokinetics. Unfortunately, previous studies have not yielded any tools for clinical decision making.

It is conceivable that patients with glucocorticoid-related adverse effects also have reduced adrenal cortisol production. However, adult patients with Cushingoid appearance may have cortisol levels as high as or even higher than non-Cushingoid subjects (8, 9). It seems that adipose tissue and the hypothalamic-adrenal axis have differential sensitivities to glucocorticoids, i.e. Cushingoid features are not always associated with adrenal suppression and vice versa (8). However, we have previously reported a clear association between adrenal suppression and growth inhibition in children with liver transplants (2, 3). Thus, the sensitivities of the growth plate and the hypothalamic-adrenal axis may be similar.

Previous studies using specific assay methodology have not been able to document an association between low prednisolone plasma clearance and a Cushingoid appearance in adults (8, 9). Similar studies have not previously been performed in children. The present study is the first to show the predictive value of one pharmacokinetic parameter on the appearance of two important adverse effects of glucocorticoids. We have documented a significant relation between an increasing AUC of total MP and adrenal suppression, and also growth inhibition in children with liver and renal transplants.

Growth inhibition is the most important of the adverse effects of glucocorticoids in children, and may cause permanent psychosocial problems. rhGH treatment has been successfully used in children with liver (10) and renal (11) transplants. But rhGH treatment is expensive, has to be given in daily injections, fails to improve growth in some patients (12), and may cause adverse effects, such as graft rejection (13). By adjusting the glucocorticoid dose according to the AUC, growth could be improved significantly, and the need for rhGH treatment minimized.

We suggest that in children receiving long-term glucocorticoid treatment, the dose should be determined based on the AUC. We have previously demonstrated the feasibility of such a procedure in children receiving cyclosporine (14). In our setting, the upper limit of the AUC of MP, above which adrenal suppression and growth inhibition were common, seems to be 650 µg/L. If glucocorticoid dosing is individualized according to the AUC, it is also imperative to determine a threshold that guarantees therapeutic efficacy, i.e. sufficient immunosuppression.

In conclusion, the AUC of MP predicts adrenal suppression and growth inhibition better than the dose, especially in glucocorticoid-treated children with liver transplants. Thus, dosing according to the AUC in children receiving long-term glucocorticoid treatment may substantially reduce the incidence of adverse effects, e.g. adrenal suppression and growth inhibition, without affecting therapeutic efficacy.

	Acknowledgments

 
The authors thank Mrs. Jean Margaret Perttunen, B.Sc. (Hons.) for revising the manuscript.

	Footnotes

 
¹ This work was supported by grants from the Sigrid Jusélius Foundation and the Paediatric Research Foundation.

Received June 14, 1996.

Revised August 1, 1996.

Accepted August 26, 1996.

	References

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9. Öst L, Björkhem I, von Bahr C. 1984 Clinical value of assessing prednisolone pharmacokinetics before and after renal transplantation. Eur J Clin Pharmacol. 26:363–369.[Medline]
10. Sarna S, Sipilä I, Koistinen R, Holmberg C. 1996 Recombinant human growth hormone improves growth after liver transplantation in childhood. J Clin Endocrinol Metab. 81:1476–1482.[Abstract]
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