Jul 30, 2014 - Prednisone versus. Hydrocortisone in Treating children with. Congenital Adrenal. Hyperplasia : Effect on Growth. ASHRAF T SOLIMAN MD ...
Prednisone versus Hydrocortisone in Treating children with Congenital Adrenal Hyperplasia : Effect on Growth ASHRAF T SOLIMAN MD PHD FRCP P R O F E S S O R O F P E D I AT R I C S A N D E N D O C R I N O LO G Y UNIVERSITY OF ALEXANDRIA, EGYPT S E N I O R C O N S U LT A N T P E D E N D O C R I N O L O G Y H A M A D M E D I C A L C E N T E R , D O H A , Q AT A R
Congenital adrenal hyperplasia (CAH) Is due to loss or severe decrease in activity in one of the five steroidogenic enzymes involved in cortisol biosynthesis.
It is caused by mutations in the 21-hydroxylase gene (CYP21).
21-hydroxylase deficiency is found in 90 –95% of cases.
Presentations In salt wasting type (SW-CAH) Renal salt loss occurs due to aldosterone deficiency.
Overproduction of androgens causes :
Virilization of females
Hyponatremia
Accelerated growth
Hyperkalemia
Advanced skeletal maturation, and
Acidosis
Early epiphyseal fusion.
Traditional treatment of Substitution of cortisol to reduce excessive androgen production and its consequences.
Fludrocortisone to compensate for aldosterone deficiency
Guidelines Medical Treatment of CAH in Growing Patients The GC of first choice for maintenance therapy of children with CAH is hydrocortisone in tablet form. For infants, tablets may be crushed, weighed, and mixed with a small amount of liquid and delivered immediately by medication syringe, rather than from bulk suspension preparations that deliver uneven doses It is recognized that prednisolone and dexamethasone are sometimes useful in treating patients refractory to hydrocortisone The Task Force recommends against the routine chronic use of long-acting potent GCs in growing patients All patients with classic CAH should receive mineralocorticoid (MC) supplementation in the form of oral fludrocortisone and sodium chloride supplements in the newborn period and early infancy, and as needed throughout life.
Hydrocortisone (HC) is the preferred glucocorticoid (GC) 1. Hydrocortisone acetate, is most similar to endogenous cortisol (physiological). 2. RCT study concluded that 25 mg/m2 depressed growth in children with congenital adrenal hyperplasia compared to 15 mg/m2 of hydrocortisone . 3. Full suppression, or normalization, of plasma concentrations of 17OHP and androgens should not be considered a treatment goal, but instead an indication of corticosteroid treatment excess
Hydrocortisone Pharmachokinetics Rapidly absorbed after an oral dose, and concomitant food intake does not appear to prevent absorption Has a high degree of intestinal permeability, crossing the intestinal mucosa in a passive fashion. The bioavailability after oral administration is high, >90% The time to peak concentration (Tmax) is roughly 1-2 hours. The elimination half-life (T1/2) of hydrocortisone is also short, 1.8–2 hours following either oral or intravenous administration. The pharmacokinetics of hydrocortisone are nonlinear, in part due to extensive protein binding. As a result, higher doses result in more rapid clearance rates Hence, doubling the dose does not lead to doubling of the area under the curve of plasma hydrocortisone versus time.
Adjusting Hydrocortisone Therapy OVERTREATMENT
UNDER-TREATMENT
Growth impairment
Rapid linear growth
Osteopenia ?
Rapid skeletal maturation
Hypertension?
Early puberty Reduced final adult height
In Human Excess GCs leads to: 1. Decrease in GH response to growth hormone releasing hormone (GHRH) 2. Paradoxical increase in IGF-1 levels 3. A state of GH resistance. 4. GCs may promote apoptosis of chondrocytes
(through activation of caspases and inhibit the phosphatidylinositol 3 -kinase (PI3K) signaling pathway.)
Linear Growth in children with CAH on treatment
Compromised final adult height
Todd D. Nebesio ,International Journal of Pediatric Endocrinology Volume 2010, Article ID 298937, 10 pages
Bone mineral density in CAH on long term GC therapy
Debate : Prednisone versus Hydrocortisone
Debate still exists about the safety of long-term use of prednisone versus hydrocortisone for treating children with congenital adrenal hyperplasia (CAH) 21OH D.
Risks versus benefits of using Prednisone versus hydrocortisone
01
02
03
04
05
Tendency for overtreatment with side effects of excess GC.
The physiological dose of prednisone is not accurately known.
The bioequivalence dose ratio is based upon antiinflammatory potency, (1/4)
Even “? physiologic doses” may impair growth velocity and restrict final height.
The cost is lower when compared to formulated hydrocortisone.
Potential benefits of using Prednisone versus hydrocortisone
1.
Prednisolone (PD) has a molecular structure that resembles that of cortisol.
2.
The pharmacokinetic profile of prednisolone showed similarity to the published profile of dual-release hydrocortisone and mimicking the physiological cortisol profile
3.
A longer half-life allows single daily dose administration. (better compliance vs hydrocortisone TID)
4.
Convenient commercially available formulation (homogeneous oral solution) permits fine therapeutic adjustments.
Similar to hydrocortisone, prednisone is also rapidly and nearly completely absorbed after an oral dose.
Prednisone itself is biologically inactive, must be reduced by hepatic 11-βhydroxysteroid dehydrogenase to form active prednisolone. This transformation occurs rapidly, it does account for the delayed Tmax of prednisone versus prednisolone (2.6 hours versus 1.3 hours, resp) The T1/2 of both prednisone and prednisolone have been reported to be 3-4 hours. Prednisone/prednisolone has complex, nonlinear pharmacokinetics due to protein binding which becomes saturated at higher doses. This leads to increasing clearance rates and a decrease in the peak concentration achieved per milligram dose when higher doses are given.
Prednisone/PrednisolonePharmachokinetics
Bioactivity of Prednisone vs hydrocortisone The physiological dose of prednisolone is not certain.
For anti-inflammatory effects prednisolone is four-fold more potent than hydrocortisone.
Using luciferase transactivation assay in CV-1 cells transfected with the human GC receptor, prednisolone is 1.7 fold more potent than hydrocortisone.
The relative potency for mineralocorticoid effects is less clear. When transfected with the human mineralocorticoid receptor hydrocortisone is 4.2 fold more potent than prednisolone.
Bioequivalence of prednisolone and hydrocortisone derived from growth data in patients with congenital adrenal hyperplasia suggest prednisolone to be 6 - 8 fold more potent than hydrocortisone.
Prednisone recommended initial dose
3 MG / M², REPRESENTING ONE FOURTH TO ONE FIFTH OF THE HYDROCORTISO NE DOSE.
Studies comparing Prednisone vs Hydrocortisone in treating CAH
Consecutive use of Hydrocortisone and prednisone for 1 year Growth of 15 children with CAH on two consecutive 1-year periods.
In the first year, hydrocortisone (17.5mg / m 2/ day, divided in three doses) was used in the treatment,
Followed by using prednisolone (3 mg / m² / day, once in the morning) in the second year.
No significant difference in relation to the Delta Height SDS, Delta Bone age SDS and Delta BMI SDS. No significant difference was observed in the serum levels of androstenedione.
One-year treatment period with a single morning oral dose of receiving PD (2.4-3.5 mg/m2 BSA) (n=23) versus TID HC (10-15 mg/m2 BSA) (n=21) After 1 year, bone maturation ratio was kept stable in the PD group (from 1.20 to 1.14), whereas a slight increase was seen in the HC group (from 1.21 to 1.29).
Growth velocity (SDS) was preserved in the PD group (from 0.79 to 1.13 in prepubertal children)
HtSDS for bone age (BA) increased significantly in the PD group.
A slight increase occurred in the pre-pubertal HC-treated patients (from 1.1 to 1.9).
Thus, a single morning dose of PD appeared to achieve a better clinical control than those on TID HC, permitting a reduction of the replacement dose.
2/5th of the total dose of hydrocortisone was administered in the morning and 1/5th administered at noon in all the regimens.
Prospective cross-over study using 1015 mg/m2 total dose of hydrocortisone
The regimens differed in the timing of the evening dose of hydrocortisone, 06.00-07.00 pm in regimen 1 and 09.0010.00 pm in regimen 2. The third regimen had the evening dose of hydrocortisone replaced by an equivalent dose of prednisolone suspension which was administered at 10.00 pm. The three different regimens were found to be similar in their ability to control 17-hydroxyprogesterone and testosterone levels. The biochemical control was similar in all the three regimens.
Trend toward better control of 17-hydroxyprogesterone levels in patients receiving evening dose of prednisolone.
Studies in favor of hydrocortisone use vs prednisone.
Alternate day prednisone therapy (20 mg every other day, (pharmacological dose) 11-yr-old girl with salt-losing 21-hydroxylase deficiency and severe asthma treated with for over 3 yr.
During this period her linear growth was along the 65th percentile, and her bone age paralleled her chronological age.
Pubertal development was normal, and she had no signs of androgen or GC excess.
24-h urinary 17-ketosteroid excretion were low on both the day on and the day off prednisone. However, her plasma ACTH and 17-hydroxyprogesterone levels were markedly elevated on both days.
Prednisone followed by hydrocortisone therapy in CAH Growth of children with CAH who were on Prednisone therapy for a mean of 4.6 years and have been shifted to hydrocortisone for a year.
The mean height Z score was -0.42 on prednisone and improved slightly to -0.27 after 1 year of hydrocortisone therapy.
Total pubertal growth was significantly decreased in both groups
Prednisone (Relative GC potency 1:4) (twice daily) (N =33) versus hydrocortisone (N = 92)
Treatment with prednisone resulted in lower final HtSDS by 0.4 SD ( about 2-3 cm) compared to hydrocortisone group (−1.0 ± 0.9 SDS vs.−0.6 ± 0.9 SDS; P < 0.05). Final height in all 125 patients showed no correlation with the hydrocortisone dose or hydrocortisone equivalent dose given at 2 yr. of age. Children on < 20 mg of hydrocortisone/m2 at the start of puberty had better FHtSDS vs those on > 20 mg hydrocortisone/m2 (P < 0.05). Pubertal development started early in boys and was timely in girls.
Summary based on the results of the Previous Studies
1. In case of hydrocortisone is not available 2. TID dosing is difficult (noncompliance) or 3. the biochemical control is not achieved by TID hydrocortisone
Using once daily dose of prednisone in treating CAH has the following effects vs hydrocortisone
1.Mild or no effect on final adult height on Pred.
3. No difference on BMI, Fasting glucose level, or HOMA-IR among the two drugs.
2. 17hydroxprogesterone levels is lower with prednisone therapy.
1 The convenience of a single daily dose, compliance and costeffectiveness are better with once daily dose.
2
3
Prednisone appears to be a good and relatively safe alternative to hydrocortisone for the continuing medical treatment of 21OHD.
However, long-term follow-up is still necessary to demonstrate individual clinical benefits upon final stature and cardiovascular risk.
Summary
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