Hydrocortisone is the standard replacement therapy for children with congenital adrenal hyperplasia (CAH). Relationships between cortisol exposures and pharmacodynamic responses of 17-hydroxyprogesterone and androstenedione exposures have not been systematically evaluated.
Objectives (1) Assess individual oral hydrocortisone pharmacokinetics; (2) relate the observed cortisol exposure in each subject to the observed exposures of 17-hydroxyprogesterone and androstenedione; (3) determine potential individualized treatment regimens based on each subject’s pharmacokinetic and pharmacodynamic parameters.
Methods Thirty-four patients (18 boys, 16 girls, aged 1.4 to 18.1 years) with CAH underwent 6-hour pharmacokinetic studies. Results were analyzed by noncompartmental methods to obtain the area under the curve (AUC) for cortisol, 17-hydroxyprogesterone, and androstenedione; maximum concentration and time-to-maximum concentration for cortisol; and minimum and time-to-minimum concentration for 17-hydroxyprogesterone and androstenedione.
Results Mean (SD) cortisol half-life and Cmax were 1.01 (0.20) hours and 24.4 (5.4) μg/dL, respectively. The AUCs for cortisol, 17-hydroxyprogesterone and androstenedione were 40.8 (14.5) μg hour/dL, 29,490 (23,539) ng hour/dL, and 680 (795) ng hour/dL, respectively. No significant relationships existed between cortisol AUCs and the AUCs of either 17-hydroxyprogesterone (P = 0.32) or androstenedione (P = 0.99); nor were there differences between the change-from-baseline concentrations for cortisol with either 17-hydroxyprogesterone (P = 0.80) or androstenedione (P = 0.40). Cortisol simulations indicated that although four daily doses decreased 24-hour hypercortisolemia and hypocortisolemia, substantial periods of each remained.
Conclusions Concentration profiles of cortisol, 17-hydroxyprogesterone, and androstenedione are highly variable in children with CAH, and knowledge of them can assist in personalizing the therapy of CAH patients. Hydrocortisone’s rapid half-life and the lack of a sustained-released product make it difficult to closely approximate normal circadian profiles.
- congenital adrenal hyperplasia
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Hydrocortisone is the standard replacement therapy for pediatric patients with congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase deficiency. The recommended dose is 10–15 mg/m2/day administered orally three times daily.1The approach to treatment of children with CAH is to find the balance between providing adequate cortisol replacement and, at the same time, suppressing the excess secretion of adrenal androgens. One of the challenges to treatment is that with current hydrocortisone regimens, it is difficult to achieve the circadian rhythm of cortisol secretion. In unaffected children, cortisol concentrations vary throughout the day with the lowest levels occurring around 11:00 pm to 12 midnight, increasing through the night, and reaching peak levels around 6:00 to 8:00 AM.2–4In children with CAH being treated with oral hydrocortisone, periods of hypocortisolemia and/or hypercortisolemia throughout the course of the day are inevitable consequences of the short half-life and short time to maximum concentration. Increasing the challenge of treatment is the extent of interindividual variability of cortisol pharmacokinetics and of adrenal androgen suppression response to hydrocortisone, as measured by 17-hydroxyprogesterone (17OHP) and androstenendione (D4A).5–7
Working under the premise that replacement therapy should be individualized, the aims of this study were (1) to determine the subjects’ cortisol pharmacokinetics of orally administered hydrocortisone; (2) relate the observed cortisol exposure in each subject to the observed exposures of 17-hydroxyprogesterone and androstenedione; and (3) determine potential treatment regimens based on each subject’s pharmacokinetic parameters and pharmacodynamic response as measured by 17OHP and D4A concentrations.
MATERIALS AND METHODS
All patients (n=34; 18 boys, 16 girls), age range of 1.4 to 18.1 years (median 6.8 years), had a confirmed diagnosis of CAH based on hormonal and molecular testing (22 salt wasting; 8 simple virilizing; 4 nonclassic). Onset of puberty was determined in girls by Tanner stage 2 for breasts; in boys by testicular size of 4 cm3. One female patient (46, XX) is being raised as a male. Puberty was being suppressed with histrelin acetate in 7 patients (5 girls; 2 boys). Puberty was adequately suppressed as indicated by clinical and hormonal measures. Seven patients (2 girls; 5 boys) were on growth hormone therapy. Target therapeutic range for 17OHP was 200 to 1000 ng/dL and for D4A was less than 2 SDs from the means, categorized based on the respective age and sex-specific normal ranges.8,9
On the day before the pharmacokinetic study, patients received their regular evening dose and were asked to fast after midnight. The following morning, a baseline blood sample was obtained at approximately 8:00 AM, and the patient then received their usual oral hydrocortisone morning dose. The doses ranged from 1.9 to 9.3 mg/m2. Serial blood samples were obtained at 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, and 360 min following the dose. A total of 15 mL of blood was drawn. Patients were given a standard breakfast 1 hour after dose administration. The study was approved by the University of Minnesota Institutional Review Board. Informed consents and assents were obtained.
The samples were centrifuged at 3500 rpm for 8 minutes; serum was removed and frozen at −80 ° C. Serum samples were assayed by Mayo Clinic Laboratories for total cortisol, 17OHP, and D4A concentrations using high performance liquid chromatography tandem mass spectrometry.10The lower limit of quantification for the total cortisol assay was 0.2 μg/dL, 40 ng/dL for 17OHP, and 15 ng/dL for D4A. The within-assay coefficients of variation (CV) for all three compounds were less than 10%, and the interassay CV for all three compounds was less than 15%.
The cortisol concentrations were analyzed by standard noncompartmental methods11using the linear trapezoidal rule in Phoenix WinNonlin 6.3. The peak concentration (Cmax) for cortisol and the minimum concentration (Cmin) for 17OHP and D4A, as well as the time at which Cmax (tmax), and Cmin (tmin) occurred were determined by direct observation of the concentration-time data. Area under the curves (AUCs) from 0 to 6 hours were computed as a measure of cortisol exposure after the morning hydrocortisone dose. Because 17OHP and D4A concentrations decrease in response to cortisol, we computed a change-from-baseline AUC as the area between the baseline concentration and the observed values over six hours. Because endogenous concentrations without dosing were not available, we assumed the baseline was constant over the 6-hour study.
Development of Potential Dosing Regimen
Based on the cortisol pharmacokinetic parameters obtained for each individual during the 6-hour study, 24-hour simulations (STELLA 9.1.3; isee Systems) were performed to explore the potential of personalizing the dosing schedule to more closely mimic the concentration-time profile described in Knutsson et al.12Five daily doses were not considered for adherence reasons.
The calculations of descriptive statistics, t tests (paired and unpaired) for comparing group means, and the strength of relationships between two variables using Spearman nonparametric correlation analysis were carried out GraphPad InStat 3. All levels of statistical significance were taken at 0.05.
Table 1 lists patient population and the dose of hydrocortisone administered for the pharmacokinetic studies. Figure 1 depicts the concentration-time profiles of cortisol (A), 17OHP (B) and D4A (C) in our subjects and Figure 2 shows individual concentration-time profiles of these three steroids in 6 representative patients.
Table 2 reports the noncompartmental cortisol parameters in the 34 pediatric patients. Considering the range of doses, the %CV for Cmax was only 21.6%, which reflects the body surface area (BSA)–adjusted dosing. The large interpatient variability in apparent clearance (CL/F) (64.2%) and apparent volume of distribution (V/F) (60.1%) were significantly decreased when the parameters were normalized for BSA, 33.0% and 25.0%, respectively. As expected, BSA accounted for a substantial portion of the interpatient variability observed in pharmacokinetic parameters. There was no difference in the BSA-normalized CL/F between patients receiving growth hormone and those who did not (P = 0.7); nor was there any difference in the BSA-normalized volumes of distribution (P = 0.6).
Adrenal Steroid Responses
The baseline concentrations for cortisol, 17OHP, and D4A are summarized in Table 3, as are the maximum observed concentrations for cortisol and the lowest observed nadir concentrations for 17OHP and D4A. We calculated the change from baseline to the maximal concentration for cortisol, and as a measure of adrenal steroid response to cortisol, the change in concentration from baseline to the nadir concentration for 17OHP and D4A was calculated and presented in Table 3. The analysis of the change-from-baseline bivariate relationships demonstrated that there were no significant relationships between the increase in cortisol concentrations (Cmax-baseline) and the magnitude of decrease in either 17OHP (P = 0.80, r=0.05) or D4A (P = 0.40, r=−0.15) concentrations (baseline-Cmin). A significant relationship was observed in the change-from-baseline between 17OHP and D4A (P = 0.0001, r=0.65).
Cortisol and adrenal steroid AUCs are presented in Table 3. The cortisol AUCs were not correlated with either the change-from-baseline AUCs of 17OHP (P = 0.32, r=0.18) or D4A (P = 0.99, r= −0.002). However, the correlation between 17OHP and D4A change-from-baseline AUCs was significant (P = 0.0001, r=0.68).
The median (min, max) time to maximum cortisol concentration was 0.75 (0.22, 1.25) hour. The median (min, max) time to reach the nadir for 17OHP was 4.0 (2.0, 6.0) hours, and the time to nadir for D4A was 3.0 (1.25,6.0) hours. Cortisol reached its maximum concentration rapidly compared to 17OHP and D4A. In terms of time frame of response to cortisol, the correlation between the times to reach nadir for 17OHP and D4A was statistically significant (P < 0.0001; r=0.64). An analysis of the test dose of hydrocortisone administered (mg/m2) and the time to 17OHP and D4A nadir was conducted. The administered hydrocortisone dose did not significantly correlate to the time it took either 17OHP (P = 0.50; r= −0.24) or D4A (P = 0.14; r=0.45) to reach nadir. An analysis was also conducted to examine the mg/m2 hydrocortisone dose and the AUC calculations. There was a moderate correlation between dose and cortisol AUC (P = 0.02; r=0.40), a moderate correlation between dose and the 17OHP AUC (P = 0.003; r=0.50), and a weak correlation between dose and D4A AUC (P = 0.21; r=0.23).
Simulation of Dosing Regimen Based on Cortisol Pharmacokinetics
Several dosing regimens based on each patient’s individual cortisol pharmacokinetic parameters were evaluated. Typically, the regimen chosen was four daily doses with the usual morning dose split into two doses 2 hours apart. Although this reduced hypercortisolemia and hypocortisolemia, it was clear that four daily doses were insufficient to closely mimic normal cortisol profiles in any of the patients. Most of our patients/families agreed to switch to four daily doses, but overall, the total daily amount of hydrocortisone based on 3 or 4 doses per day did not significantly differ, 11.4 ± 2.8 mg/m2 versus 10.7 ± 2.7 mg/m2, respectively (P = 0.07). Figure 3 presents the simulated 24-hour cortisol concentration-time profile in a representative patient receiving three daily doses (upper panel) and four daily doses (lower panel). The simulated cortisol profiles for this patient have been superimposed on the typical circadian cortisol profile in healthy children.12The simulated 24-hour profiles for all patients displayed quite similar features of periods of hypercortisolemia and hypocortisolemia.
To our knowledge, this is the first study to systematically relate oral cortisol pharmacokinetics in children with CAH with both 17OHP and D4A time-concentration profiles. There are few previous reports of cortisol pharmacokinetics in CAH children. The mean terminal half-life of orally administered hydrocortisone in our CAH cohort, mostly prepubertal children (31 of 34) was 1.01 ± 0.20 hours (Table 1). This was analogous to the average hydrocortisone half-life of 1.34 ± 0.32 hours in CAH children reported by Charmandari et al., who studied the pharmacokinetics of intravenously administered hydrocortisone in prepubescent, pubescent, and postpubescent patients, and did not find any significant difference in the cortisol half-life among those groups of CAH children.13There are no studies of cortisol pharmacokinetics in healthy children for comparison.
In comparison with adults, the results of our study and Charmandari’s show that the hydrocortisone half-life in CAH children is shorter compared to healthy adults (1.8 hours)14,15or adults with other forms of adrenal insufficiency (1.7–1.8 hours).5,16
Our mean oral CL/F of 124 dL/hour was slightly lower than the IV CL of 149 dL/hour in prepubertal children reported by Charmandari et al.13; we would have expected our value of CL/F to be higher because the bioavailability of oral hydrocortisone is less than 100% (94.2%).17Also affecting clearance, our subjects were younger overall with a median age of 6.8 years compared to 9.4 years for their prepubertal group.13There were study design differences as well; we obtained 12 observations over 6 hours, whereas the Charmandari study had 36 observations over the same period13; we measured cortisol, 17OHP, and D4A by liquid chromatography tandem mass spectrometry, whereas Charmandari used radioimmunoassay to measure cortisol and 17OHP. All of these factors could contribute to differences in pharmacokinetic results. Cortisol CL/F in healthy adults has been reported at 180 dL/hour.14
Cortisol pharmacokinetics in CAH children are unique in comparison to individuals with other forms of adrenal insufficiency. Congenital adrenal hyperplasia patients have intermittently increased adrenal sex steroid production throughout the day that could alter the enzyme activity of 11β-hydroxysteroid dehydrogenase (11β-HSD) isoenzymes and other enzymes that have a role in cortisol metabolism.18–20Additionally, the efficiency with which individuals inactivate cortisol to cortisone, mediated by 11β-HSD2, varies by age.21The reverse reaction, mediated by 11β-HSD1, varies by sex and adiposity.22
There were no significant correlations between cortisol and 17OHP or D4A when absolute changes from baseline AUCs and absolute concentrations at specific times (3 and 6 hours) of these steroids were examined. This wide interindividual variability in response of hypothalamic-pituitary adrenal (HPA) axis to hydrocortisone dosing as reflected by 17OHP and D4A concentrations suggest that additional factors, such as variation in end-organ glucocorticoid sensitivity and cortisol binding globulin production and binding, likely contribute to the observed interindividual variability.5
The variable duration and degree of adrenal steroid suppression in response to hydrocortisone seen in our patients highlights the limitations of a single time point 17OHP and D4A measurement and/or using just one adrenal steroid (17OHP or D4A) as a way of monitoring adequacy of adrenal control during follow-up clinic visits. For example, at 3 hours after morning hydrocortisone dose, patient 11’s (Fig. 2) 17OHP and D4A levels were within the recommended range for a prepubertal child8,9at 512 and 38 ng/dL, respectively. However, his levels quickly rose after reaching nadir as shown by his 6-hour postdose measurement of 17OHP (7000 ng/dL) and D4A (129 ng/dL). He was only 1 of 2 patients whose 6-hour postdose measurement of 17OHP ended higher than their baseline measurement (4490 ng/dL). His individual pharmacokinetics explains his response as this prepubertal patient had a high clearance (top quartile) and short half-life (bottom quartile) among the patients in the study (Table 2).
Patients 9, 21, and 25 (Fig. 2) show the importance of measuring both 17OHP and D4A as a measure of disease control because some patients in response to hydrocortisone dose may show recovery of one adrenal steroid in the target therapeutic range but not in the other. Patient 9 showed persistently elevated 17OHP levels (>1000 ng/dL), whereas D4A levels were less than 30 ng/dL. On the other hand, in patients 21 and 25, 17OHP levels decreased to less than 1000 ng/dL in response to hydrocortisone but D4A levels remained elevated around 100 ng/dL. Patients 9 and 25 had identical cortisol half-life and similar clearance values (see Table 2) but the degree and duration of suppression of their D4A levels varied dramatically (Fig. 2).
Patient 7’s time-concentration profile (Fig. 2) showed undetectable D4A levels and very low 17OHP levels, suggesting her HPA axis was suppressed. However, her daily hydrocortisone dose was 10.4 mg/m2/day, which is at the low end of the suggested range of hydrocortisone dosing.1The patient’s cortisol half-life and CL/F (dL/hour m2) were in the intraquartile range among the CAH children tested (Table 2). Her results suggest possible interindividual variations in tissue sensitivity to glucocorticoids among children with CAH. About 7% of the general population harbor polymorphisms in the human glucocorticoid receptor that enhance responsiveness to hydrocortisone.23This patient exemplifies the need for close monitoring and constant reassessment of the total daily hydrocortisone dose, even if it is near physiological range, to avoid overtreatment.
Patient 12 highlights the conundrum clinicians face in trying to determine whether compliance or individual pharmacokinetics or glucocorticoid insensitivity is responsible for the undersuppression of the HPA axis. Her very high 17OHP and D4A levels failed to normalize during the test (Fig. 2). Earlier to the test, we suspected noncompliance, partly due to high levels seen during previous visits and that the parents were highly concerned with her weight and the effect that steroids may have on her weight gain. Her daily hydrocortisone dose of 16.4 mg/m2/day was above the suggested range.1However, our understanding of this patient changed as the time-concentration profile showed that this 3 year old had the lowest half-life (0.68 hour) among all the patients, and she had a high clearance in the top quartile (156.6 dL/hour m2) (Table 2). Polymorphisms or epigenetic changes of 11β-HSD isoenzymes in this patient (and others) could conceivably be responsible for the fast cortisol half-life because changes in their enzyme activity could affect the rate of cortisol production and metabolism by favoring either increased or decreased cortisol clearance.21
One of our study objectives was to attempt to better mimic normal circadian cortisol concentrations. It became clear that numerous doses throughout the day would be needed to avoid periods of hypercortisolemia and hypocortisolemia. The intent to replicate cortisol circadian variation is of course countered by the feasibility of how often parents can practically administer oral doses and adherence becomes an issue. Even if the regimen is changed to 4 times a day dosing by splitting the morning dose in 2 separated by 2 hours, there would still be considerable periods of hypercortisolemia and hypocortisolemia as can be seen in Figure 3. This exemplifies the need for the development of alternative drug delivery systems to better control cyclical cortisol concentrations to avoid long-term consequences of hypocortisolemia and hypercortisolemia. Studies in adults with adrenal insufficiency that used glucocorticoid therapy regimens that provide more circadian-based cortisol concentration time profiles were associated with improvement of body weight, HbA1c, blood pressure, and bone formation markers.24,25In comparison, other studies where hydrocortisone doses were decreased by 30% to 50% but did not mimic circadian rhythm of cortisol secretion, no changes in metabolic factors were noted.26–28
We believe that the interindividual variability in the cortisol pharmacokinetic parameters and the pharmacodynamic response to hydrocortisone found in the present study support several changes to consider in the care of CAH patients, specifically: (1) that the treatment of pediatric patients with CAH should move toward more personalized dosing and monitoring regimens based on pharmacokinetic and pharmacodynamic parameters; (2) the development of alternate methods of home monitoring29,30that would allow for more frequent than a single serum measurement taken every 3 to 4 months during a clinic visit6,7,31; (3) measurement should include both 17OHP and D4A; (4) the timing of measurements of 17OHP and D4A relative to the last steroid dose should be documented for comparing across clinic visits; (5) the importance of measuring concentrations at the time of maximal adrenal steroid suppression in response to the preceding hydrocortisone dose around 3 to 4 hours,6,7at 6 hours when some CAH patients rebound to levels above the baseline, and before the next hydrocortisone dosing.
Evaluation of glucocorticoid pharmacokinetics and adrenal steroid suppression based on concentration-time profiles of D4A and 17OHP in the clinical setting can be used to guide CAH therapy by individualizing the dosing regimen. Pharmacokinetic studies can also help distinguish those patients who are not compliant from those who have a high clearance and short hydrocortisone half-life. In addition, patients with increased responsiveness can be identified because it is extremely difficult to assess overtreatment from a single value of any of these hormones because values within the normal range may reflect either overtreatment or increased glucocorticoid responsiveness.
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