Rationale of a lower dexamethasone dose in prenatal congenital adrenal hyperplasia therapy based on pharmacokinetic modelling

2021 ◽  
Author(s):  
Viktoria Stachanow ◽  
Uta Neumann ◽  
Oliver Blankenstein ◽  
Uwe Fuhr ◽  
Wilhelm Huisinga ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
External Genitalia ◽  
Stochastic Simulations ◽  
Minimum Effective Dose ◽  
Adrenal Hyperplasia ◽  
Androgen Excess ◽  
Nonlinear Mixed Effects Model ◽  
Dexamethasone Therapy ◽  
Fit For Purpose ◽  
Pituitary Adrenal Axis

Context: Prenatal dexamethasone therapy is used in female foetuses with congenital adrenal hyperplasia to suppress androgen excess and prevent virilisation of the external genitalia. The traditional dexamethasone dose of 20 µg/kg/d has been used since decades without examination in clinical trials and is thus still considered experimental. Objective: Because the traditional dexamethasone dose potentially causes adverse effects in treated mothers and foetuses, we aimed to provide a rationale of a reduced dexamethasone dose in prenatal congenital adrenal hyperplasia therapy based on a pharmacokinetics-based modelling and simulation framework. Methods: Based on a published dexamethasone dataset a nonlinear mixed-effects model was developed describing maternal dexamethasone pharmacokinetics. In stochastic simulations (n=1000) a typical pregnant population (n=124) was split into two dosing arms receiving either the traditional 20 µg/kg/d dexamethasone dose or reduced doses between 5 and 10 µg/kg/d. Target maternal dexamethasone concentrations, identified from literature, served as threshold to be exceeded by 90% of mothers at steady state to ensure foetal hypothalamic‐pituitary‐adrenal axis suppression. Results: A two-compartment dexamethasone pharmacokinetic model was developed and subsequently evaluated to be fit for purpose. The simulations, including a sensitivity analysis regarding the assumed foetal:maternal dexamethasone concentration ratio, resulted in 7.5 µg/kg/d to be the minimum effective dose and thus our suggested dose. Conclusions: We conclude that the current experimentally used dexamethasone dose is 3-fold higher than needed, possibly causing harm in treated foetuses and mothers. The clinical relevance and appropriateness of our recommended dose should be tested in a prospective clinical trial.

scholarly journals Validation and Preliminary Results of the Parental Assessment of Children's External Genitalia Scale for Females (PACE-F) for Girls With Congenital Adrenal Hyperplasia

Urology ◽  
2019 ◽  
Vol 130 ◽  
pp. 132-137
Author(s):  
Konrad M. Szymanski ◽  
Benjamin Whittam ◽  
Patrick O. Monahan ◽  
Martin Kaefer ◽  
Heather Frady ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
External Genitalia ◽  
Adrenal Hyperplasia ◽  
Preliminary Results ◽  
Parental Assessment

Therapeutic challenges in a patient with the simple virilizing (SV) form of congenital adrenal hyperplasia (CAH) due to the P30L/I172N genotype

2019 ◽  
Vol 32 (5) ◽  
pp. 543-547 ◽  
Author(s):  
Maja Tankoska ◽  
Violeta Anastasovska ◽  
Marina Krstevska-Konstantinova ◽  
Michel Naydenov ◽  
Mirjana Kocova
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Polymerase Chain Reaction Amplification ◽  
Point Mutations ◽  
External Genitalia ◽  
High Serum ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Her Family ◽  
Simple Virilizing ◽  
21 Hydroxylase Deficiency

Abstract Background Steroid 21-hydroxylase deficiency is an autosomal recessive disorder, present in 90–95% of all cases with congenital adrenal hyperplasia (CAH). The classical simple virilizing (SV) form of the disease causes virilization of the external genitalia in newborn females and pseudo-precocious puberty in both sexes, due to reactive androgen overproduction. Case presentation We describe a 3.5-year-old girl presenting with pubarche, P2 according to Tanner, advanced bone age of 6 years and 10 months, and high serum levels of 17-hydroxyprogesterone (17-OHP). Molecular analysis of the nine most common pseudogene-derived CYP21A2 point mutations was performed in the patient and her family members using the polymerase chain reaction/amplification-created restriction site (PCR/ACRS) method. We detected the P30L/I172N genotype in the patient. She had inherited a mild P30L mutation from her mother and a severe I172N mutation from her father. Conclusions Although the CAH phenotype is determined by the allele that produces most of the enzyme activity and the mild non-classical (NC) phenotype should be expected, the mild P30L known to be more virilizing probably induced the classical SV phenotype in our patient. A continuous regimen of hydrocortisone at a recommended dose failed to decrease the 17-OHP sufficiently. Careful tapering of the dose did not help, and her pubic hair advanced to P3 according to Tanner. Individually tailored treatment is warranted in this patient.

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update on the management of adult patients and prenatal treatment

2017 ◽  
Vol 176 (4) ◽  
pp. R167-R181 ◽  
Author(s):  
Anne Bachelot ◽  
Virginie Grouthier ◽  
Carine Courtillot ◽  
Jérôme Dulon ◽  
Philippe Touraine
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Management Strategies ◽  
The United States ◽  
Fertility Treatment ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Androgen Excess ◽  
Classic Cah ◽  
21 Hydroxylase Deficiency ◽  
And Control

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by cortisol and in some cases aldosterone deficiency associated with androgen excess. Goals of treatment are to replace deficient hormones and control androgen excess, while avoiding the adverse effects of exogenous glucocorticoid. Over the last 5 years, cohorts of adults with CAH due to 21-hydroxylase deficiency from Europe and the United States have been described, allowing us to have a better knowledge of long-term complications of the disease and its treatment. Patients with CAH have increased mortality, morbidity and risk for infertility and metabolic disorders. These comorbidities are due in part to the drawbacks of the currently available glucocorticoid therapy. Consequently, novel therapies are being developed and studied in an attempt to improve patient outcomes. New management strategies in the care of pregnancies at risk for congenital adrenal hyperplasia using fetal sex determination and dexamethasone have also been described, but remain a subject of debate. We focused the present overview on the data published in the last 5 years, concentrating on studies dealing with cardiovascular risk, fertility, treatment and prenatal management in adults with classic CAH to provide the reader with an updated review on this rapidly evolving field of knowledge.

scholarly journals Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency*

2000 ◽  
Vol 21 (3) ◽  
pp. 245-291 ◽  
Author(s):  
Perrin C. White ◽  
Phyllis W. Speiser
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
External Genitalia ◽  
Clinical Severity ◽  
Sodium Balance ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Gene Encoding ◽  
Salt Wasting ◽  
Direct Mutation ◽  
21 Hydroxylase Deficiency

Abstract More than 90% of cases of congenital adrenal hyperplasia (CAH, the inherited inability to synthesize cortisol) are caused by 21-hydroxylase deficiency. Females with severe, classic 21-hydroxylase deficiency are exposed to excess androgens prenatally and are born with virilized external genitalia. Most patients cannot synthesize sufficient aldosterone to maintain sodium balance and may develop potentially fatal “salt wasting” crises if not treated. The disease is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombinations between CYP21 and the closely linked CYP21P pseudogene. Approximately 20% are gene deletions due to unequal crossing over during meiosis, whereas the remainder are gene conversions—transfers to CYP21 of deleterious mutations normally present in CYP21P. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disease in patients carrying it. Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females to minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before salt wasting crises develop, reducing mortality from this condition. Glucocorticoid and mineralocorticoid replacement are the mainstays of treatment, but more rational dosing and additional therapies are being developed.

scholarly journals Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia

2021 ◽  
Author(s):  
Deborah P Merke ◽  
Ashwini Mallappa ◽  
Wiebke Arlt ◽  
Aude Brac de la Perriere ◽  
Angelica Lindén Hirschberg ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Disease Control ◽  
Standard Therapy ◽  
Extension Study ◽  
Modified Release ◽  
Adrenal Hyperplasia ◽  
Androgen Excess ◽  
Phase 3 ◽  
Patient Reported ◽  
17 Hydroxyprogesterone

Abstract Context Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes. Objective We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control. Methods A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study. Results The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP (< 1200 ng/dL) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P = .002), and 80% for MR-HC at 18 months’ extension. The median daily hydrocortisone dose was 25 mg at baseline, at 6 months 31 mg for standard therapy, and 30 mg for MR-HC, and after 18 months 20 mg MR-HC. Three adrenal crises occurred in phase 3, none on MR-HC and 4 in the extension study. MR-HC resulted in patient-reported benefit including menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy). Conclusion MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.

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