Pharmacokinetic parameters

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Comment

The accumulation of corticosteroids can cause Cushing's syndrome (moon face, excitation/insomnia, hypertension, increased appetite and weight, ease of doing bruising) and potentially a suppression of the hypothalamic-pituitary axis, which could lead to adrenal insufficiency.

Ref #2682 : Case report of a patient HIV+ who developed a cushing’s syndrome with budesonide/formoterol as well as ritonavir/lopinavir, tenofovir and emtricitabine. The patient was taking budesonide because she had previously presented a cushing ‘s syndrome with fluticasone, and the symptoms quickly reappeared with budesonide. The dose of ritonavir was decreased without any improvement, and only the replacement of the budesonide by the montelukast allowed to go back to normal.

Réf #2683 : Publication of 3 case reports of children HIV positive who were treated with ritonavir and who have developed a cushing’s syndrome with budesonide inhaled. The first case is with a 4-year-old girl treated with budesonide inhaled and nasal for a daily dose maximal of 1200µg and with ritonavir 300mg/m2. The diagnosis of cushing’s syndrome was done 3 months after the initiation of budesonide. The dose was decreased until 200µg a day but showed no improvement one week later so budenoside was thus stopped. The cortisol went back to the normal 3 weeks after the end of the treatment. The second case presents a 4-year-old girl under lopinavir/ritonavir (ritonavir 235mg / m2) and budesonide 200µg a day. She has presented a cushing’s syndrome 2 years after the initiation of the budesonide. Lopinavir/ritonavir was changed for efavirenz, and the cortisol went back to normal 4 weeks later. The last case presents a 7-year-old boy having presented a cushing’s syndrome with fluticasone.

Ref #2807 : A 48-year-old woman with HIV infection developed Cushingoid features while she was taking ritonavir-boosted darunavir. Cushing's syndrome was confirmed due to the drug interaction between ritonavir and budesonide.

Ref #2806, 2851, 2852 and 2853 : Cases of Cushing's syndrome have been reported with the use of itraconazole (a potent CYP3A4 inhibitor) and budesonide.

The safest corticosteroid is beclomethasone (Qvar) since its metabolism is mainly by an esterification mechanism.

Ref #2550 and #2551 : A cross-sectional study (n = 11 783) suggests lower prevalence of adrenal insufficiency with beclomethasone than with other corticosteroids currently available on the market. Pharmacokinetic studies with beclomethasone and ritonavir or combination darunavir/ritonavir demonstrated that there were no clinically significant pharmacokinetic interactions. No variation of blood cortisol have been observed.

Budesonide should not be stopped without consultation with a physician. If the axis hypothalamo-hypophyseal is eliminated, stopping suddenly budesonide can lead to signs and symptoms of adrenal incapacity. It is recommended to decrease slowly the corticosteroid to avoid the symptoms of craving (fatigue, loss of weight, intoxications, weakness, low postural blood pressure and acute adrenal crisis). Plasma cortisol and ACTH test will document the presence or absence of adrenal insufficiency.

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