JERUSALEM—The device used for drug delivery may affect the extent to which inhaled corticosteroids suppress adrenal function. The clinical implications of that finding are currently under debate.

Lung deposition of inhaled budesonide is greater when the drug is administered with a dry powder inhaler (DPI) rather than a pressurized metered-dose inhaler (pMDI). While that translates into an enhanced therapeutic effect in the asthmatic lung, it also raises the possibility of increased systemic absorption and thus a heightened risk of adverse effects.

Investigators recently assessed the prevalence of one possible adverse effect—hypothalamic-pituitary-adrenal (HPA) axis suppression—among 15 asthmatic children who were receiving low-dose inhaled budesonide.[1] “A low daily dose of 400 µg given with a DPI was associated with HPA axis suppression in these children,” reported Eitan Kerem, MD, one of the investigators. “This effect was not observed when the same dose of budesonide was delivered with a pMDI attached to a large volume spacer,” he added.

A CROSSOVER DESIGN

The children in the study, who ranged in age from 5 to 15 years, were randomized to 200 µg of inhaled budesonide twice daily for one month via a DPI or pMDI attached to a 750-mL spacer. Both groups were then switched to one month of the opposing therapy after they completed their initial treatment assignments.

Evaluation of HPA axis function consisted of 24-hour urine collection at baseline and after completion of each treatment course; the investigators looked specifically at urine creatinine and cortisol levels. Urinalysis was corrected for 24-hour urine creatinine excretion to account for body mass differences among the children.

STATISTICAL VERSUS CLINICAL SIGNIFICANCE

Treatment compliance (measured with medication diaries completed daily by the children’s parents and validated by weighing the returned canisters) was 85% in both groups. The baseline urine cortisol:creatinine ratio was also the same in the two groups—0.038 µg/mg.

However, a statistically significant HPA axis suppression occurred during DPI use; the urine cortisol:creatinine ratio declined 27% after one month of therapy. There was only a nonsignificant 5.9% decline in that ratio when the children used a pMDI for one month. The order of treatment did not affect the results.

Whether the adrenal suppression observed was clinically significant is unclear, the investigators acknowledge, because the children’s mean urine cortisol:creatinine ratio was within the normal range before and after both forms of treatment. Nevertheless, Dr. Kerem, who heads the Department of Pediatrics at Hadassah University Hospital in Jerusalem, suggests that clinicians use pMDIs as the preferred mode of delivery in children requiring long-term budesonide therapy.

DOSAGE AND DELIVERY

Not all experts agree, however. Inhaled budesonide’s greater effect on the HPA axis with DPI administration reflects superior drug delivery to the lung and is a good thing, argues David B. Allen, MD, in an editorial.[2] He believes that the clinical significance of the Israeli researchers’ finding is that a drug’s dosage may have to be altered to match a delivery device.

“Although 400 µg daily is a low-dose treatment with [budesonide] by MDI, it probably should not be characterized as such via DPI,” explained Dr. Allen, a pediatric endocrinologist at the University of Wisconsin Children’s Hospital in Madison. “Therefore, it is not correct to conclude from this article that [budesonide] by pMDI + spacer is safer or preferable,” he asserted. “It is merely a less effective means of delivering the medication.”

—Timothy Begany