Novel treatment of adrenal crisis: an early clinical trial with nebulized prednisolone

Patients with adrenal insufficiency rely on glucocorticoid substitution therapy
(hydrocortisone or cortisone acetate). In case of an acute stressful situation,
e.g. illness, trauma or psychological stress, the standard substitution dose
fall short and patients need to increase their glucocorticoid dose to prevent a
cortisol deficiency which could ultimately lead to an adrenal crisis. The
incidence of an adrenal crisis is about 5-10 per year 100 patient years and is
characterized by hypotension, nausea, hyponatremia, hyperkalemia, hypoglycemia,
and a circulatory shock with the risk of a fatal outcome. Acute administration
of glucocorticoids in case of an adrenal crisis is of vital importance.
Currently, patients have to inject themselves with an intramuscular injection
of 100 mg hydrocortisone. Hydrocortisone is an unstable product in solution, it
is therefore given to the patient as a powder and the patient must prepare the
medication (with the so-called *Act-O-Vial*), and then self-administer the
hydrocortisone solution by an intramuscular injection. If the injection is
insufficient, sometimes a second injection is necessary.
Patients with an adrenal crisis in an early stage can already experience
confusion, drowsiness, dizziness and nausea. Furthermore, many patients fear
needles, because the procedure of preparing the emergency medication is not
routine for them. It is therefore logical that this method of drug
administration is often not sufficiently used and easily leads to errors. The
patients always have to carry the Solu-Cortef® Carry Act-O-vial, syringe and
needle with them. This is often believed to be impractical and many patients do
not carry their emergency medication with them. In addition, we recently
published data about adrenal crisis in our own UMCG population, and concluded
that less than half of the patients who experienced an adrenal crisis used
their emergency medication.
A small inhaler containing prednisolone could possibly replace the
hydrocortisone injection. It is known that for several drugs that the time from
administration to its effect is similar after inhalation and after injection.
Examples are adrenaline, levodopa, morphine and insulin. Based upon of the
physicochemical properties, prednisolone is expected to be as rapidly
distributed in the bloodstream after inhalation compared to an intramuscular
injection. In addition, previous application of inhaled prednisolone for
patients with asthma and COPD has proven that the inhalation of prednisolone is
safe. The patient*s resistance against inhalation is much smaller than against
the injection.
The above advantages make the prednisolone inhaler a much safer and more
patient-friendly product than the injection currently being used.

As the first step in the development of this prednisone inhaler we will
investigate if therapeutic plasma concentrations of prednisolone can be reached
by nebulizing prednisolone. In this study, we administer nebulized prednisolone
in two different dosages to healthy volunteers.
*

The aim of this study is to establish pharmacokinetic data on inhaled nebulized
prednisolone: Time from start nebulizing to serum peak prednisolone
concentration (Tmax) and prednisolone area under. We derive this
pharmacokinetic data from two different dosages of nebulized prednisolone: a
lower and a higher dose

Single center, open label

Every subject receives a lower dose of nebulized prednisolone. After a wash out
of one week, every subject receives a higher dose of nebulized prednisolone.

The chance of serious or long term side-effects is very limited. There is a
small risk of an AE during blood-sampling (formation of hematoma, infection and
bruising). If the prednisolone inhaler is a reliable alternative for a
hydrocortisone injection, the patients with adrenal insufficiency will greatly
benefit.