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NEUROPHARMACOLOGY

A Pulmonary Formulation of L-Dopa Enhances Its Effectiveness in a Rat Model of Parkinson's Disease

Alkermes Inc., Cambridge, Massachusetts (R.T.B., D.E., P.S., K.F., H.S.-B., D.L., L.N., A.S.B.); and The Nathan Kline Institute, Orangeburg, New York (E.-S.L., T.C.)

The efficacy of oral L-dopa becomes problematic with the progression of Parkinson's disease, due in large part to a lost ability to accommodate L-dopa's inherently poor pharmacokinetics. Pulmonary delivery represents a novel approach to reducing this problem. L-dopa was formulated into inhalable (Alkermes AIR) particles, and its pharmacokinetics and pharmacodynamics compared with those of an oral formulation. Pulmonary administration of L-dopa (2 mg) to rats resulted in a rapid elevation of plasma levels (C_max = 4.8 ± 1.10 µg/ml at 2 min), whereas oral administration of L-dopa produced a much delayed and lower C_max (1.8 ± 0.40 µg/ml at 30 min). In a rat model of Parkinson's disease (unilateral 6-hydroxydopamine lesion), the pulmonary formulation of L-dopa (0.5-2.0 mg) yielded more rapid and robust elevations in striatal L-dopa, dopamine, and dihydroxyphenylacetic acid levels, as well as 2.5 to 3.7 times as many c-fos-expressing striatal neurons. Moreover, motor function was significantly improved by 10 min after administration, with peak improvements occurring within 15 to 30 min. In contrast, considerably higher doses (6.8-10 mg) of orally administered L-dopa took over three times longer to produce similar effects. These results suggest that an inhalable formulation of L-dopa has superior pharmacokinetic properties and may provide patients with a more effective form of rescue therapy as well as being a reliable adjuvant or replacement for first-line oral therapy.

Address correspondence to: Dr. Raymond T. Bartus, Ceregene, Inc., 9381 Judicial Dr., San Diego, CA 92121. E-mail: rtbartus{at}ceregene.com.