Comparison of the Pharmacokinetics of Droxidopa After Dosing in the Fed Versus Fasted State and with 3-Times-Daily Dosing in Healthy Elderly Subjects

Jack J Chen, L Arthur Hewitt, Jack J Chen, L Arthur Hewitt

Abstract

Background: Droxidopa is an oral prodrug of norepinephrine approved for the treatment of symptomatic neurogenic orthostatic hypotension. This two-part, randomized, crossover study evaluated the 24-h pharmacokinetic profile of droxidopa in 24 healthy elderly subjects.

Methods: Noncompartmental analysis was used to calculate the area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), time of Cmax (tmax), and elimination half-life (t½e) of droxidopa and metabolites. Droxidopa was administered in the fed (high-fat/high-calorie meal) or fasted state either as a single 300-mg dose (three 100-mg capsules) or 3 times/day (TID) (three 100-mg capsules) at 4-h intervals.

Results: Administration of a single droxidopa dose in the fed versus fasted state decreased mean Cmax (2057 vs 3160 ng/mL) and mean AUC (10,927 vs 13,857 h × ng/mL) and increased median tmax twofold (4.00 vs 2.00 h). Differences between the fed and fasted state for mean t½e (2.58 vs 2.68 h) were not observed. Fed versus fasted geometric mean ratios for Cmax and AUC were 66% [90% confidence interval (CI) 60.7-71.7] and 80% (90% CI 72.6-88.1), respectively. With TID dosing, similar values for Cmax were observed after each dose (range 2789-3389 ng/mL) with no return to baseline between doses. Norepinephrine Cmax was 895 pg/mL following dose 1, with no further increases upon subsequent doses; norepinephrine levels remained above baseline for 12-16 h after dose 1.

Conclusions: Absorption of a single dose of droxidopa is slowed after a high-fat/high-calorie meal; for consistent effect, administer droxidopa in the same manner (with or without food). Pharmacokinetic parameters of droxidopa are similar after single and TID dosing. ClinicalTrials.gov Identifier: NCT01149629.

Conflict of interest statement

Author Jack J. Chen is an employee at the Department of Pharmacy Practice, College of Pharmacy, Marshall B. Ketchum University, and provides consulting services to Lundbeck. L. Arthur Hewitt is an employee of Lundbeck.

Figures

Fig. 1
Fig. 1
Metabolism of droxidopa
Fig. 2
Fig. 2
Study design. TID 3 times daily
Fig. 3
Fig. 3
Comparison of mean droxidopa plasma concentrations* for fed† vs fasted administration (linear axes). *Mean (SD) concentration per time point. †High-fat, high-calorie meal. SD standard deviation
Fig. 4
Fig. 4
Mean (SD) plasma concentrations (linear axes) after droxidopa TID administration: a droxidopa, b norepinephrine, and c 3-methoxylated dihydroxyphenylserine. Arrows indicate time of dose administration. SD standard deviation, TID 3 times daily

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