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

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. Noncompartmental analysis was used to calculate the area under the plasma concentration–time curve (AUC), maximum plasma concentration ( C max ), time of C max ( t max ), and elimination half-life ( t ½e ) 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. Administration of a single droxidopa dose in the fed versus fasted state decreased mean C max (2057 vs 3160 ng/mL) and mean AUC (10,927 vs 13,857 h × ng/mL) and increased median t max twofold (4.00 vs 2.00 h). Differences between the fed and fasted state for mean t ½e (2.58 vs 2.68 h) were not observed. Fed versus fasted geometric mean ratios for C max 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 C max were observed after each dose (range 2789–3389 ng/mL) with no return to baseline between doses. Norepinephrine C max 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. 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.