Pharmacokinetics, safety, and cardiovascular tolerability of phenylephrine HCl 10, 20, and 30 mg after a single oral administration in healthy volunteers

Abstract

Background and objectives: Phenylephrine HCl 10 mg has been used as a nasal decongestant for over 50 years, yet only limited pharmacokinetic and metabolic data are available. The purpose of this study was to evaluate single-dose pharmacokinetics and safety of phenylephrine HCl 10, 20, and 30 mg and to assess cardiovascular tolerability compared with baseline and placebo in healthy volunteers.

Methods: Twenty-eight adults were enrolled in this randomized, double-blind, placebo-controlled, single-dose, four-treatment crossover study. Subjects remained housed for 6 days to permit time-matched, serial measurements of pulse, blood pressure, and electrocardiograms (ECGs) for baseline and complete treatments on consecutive days. After fasting overnight, subjects were dosed with oral phenylephrine HCl 10, 20, or 30 mg or placebo. Pharmacokinetic blood samples were collected over 7 h, whereas pulse, blood pressure, and ECGs were measured over 12 h. Urine was collected over each 24-h period to quantify phenylephrine and metabolites.

Results: After oral administration, phenylephrine was rapidly absorbed with median times to maximum plasma concentrations (t max) from 0.33 to 0.5 h. For phenylephrine HCl 10, 20, and 30 mg, the mean (standard deviation) maximum concentration (C max) was 1354 (954), 2959 (2122), and 4492 (1978) pg/mL, and total systemic exposure [area under the plasma concentration-time curve from time zero to infinity (AUC∞)] was 955.8 (278.5), 2346 (983.8), and 3900 (1764) pg·h/mL, respectively. Both parameters increased disproportionally with increasing dose, as β >1 in the power model. Negligible amounts of phenylephrine and phenylephrine glucuronide were excreted in urine. With increasing dose, percentages by dose of phenylephrine sulfate decreased, whereas percentages of 3-hydroxymandelic acid increased. Eight subjects reported nine mild adverse events; one (somnolence) was deemed to be treatment related. Means of time-matched differences in pulse and blood pressure from baseline showed similar fluctuations over 12 h among phenylephrine HCl doses and placebo, although small differences in systolic pressure were observed during the initial 2 h. No apparent dose-related effects were observed for Fridericia-corrected QT interval (QTcF) values, and individual changes from time-matched baseline (DQTcF).

Conclusions: Maximum and total systemic exposures following singe doses of phenylephrine HCl 10, 20, and 30 mg increased disproportionally with increasing dose. Safety and cardiovascular tolerability were comparable among doses and placebo.

Fig. 1

Study design scheme where phenylephrine HCl 10, 20, and 30 mg doses are designated as A, B, and C, respectively, and the placebo dose is designated as D. BP blood pressure, ECG electrocardiogram, PK pharmacokinetic

Fig. 2

Mean phenylephrine plasma concentration–time profiles by dose from 0 to 7 h (a), and an expanded view from 0 to 4 h (b). The error bars represent standard deviations at each sampling time

Fig. 3

Mean (standard deviation) time-matched change from baseline for pulse over 12 h for the three phenylephrine HCl doses and placebo. bpm beats per min, PBO placebo

Fig. 4

Mean (standard deviation) time-matched change from baseline for a diastolic and b systolic blood pressure over 12 h for the three phenylephrine HCl doses and placebo. BP blood pressure, PBO placebo

Fig. 5

Box plots for DQTcF over 12 h for a 10, b 20, and c 30 mg doses of phenylephrine HCl and d placebo. The rectangle spans the first to third quartiles with the median segment inside, while the whiskers span 1.5 times the interquartile range. The solid circles are outliers. DQTcF difference in Fridericia-corrected QT interval from time-matched baseline

Fig. 6

Scatter plot of DDQTcF versus measured and interpolated phenylephrine concentrations on the logarithm scale for timepoints up to 4.5 h after the dose. DDQTcF difference in Fridericia-corrected QT interval values between each phenylephrine HCl dose and placebo