Regulatory Toxicology and Pharmacology 95 (2018) 333–338

Contents lists available at ScienceDirect

Regulatory Toxicology and Pharmacology

journal homepage: www.elsevier.com/locate/yrtph

An open-label, randomized, four-treatment crossover study evaluating the T

effects of salt form, acetaminophen, and food on the pharmacokinetics of
phenylephrine
Cathy K. Gelotte
Johnson & Johnson Consumer, Inc, 7050 Camp Hill Road, Fort Washington, PA 19034, USA

A R T I C LE I N FO A B S T R A C T

Keywords: Phenylephrine hydrochloride (HCl) is a decongestant available in over-the-counter (OTC) medicines. Previously
Phenylephrine marketed prescription products contained phenylephrine tannate, an extended-release salt, which allowed
Pharmacokinetics dosing every 8–12 h. Given the regulatory history that cold medicines marketed before 1962 had limited sup-
Food effect porting clinical data, and with widespread replacement of pseudoephedrine by phenylephrine in OTC products
Phenylephrine tannate
over the last ten years, the need for contemporary studies grew. This exploratory crossover study evaluated
Phenylephrine hydrochloride
effects of salt form, acetaminophen, and food on phenylephrine pharmacokinetics and metabolites in healthy
Phenylephrine-acetaminophen combination
product adults. Test treatments were 25 mg phenylephrine tannate (equivalent to 10 mg phenylephrine HCl) combined
with 200 mg guaifenesin, fasted; 10 mg phenylephrine HCl combined with 650 mg acetaminophen, fasted; and
10 mg phenylephrine HCl, fed. The reference treatment was 10 mg phenylephrine HCl, fasted. Plasma pheny-
lephrine pharmacokinetics and urine metabolites were determined. Although the tannate salt slowed pheny-
lephrine absorption compared with the HCl salt, terminal concentrations were similar, suggesting that products
containing the tannate salt should not be dosed less frequently than those containing the HCl salt. The premise
that acetaminophen increases phenylephrine bioavailability by competition for presystemic sulfation was cor-
roborated by increased phenylephrine sulfate in urine. Food delayed phenylephrine absorption, but not the total
amount absorbed.

1. Introduction
Phenylephrine hydrochloride (HCl) is a nasal decongestant used in
single- and multiple-ingredient over-the-counter (OTC) medicines and
is indicated for the temporary relief of nasal congestion caused by the
common cold or allergies. In the United States (US), the adult dosage is
10 mg every 4 h with a total allowable daily dose of 60 mg.
Phenylephrine HCl has been available prior to the 1960's before the
advent of rigorous clinical development. It was studied in several pla-
cebo-controlled, crossover clinical trials that were reviewed by an ex-
pert panel and provided the basis for phenylephrine HCl and bitartrate
salts being generally recognized as safe and effective in the US OTC
drug monograph for Cold, Cough, Allergy, Bronchodilator, and
Antiasthmatic Drug Products in 21 Code of Federal Regulations (CFR)
Part 341 (FDA, 1994).
Phenylephrine's use in commercial OTC drug products was in-
substantial compared with pseudoephedrine, the longer-acting nasal
decongestant, until 2006. Illicit use of pseudoephedrine as a precursor
in the synthesis of methamphetamine had grown significantly, which
prompted the US Congress to enact the Combat Methamphetamine
Epidemic Act that limits the sale of products containing pseudoephe-
drine to behind-the-counter placement in pharmacies and the amount
sold to each customer (CDC, 2013). To expand consumer access to OTC
cold products beyond pharmacies, manufacturers replaced pseudoe-
phedrine sulfate with phenylephrine HCl in many products.
With the transition to phenylephrine-containing OTC cold products,
lack of contemporary clinical pharmacology data created the need to
study phenylephrine, beginning with the development of a sensitive,
validated assay for plasma concentrations (Ptacek and Macek, 2007).
Subsequent studies identified a pharmacokinetic drug-drug interaction
between the analgesic, acetaminophen, and phenylephrine (Atkinson
et al., 2014, 2015a), and evaluated the pharmacokinetics, metabolism,
and cardiovascular tolerability of 10, 20, and 30 mg phenylephrine HCl
(Gelotte and Zimmerman, 2015). Collectively these published studies,
along with an early study on radio-labeled phenylephrine (Hengstmann
and Goronzy, 1982), found that phenylephrine is rapidly absorbed after
oral administration, ranging from 20 to 75 min, and has a short term-
inal exponential half-life, ranging from 0.5 to 2.5 h, and low bioavail-
ability (38%) due to high first-pass metabolism. For the 10-mg pheny-
lephrine HCl dose, mean total exposure (AUC∞) ranged from 956 to

E-mail address: cathy.k.gelotte@gmail.com.

https://doi.org/10.1016/j.yrtph.2018.04.008
Received 30 December 2017; Received in revised form 4 April 2018; Accepted 5 April 2018
Available online 07 April 2018
0273-2300/ © 2018 Published by Elsevier Inc.
C.K. Gelotte
1916 pg h/mL across studies and mean maximum exposure (CMAX)
ranged from 874 to 1600 pg/mL. The high degree of intersubject
variability noted in these exposure parameters is characteristic of drugs
that undergo high first-pass metabolism. The large study-to-study dif-
ferences may reflect differences in the plasma assays or study popula-
tions.
Phenylephrine tannate, a reportedly extended-release salt form of
phenylephrine, was formulated in prescription cold and allergy pro-
ducts that allowed dosing every 8–12 h. A 25-mg dose of phenylephrine
tannate contains approximately the same amount of free base pheny-
lephrine (∼8 mg) as the 10-mg dose of phenylephrine HCl. At the time
of this study, phenylephrine tannate was on the list of unapproved
drugs pending review under the Drug Efficacy Study Implementation
program, which classified pre-1962 drugs that were already on the
market as either effective, ineffective, or needing further study
(Guidance for FDA Staff and Industry, 2011).
The objective of this exploratory study was to learn more about the
clinical pharmacology of phenylephrine, specifically whether the tan-
nate salt is absorbed at a slower rate than the hydrochloride salt;
whether acetaminophen alters the metabolism of phenylephrine, which
would impact pharmacokinetics; and whether a high-fat meal affects
phenylephrine bioavailability.
2. Methods
2.1. Ethics and study design
The study was conducted at a phase 1 clinic (Cetero Research,
Fargo, ND) between March and May 2008 in compliance with the
International Conference on Harmonization: Good Clinical Practice and
the Health Insurance Portability and Accountability Act. The protocol
and informed consent form were reviewed and approved by the PRACS
Institutional Review Board (Fargo, ND). All subjects were informed of
the nature and purpose of the study and gave written informed consent
before screening.
The study had an open-label, randomized, four-treatment, crossover
design to evaluate the effects of salt form, acetaminophen, and food on
single-dose pharmacokinetics of phenylephrine in 20 healthy adults.
Subjects were admitted to the clinic the evening before each treatment
period and remained on site until after the last blood and urine samples
were collected 24 h after dosing. Given the short half-life of pheny-
lephrine, the periods were separated by at least a 3-day washout after a
dose. Site personnel administered study drug following a four-treatment
sequence randomization. During these treatments, subjects abstained
from caffeine-containing products for 24 h before the study start until
discharge. Standardized beverages and meals were free from grapefruit
and xanthine containing products.
2.2. Subjects
Men and women ages 18 through 58 years with a body mass index
approximately 18–29 kg/m2 and a total body weight > 50 kg (110 lb)
were eligible to participate if they were deemed healthy by medical
history, physical examination, clinical laboratory profile (blood chem-
istry profile, hematology, urinalysis), vital signs, and 12-lead electro-
cardiogram (ECG). Prospective nonsmoking subjects were excluded if
they had a history of clinically significant systemic conditions; hepatitis
B or C, or antibodies to human immunodeficiency virus; taken any
prescription or nonprescription medications or monoamine oxidase
inhibitors within 7 days or 5 half-lives (whichever is longer) before dose
administration; a history of excessive alcohol use; a positive urine drug
screen; or a known sensitivity or allergy to phenylephrine. Women who
were pregnant or nursing were excluded.
334
Regulatory Toxicology and Pharmacology 95 (2018) 333–338
2.3. Treatments and investigational products
Commercially available drug products were supplied to the clinic in
their original packages. For Treatments A, B, and D, subjects were ad-
ministered the dose with 250 mL water after fasting overnight for at
least 10 h and remained fasted until 4 h after dosing. These three fasting
treatments were A: single dose of 25 mg phenylephrine tannate
(equivalent to phenylephrine HCl 10 mg) administered as one combi-
nation tablet of SINA-12X® (MedPointe Healthcare Inc, Somerset, NJ;
phenylephrine tannate 25 mg, guaifenesin 200 mg per tablet); B: single
dose of 10 mg phenylephrine HCl administered as two combination
caplets of Tylenol® Sinus Congestion & Pain Daytime (McNeil-PPC,
Lancaster, PA; phenylephrine HCl 5 mg, acetaminophen 325 mg per
caplet); and D: single dose of 10 mg phenylephrine HCl administered as
one tablet of Sudafed® PE (Pfizer, Inc, Morristown, NJ). For Treatment
C, following an overnight fast of at least 10 h, subjects were adminis-
tered a single dose of 10 mg phenylephrine HCl as one tablet of
Sudafed® PE with 250 mL water 30 min after the start of a standard
high-fat breakfast (Guidance for Industry, 2002).
2.4. Pharmacokinetics
2.4.1. Sample collection and assays
Fifteen blood samples (5 mL) for the pharmacokinetic evaluation of
phenylephrine in each treatment were collected by direct venipuncture
into tubes containing tripotassium ethylenediamine tetra-acetic acid as
the anticoagulant. Because Treatment A included the long-acting tan-
nate salt of phenylephrine and Treatment C would access potential food
effects, blood sampling times were scheduled up to 8 h after each dose
at predose; 10, 20, 30, 45, and 60 min; and 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and
8 h. Based on previous studies of phenylephrine HCl being rapidly ab-
sorbed and eliminated, blood collections were adjusted to earlier times
for Treatments B and D at predose; 5, 10, 15, 20, 30, 35, 45, 50, and
60 min; and 1.5, 2, 3, 4, and 5 h. Plasma was harvested from the blood
samples and stored frozen at −70 °C until assayed.
For the urine metabolite evaluation, subjects completely voided
their bladders within 20 min of dosing for each treatment period, and a
predose aliquot of urine was collected from this volume. All urine was
collected throughout 24 h beginning immediately after the dose was
administered and ending with the final, scheduled void. For each 24-h
interval, urine was pooled into a covered container and stored re-
frigerated. The total amount collected was measured by weight and,
after thorough mixing, aliquots were transferred and frozen at −70 °C
until assayed.
Bioanalytical assays were conducted by PPD, Inc. (Madison, WI).
Plasma samples were analyzed for phenylephrine (unconjugated, free
base) using a commercial, validated liquid chromatography–tandem
spectrometry (LC/MS/MS) method with quantification limits from 10.0
to 2500 pg/mL (PPD Bioanalytical Laboratory, 2007). The interassay
accuracy ranged from 2.68% to 13.0%, and interassay variability
ranged from 4.01 to 26.0% for quality control samples run during
sample analysis.
Urine samples were analyzed for phenylephrine (unconjugated, free
base), total phenylephrine (unconjugated plus enzyme-digested con-
jugates), phenylephrine-glucuronide, and 3-hydroxymandelic acid (3-
HMA) using commercial, validated LS/MS/MS methods (PPD
Bioanalytical Laboratory, 2008a; PPD Bioanalytical Laboratory, 2008b;
PPD Bioanalytical Laboratory, 2008c). The quantification limits were
2.0–200 ng/mL for phenylephrine and phenylephrine-glucuronide, and
100–5000 ng/mL for total phenylephrine and 3-HMA. The interassay
precision and accuracy of quality control samples were < 13.6%
and < 5.27%, respectively, for phenylephrine; < 15.7% and < 7.02%,
respectively, for phenylephrine-glucuronide; < 3.41% and < 1.29%,
respectively, for total phenylephrine; and < 12.0% and < 4.42%, re-
spectively, for 3-HMA.
C.K. Gelotte Regulatory Toxicology and Pharmacology 95 (2018) 333–338

2.4.2. Pharmacokinetic and statistical analysis

No specific sample size calculation was applied, as this study was
exploratory. A sample size of 20 subjects was considered sufficient to
describe phenylephrine pharmacokinetics and metabolism adequately.
Phenylephrine pharmacokinetic parameters were derived or observed
from individual plasma concentration-time data and included max-
imum concentration (CMAX), time to maximum concentration (TMAX),
area under the plasma concentration-time curve extrapolated to infinity
(AUC∞), and terminal exponential half-life (t½). Data were analyzed
with actual sampling times using WinNonlin® Version 5.2.1 (PharSight,
Mountain View, CA) and noncompartmental methods (e.g., linear-log
trapezoidal method for AUC). Concentrations below the lower limit of
quantitation that occurred before and after CMAX were imputed as zero
and missing, respectively.
For the urine pharmacokinetic analysis, the total amounts of phe-
nylephrine (unconjugated), total phenylephrine, and two metabolites
(phenylephrine-glucuronide and 3-HMA) excreted in urine over 24 h
were quantified. Because the sulfate metabolite could not be synthe-
sized and assayed directly in urine, the amount excreted was estimated
indirectly as described previously using the amount of total pheny-
lephrine (Gelotte and Zimmerman, 2015). The excreted amounts (Ax)
were expressed as percentages of the administered phenylephrine dose
(PDx), using the following equation: PDx (%) = [Ax (μmol)/(free-base
dose (μmol)] x 100.
Statistical analyses were conducted using SAS®, Version 9.2. (SAS
Institute Inc., Cary, NC). Pharmacokinetic parameters were summarized
with descriptive statistics, and natural logarithmic transformed AUC∞
and CMAX were analyzed using a mixed-effect analysis of variance
(ANOVA). The general linear model procedure of SAS was used in the
ANOVA for a four-treatment crossover design. Four factors in the
ANOVA tested for effects of treatment, treatment sequence, subjects
within sequence, and study period. The ratios of least-squares geo-
metric means for phenylephrine AUC∞ and CMAX, comparing
Treatments A, B, and C to Treatment D (reference), and associated 90%
Fig. 1. Mean plasma phenylephrine concentrations over time for each treat-
confidence intervals at α = 0.05 were determined. ment on the (a) linear and (b) semi-logarithmic scales.

2.5. Safety Table 1

Phenylephrine pharmacokinetic parameters summarized by mean, standard
deviation (SD), and % coefficient of variation (N = 20).
For safety monitoring, vital signs were measured at screening,
during each study period, and at the completion of the study. Safety Treatment AUC∞ (pg·h/ CMAX (pg/ TMAXa (h) t½ (h)
mL) mL)
was assessed by observed or spontaneously reported treatment-emer-
gent adverse events throughout the study and review of vital signs A: Phenylephrine tannate 942.9 926.0 0.63 1.51
(blood pressure and pulse measurements), laboratory values, and phy- 25 mgb
sical examinations. [Guaifenesin 200 mg] (224.6) (397.9) (0.33–3.0) (1.05)
(fasted) 23.8% 43.0% 69.5%
B: Phenylephrine HCl 10 mg 1246 2458 0.42 1.14
[Acetaminophen 650 mg] (281.2) (1287) (0.25–1.5) (0.63)
3. Results and discussion (fasted) 22.6% 52.4% 55.4%
C: Phenylephrine HCl 10 mg 740.6 591.2 0.50 1.20
Twenty enrolled healthy adults (10 men and 10 women), ranging in (fed high fat meal) (120.3) (231.1) (0.33–2.0) (0.55)
16.2% 39.1% 45.4%
age from 19 to 52 years, completed the study and were included in the
D: Phenylephrine HCl 10 mg 815.6 1053 0.33 1.22
pharmacokinetic and safety analyses. The study population had a mean (fasted) (464.5) (844.6) (0.25–0.83) (0.60)
body mass index of 24.8 ( ± 2.0) kg/m2, and included 1 Hispanic Black, 57.0% 80.2% 49.7%
2 Native American, 1 Asian, and 16 White subjects. Mean plasma
concentration-time profiles for phenylephrine are shown by treatment Abbreviations: AUC∞: area under the plasma concentration-time curve from
in Fig. 1 on the linear and semilogarithmic scales, and pharmacokinetic time zero to infinity; CMAX: maximum concentration; TMAX: time to maximum
concentration; t½;: terminal exponential half-life.
parameters are summarized in Table 1. Fig. 2 shows the pharmacoki- a
median (minimum – maximum).
netic profiles for each pairwise comparison with the reference treat- b
25 mg of phenylephrine tannate is equivalent to 10 mg phenylephrine HCl,
ment, 10 mg phenylephrine HCl after fasting. Results from the statis-
as they both contain approximately 8 mg phenylephrine free base.
tical analysis comparing phenylephrine exposure parameters (AUC∞
and CMAX) for each combination product with the reference product
3.1. Effect of salt form on phenylephrine pharmacokinetics
after fasting are summarized in Table 2 along with results for the effect
of food on phenylephrine absorption. Results from the urine analysis of
Tannic acid forms complexes or salts with drug molecules that have
phenylephrine and its metabolites are summarized by treatment in
an amine group, producing tasteless substances with lower water so-
Table 3.
lubility (Kaplan et al., 1963; Rahman et al., 2012). This leads to slower

335
C.K. Gelotte Regulatory Toxicology and Pharmacology 95 (2018) 333–338

Fig. 2. Pairwise comparisons (a, b, c) of mean (SD) phenylephrine pharmacokinetic profiles for each test treatment with the reference phenylephrine 10-mg HCl
product. Key: ACM – acetaminophen, PE – phenylephrine, SD – standard deviation.

Table 2 Table 3
Statistical analysis of phenylephrine exposure parameters comparing two Mean (SD) percent of phenylephrine, metabolites, and total dose recovered in
combination products with the reference product after fasting, and the effect of the 24-h urine samples collected during each treatment.
food on the reference product.
Parent or Metabolite Treatment A Treatment B Treatment C Treatment D
CMAX (pg/mL) AUC∞ (pg·h/mL) (fasted) (fasted) (fed) (fasted)

Geometric Mean Geometric Mean PE 0.56% 0.52% 0.49% 0.47%

(0.103) (0.088) (0.083) (0.098)
Treatment A, fasted 839.58 911.04 PE-S 49.6% 33.5% 44.3% 43.3%
Treatment B, fasted 2073.62 1243.39 (10.2) (6.74) (11.4) (12.6)
Treatment C, fed 544.02 730.83 PE-G 0.021% 0.025% 0.005% 0.002%
Treatment D, fasted 892.10 769.69 (0.014) (0.015) (0.010) (0.007)
3-HMA 34.2% 36.6% 29.8% 32.1%
LS Mean Ratio (90% CI) LS Mean Ratio (90% CI) (6.11) (8.60) (5.29) (7.53)
A/D, fasted/fasted 94.11 (72.09, 122.86) 118.37 (107.39, 130.46) Total % Dose 84.3% 70.7% 74.6% 75.9%
B/D, fasted/fasted 232.44 (178.06, 303.44) 161.55 (146.57, 178.05) Collected (11.4) (8.59) (11.4) (12.3)
C/D, fed/fasted 60.98 (46.71, 79.61) 94.95 (86.15, 104.66)
Treatment A: phenylephrine tannate 25 mg, guaifenesin 200 mg; Treatment B:
Treatment A: phenylephrine tannate 25 mg, guaifenesin 200 mg; Treatment B: phenylephrine HCl 10 mg, acetaminophen 650 mg; Treatment C: phenylephrine
phenylephrine HCl 10 mg, acetaminophen 650 mg; Treatment C: phenylephrine HCl 10 mg after a high-fat meal; Treatment D: phenylephrine HCl 10 mg.
HCl 10 mg after a high-fat meal; Treatment D: phenylephrine HCl 10 mg (re- Abbreviations: PE: unconjugated phenylephrine; PE-S: phenylephrine-sulfate;
ference). PE-G: phenylephrine-glucuronide; 3-HMA: 3-hydroxymandelic acid; SD: stan-
Abbreviations: AUC∞: area under the plasma concentration-time curve from dard deviation.
time zero to infinity; CI: confidence interval; CMAX: maximum concentration; LS:
least square. 25 mg phenylephrine tannate was administered as a combination tablet
containing 200 mg guaifenesin (Treatment A) and compared with
dissolution in the presence of electrolytes and, hence, a slower, more 10 mg phenylephrine HCl (Treatment D) (Fig. 2a, Table 1). Both pro-
prolonged absorption. This approach was commercially applied many ducts provided the same dose of free-base phenylephrine, permitting a
years ago to develop extended-release products and reduce the fre- direct comparison of systemic exposure.
quency of administration of drugs with short half-lives. In this study,

336
C.K. Gelotte
Phenylephrine was absorbed more slowly from the tannate salt,
showing a delayed median TMAX (0.63 h) and lower mean CMAX
(926.0 pg/mL) compared with the HCl salt (0.33 h and 1052 pg/mL,
respectively). The statistical analysis comparing the tannate to HCL salt
in Table 2 found that the ratio of least-squares geometric means for
CMAX was 94.11 with the confidence interval (72.09%, 122.86%) ex-
tending below the lower bound (80.00%) for equivalence. However, the
ratio for AUC∞ was 118.37 with the confidence interval (107.39%,
130.46%) extending above the upper bound (125.00%), indicating
about 20% more systemic exposure from the tannate salt form.
Although guaifenesin or other formulation factors may have con-
tributed to the observed differences in phenylephrine pharmacokinetics
between the tannate and HCl salt forms (i.e., delayed absorption, lower
CMAX, and higher AUC∞), the pharmacokinetic profile in Fig. 2a does
not support a long-acting product that is intended for dosing every
8–12 h. Mean phenylephrine plasma concentrations were similar from 2
to 5 h after administration for both salt forms. In addition, the terminal
exponential t½ was short and comparable (1.51 and 1.22 h), and more
aligned with the dosing frequency of 10 mg phenylephrine HCl every
4 h.
Although the tannate salt of phenylephrine slowed absorption as
expected by its mechanism of slowing dissolution, its use as an ex-
tended-release product with a lower dosing frequency does not appear
justified. Indeed, since the time of this study, the US Food and Drug
Administration, has reviewed publicly available scientific literature on
pre-1962 prescription cough, cold, and allergy products, and those that
contain tannate salts, including phenylephrine tannate, are not gen-
erally recognized as safe and effective (Guidance for FDA Staff and
Industry, 2011). Tannate complexes or salts of active ingredients may
be useful for tastemasking, but these would require approval under new
drug applications. (Rahman et al., 2012).
3.2. Effect of acetaminophen on phenylephrine pharmacokinetics
Phenylephrine was rapidly absorbed when administered after
fasting as either two combination tablets in Treatment B (10 mg phe-
nylephrine HCl, 650 mg acetaminophen) or one tablet in Treatment D
(10 mg phenylephrine HCl) with median TMAX of 0.42 and 33 h, re-
spectively (Fig. 2b, Table 1). However, when combined with acet-
aminophen, mean phenylephrine CMAX was approximately 200% higher
than when administered alone (2458 pg/mL versus 1053 pg/mL) and
mean AUC∞ was approximately 50% higher (1246 pg h/mL versus
815.6 pg h/mL). The statistical analysis in Table 2 comparing pheny-
lephrine exposure with and without acetaminophen found that the ratio
of least-squares geometric means for CMAX was 232.44 with the con-
fidence interval (178.06%, 303.44%) extending well above the upper
bound for equivalence. Likewise, the ratio for AUC∞ was 161.55 with
the confidence interval (146.57%, 178.05%) extending well above the
upper bound.
This approximate doubling of CMAX was reported previously in four
studies assessing the pharmacokinetics of 5 mg or 10 mg phenylephrine
HCl administered with 500 mg or 1000 mg acetaminophen in combi-
nation tablets (Atkinson et al., 2014, 2015a). The drug-drug interaction
was attributed to competition for presystemic sulfation, a metabolic
pathway shared by both phenylephrine and acetaminophen. Although
no changes in blood pressure were observed at phenylephrine plasma
concentrations that correlated with a 20-mg phenylephrine dose in
these studies (Atkinson et al., 2015a), the potential safety implication of
increased phenylephrine bioavailability was explored in a pharmaco-
kinetic modeling and simulation analysis (Atkinson et al., 2015b). Si-
mulations using previously published data on blood pressure changes
with administration of phenylephrine topical eye drops during oph-
thalmic surgery predicted an increase in mean diastolic and systolic
pressure of 16 and 20 mmHg, respectively, for a 45-mg oral dose of
phenylephrine HCl. However, in a crossover study in which healthy
subjects received single oral doses of 10, 20, and 30 mg phenylephrine
337
Regulatory Toxicology and Pharmacology 95 (2018) 333–338
HCl or placebo, serial pulse, blood pressure, and electrocardiograms
over 12 h were comparable, showing similar fluctuations and no, or
minimal, effects (Gelotte and Zimmerman, 2015).
3.3. Effect of food on phenylephrine pharmacokinetics
Following the standard high-fat breakfast, phenylephrine was ab-
sorbed more slowly from the 10-mg HCl tablet, showing a delayed
median TMAX (0.50 h) and lower mean CMAX (591.2 pg/mL) compared
with the fasted state (0.33 h and 1053 pg/mL, respectively) (Fig. 2c,
Table 1). The statistical analysis comparing the fed to fasted states in
Table 2 found that the ratio of least-squares geometric means for CMAX
was 60.98 with the confidence interval (46.71%, 79.61%) extending
well below the lower bound for equivalence. Mean total exposure
(AUC∞ fed = 713.4 pg h/mL; AUC∞ fasted = 782.5 pg h/mL) was not
affected by food, as the ratio of least-squares geometric means was
94.95 with the confidence interval (86.15%, 104.66%) falling within
the equivalence range (80.00%, 125.00%).
3.4. Urine pharmacokinetic analysis
In urine, the percentages of dose across treatments excreted as
phenylephrine-sulfate and 3-HMA were generally comparable with
previously reported data for a 10-mg dose (46.6% and 25.3%, respec-
tively, Gelotte and Zimmerman, 2015). Likewise, the percentages ex-
creted as unconjugated phenylephrine and phenylephrine-glucuronide
were similarly negligible as previously reported (0.443% and 0.033%,
respectively, Gelotte and Zimmerman, 2015). Notably, the percent of
the 10-mg phenylephrine dose excreted as phenylephrine sulfate when
administered as the combination product in Treatment B was slightly
lower (33.5%) than other treatments in this study (43.3%–49.6%,
Table 3). These data support the premise that acetaminophen competes
with presystemic sulfation during first-pass metabolism resulting in a
lower fraction of the phenylephrine dose being excreted as pheny-
lephrine sulfate. In this study, the amounts of sulfate conjugate excreted
were estimated indirectly after sulfatase digestion of urine samples.
Availability of validated assays to quantitate phenylephrine sulfate and
another metabolite of phenylephrine, m-hydroxyphenylglycol-sulfate,
directly would improve the precision of the urine metabolite data col-
lected.
3.5. Safety
No serious or severe adverse event was reported, and no subject
discontinued due to an adverse event. During the study, six of 20
subjects reported two moderate and seven mild adverse events. Two
adverse events (nasal congestion and vomiting) were considered re-
motely related to phenylephrine tannate-guaifenesin in Treatment A.
The remaining seven adverse events were considered unrelated to study
drug: cough (2), nausea, dizziness, pharyngolaryngeal pain, nodule on
extremity, and headache. No clinically relevant changes in vital signs or
physical findings were observed.
4. Conclusion
Results of this exploratory study add to our understanding of the
clinical pharmacology of phenylephrine and may provide preliminary
data to design studies in the development of future phenylephrine-
containing products. For example, food was found to delay the ab-
sorption of phenylephrine, but not the total amount absorbed.
Additionally, the finding that the combination product containing the
tannate salt had similar terminal plasma concentrations as the reference
product containing the HCl salt, and hence, should not be dosed less
frequently, aligns with the regulatory action to remove prescription
products containing phenylephrine tannate from the market.
C.K. Gelotte
Funding
Funding for the clinical study and preparation of the manuscript
was provided by Johnson & Johnson Consumer, Inc, McNeil Consumer
Healthcare Division, Fort Washington, PA.
Declaration of interest
Cathy Gelotte was an employee at the time the study was conducted
and holds Johnson & Johnson stock and stock options.
Acknowledgements
Katherine McGinley, BS, a former Johnson & Johnson employee,
managed the clinical operations of the study. Kathleen Boyle, PhD, from
KE Boyle Consultants, LLC (Exton, PA) supported manuscript prepara-
tion and managed the review process.
Transparency document
Transparency document related to this article can be found online at
http://dx.doi.org/10.1016/j.yrtph.2018.04.008.
References
Atkinson, H.C., Stanescu, I., Anderson, B.J., 2014. Increased phenylephrine plasma levels
with administration of acetaminophen. N. Engl. J. Med. 370, 1171–1172.
Atkinson, H.C., Stanescu, I., Salem II, , Potts, A.L., Anderson, B.J., 2015a. Increased
bioavailability of phenylephrine by co-administration of acetaminophen: results of
four open-label, crossover pharmacokinetic trials in healthy volunteers. Eur. J. Clin.
Pharmacol. 71, 151–158.
Atkinson, H.C., Potts, A.L., Anderson, B.J., 2015b. Potential cardiovascular adverse events
when phenylephrine is combined with paracetamol: simulation and narrative review.
338
Regulatory Toxicology and Pharmacology 95 (2018) 333–338
Eur. J. Clin. Pharmacol. 71, 931–938.
Center for Disease Control (CDC) Public Health Law, 2013. Pseudoephedrine: Legal
Efforts to Make it a Prescription-only Drug. https://www.cdc.gov/phlp/docs/
pseudo-brief112013.pdf, Accessed date: 2 December 2017.
Food and Drug Administration (FDA), 1994. Cold, cough, allergy, bronchodilator, and
antiasthmatic drug products for over-the-counter human use: 21 CFR Parts 310, 341
and 369. Fed. Regist. 59, 43386–43412.
Gelotte, C.K., Zimmerman, B.A., 2015. Pharmacokinetics, safety, and cardiovascular
tolerability of phenylephrine HCl 10, 20, and 30 mg after a single oral administration
in healthy volunteers. Clin. Drug Invest. 35, 547–558.
Guidance for Industry, 2002. Food-effect Bioavailability and Fed Bioequivalence Studies.
US Department of Health and Human Services, FDA. Center for Drug Evaluation and
Research. https://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM070241.pdf, Accessed
date: 19 November 2017.
Guidance for FDA Staff and Industry, 2011. Marketed Unapproved Drugs – Compliance
Policy Guide. US Department of Health and Human Services, FDA. Center for Drug
Evaluation and Research. https://www.fda.gov/downloads/drugs/
guidancecomplianceregulatoryinformation/guidances/ucm070290.pdf, Accessed
date: 19 November 2017.
Hengstmann, J.H., Goronzy, J., 1982. Pharmacokinetics of 3H-phenylephrine in man.
Eur. J. Clin. Pharmacol. 21, 335–341.
Kaplan, H., Sherwood, H., Epstein, J.I., 1963. Evaluation of a long-acting oral anti-
histaminic decongestant (Rynatan®) for nasal allergies. Ann. Allergy 21, 41–47.
PPD Bioanalytical Laboratory, 2007. Method P898. Quantitation of Unconjugated
Phenylephrine in Human Plasma via HPLC with MS/MS Detection. Middleton, WI.
PPD Bioanalytical Laboratory, 2008a. Method P956. Quantitation of Phenylephrine and
Phenylephrine Glucuronide in Human Urine via HPLC with MS/MS Detection.
Middleton, WI.
PPD Bioanalytical Laboratory, 2008b. Method P957. Quantitation of 3-hydroxymandelic
Acid in Human Urine via HPLC with MS/MS Detection. Middleton, WI.
PPD Bioanalytical Laboratory, 2008c. Method P958. Quantitation of Total Phenylephrine
in Human Urine via HPLC with MS/MS Detection. Middleton, WI.
Ptacek, P., Macek, J.K., 2007. Development and validation of a liquid chromatography-
tandem mass spectrometry method for the determination of phenylephrine in human
plasma and its application to a pharmacokinetic study. J. Chromatogr. B 858,
263–268.
Rahman, Z., Zidan, A.S., Berendt, R.T., Khan, M.A., 2012. Tannate complexes of anti-
histaminic drug: sustained release and taste masking approaches. Int. J. Pharm. 422,
91–100.