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PHARMACOKINETICS AND PHARMACODYNAMICS

Evaluation of the Potential for Pharmacodynamic and Pharmacokinetic Drug Interactions Between Selegiline Transdermal System and Two Sympathomimetic Agents (Pseudoephedrine and Phenylpropanolamine) in Healthy Volunteers

Albert J. Azzaro, PhD, Chad M. VanDenBerg, PharmD, John Ziemniak, PhD, Eva M. Kemper, BS, Lawrence F. Blob, MD and Bryan J. Campbell, PharmD

From Somerset Pharmaceuticals, Inc (Dr Azzaro, Dr VanDenBerg, Ms Kemper, Dr Blob), Gwynedd Pharmaceutical Consultants, Gwynedd Valley, Pennsylvania (Dr Ziemniak), and Bristol-Myers Squibb Company, Plainsboro, New Jersey (Dr Campbell).

Address for correspondence: Albert J. Azzaro, PhD, AJA PharmaServices, 502 Seaview Drive, Tarpon Springs, FL 34689.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Selegiline transdermal system is a recently approved monoamine oxidase inhibitor antidepressant. Medications that inhibit monoamine oxidase type A can augment the pressor effects of sympathomimetic amines, increasing the potential for hypertensive crisis. This study examined the potential for drug-drug interactions during treatment with selegiline transdermal system and pseudoephedrine or phenylpropanolamine. Two studies were conducted with 25 healthy volunteers to assess changes in blood pressure and heart rate during administration of pseudoephedrine or phenylpropanolamine alone or together with selegiline transdermal system. No significant differences in mean maximum changes in vital signs occurred with pseudoephedrine. No significant differences were found in mean maximum changes in systolic heart rate with phenylpropanolamine; however, 4 of 12 subjects each experienced 1 isolated protocol-defined minimal pressor response without concurrent adverse effects (1 with phenylpropanolamine alone; 3 with phenylpropanolamine + selegiline transdermal system). Pharmacokinetic parameters obtained following selegiline transdermal system and pseudoephedrine or phenylpropanolamine were unremarkable. The results suggest that selegiline transdermal system 6 mg/24 h does not significantly alter the pharmacodynamics or pharmacokinetics of either pseudoephedrine or phenylpropanolamine when administered to healthy volunteers; however, it is prudent to avoid coadministration of selegiline transdermal system and sympathomimetics.

Key Words: Selegiline transdermal system • drug-drug interactions • pharmacodynamics and pharmacokinetics • sympathomimetic agents • EMSAM

Monoamine oxidase inhibitors (MAOIs), the first class of antidepressant agents, have been shown to be efficacious across an array of depressive disorders.1 Despite their clinical utility in the treatment of depression, widespread use of these agents has been limited by concerns about drug-food interactions. The inhibition of monoamine oxidase A (MAO-A) in the gastrointestinal tract permits ingested tyramine, a vasoactive sympathomimetic amine found in certain foods (eg, aged cheese), to enter the bloodstream and cause a rapid increase in blood pressure (BP) and, potentially, a hypertensive crisis.2,3

Similarly, drug-drug interactions can also occur between MAOIs and other sympathomimetic amines. Acute hypertensive reactions, with associated headaches, anaphylaxis, and high fever, have been reported over the past several decades with concomitant use of MAOIs and sympathomimetic amines.4-9 These reports suggest that patients taking oral MAOIs should avoid using over-the-counter (OTC) or prescription medications containing sympathomimetic amines.

Pseudoephedrine (PSE) and phenylpropanolamine (PPA) are mixed-acting sympathomimetic amines that have been used commonly as decongestants in the treatment of coughs and colds.10-14 The effectiveness of PSE and PPA as decongestants is specifically related to the activation of {alpha}-adrenergic receptors in the nasal mucosa, resulting in vasoconstriction, reduced blood flow, decreased mucosal edema, and, ultimately, improved nasal patency.15,16 At mucosal sympathetic nerve endings, these agents directly stimulate adrenergic receptors (direct action) and displace norepinephrine from neuronal storage sites (indirect action). However, these same actions can also have a generalized effect on the peripheral cardiovascular system that can be exaggerated in the presence of an MAOI. When a nonselective MAOI (eg, phenelzine, tranylcypromine) is coadministered with one of these agents, an acute marked pressor response, and potentially a hypertensive crisis, can result.9,13

Selegiline is a selective MAO-B inhibitor at low doses. Oral selegiline at a dose of 5 mg twice daily is currently approved as an adjunct to levodopa for the treatment of Parkinson's disease.17,18 At this oral dose, the concomitant use of sympathomimetic decongestants with oral selegiline is not contraindicated because acute hypertensive events are associated with the inhibition of MAO-A activity within adrenergic, sympathetic neurons. The selegiline transdermal system (STS) has been recently approved by the US Food and Drug Administration for the treatment of major depressive disorder (MDD). The STS has unique pharmacokinetic and pharmacodynamic properties that allow substantial inhibition of MAO-A and MAO-B in the central nervous system, potentiating the activity of 3 key neurotransmitters (serotonin, norepinephrine, and dopamine) for the treatment of depression while largely avoiding inhibition of MAO-A in peripheral tissues such as the adrenergic neuron, intestinal mucosa, and liver.19,20 Both short- and long-term clinical trials (6-52 weeks in duration) have demonstrated that STS 6 mg/24 h is an effective, safe, and well-tolerated antide-pressant,21-23 and human tyramine challenge studies support the use of STS 6 mg/24 h without dietary tyramine modifications.24

Because there is a possibility that depressed patients may intentionally or unintentionally use various prescription or OTC cough or cold preparations containing sympathomimetics during treatment with STS, 2 Phase I studies were conducted with PSE or PPA to examine the impact of concomitant use of STS 6 mg/24 h on the pharmacokinetic and pharmacodynamic properties of these agents. The primary objective of these studies was to define the effects of coadministration of these drugs with STS on the cardiovascular parameters of BP and heart rate (HR), particularly alterations that might result in acute clinical consequences and, potentially, a hypertensive crisis. Pharmacokinetic parameters were also examined to confirm that selegiline was present at steady-state levels during cardiovascular assessments and to assess pharmacokinetic parameters of the test agents (PSE and PPA) for drug-drug interactions with STS.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Two separate, single-center, open-label studies were conducted to evaluate the effects of steady-state administration of STS 6 mg/24 h on the pharmacodynamics and pharmacokinetics of PSE and PPA in healthy subjects. Each study conformed with all applicable requirements regarding ethical committee review and informed consent, including the ethical principles of the Declaration of Helsinki (and subsequent amendments), the International Conference on Harmonization, Good Clinical Practices, and US Food and Drug Administration regulations (21 CFR Parts 50 and 56) for the protection of the rights and welfare of human subjects participating in biomedical research. An independent Institutional Review Board (Western Institutional Review Board, Olympia, Wash) reviewed the protocol. Subjects entered the studies only after they reviewed and signed written consent forms.

Study Population
Subjects were males and females 18 to 45 years of age in general good health and within 10% of desirable weight for their frame size. Subjects were excluded from the studies if they had any cardiovascular, gastrointestinal, digestive, neurologic, pulmonary, hepatic, renal, hematologic, endocrine, metabolic, or psychiatric diseases or disorders. They were also excluded if they had any substance abuse or addiction, significant allergy, or hypersensitivity related to any drug used in the studies. Other exclusion criteria included pregnancy or use of oral contraceptives within 6 months prior to the studies; the use of any prescription medications within 35 days prior or any OTC medication within 14 days prior to the studies; anticipated use of any central nervous system medication; use of a diet that deviated from normal in the amount of protein, carbohydrates, and fat, as judged by the investigator; or consumption of any alcohol or caffeine- or xanthine-containing drinks or foods within 24 hours prior to the studies. Female subjects of childbearing age were required to have a negative pregnancy test and to use adequate double-barrier methods of birth control.


Figure 1
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  		Figure 1. Pseudoephedrine (PSE) interaction study design: PSE was administered alone (period I) and together with selegiline transdermal system (STS) 6 mg/24 h (period III) to test for the possibility of cardiovascular pharmacodynamic or pharmacokinetic drug interactions. Healthy subjects were administered STS 6 mg/24 h daily to steady-state concentrations during period II. Vital signs—systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR)—were generally monitored every 15 minutes for pharmacodynamic changes and every 5 minutes if SBP was >30 mm Hg above baseline. aVital signs measured every 5 minutes if SBP was >30 mm Hg above baseline.

 
Study Design
The 2 studies were similar in design. They consisted of 3 treatment periods with protocol-defined time intervals for pharmacodynamic measurements (Figures 1 and 2). Subjects received PSE or PPA alone for 3 days, STS alone for 7 days, and STS coadministered with PSE or PPA for 3 days during treatment periods I, II, and III, respectively. Dosing over the treatment periods was sequential, with the exception of a single day without treatment between treatment periods I and II in the PPA interaction study (day 4 of treatment period I; Figure 2). Subjects reported to the clinic on the evenings before day 1 of treatment periods I and III and were confined to the clinic to undergo all procedures during these periods. During treatment period II, subjects reported to the clinic for procedures as outpatients.


Figure 2
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  		Figure 2. Phenylpropanolamine (PPA) interaction study design: PPA was administered alone (period I) and together with selegiline transdermal system (STS) 6 mg/24 h (period III) to test for the possibility of cardiovascular pharmacodynamic or pharmacokinetic drug interactions. Healthy subjects were administered STS 6 mg/24 h daily to steady-state concentrations during period II. Vital signs—systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR)—were obtained as follows. aThirty minutes prior to each dose of PPA, after a 5-minute acclimation period, BP measurements taken every 3 minutes until 3 consecutive readings were within 7 mm Hg of the prior reading and all 3 readings within 10 mm Hg; the mean of these 3 readings = baseline BP for dosing period. bVital signs every 10 minutes. cVital signs every 5 minutes if SBP was >30 mm Hg above baseline. dVital signs every 10 minutes for 2 hrs after dosing, then every 30 minutes until next baseline procedure.

 
There were no dietary tyramine restrictions during either study; however, subjects were instructed to refrain from excessive intake of caffeine-containing beverages or significant changes in dietary habits over the course of the study. During inpatient periods, subjects were to consume only the meals provided at the study site. Subjects were given a meal diary and required to complete the diary for the 48 hours prior to each clinic check-in period.

Drug Administration
Selegiline was administered as a transdermal patch (STS 6 mg/24 h [20 cm2]) applied to the upper torso once daily at 8:00 AM ± 30 minutes and removed after 24 hours. PSE (Sudafed® 30-mg nasal decongestion tablets, Warner-Lambert [currently Pfizer Pharmaceuticals, Inc, New York, NY]) and PPA (Propagest® 25-mg nasal decongestion tablets, Carnrick Laboratories, Inc, Cedar Knolls, NJ) were administered orally at 60 mg (PSE) up to 3 times daily (every 8 hours) and 25 mg (PPA) up to 6 times in 24 hours (every 4 hours), as recommended in the respective product information. Dosing schedules for each of the agents can be found in Figures 1 and 2.

Subjects were required to fast for at least 8 hours prior to the initial drug administration and for 2 hours after while confined to the clinic (periods I and III). All other doses of PSE, PPA, or STS were administered without food for 1 hour prior to and 2 hours after administration.

Pharmacodynamic Measurements and Analysis
Measurement. BP monitoring was conducted using a SunTech Accutracker II® 24-hour ambulatory BP monitor (SunTech Medical, Morrisville, NC). A predose (baseline) measurement in the PPA study consisted of the average value of 3 consecutive readings that were within 7 mm Hg of the prior reading and within 10 mm Hg of each other. Baseline values for the PSE study consisted of the average of all available data prior to dosing (minimum 3 measurements). In both studies, daily postdose values were defined as the average value of measurements taken after each dose in the treatment period.

During treatment periods I and III, subjects remained in a semirecumbent position for 90 to 120 minutes following drug administration and then were allowed to move about freely, but without excessive activity. Postdose vital sign measurements were obtained every 10 (PPA) to 15 minutes (PSE). Vital sign measurements were repeated every 5 minutes if the systolic blood pressure (SBP) was ≥30 mm Hg above the last baseline measurement (PPA). During treatment period II, baseline vital signs were measured just prior to STS patch administration each day. SBP, diastolic blood pressure (DBP), and HR measurements were taken at prespecified times throughout the 3 treatment periods (Figures 1 and 2).

A minimal pressor response was defined as 3 consecutive SBP measurements ≥30 mm Hg above the individual subject's baseline value. Labetolol was to be administered for SBP increases ≥60 mm Hg over the subject's baseline or increases in SBP with symptom or at the discretion of the investigator.

Analysis. A pharmacodynamic drug interaction was declared between STS and the test drug (PSE or PPA) by statistical comparisons made between the mean values of the maximal changes from baseline in vital sign measures (SBP, DBP, and HR) obtained from measurements during treatment periods I (PSE or PPA alone) and III (STS + PSE or STS + PPA) using a 1-way repeated analysis of variance (ANOVA) with baseline as covariate and significance defined as P ≤ .05.

Pharmacokinetic Sample Collection and Analysis
Sample collection. Serial blood samples were collected at protocol-defined time points throughout the studies for pharmacokinetic analysis of PSE, PPA, and selegiline and its metabolites. In treatment periods I and III, day 1, samples were collected 30 minutes prior to dosing with PSE or PPA and after dosing at protocol-specified intervals (PSE: 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours; PPA: 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours); on days 2 and 3, samples were collected 30 minutes prior to dosing with PSE or PPA and at 1 and 6 hours (PSE) or 1 and 4 hours (PPA) after each dose. End-of-dose selegiline plasma concentrations were obtained in period II prior to daily STS removal (24 hours) to establish the presence of pharmacokinetic steady state (PSE study, days 4-10; PPA study, days 8-11).

Laboratory analysis. Plasma samples were analyzed for selegiline and its 3 principal metabolites by MDS Pharma Services (Quebec, Canada), formerly known as Phoenix International Life Sciences, Inc (Montreal, Canada), with a highly sensitive, validated assay using high-performance liquid chromatography (HPLC) and tandem mass spectrometry (HPLC/MS/MS) and amitriptyline as the internal standard. Heparinized plasma samples were liquid/liquid extracted with 1-chlorobutane, evaporated to dryness, and reconstituted in methanol for analysis. The LC separation was performed on a 33 x 4.6 mm (3-µm) LC-CN analytical column (SUPELCOSILTM, Sigma-Aldrich/Supelco, Bellefonte, Pa) operated at room temperature. The mobile phase was a mixture of methanol, 0.025 M ammonium acetate, and water (86:2:12, by volume), delivered at a flow rate of 1 mL/min. Detection was performed using a SCIEXTM (MDS Sciex, San Francisco, Calif) MS/MS atmospheric pressure ionization spectrometer, in the multiple-reaction monitoring mode. The following transition mass to charge ratios (m/z) were monitored: 278.3 to 191.2 (internal standard, amitriptyline), 188.3 to 91.1 (selegiline), 174.1 to 91.1 (N-desmethylselegiline), 150.2 to 61.1 (R(-)-methamphetamine), and 136.3 to 91.1 (R(-)-amphetamine). The approximate assay calibration range in plasma was 25 to 8000 pg/mL for selegiline, 50 to 15 000 pg/mL for N-desmethylselegiline, 100 to 15 000 pg/mL for R(-)-amphetamine, and 100 to 15 000 pg/mL for R(-)-methamphetamine. Interassay accuracy was between 96% and 107%, and the interassay precision (expressed as the percent coefficient of variation) was between 3.0% and 15.0% for all analytes.

Plasma samples were analyzed for PSE by PPD Development (Richmond, Va) using a validated HPLC assay and PPA as the internal standard. Heparinized plasma was liquid/liquid extracted with a mixture of hexane/ethyl ether (50:50, v/v). The organic layer was back-extracted with 0.05 M sulfuric acid, and the acidified sample extracts were analyzed with an HPLC system, equipped with an ultraviolet detector (205 nm) and a 250 x 4.6 mm (5-µm) octadecylsilane ultrasphere analytical column (BeckmanTM, Beckman Coulter, Inc, Fullerton, Calif). The chromatographic separation was performed at room temperature using a mobile phase consisting of a mixture of ammonium phosphate buffer (pH = 3.0) and acetonitrile (91:10, v/v) and a flow rate of 1.3 mL/min. The assay calibration range was 10.0 to 1000.0 ng/mL. The intra-assay accuracy was between 96.1% and 102.0%, and the intra-assay precision, expressed as the coefficient of variation, was between 3.3% and 5.6%.

Plasma samples were analyzed for PPA by PPD Development (Richmond, Va) using a validated HPLC assay and PSE as the internal standard (see above assay method for PSE for summary details). The assay calibration range was 5.0 to 1000.0 ng/mL. The intra-assay accuracy was between 99.0% and 101.6%, and the intra-assay precision, expressed as the coefficient of variation, was between 1.8% and 10.2%.

Statistical Analysis
A noncompartmental approach was used for pharmacokinetic data analysis. Plasma concentration data and the estimated pharmacokinetic parameters were summarized using arithmetic means and percent coefficient of variation (% CV). All computations were made using actual sampling times. The following noncompartmental pharmacokinetic parameters were estimated from the plasma concentration profiles for each subject: area under the plasma concentration-time curve over the selegiline dosing interval (AUC(0-24 h)); area under the plasma concentration-time curve, time 0 to time of last quantifiable concentration, tau (AUC(0-tau)); area under the plasma concentration-time curve extrapolated to infinity (AUC(0-{infty})); maximum plasma concentration over the entire sampling phase (Cmax); time to attain Cmax (Tmax); steady-state concentration of drug (Css); and plasma clearance (CL). All pharmacokinetic parameters were derived using validated programs prepared with PC-SAS® (SAS Institute, Cary, NC) version 6.12. Plots representing mean (% CV) values were generated using both Sigma Plot version 5.0 and PC-SAS® (SAS Institute) version 6.12.

Selegiline pharmacokinetic parameters were assessed based on steady-state values. Attainment of steady state was evaluated through linear regression of the end-of-dose trough levels plotted against time. The slope of the regression line of the daily trough levels plotted against time for each individual was examined for differences from zero at the {alpha} = .05 level of significance for each analysis. A zero slope in the assessment of the daily (24-hour) selegiline concentration versus time curve indicated that the selegiline plasma levels were consistently similar from day to day and had achieved steady state. PSE and PPA pharmacokinetic parameters were assessed for pharmacokinetic differences based on single-dose data collected during treatment periods I and III. Loge-transformed AUC(0-{infty}), Cmax, and other values of interest were examined by ANOVA and compared with those in the presence of selegiline (PROC GLM and PROC MIXED, version 6.12; SAS Institute). The mean squares error of the model was used to evaluate treatment and phase effects at an {alpha} = .05 level of significance.

The pharmacokinetic drug interaction boundary criteria used to demonstrate the presence of a drug interaction were defined a priori as a difference of greater than ±30% in the point estimates of the pharmacokinetic value of interest. Accordingly, the least squares mean ratios of the loge-transformed Cmax and AUC(0-{infty}) values obtained during the single and concomitant treatment were constructed (period III/period I), and their 90% confidence intervals (CIs), based on the ±30% difference in treatment means, were to be contained within the range of 70% to 130%. Converting this range to the loge-transformed scale, the no-effect 90% confidence intervals should fall within the 70% to 143% range. In addition, the standard no-effect boundary of 80% to 125% rule for bioequivalence was evaluated.

Safety Analysis
Safety assessments included adverse event reports, vital sign measurements, and results of physical examinations, clinical laboratory tests, and electrocardiograms (ECGs). ECGs were performed and blood samples for clinical laboratory analysis were collected just prior to test drug dosing on day 1 of periods I and III and 1 day after the last dose of study drug; physical examinations were performed at study entry and 1 day after the last dose of study drug.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subject Demographics
Pseudoephedrine interaction study. Twelve subjects (9 males and 3 females) were enrolled. The mean age of subjects was 20.9 years (range, 19.1-27.1 years). Two subjects discontinued after dosing with PSE (period I) because of difficulty in providing blood samples for pharmacokinetic evaluation. Ten subjects completed the study.

Phenylpropanolamine interaction study. Thirteen male subjects were enrolled. Their mean age was 34.2 years (range, 20.5-44.7 years). Twelve subjects received study drug. One subject discontinued prior drug administration because of elevated BP at base-line. One subject discontinued the study after dosing with PPA and 3 doses of STS because of excluded medication necessary to treat a dislocated shoulder sustained during treatment period II. Eleven subjects completed the study.

Pharmacodynamic Results
Pseudoephedrine interaction study. Figure 3 summarizes the mean cardiovascular vital signs recorded from subjects during periods I and III. Baseline (predose) values for SBP, DBP, and HR obtained during period III (PSE + STS) were slightly lower than those obtained during period I (PSE); however, all other values obtained during each of the PSE dosing phases were essentially identical. Trends toward an increase in SBP or DBP over the 3-day course of PSE treatment were not observed with or without the addition of selegiline. There was, however, a small increase above baseline in HR over this same time period, but this effect was unrelated to treatment with the STS.


Figure 3
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  		Figure 3. Mean (SD) vital sign values for pseudoephedrine (PSE) alone (period I) versus PSE + selegiline transdermal system (STS) (period III): mean (SD) values for vital signs—systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR)—obtained prior to (predose) and during treatment for PSE alone (period I) were compared with those obtained during coadministration of PSE and STS (period III). No differences were observed during treatment with PSE or PSE + STS. an = 10.

 

The mean values of the maximum change from baseline in SBP obtained during periods I (PSE) and III (PSE + STS) are summarized in Table I. The values represent those obtained during the initial 90-minute period following dosing, when the subjects remained in a resting and recumbent position. A modest increase in the maximum change in SBP following PSE administration was observed during both treatment periods. During multiple PSE dosing on days 2 and 3, the maximum change appeared to increase slightly with each PSE dose, with or without STS treatment. The mean of the maximum changes in SBP appeared to be greater during PSE + STS treatment; however, when compared with the values obtained during treatment with PSE alone, there were no statistical differences on any day or any PSE dose, and none of the changes resulted in any clinical consequences (eg, persistent cardiovascular adverse events, administration of labetolol, discontinuation from the study). In addition, none of the subjects experienced a minimal pressor response during the study or any adverse events considered related to the study drugs.


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  		Table I Mean Value of the Maximum Change in Systolic Blood Pressure (SBP) From Baseline to 90 Minutes Postdose in Treatment Periods I and III for Subjects Who Completed the Study: Pseudoephedrine

 

In treatment period II (STS alone), the mean SBP, DBP, and HR decreased from predose values. However, these mean decreases were small and asymptomatic, and no trends over time were observed (data not shown).

Phenylpropanolamine interaction study. Mean cardiovascular vital sign values recorded for subjects during periods I and III are summarized in Figure 4. During both periods I (PPA alone) and III (PPA + STS), predose values were similar. Small fluctuations in each of these vital sign values were observed over the course of the 3-day dosing periods but without any particular pattern, and none resulted in any clinical consequence.


Figure 4
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  		Figure 4. Mean (SD) vital sign values for phenylpropanolamine (PPA) alone (period I) versus PPA + selegiline transdermal system (STS) (period III): mean (SD) values for vital signs—systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR)—obtained prior to (predose) and during treatment for PPA alone (period I) were compared with those obtained during coadministration of PPA + STS (period III). No differences were observed during treatment with PPA or PPA + STS. an enrolled = 13; 1 subject discontinued prior to drug administration because of elevated BP at baseline. n = 12 receiving study drug; 1 subject discontinued during treatment period II (dislocated shoulder). n = 11 completing treatment period III.

 
The results of a statistical comparison of mean maximum SBP changes from baseline for PPA alone and PPA + STS are summarized in Table II. The mean maximum change in SBP during single-dose administration of PPA alone on day 1 was 16.9 ± 8.37 mm Hg compared with 24.2 ± 8.61 mm Hg for PPA + STS. Although the maximum change appeared greater during combined treatment with PPA + STS, the difference between these values was not statistically significant. Furthermore, no statistically significant differences were found between the mean maximum changes in SBP for PPA alone and those for PPA + STS on each of days during which multiple doses of PPA were administered. In fact, following most of the PPA doses, the mean change values were similar between periods I and III. None of the observed values resulted in any clinical consequence.


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  		Table II Mean Value of the Maximum Change in Systolic Blood Pressure (SBP) From Baseline in Treatment Periods I and III: Phenylpropanolamine

 

For period II (STS alone), mean changes from day 4 (mean predose values on day 4 were used as baseline values) in SBP and DBP were small (±3 mm Hg) through day 7, with no trends observed over time. Mean HR increased from day 4 through day 7 of this treatment period, compared with baseline day 4 values; however, maximum HR never exceeded 93 beats/min (range, 67-93 beats/min), and none of the changes resulted in any clinical consequence (data not shown).

Four subjects each had 1 isolated protocol-defined minimal pressor response, that is, 3 consecutive SBP measurements ≥30 mm Hg above their individual previous baseline values (Table III). One incident occurred during treatment period I (PPA alone), and 3 incidents occurred during treatment period III (PPA + STS). Subsequent doses of PPA in the same subjects did not produce any additional pressor response. There was no correlation between these events and PPA plasma concentration or time after dosing. None of these incidents was associated with adverse events or clinically relevant symptoms, and no subject required treatment for elevated BP.


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  		Table III Four Subjects With a Minimal Pressor Responsea During the Study Period: Phenylpropanolamine

 

Pharmacokinetic Results
Steady-state levels of selegiline. Attainment of selegiline steady-state plasma concentrations was evaluated during treatment period II through linear regression of end-of-dose (24-hour trough) plasma concentration levels of selegiline over the 7-day dosing period. After 5 days of dosing, the slope of the regression line of individual trough levels versus time did not differ from zero at an {alpha} = .05 level of significance, indicating that steady-state was achieved prior to the initiation of treatment period III.

Pharmacokinetic parameters: PSE and PPA. The pharmacokinetic parameters for PSE, PPA, and selegiline and its metabolites are summarized in Tables IV and V. The single-dose pharmacokinetic parameters of PSE and PPA were assessed during treatment periods I (PSE or PPA alone) and III (PSE + STS or PPA + STS). Statistical evaluations suggested that none of the pharmacokinetic parameters of interest were altered by coadministration with STS (ie, P > .05). Furthermore, examination of the least squares mean ratio of the loge-transformed Cmax and AUC(0-{infty}) values of PSE and PPA during treatment periods I and III also indicated that no clinically relevant pharmacokinetic interactions occurred between selegiline and PSE or PPA (Table VI). In the 2 studies, the 90% confidence intervals for the ratio of assessed loge-transformed pharmacokinetic parameters obtained during periods I and III fell within the 70% to 143% boundary (ie, protocol defined as no drug-drug pharmacokinetic interaction); in fact, these values fell within the standard bioequivalence range of 80% to 125%.


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  		Table IV Mean (% Coefficient of Variation) Pharmacokinetic Parameters for Pseudoephedrine Interaction Study

 

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  		Table V Mean (% Coefficient of Variation) Pharmacokinetic Parameters for Phenylpropanolamine Interaction Study

 

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  		Table VI Least Squares Mean Pharmacokinetic Values

 

Safety Results
In the PSE interaction study, there were no deaths, serious adverse events, or discontinuations attributable to adverse events. Nine of 12 subjects reported at least 1 adverse event. The most frequently reported adverse events during coadministration of STS with PSE were headache, abdominal pain, pain at injection site (ie, indwelling venous catheter site for medication or fluid administration), and nervousness (in 1 subject each). The most frequently reported adverse events were nervousness and application site reaction (in 2 subjects each) during administration of STS alone and headache and injection site reaction (in 3 subjects each) during PSE dosing alone. One subject experienced heart palpitations, mild in intensity and 1 minute in duration, after dosing with PSE alone. No other adverse event related to vital signs or the cardiovascular system was reported. No clinically meaningful changes were observed in vital signs, clinical laboratory test results, or ECG parameters.

There were no deaths in the PPA interaction study. Seven of 13 subjects reported at least 1 adverse event. The most frequently reported adverse events were headache and somnolence (in 2 subjects each). One subject experienced a serious adverse event of a dislocated shoulder (unrelated to the study drugs) and discontinued the study because of a prohibited concomitant medication required to treat the injury. Another subject had hot sweats (vasodilation) of mild intensity during coadministration of STS with PPA. This adverse event was considered to be unrelated to the study drugs and was not associated with any clinically significant changes in BP or HR. No other adverse event related to vital signs or the cardiovascular system was reported. No clinically meaningful changes were observed in vital signs, clinical laboratory test results, or ECG parameters.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Sympathomimetic amines are found as pharmacologic agents within a variety of OTC and prescription cough-and-cold preparations to combat nasal congestion. In addition, some weight-reduction products contain sympathomimetics as medication to suppress appetite. Ample warning is provided in product labeling to advise both physicians and patients to avoid coadministration of sympathomimetics with irreversible MAOI antidepressants because of the potential for enhancement of cardiovascular effects of sympathomimetic amines.

The STS is a recently approved transdermal MAOI antidepressant that does not enhance the cardiovascular sensitivity to orally administered tyramine and, therefore, does not require dietary tyramine modification at the 6 mg/24 h dose.24 It was of interest to investigate the possibility that the 6 mg/24 h dose of STS also would not enhance the cardiovascular actions of other sympathomimetic amines. PSE was chosen as a study drug because of its popularity in OTC products, whereas PPA, although no longer available because it is associated with risk of stroke,25 was studied because of its increased potency as a sympathomimetic cardiovascular agent.13

The 2 studies summarized in this report demonstrate that the cardiovascular actions of PSE or PPA were not significantly altered by coadministration with STS 6 mg/24 h in healthy volunteers. Both studies examined the single-and-multiple dose pharmacodynamic effects of PSE or PPA in subjects dosed to steady-state with the STS. Both studies demonstrated that the mean of all cardiovascular vital signs and the mean of the maximum changes in SBP observed during treatment with PSE or PPA were essentially unchanged in the presence of STS. Three of 12 subjects experienced a minimal pressor response during coadministration of PPA with STS, suggesting a possible pharmacodynamic interaction. However, each occurred as a single isolated event, and the magnitude of these events (+42 to +46 mm Hg) was similar to that experienced by a fourth subject following dosing with PPA alone (+41 mm Hg). In addition, none of the incidents was associated with adverse events or other symptoms of clinical consequence, and no subject experienced an increase from baseline in SBP of ≥60 mm Hg (the protocol-defined threshold for administration of labetolol) or required treatment for elevated BP at any time during either of the studies. Subsequent doses of PPA in the same subjects did not produce any additional pressor response.

The effect of STS on the pharmacokinetic parameters of PSE or PPA was also examined. These data were obtained to rule out the possibility of a pharmacokinetic drug interaction between selegiline or its metabolites and PSE and PPA. The single-dose pharmacokinetics of PSE and PPA in the presence of STS 6 mg/24 h were not altered from that observed during treatment with PSE or PPA alone. This conclusion was based on a statistical comparison of individual pharmacokinetic parameters obtained during treatment periods I (PSE or PPA alone) and III (PSE or PPA + STS) and the 90% CI of the ratio of individual pharmacokinetic parameters of interest (AUC and Cmax) meeting predefined boundary criteria. In this regard, no statistically significant differences were observed for any of the pharmacokinetic parameters obtained (Tables IV and V), and the 90% CI of the loge-transformed ratio of each individual pharmacokinetic parameter of interest (Table VI) fell within the 80% to 125% bioequivalence standard.26 These data suggest that STS 6 mg/24 h is not likely to cause a pharmacokinetic-induced drug interaction when administered with PSE or PPA. In addition, these data support the pharmacodynamic findings between PSE or PPA and STS.

Although a formal assessment of the pharmacokinetic effects of PSE and PPA on STS could not be performed, given the study design, the selegiline AUC and Cmax values and metabolite-to-selegiline AUC ratios in the current study were similar to those reported in previous studies characterizing the pharmacokinetics of STS.27,28 These data suggest that neither PSE nor PPA altered the pharmacokinetics of selegiline administered transdermally.

Although the results presented are encouraging, one must be cautious about their application to the clinical setting. First, these phase I studies were conducted with a small number of healthy subjects, the majority of whom, in both studies, were males. The age range of subjects, male or female (PSE, 19-27 years; PPA, 21-45 years), was limited as well. Therefore, the results may not necessarily generalize to the population of patients who will use STS. Second, the doses studied do not encompass the full antidepressant range for STS (6-12 mg/24 h), and no drug interaction data of this kind are available for the 9 mg/24 h and 12 mg/24 h STS doses. However, clinical trials have demonstrated the efficacy, safety, and tolerability of STS 6 mg/24 h for acute and continuation treatment of MDD,21-23 suggesting that the 6 mg/24 h dose is likely to be commonly prescribed in clinical practice.


   CONCLUSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
ACKNOWLEDGEMENTS
 REFERENCES
 
STS 6 mg/24 h did not significantly alter the cardiovascular pharmacodynamics or the pharmacokinetics of either PSE or PPA in healthy subjects. However, the number of subjects studied is limited and because of the historical implications of oral MAOIs when coadministered with sympathomimetics, the administration of products containing sympathomimetics should be avoided during treatment with the STS.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 ACKNOWLEDGEMENTS
REFERENCES
 
Financial disclosure: When this study was conducted, Drs Azzaro, VanDenBerg, and Blob and Ms Kemper were employees of Somerset Pharmaceuticals, Inc. Their current affiliations are as follows: Dr Azzaro, AJA PharmaServices, Tarpon Springs, Florida; Dr VanDenBerg, Mercer University Southern School of Pharmacy, Atlanta, Georgia; Dr Blob, Blob and Associates, Washington, DC; Ms Kemper, Cognitive Research Corporation, St Petersberg, Florida. Dr VanDenBerg has received honoraria from Bristol-Myers Squibb Co for speaking engagements. Dr Ziemniak is an employee of Gwynedd Pharmaceutical Consultants and a consultant to Somerset Pharmaceuticals, Inc. Dr Campbell is an employee of Bristol-Myers Squibb Co.

DOI: 10.1177/0091270007302950


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

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