HENDERSHOT ET ALLINEZOLIDDRUG INTERACTIONS

Linezolid: Pharmacokinetic andPharmacodynamic Evaluation of

Coadministration with PseudoephedrineHCl, Phenylpropanolamine HCl, and

Dextromethorphan HBr

Pamela E. Hendershot, BS, Edward J. Antal, PhD, Ian R. Welshman, MS,Donald H. Batts, MD, and Nancy K. Hopkins, BS

The oxazolidinone antibiotics are a new syntheticclass of antibacterial agents that selectively inhibit

bacterial protein synthesis. As a class, they are knownto inhibit monoamine oxidase (MAO).1 In humans, twoforms of MAO exist: Type A and Type B. MAO-A pref-erentially deaminates noradrenaline, adrenaline, and5-hydroxytryptamine (serotonin, 5HT), whereasMAO-B preferentially deaminates dopamine. The useof drugs with monoamine oxidase inhibitory action is

limited by their interaction with other drugs andtyramine-containing foods. Interaction with somedrugs has the potential to result in serious adverseevents, such as a sudden rise in body temperature, se-vere hypertension, severe seizures, central nervoussystem (CNS) stimulation/excitement, mental confu-sion, an increase in the depressant effects of CNS de-pressants, and breathing difficulty. The most commoninteraction is the hypertensive interaction withsympathomimetic amines and tyramine.

Linezolid, a derivative of the template compound ofthe oxazolidinone series, has been screened using in vi-tro and in vivo test systems for monoamine oxidase in-hibitor (MAOI) activity. The results of these studiessuggest that linezolid is a weak, competitive (revers-ible) inhibitor of human MAO-A.1

J Clin Pharmacol 2001;41:563-572 563

From Clinical Pharmacology (Ms. Hendershot, Dr. Antal, Mr. Welshman,

Ms. Hopkins) and Clinical Development (Dr. Batts), Pharmacia & Upjohn,

Kalamazoo, Michigan. Submitted for publication February 28, 2000; re-

vised version accepted December 4, 2000. Address for reprints: Edward J.

Antal, PhD, Clinical Pharmacology, 7215-24-205, Pharmacia & Upjohn,

301 Henrietta St., Kalamazoo, MI 49007-4940.

Linezolid is a novel oxazolidinone antibiotic with mild re-versible monoamine oxidase inhibitor (MAOI) activity. Thepotential for interaction with over-the-counter (OTC) medica-tions requires quantification. The authors present data evalu-ating the pharmacokinetic and pharmacodynamic responsesto coadministration of oral linezolid with sympathomimetics(pseudoephedrine and phenylpropanolamine) and a seroto-nin reuptake inhibitor (dextromethorphan). Followingcoadministration with linezolid, minimal but statistically sig-nificant increases were observed in pseudoephedrine andphenylpropanolamine plasma concentrations; a minimalbut statistically significant decrease was observed indextrorphan (the primary metabolite of dextromethorphan)

plasma concentrations. Increased blood pressure (BP) wasobserved following the coadministration of linezolid with ei-ther pseudoephedrine or phenylpropanolamine; no signifi-cant effects were observed with dextromethorphan. None ofthese coadministered drugs had a significant effect onlinezolid pharmacokinetics. Minimal numbers of adverseevents were reported. Potentiation of sympathomimetic ac-tivity by linezolid was judged not to be clinically significant,but patients sensitive to the effects of increased BP due to pre-disposing factors should be treated cautiously. No restric-tions are indicated for the coadministration of dextro-methorphan and linezolid.

Journal of Clinical Pharmacology, 2001;41:563-572©2001 the American College of Clinical Pharmacology

Clinical data show that linezolid is well tolerated insingle oral doses up to 750 mg, in repeated oral dosesup to 625 mg given twice daily for 14 days, and in intra-venous (IV) doses of 500 mg given three times daily for7 days. Linezolid is rapidly and extensively absorbedafter oral dosing, and maximum concentrations arereached within 2 hours. The compound has an elimi-nation half-life of 5 to 7 hours.2 Approximately 35% ofan administered dose of linezolid appears as the parentcompound in the urine, and approximately 50% ap-pears in the urine as two major inactive metabolites.Following a single intravenous dose of 375 mg, a meanclearance of 121 ± 23 mL/min was reported.2-6 Oral dos-ing of 400 mg and 600 mg every 12 hours to steady stateprovides maximum and minimum plasma concentra-tions (Cmax and Cmin) that are at or above the minimuminhibitory concentrations of target pathogens.4

A study in normal volunteers examined the effect oflinezolid or moclobemide in the pharmacodynamic re-sponse to tyramine, an indirectly acting sympathomi-metic agent. Volunteers received doses of tyramine un-til a rise of at least 30 mmHg in systolic blood pressure(SBP) was observed. This tyramine challenge was ad-ministered before and while receiving linezolid 625 mgtwice daily at steady state or moclobemide 150 mg ev-ery 8 hours at steady state. Results of the study indi-cated that at least 100 mg tyramine is necessary to causethe 30 mmHg rise in SBP during treatment withlinezolid. The magnitude of the effect due to linezolidappeared to be similar to, or slightly less than, that dueto moclobemide, a medication used in clinical practicewithout food restriction. Reversal of sympathomimeticeffects appeared to occur within 2 days followingdiscontinuation of linezolid. The study concludedthat restrictions to normal dietary intake of tyramine-containing foods was not warranted when takinglinezolid (in common with the product labeling formoclobemide).7

In addition to the sympathomimetics, another com-mon over-the-counter (OTC) drug is the serotoninreuptake inhibitor dextromethorphan. Coadministra-tion of drugs that possess MAOI activity and those thatinhibit serotonin reuptake has been reported to resultin a potentially severe interaction, termed the seroto-nin syndrome. This syndrome, which may include al-tered mental status, autonomic dysfunction, andneuromuscular abnormalities, is most often seen whenMAOIs and certain antidepressants are used together.8,9

Common findings include confusion, diaphoresis, andhyperthermia. The syndrome is probably due to excessneural serotonin (5HT), with stimulation of the 5HT1A

receptors, particularly in the brainstem and spinal

cord.8 Dextromethorphan has been shown to block se-rotonin reuptake and has been implicated inprecipitating the serotonin syndrome whencoadministered with MAOIs8,10-12 or when a washoutperiod of insufficient duration separates the adminis-tration of each class of medication.

The potential for drug interaction due to the con-comitant administration of linezolid with sympatho-mimetic medications, such as pseudoephedrine andphenylpropanolamine, required evaluation to deter-mine if clinically significant changes in BP and heartrate (HR) occur. Since the potential for coadministra-tion of linezolid and dextromethorphan-containingcough suppressant medications exists, the interactionbetween the compounds, as measured by clinically sig-nificant changes in body temperature and/or subjectalertness and mental performance, also requiredevaluation.

We present data from three clinical trials in healthyvolunteers, evaluating the pharmacokinetic and phar-macodynamic responses to coadministration of line-zolid with pseudoephedrine, phenylpropanolamine,and dextromethorphan.

METHODS

Subjects and Ethical Approval

All subjects were healthy nonsmoking male and femalevolunteers who provided written informed consentprior to enrollment. They were between ages 18 and 45years and were within 15% of ideal body weight. Theyhad negative drug (amphetamines, opiates, barbitu-rates, benzodiazepines, cocaine, cannabinoids, and al-cohol), hepatitis B and C, human immunodeficiencyvirus (HIV), and pregnancy (females) screens. Subjectswere also required to abstain from alcohol and vigorousexercise during the 48-hour period prior to each admis-sion and throughout the study. The study protocolswere reviewed and approved by the Bronson Method-ist Hospital Human Use Committee. Each study wasconducted at the Pharmacia and Upjohn Clinical Re-search Unit, Kalamazoo, Michigan.

Sample Size

The sample size for these studies was based on litera-ture accounts describing similar clinical trials. Thenumber of subjects enrolled for each study, 14, wasbased on power calculations to detect a 100% differ-ence in pharmacodynamic measures at an α level of0.05 for a power of greater than 90%, assuming a coeffi-

564 J Clin Pharmacol 2001;41:563-572

HENDERSHOT ET AL

cient of variation (CV) of 50%. Pharmacodynamic mea-sures were used as the basis for sample size determina-tion due to greater variability than pharmacokineticparameters. These CV estimates were confirmed in re-view of the actual data for the main parameters ofinterest.

Study Design

The three studies followed a randomized, double-blind, placebo-controlled design. Subjects receivedtwo doses of OTC drug (or matching placebo) 4 hoursapart, alone on Days 1 and 3, and with concomitantlyadministered linezolid tablets 600 mg (given orally ev-ery 12 hours on Days 4 to 9) on Days 7 and 9 (Table I).

Pseudoephedrine hydrochloride (HCl) and phenyl-propanolamine HCl were administered orally as 60 and25 mg capsules, respectively. It was not possible toblind a dextromethorphan single-agent capsule due toits size and unique shape. Therefore, a cough syrupcontaining dextromethorphan hydrobromide (HBr) (20mg/5 mL) was compared to an identical cough syrupthat did not contain dextromethorphan HBr (placebo).Both cough syrups contained guaifenesin (200 mg/5 mL).The pharmacokinetics of guaifenesin and its lack of ef-fect on the pharmacokinetics of dextromethorphanhave been described in the literature,13 so no influenceof guaifenesin on study results was expected.

Study Procedures

BP and HR were measured at intervals over 24 hours onDays 1, 3, 7, and 9. Blood samples were collected at in-tervals over a 24-hour period on Days 1, 3, 7, and 9 andwere assayed for linezolid and respective OTC drug.

In addition, for the dextromethorphan study, bodytemperature was measured at intervals over 24 hours

following the initial dose on Days 1, 3, 7, and 9. Also forthis study, subject alertness and subject task perfor-mance (nurse-rated sedation evaluation and digit sym-bol substitution test) were evaluated for 12 hours fol-lowing the initial dose of cough syrup on Days 1, 3, 7,and 9. Neurological examinations were also performedon these days. Safety was assessed by the recording ofmedical (adverse) events and evaluation of electrocar-diograms (ECGs), vital signs, clinical chemistry, andhematology.

Pharmacokinetic andAnalytical Methods

Blood samples were collected on Days 1, 3, 7, and 9prior to dosing and at 1, 2, 4, 5, 6, 8, 12, and 24 hoursfollowing the initial dose of that day. Plasma washarvested from the samples after centrifugation andfrozen at –20°C. All plasma samples collected were as-sayed for OTC drug and metabolite, as appropriate,and samples collected on Days 7 and 9 were assayed forlinezolid.

Dextromethorphan is characterized by a very rapidabsorption and elimination; minimal blood levels areobserved following typical doses, making the accuratedetermination of pharmacokinetic parametersdifficult. Levels of dextrorphan, a primary metabo-lite, and measurements of its exposure have beenused as a surrogate for determining changes in dex-tromethorphan pharmacokinetics.14 Blood sampleswere therefore also assayed for both dextromethor-phan and dextrorphan.

Linezolid was quantified in plasma samples using afully validated high-performance liquid chromatogra-phy (HPLC) method.15 Pseudoephedrine, phenylpro-panolamine, dextromethorphan, and dextrorphan werequantified using HPLC-UV (ultraviolet) methods.16,17

DRUG INTERACTIONS 565

LINEZOLID

Table I Summary of Treatments

Study Day Treatment

Day 1 Two doses of active compounda or placebo 4 hours apartDay 2 No medication administeredDay 3 Two doses of active compound or placebo (whichever was not administered on Day 1) 4 hours apartDays 4-6 Linezolid tablet 600 mg every 12 hoursDay 7 Linezolid tablet 600 mg every 12 hours

Two doses of active compound or placebo 4 hours apartDay 8 Linezolid tablet 600 mg every 12 hoursDay 9 Linezolid tablet 600 mg every 12 hours

Two doses of active compound or placebo (whichever was not administered on Day 7) 4 hours aparta. Active compound = pseudoephedrine, phenylpropanolamine, or dextromethorphan.

Data Analysis

Pharmacokinetic parameters were calculated using theClinical Pharmacokinetics Analysis Package, version1.0,18 using noncompartmental methods.19 Parameters,including area under the plasma concentration-timecurve to infinity (AUC0-∞), peak concentration achieved(Cmax), and the time of Cmax (tmax), were determined forlinezolid, pseudoephedrine, phenylpropanolamine,dextromethorphan, and dextrorphan.

Area under the pharmacodynamic response vari-able versus time curves, the maximum increase in thepharmacodynamic response variable, the maximumvalue attained, and the incidence of treatment-emergent SBP greater than 160 mmHg were deter-mined. The pharmacodynamic response to pseudo-ephedrine and phenylpropanolamine, measured byBP and HR, was compared before and after linezolidtreatment.

The pharmacodynamic response to dextrometh-orphan, as measured by autonomic function (tempera-ture, BP, and HR) and altered mentation (nurse-ratedsedation evaluation and digit symbol substitutiontesting), was compared before and after linezolidtreatment.

Changes in OTC drug and linezolid pharmacoki-netic parameter values were assessed using pairedt-tests. Pharmacodynamic response variables werecompared using a two-way analysis of variance(ANOVA). Comparison between individual treatmentswas made using the least squares means (LSMEANS)procedure. Statistical significance was assumed if p <0.05. Relationships between pharmacokinetic andpharmacodynamic variables in the pseudoephedrineand phenylpropanolamine studies were evaluated byregression analysis. All statistical analyses were per-formed using SAS.20

RESULTS

Safety

Forty-two subjects were enrolled in total, 14 in eachstudy. Forty of these completed their respective studysatisfactorily. One subject withdrew following admin-istration of placebo due to nonserious adverse events:ventricular tachycardia, palpitations, and sweating.One subject withdrew from the pseudoephedrinestudy for personal reasons. Thirty-three subjects re-ported adverse events. There were no serious adverseevents, and all adverse events reported were eithermild or moderate in intensity.

In the pseudoephedrine and phenylpropanolaminestudies, the most commonly reported adverse event forthe linezolid-alone treatment (Days 4-6) was headache(reported by 4 and 5 subjects, respectively). Whenlinezolid was coadministered with placebo, the mostcommonly reported adverse events in the pseudo-ephedrine study were dizziness and skin irritation (2subjects); headache, diarrhea, and pharyngitis (2 sub-jects) were most commonly reported in the phenyl-propanolamine study. Dizziness (3 subjects) was themost frequent adverse event when linezolid andpseudoephedrine were given concomitantly; dizziness(5 subjects) and headache (3 subjects) were most com-mon when linezolid and phenylpropanolamine weregiven concomitantly. Dizziness (1 subject) was the onlyreported adverse event following administration ofpseudoephedrine alone; palpitations (2 subjects) weremost frequently reported following phenylpropa-nolamine administered alone. Headache (pseudo-ephedrine study, 3 subjects; phenylpropanolaminestudy, 2 subjects) was most commonly reported follow-ing placebo administration in both of these studies,with abdominal distension reported with the samefrequency as headache in the phenylpropanolaminestudy.

Only four adverse events were reported by morethan 1 subject during any treatment combination in thedextromethorphan study: abdominal distension (3subjects) and nausea (2 subjects) following coadminis-tration of linezolid and placebo, as well as vasodilation(2 subjects) and dizziness (2 subjects) followingcoadministration of linezolid and dextromethorphan.

Pharmacokinetics

Pharmacokinetic results from the three studies are pre-sented in Table II. Linezolid plasma concentrationswere comparable to those seen in previous clinical tri-als at this dosage regimen. Dextromethorphan levelswere below the limit of quantification at most timepoints for most subjects; therefore, the concentrationlevels for the metabolite dextrorphan were used in theanalyses.

Plasma concentrations of pseudoephedrine wereslightly increased when coadministered with line-zolid. AUC0-∞ was increased by approximately 20%(p = 0.0001) and Cmax by 10% (not statistically signifi-cant). Similarly, AUC0-∞ of phenylpropanolamine wasincreased by approximately 30% (p = 0.0001) and Cmax

by 20% (p = 0.0006), following coadministration withlinezolid.

Statistically significant decreases were observed inAUC0-∞ and Cmax of dextrorphan (approximately 30%

566 J Clin Pharmacol 2001;41:563-572

HENDERSHOT ET AL

DRUG INTERACTIONS 567

LINEZOLID

Tab

leII

Su

mm

ary

ofP

har

mac

okin

etic

Res

ult

s

Lin

ezol

idO

TC

Dru

g

Par

amet

erL

IN+

PB

OL

IN+

OT

Cp

-Val

ue

OT

CL

IN+

OT

Cp

-Val

ue

Lin

ezol

idp

seu

doe

ph

edri

ne

stu

dy

AU

C0-

∞(u

nit

a •h

/mL

)17

3±

118

(60-

416)

161

±94

(60-

367)

ns

4097

±83

2(2

920-

6193

)49

81±

1147

(352

9-74

88)

0.00

01C

max

(un

ita /m

L)

16.3

±3.

8(8

.9-2

1.8)

14.7

±2.

8(1

0.6-

19.3

)0.

0254

339

±56

(281

-433

)36

9±

91(2

63-5

90)

ns

t max

(h)

1.38

±0.

51(1

.00-

2.00

)2.

00±

1.00

(1.0

0-4.

00)

0.01

365.

92±

0.76

(5.0

0-8.

00)

6.46

±1.

13(5

.00-

8.00

)n

sL

inez

olid

ph

enyl

pro

pan

olam

ine

stu

dy

AU

C0-

∞(u

nit

a •h

/mL

)16

5±

92(6

5-32

5)14

5±

93(6

3-41

5)n

s11

04±

334

(503

-162

8)14

40±

390

(916

-233

6)0.

0001

Cm

ax(u

nit

a /mL

)16

.3±

3.7

(10.

6-23

.8)

16.3

4±

4.1

(10.

8-24

.7)

ns

107

±16

(80-

137)

128

±24

(74-

166)

0.00

06t m

ax(h

)1.

62±

0.51

(1.0

0-2.

00)

1.46

±0.

52(1

.00-

2.00

)n

s5.

38±

2.14

(1.0

0-8.

00)

5.62

±1.

33(2

.00-

8.00

)n

sL

inez

olid

dex

trom

eth

orp

han

stu

dy

AU

C0-

∞(u

nit

a •h

/mL

)26

5±

140

(87-

566)

277

±12

0(8

4-46

3)n

s21

11±

975

(210

-382

4)15

14±

728

(110

-271

0)0.

0003

Cm

ax(u

nit

a /mL

)17

.7±

4.3

(11.

3-24

.2)

17.2

±3.

5(9

.2-2

3.4)

ns

283

±16

7(9

-491

)19

1±

109

(6-3

74)

0.01

09t m

ax(h

)2.

00±

0.96

(1.0

0-4.

00)

2.36

±0.

93(1

.00-

4.00

)n

s5.

64±

1.78

(1.0

0-8.

00)

5.86

±1.

03(5

.00-

8.00

)n

sO

TC

,ove

r-th

e-co

unte

rdru

g;LI

N,l

inez

olid

,ns,

nosi

gnif

ican

tdif

fere

nce;

PBO

,pla

cebo

.Dat

are

pres

entm

eans

±1

stan

dard

devi

atio

n,w

ith

conc

entr

atio

nra

nges

inpa

rent

hese

s.S

tati

stic

alsi

gnif

ican

ce=

p<

0.05

.Val

ues

for

the

lin

ezol

id/d

extr

omet

hor

ph

anst

ud

yar

eth

ose

for

dex

tror

ph

an.

a.U

nit

for

lin

ezol

id=

µg;u

nit

for

OT

Cd

rug

=n

g.

for both AUC0-∞ [p = 0.0003] and Cmax [p = 0.0109]) fol-lowing coadministration with linezolid.

Significant differences in linezolid pharmacokineticparameters of Cmax and tmax were observed whenlinezolid was coadministered with pseudoephedrine.However, the magnitude of these differences was small.There were no significant changes in pharmacokineticparameters of linezolid when coadministered withphenylpropanolamine or dextromethorphan.

Pharmacodynamics

BP and HR data from the pseudoephedrine andphenylpropanolamine studies are shown in Table III.

Statistically significant increases in SBP were ob-served following the coadministration of linezolidwith either pseudoephedrine or phenylpropanola-mine, as compared with the other placebo combina-tions or the OTC treatments alone. The mean maxi-mum increase from baseline in SBP was 11 mmHg withplacebo, 18 mmHg with pseudoephedrine, and 15mmHg with the coadministration of linezolid with pla-cebo, but it was 32 mmHg with coadministration oflinezolid and pseudoephedrine. Similarly, in thephenylpropanolamine study, the combination oflinezolid and phenylpropanolamine produced a meanmaximum increase of 38 mmHg compared to 14 mmHgwith phenylpropanolamine alone. Treatment-emergent SBP greater than 160 mmHg was observedfollowing the coadministration of linezolid withpseudoephedrine (5 subjects, maximum value 174mmHg) and linezolid with phenylpropanolamine (2subjects, maximum value 176 mmHg). One subject ex-perienced SBP greater than 160 mmHg (maximumvalue 161 mmHg) when administered pseudoephed-rine alone. Five of the elevations above 160 mmHglasted for 0.5 hours. The remaining three elevations re-turned below 160 mmHg within 2 hours.

Smaller but similar statistically significant increasesin diastolic blood pressure (DBP) were observed in thepseudoephedrine and phenylpropanolamine studies.The mean maximum increase from baseline in DBPwas 10 mmHg with placebo, pseudoephedrine, and thecoadministration of linezolid with placebo, but it was17 mmHg with linezolid and pseudoephedrine. Simi-larly, in the phenylpropanolamine study, the combina-tion of linezolid and phenylpropanolamine produced amean maximum increase of 22 mmHg compared to 11mmHg with phenylpropanolamine alone.

No significant BP differences were observed be-tween treatments in the dextromethorphan study.

There were no statistically or clinically significanttreatment effects on HR in any of the three studies.

In the dextromethorphan study, there were no statis-tically significant differences in temperature. Digitsymbol substitution test scores were unaffected, andnurse-rated sedation scores were rated as “no sedation”for all subjects at all time points. No abnormal neuro-logical examination results were reported.

Pharmacodynamic versusPharmacokinetic Results

Pharmacodynamic response variables were regressedagainst the pharmacokinetic estimates of OTC drugexposure in the pseudoephedrine and phenylpro-panolamine studies. No significant correlations wereobserved between any cardiac parameter or pseudo-ephedrine parameter.

Significance was observed in regressions betweenthe following: area under the SBP curve corrected forbaseline treatment area and the area under the phenyl-propanolamine plasma concentration-time curve (r 2 =0.421, p = 0.003), maximum SBP corrected for baselinetreatment and the AUC phenylpropanolamine (r 2 =0.502, p = 0.0001), and maximum SBP corrected forbaseline treatment and the maximum phenylpro-panolamine concentration achieved (r 2 = 0.504, p =0.0001). A significant regression was also observed be-tween the maximum DBP corrected for baseline treat-ment and the maximum concentration of phenylpro-panolamine achieved (r 2 = 0.328, p = 0.0022). Trendstoward significance were observed in all regressionsbetween systolic and diastolic parameters and phenyl-propanolamine exposure parameters, but all regres-sions were characterized by high degrees of intersub-ject variability. In all significant regressions, no differ-ences were observed in the slopes of the regressionlines between phenylpropanolamine and the linezolidplus phenylpropanolamine treatments. A representa-tive graph of these significant correlations is depictedin Figure 1.

DISCUSSION

Any potential MAOI activity for drugs in which this isnot the therapeutic mechanism of action must be evalu-ated to determine potential clinical consequences, es-pecially as it pertains to drug and food interactions. Inthe past, tyramine challenge tests have been used to as-sess this. However, these tests are difficult to translateto potential everyday interactions. Other tests havebeen employed that evaluate specific drug interactions.Interaction studies with drugs such as sympatho-mimetics administered at common OTC dose levelshelp to quantify potential interactions in clinical prac-

568 J Clin Pharmacol 2001;41:563-572

HENDERSHOT ET AL

DRUG INTERACTIONS 569

LINEZOLID

Tab

leII

IS

um

mar

yof

Vit

alS

ign

sR

esu

lts

Blo

odP

ress

ure

(mm

Hg)

Sys

toli

cD

iast

olic

Hea

rtR

ate

(bp

m)

Max

(+)∆

Max

(+)∆

Max

(+)∆

Tre

atm

ent

from

t=0

Max

Val

ue

AU

C0-

12fr

omt=

0M

axV

alu

eA

UC

0-12

from

t=0

Max

Val

ue

AU

C0-

12

Lin

ezol

id/p

seu

doe

ph

edri

ne

stu

dy

PB

O11

±7

130

±16

1417

±17

110

±4

72±

978

3±

927

±4

71±

1072

5±

104

PS

E18

±9

133

±17

1450

±15

710

±5

73±

878

4±

8711

±7

75±

1275

0±

108

LIN

+P

BO

15±

913

2±

1614

25±

156

10±

472

±6

762

±72

8±

673

±8

747

±75

LIN

+P

SE

32±

1015

1±

1515

90±

168

17±

880

±8

845

±84

11±

775

±8

737

±56

Sta

tist

ics

(p-v

alu

es)

PS

Evs

.PB

On

sn

sn

sn

sn

sn

sn

sn

sn

sL

INvs

.PB

On

sn

sn

sn

sn

sn

sn

sn

sn

sL

IN+

PS

Evs

.PB

O0.

0001

0.00

150.

0095

0.00

070.

0163

ns

ns

ns

ns

LIN

+P

SE

vs.P

SE

0.00

010.

0082

0.03

310.

0023

0.02

94n

sn

sn

sn

sL

inez

olid

/ph

enyl

pro

pan

olam

ine

stu

dy

PB

O8

±7

121

±15

1315

±98

6±

472

±5

782

±59

7±

474

±8

768

±88

PPA

14±

1112

5±

1213

44±

112

11±

675

±8

789

±74

7±

474

±8

771

±89

LIN

+P

BO

11±

712

0±

1113

34±

107

10±

472

±5

778

±58

6±

477

±7

804

±88

LIN

+P

PA38

±20

147

±15

1476

±94

22±

884

±7

856

±64

6±

675

±8

778

±87

Sta

tist

ics

(p-v

alu

es)

PPA

vs.P

BO

ns

ns

ns

0.02

48n

sn

sn

sn

sn

sL

INvs

.PB

On

sn

sn

sn

sn

sn

sn

sn

sn

sL

IN+

PPA

vs.P

BO

0.00

010.

0001

0.00

020.

0001

0.00

010.

0045

ns

ns

ns

LIN

+P

PAvs

.PPA

0.00

010.

0001

0.00

200.

0001

0.00

030.

0096

ns

ns

ns

LIN

,lin

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tice and allow the development of relevant product la-bel information. Interactions between compounds thatpossess MAOI activity and those that inhibit serotoninreuptake, such as dextromethorphan, have been re-ported to result in a potentially severe interaction,termed the serotonin syndrome.

In these studies, the MAOI activity of linezolid wasquantified with respect to its effect on the pharmacoki-netics and pharmacodynamics of the sympathomi-metics pseudoephedrine and phenylpropanolamine,as well as the serotonin-reuptake inhibitor dextrometh-orphan. All drugs were administered at the maximumrecommended OTC dose regimen. Assessment of theseparameters in normal healthy volunteers allows the di-rect quantification of potentially enhanced responsesin a typical baseline patient population, with extrapo-lation to a more sensitive patient population with pre-disposing factors.

Linezolid had minimal effect on the pharmacokinet-ics of pseudoephedrine and phenylpropanolamine,with increases of 20% in AUC0-∞ and 10% in Cmax forpseudoephedrine and increases of 30% in AUC0-∞ and20% in Cmax for phenylpropanolamine. A minimal ef-fect (less than 10%) of pseudoephedrine or phenylpro-panolamine was observed on the resultant linezolidplasma concentrations. These results are consistentwith the known pharmacokinetics of the drugs.Pseudoephedrine and phenylpropanolamine are elim-inated primarily through renal elimination of un-changed drug, and linezolid is primarily metabolized

by nonenzymatic chemical oxidation with a minor re-nal elimination component of unchanged drug.Therefore, minimal pharmacokinetic interactionswould be expected.

Most plasma levels of dextromethorphan remainedbelow assay sensitivity both before and after linezolidadministration. This is consistent with literature re-ports of observed levels of dextromethorphan follow-ing doses similar to those employed in this study.14,21,22

A significant decrease in dextromethorphan metabo-lism should have significantly increased the levels ofthis compound. This does not rule out minor increasesin dextromethorphan levels, but dextromethorphanstill remained below detectability. An approximately30% decrease in the mean AUC0-∞ and Cmax ofdextrorphan, a primary metabolite of dextromethor-phan, was also observed, further supporting the con-clusion of a modest effect of linezolid on dextrometh-orphan pharmacokinetics. No effect of dextromethor-phan was observed on the resultant linezolid plasmaconcentrations.

The conversion of dextromethorphan to dex-trorphan by O-demethylation in humans is by thecytochrome P450 enzyme, CYP2D6.23 Linezolid wasnot found to affect this enzyme at concentrationshigher than those encountered in this trial in the in vi-tro evaluations.24 In another interaction study of quini-dine (a true inhibitor of CYP2D6) with dextromethor-phan, the levels of dextromethorphan increased by anaverage 18-fold (Cmax) and 43-fold (AUC). The Cmax val-ues of dextrorphan were reduced by 3.5-fold,21 an effectsubstantially greater than that observed in this study.Therefore, the actual mechanism behind the minimalchange in dextrorphan levels in this present study isnot clear.

Pseudoephedrine and phenylpropanolamine are in-direct acting sympathomimetics. Their effect is due toincreased concentrations of biologically active aminesat neurologic synapses. Linezolid, due to its MAOIactivity, could block removal of amines, leading topressor effect enhancement. Therefore, pharmacody-namic interactions could not be ruled out and requiredquantification. The pressor effects of pseudoephedrineand phenylpropanolamine were increased by line-zolid. Increases in the maximum positive change inSBP and DBP and the mean increase in the maximumBP attained, as well as the incidence of treatment-emergent SBP above 160 mmHg, were seen whenlinezolid was coadministered with either pseudo-ephedrine or phenylpropanolamine. However, the en-hanced pressor effects were transient. No statisticallysignificant effect on HR was observed in any treatment,although a trend to slower HRs was observed with

570 J Clin Pharmacol 2001;41:563-572

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575 712 849 986 1123 1260

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Figure 1. Correlation of individual phenylpropanolamine (PPA)AUC0-12 with change in systolic blood pressure AUC0-12 from baselineAUC0-12 following two doses of phenylpropanolamine HCl 25 mg q4hbefore and after linezolid 600 mg q12h.

phenylpropanolamine treatments. The means of eachsubject’s ratios of combination/OTC drug treatmentvalues for the maximum changes in SBP and DBP were2.17 ± 1.05 and 2.02 ± 1.27 (pseudoephedrine) and 3.92± 4.01 and 2.76 ± 2.29 (phenylpropanolamine), respec-tively. These increased effects were similar to the mag-nitude of the enhancement observed when moclo-bemide was administered with ephedrine.25 Althoughthe increased effect is due to the addition of linezolid tothe OTC sympathomimetic, the magnitude of effect iswell within the fluctuations observed in normal dailyactivity.26 Wide variability in individual responsesmeant that correlations between the effect of OTC drugon pharmacodynamic response and drug exposurewere difficult to interpret. This is consistent with otherattempts to relate exposure to effect.27

Linezolid had no effect on any dextromethorphanpharmacodynamic variables. These evaluations as-sessed both autonomic function (including tempera-ture, BP, and HR) and mentation (including sedationand performance testing). This is consistent with theobserved minimal pharmacokinetic changes.

The level of sympathomimetic potentiation due tolinezolid was not judged to be clinically significant inthese populations representing the typical uncompro-mised patient. There were few adverse events reported,and none were severe. However, patients sensitive tothe effects of increased BP due to predisposing factorsshould be treated cautiously. The package insert forpseudoephedrine and phenylpropanolamine recom-mends that patients with heart disease and high bloodpressure not take these drugs. Substitution with anagent with a different therapeutic mechanism of actionfor these patients is advised. The package insert forlinezolid also contains precautionary statements re-garding the combined use of these agents. These recom-mendations are consistent with the precautions associ-ated with other reversible MAOIs, such as moclo-bemide.25 No restrictions are needed regarding thecoadministration of dextromethorphan and linezolid.

The authors thank Bryan Graham, DPhil, of BIOS (Consultancy &Contract Research) Ltd. for assistance with the preparation andKirsteen Donaldson, DM, of BIOS (Consultancy & Contract Research)Ltd. for review of this manuscript.

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