The Sex Influence on Pharmacokinetic

8/16/2019 The Sex Influence on Pharmacokinetic

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Chapter 2

Effects of Sex Differences

in the Pharmacokinetics of Drugs and Their Impact

on the Safety of Medicines in Women

Emmanuel ! "adiran and #ei $hang

Introduction

Inclusion of %omen in clinical trials and analysis of clinical trial data for

sex&gender effects ha'e (een an integral component of the )S "D*’sconsideration for appro'al of pharmaceutical products since the mid+,-./s 0 "D*

1uidance for Industry ,--3! The study of sex differences is no% a routine

component of drug de'elopment (ecause of existing data in drug exposure and

response differences (et%een men and %omen and the need to understand such

differences for proper dosing 04arris et al! ,--56 Sch%art7 2//6 Institute of

Medicine 0)S3 2//,6 "ranconi et al! 2//86 Parekh et al! 2/,,3! The resulting

expanding kno%ledge of sex differences in the exposure and responses to drugs

has led to a (etter under+standing of the mechanisms contri(uting to these

differences and impro'ed pharmaco+therapy for men and %omen!

Sex+(ased differences may (e due to pharmacokinetics 0differences in exposure inmen and %omen follo%ing administration of the same dose of a drug3 and&or

pharmacodynamics 0differences in the (ody’s response to the same dose of a drugin men and %omen3 and can manifest as differences in safety and&or efficacy of

pharmacotherapy! "or example9 %hen compared to men9 %omen are ,!5:,!8 times

more likely to de'elop an ad'erse drug reaction 0;ademaker 2//,39 %hich

The 'ie%s expressed are those of the authors and do not necessarily reflect official policy of the

)S "D*!


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ffice of Clinical Pharmacology9 ffice of Translational Sciences9 Center for Drug E'aluation

and ;esearch9 "ood and Drug *dministration9 Sil'er Spring9 MD 2/--9 )S*

e+mail> #ei@!$hang?fda!hhs!go'

© Springer International Pu(lishing S%it7erland 2/,5A,

M! 4arrison+Woolrych 0ed!39 Medicines For Women,DI ,/!,//8&-8.++,-+,2A/B+2

mailto:[email protected]:[email protected]:[email protected]


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A2 E!! "adiran and #! $hang

is defined as any unintended and undesired effect of a drug used at a dose for

diagnosis9 prophylaxis9 or therapy 0;ademaker 2//,6 *nderson 2//56 Tran et al!

,-..3! This chapter %ill focus on sex differences in pharmacokinetics 0P@3 and

%ill discuss ho% these differences may affect the efficacy and safety of medicines

in %omen!

Sex and 1ender

The terms sex and gender are often used interchangea(ly and it is important to

define them 0@im and


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administered on a mg&kg (asis (ut as a


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gender

meta(olite9 dehydro+

aripipra7ole9 are /:A/ G

higher in %omen than in men9

and correspondingly9 the

apparent oral clearance of

aripipra7ole is lo%er in

%omen! These differences9


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ho%e'er9 are largely

explained (y differences in

(ody %eight 025 G3 (et%een

men and %omen!


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pharmacology

plasma tiprana'ir trough con+

centrations at ,/:,A h after

dosing from the controlled

clinical trials ,,.2!,2 and

,,.2!A. demonstrated that

females generally had higher

tiprana'ir concentrations than

males! *fter A %eeks of


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*PTI)S&ritona'ir

5//&2// mg =ID9 the median

plasma trough concentration

of tiprana'ir %as A!- mM for

females and ,!, mM for

males! The difference in con+

centrations does not %arrant a


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dose adHustment!

*;$E;;*

,/&2B&/-

A&,8&,A

Clinical

1ender had a modest effect

0fatumuma(3

pharmacology

on ofatumuma( pharmacoki+

netics 0,A:25 G lo%er clear+

ance and 'olume of

distri(ution in female patients

compared to male patients3 in


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a cross+study population

analysis 0A, G of the patients

in this analysis %ere male and

5- G %ere female3! These

effects are not considered

clinically important9 and no

dosage adHustment is

recommended!


12/106

0continued3


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AA

E!! "adiran and #! $hang

Ta(le 2!, 0continued3

Date of

Date of

the cited

=rand name 0drug

drugappro'ed

#a(eling

name3

appro'alla(el

section

#a(eling statement

**STI<

2&2B&/A

,2&,B&,Clinical

The clearance of 0=e'aci7uma(3


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c 0!25 # 's! 2!BB #3 than

females!

EME


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males! The half+life of

aprepitant is 25 G lo%er in

females as compared %ith

males and Tmax occurs at

approximately the same time!

These differences are not

considered clinically mean+


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ingful!


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mately 58:8- G and B,:8 G

higher in females than in

males9 respecti'ely!

"*CTIE

A&A&/

.&,A&,

Clinical

There are no significant dif+

01emifloxacin

pharmacology

ferences (et%een

Mesylate3

gemifloxacin pharmacokinet+


19/106

ics in males and females

%hen differences in (ody

%eight are taken into account!

Population pharmacokinetic

studies indicated that follo%+

ing administration of 2/ mg

gemifloxacin9 *)C 'alues

%ere approximately ,/ G


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matched elderly and young

su(Hects %ere o(ser'ed!

Clearance of "I;*$F; is

significantly correlated %ith

(ody %eight %ith lo%er

clearance 'alues noted for

lo%er (ody%eights! 4ence9

females %ith typically lo%er

(ody %eights compared to


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males exhi(it lo%er clearance

'alues9 resulting in approxi+

mately 2+fold higher systemic

exposure 0(oth *)C and

Cmax3 compared to males!

Differences in efficacy and

safety (et%een elderly and

younger patients and male

and female patients ha'e not


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(een identified! Dose adHust+

ment (ased on age and gender

is not %arranted!

")$E<

&,&/

,/&,&,

Clinical*nalysis of plasma concen+

0Enfu'irtide3

pharmacology

tration data from su(Hects in

clinical trials indicated that

the clearance of enfu'irtide is

2/ G lo%er in females than


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males after adHusting for (ody

%eight! Enfu'irtide clearance

decreases %ith decreased

(ody %eight irrespecti'e of

gender! ;elati'e to the

0continued3


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AB



Date of

Date of

the cited

=rand name 0drug

drugappro'ed

#a(eling

name3

appro'alla(el

section

#a(eling statement

clearance of a 8/+kg male9 a


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A/+kg male %ill ha'e 2/ G

lo%er clearance and a ,,/+kg

male %ill ha'e a 2B G higher

clearance! ;elati'e to a 8/+kg

male9 a A/+kg female %ill

ha'e a B G lo%er clearance

and a ,,/+kg female %ill ha'e


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the same clearance!

"FCMP*

,/&22&,2

2&2A&,A

ClinicalIn a population pharmacoki+

0Perampanel3

pharmacology

netic analysis of patients %ith

partial+onset sei7ures recei'+

ing "FCMP* in place(o+

controlled clinical trials9

perampanel apparent clear+


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not kno%n!

I

tartrate from the (ody after

gender

su(lingual administration of a

!5 mg dose of Interme77o at

a lo%er rate than men


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02!8 m#&min&kg 's! A!/ m#&

min&kg3! Cmax and *)C

parameters of 7olpidem %ere

approximately A5 G higher at

the same dose in female su(+

Hects compared %ith male

su(Hects! 1i'en the higher

(lood le'els of 7olpidem tar+


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trate in %omen compared to

men at a gi'en dose9 the

recommended dose of Inter+

me77o for %omen is ,!85 mg9

0continued3


35/106

2 Effects of Sex Differences in the Pharmacokinetics of Drugs. . .A8


Date of

Date of the cited

=rand name 0drug

drugappro'ed

#a(eling

name3

appro'al

la(el

section

#a(eling statement


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and the recommended dose

for adult men is !5 mg!

#I*#

.&&/-

,/&,B&,

Clinical

In a pharmacokinetic study

0Pita'astatin

pharmacology

%hich compared healthy male

Calcium3

and female 'olunteers9

pita'astatin Cmax and *)C


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%ere B/ and 5A G higher9

respecti'ely in females! This

had no effect on the efficacy

or safety of #I*# in

%omen in clinical studies!

MFC*MI


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populations>

Mycamine is reuired (ased

Sodium3

race and

on gender or race! *fter

gender

,A daily doses of ,5/ mg to

healthy su(Hects9 micafungin

*)C in %omen %as greater

(y approximately 2 G com+

pared %ith men9 due to


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smaller (ody %eight!

MF;=ET;IN

B&2.&,2B&2.&,2

Clinical phar+

The Cmax and *)C of

0Mira(egron3

macology

mira(egron %ere approxi+

0also in race

mately A/:5/ G higher in

and gender

females than in males! When

section3

corrected for differences in


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(ody %eight9 the mira(egron

systemic exposure is 2/:/ G

higher in females compared

to males


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42/106


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approximately 25 G higher

exposure 'alues for the acti'e

meta(olite than males9 (ut

this difference is unlikely to

0continued3


44/106

A.



Date of

Date of

the cited

=rand name 0drug

drugappro'ed

#a(eling

name3

appro'alla(el

section

#a(eling statement


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(e of clinical rele'ance! 1en+

der %as not identified as a

significant co'ariate on the

apparent clearance of

saxagliptin and its acti'e

meta(olite in the population

pharmacokinetic analysis!


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PTI1*

B&,/&,,

-&B&,

Clinical

The impact of gender on the

0E7oga(ine3

pharmacology

pharmacokinetics of

e7oga(ine %as examined fol+

lo%ing a single dose of

PTI1* to healthy young

0aged 2,:A/ years3 and


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elderly 0aged BB:.2 years3

su(Hects! The *)C 'alues

%ere approximately 2/ G

higher in young females

compared to young males and

approximately / G higher in

elderly females compared to


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elderly males! The Cmax

'alues %ere approximately

5/ G higher in young females

compared to young males and

approximately ,// G higher

in elderly females compared

to elderly males! There %as


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no gender difference in

%eight+normali7ed clearance!

'erall9 no adHustment of the

dosage of PTI1* is

recommended (ased on

gender!

S*


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pharmacology

macokinetics in different

Chloride3

genders had conflicting

results! When a single A/ mg

S*


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compared to elderly males!

When 2/ mg S*


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years39 *)C and Cmax %ere

2B G and B. G higher9

respecti'ely9 in females %ith+

out hormone replacement

therapy than in males!

SIMP


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pharmacology

suggested no P@ differences

(et%een male and female

patients after (ody %eight

adHustment in the ;*9 Ps*

and )C trials! In the *S trial9

female patients sho%ed , G

higher apparent clearance


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than male patients after (ody

%eight adHustment! Su(group

analysis (ased on gender

sho%ed that (oth female and

male patients achie'ed clini+

cally significant response at

the proposed clinical dose!


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Dosage adHustment (ased on

gender is not needed!

TE"#*;

,/&2-&,/

,2&,B&,

Clinical

"ollo%ing administration of a

0Ceftaroline

pharmacology

single B// mg I dose of

"osamil for

Teflaro to healthy elderly

InHection3

males 0n ¼ ,/3 and females


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0n ¼ B3 and healthy young

adult males 0n ¼ B3 and

females 0n ¼ ,/39 the mean

Cmax and *)C for

ceftaroline %ere similar

(et%een males and females9

although there %as a trend for


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higher Cmax 0,8 G3 and

*)C 0B:,5 G3 in female

su(Hects! Population pharma+

cokinetic analysis did not

identify any significant dif+

ferences in ceftaroline *)C

( d d i Ph 2&


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patients %ith *=SSSI or

C*=P!


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"umarate3

mean 0_SD3 *)C and Cmax

for the acti'e meta(olite

0continued3


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5/



Date of

Date of

the cited

=rand name 0drug

drugappro'ed

#a(eling

name3

appro'alla(el

section

#a(eling statement

5+hydroxymethyl tolterodine


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in ,2 elderly men 0mean age

B8 years3 %ere

5,!. _ 2B!, hOng&m# and

!. _ ,!8 ng&m#9 respec+

ti'ely! In the same study9 the

mean 0_SD3 *)C and Cmax

in ,2 elderly %omen 0mean


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ICT$*

,&25&,/

B&,&,

Clinical=ased on the results of popu+

0#iraglutide3

pharmacology

lation pharmacokinetic ana+

lyses9 females ha'e A G

lo%er %eight+adHusted clear+

ance of icto7a compared to

males! =ased on the exposure

response data9 no dose


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adHustment is necessary (ased

on gender!

"E


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young males 0,.:A5 years39

after ta(let dosing! In the

same study9 no significant

differences in the mean Cmax

and *)Cτ %ere o(ser'ed

(et%een healthy elderly

males and healthy elderly


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females 0>B5 years3! In a

similar study9 after dosing

%ith the oral suspension9 the

mean *)C for healthy young

females %as A5 G higher than

in healthy young males

%hereas the mean Cmax %as

compara(le (et%een genders!


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The steady state trough

'oricona7ole concentrations

0Cmin3 seen in females %ere

,// G and -, G higher than

0continued3


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2 Effects of Sex Differences in the Pharmacokinetics of Drugs. . .5,


Date of

Date of the cited

=rand name 0drug

drugappro'ed

#a(eling

name3

appro'al

la(el

section

#a(eling statement


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in males recei'ing the ta(let

and the oral suspension9

respecti'ely! In the clinical

program9 no dosage adHust+

ment %as made on the (asis

of gender! The safety profile

and plasma concentrations


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men and %omen gi'en the

same mg&kg dose! In adults

ages 55:BA9 d+amphetamine

Cmax and *)C %ere ,5 G

and , G higher9 respec+

ti'ely9 in females compared


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to males!

‘one si7e fits all’ dose9 leading to higher exposures in %omen due to their generallylo%er (ody %eight!

Sex differences ha'e (een reported for all four phases of drug disposition>

a(sorption9 distri(ution9 meta(olism and excretion9 0collecti'ely a((re'iated as

‘*DME’3 in humans and are discussed in more detail (elo%! ther factors such asanatomic9 physiologic9 (iochemical and endocrine sex differences can also

influence drug disposition and response in humans 0Mattison 2/,3 and are

further discussed (elo%!

Sources of Pharmacokinetic Data for Drug #a(eling

In the maHor markets of the de'eloped %orld P@ information is no% routinely included

in appro'ed drug la(elings 0Ta(le 2!,3 04uang et al! 2//86 Copeland and Parekh

2/,,3! Most often the P@ sex difference data are deri'ed from small clinical

pharmacology studies %ith typically ,2:2A healthy su(Hects! Studies %ith small patient

num(ers may (e adeuate to detect large sex+(ased differences in clearance6 ho%e'er9

if the sex+(ased P@ difference is small9 the relati'ely small si7e of most clinical

pharmacology studies makes it difficult to interpret small differences o(ser'ed9 or to

confirm if there is no difference in P@ 04uang et al! 2//83!

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52 E!! "adiran and #! $hang

Some appro'ed drug la(elings ha'e also reported P@ sex differences from

population P@ analysis %ith sparse P@ sample data from Phase 2 and Phase

clinical trials 0Ta(le 2!,3! The population P@ model generated is used to explore

the effect of 'arious co'ariates 0factors3 such as sex9 age9 ethnic group9 and

smoking status on drug P@ and can therefore (e used to descri(e sex differences in

exposure 0"D* 1uidance for Industry ,---6 Sun et al! ,---3! Compared to

dedicated P@ e'aluation9 the population P@ approach encompasses some or all of

the follo%ing features 0"D* 1uidance for Industry ,---6 Sun et al! ,---3>

the collection of rele'ant P@ information in patients %ho are representati'e of the

target population to (e treated %ith the drug!

the identification and measurement of 'aria(ility during drug de'elopment and

e'aluation!

the explanation of 'aria(ility (y identifying factors of demographic9 pathophysio+

logical9 en'ironmental9 or concomitant drug+related origin that may influence the

P@ (eha'ior of a drug!

the uantitati'e estimation of the magnitude of the unexplained 'aria(ility in the

patient population!

Population P@ analyses are no% routinely performed during drug de'elopment

and the results for P@ sex differences are included in se'eral appro'ed )S drug

la(elings including those for ofatumuma(9 gemifloxacin9 perampanel9 golimuna(9

ceftaroline fosamil and liraglutide 0Ta(le 2!,3!

Mechanisms and (ser'ed Sex+Specific Differences

in Pharmacokinetics

=elo%9 %e %ill address t%o maHor uestions a(out the potential importance of sex+

specific P@ for applied pharmacotherapy>

What are the potential mechanisms for sex differences in P@

What are the o(ser'ed P@ differences (et%een %omen and men and are there

examples %here such P@ differences result in different pharmacological responsesand in su(seuent different dosing recommendations

In addition9 %e %ill present some examples of P@ sex differences resulting in

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different la(eling for men and %omen!


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2 Effects of Sex Differences in the Pharmacokinetics of Drugs. . . 5

What Are the Potential Mechanisms for Sex ifferences inPharmaco!inetics"

*s mentioned earlier9 sex differences ha'e (een reported for all four phases ofdrug disposition> a(sorption9 distri(ution9 meta(olism and excretion 0*DME3!

Each of these phases %ill (e discussed in more detail (elo%!

*(sorption

Sex differences in the gastrointestinal system ha'e (een demonstrated! "or example9

gastric p4 is higher in %omen than men and gastric and (o%el transit times are usually

longer in %omen 0"reire et al! 2/,,6 MoHa'erian et al! ,-.83! 4o%e'er9 it is not clearif the sex differences in gastric p4 or gastric emptying ha'e any clinical rele'ance! It

has (een sho%n in one study that the rate of a(sorption of aspirin is higher in %omen

(ut there %as no difference in the extent of a(sorption 0*arons et al! ,-.-3! The

(ioa'aila(ility of ethanol is greater in %omen compared to men partly due to

differences in 'olume of distri(ution 0d3 and gastric alcohol dehydro+genase acti'ity

0"re77a et al! ,--03 %hich may explain %hy there %as no sex difference in alcohol (lood concentrations after intra'enous administration 0=araona et al! 2//,3! There

may (e differences in a(sorption depending on the drug route of administration 0e!g!9

oral9 inhalation9 dermal9 su(cutaneous9 rectal9 'aginal9 intra+muscular9 intrathecal9

intraperitoneal3 (ecause factors that influence a(sorption are (oth drug+ and route+specific9 (ut may also (e sex+specific! Most drugs are admin+istered through the oral

route follo%ing %hich a(sorption may (e affected (y sex differences in intestinal

meta(olism cytochrome P+A5/ 0CFP3 en7ymes and acti'e transporter p+glycoprotein

0P+gp3 01andhi et al! 2//A6 Waxman and 4ollo%ay 2//-3 0see (elo%3! Some studies

ha'e sho%n that concentrations of inhaled aerosol drugs such as cyclosporine and

ri(a'irin are less in %omen compared to men (ut the clinical significance is unkno%n

0;hatagi et al! 2//06 @night et al! ,-..3 and the (ioa'aila(ility of intramuscularcephradine is lo%er in %omen 0uko'ich et al! ,-853! *dditionally9 %omen ha'e

greater minute 'entilation and a lo%er tidal 'olume9 (oth of %hich may ha'e the

potential to affect drug a(sorption 'ia the respiratory tract! Inacti'e ingredients mayaffect the (ioa'aila(ility of drug formu+lations and this could occur in a sex+specific

%ay9 at least in some cases! "or example9 the excipient polyethylene glycol enhances

the (ioa'aila(ility of ranitidine in men 0up to B G39 %hereas it is decreased in %omen

0up to 2A G3 0*shiru et al! 2//.3!

Sex differences ha'e (een reported in (ioa'aila(ility of medicines9 %hich is then used

to esta(lish (ioeui'alence 0=E3 of generic drugs! *nalysis of sex differences in

intrasu(Hect 'aria(ility and P@ from 2B =E studies sho%ed that although there %as no

sex difference in intrasu(Hect 'aria(ility9 there %as a _2/ G difference in P@

parameters in one third of the data set 0Chen et al! 2//03! The P@ sex differences%ere primarily the result of greater exposure in %omen %ho %ere gi'en the same dose

as men! When the parameters %ere corrected for %eight9 only ,5 G sho%ed

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5A E!! "adiran and #! $hang

statistically significant differences! Sex differences in the P@ parameters should

not affect =E studies since they use the crosso'er design in %hich each su(Hect

ser'es as his or her o%n control 0 "D* 1uidance for Industry 2/, 0Draft33!

Distri(ution

Since (ody composition 'aries (y sex9 there are also sex differences in drug

distri(ution! Women ha'e a higher percentage of (ody fat compared to men

0approximately 25 G 's! ,B G in men39 although this difference decreases as age

increases 0ahl et al! ,--.3! Due to this larger amount of lipophilic tissue9 %omen

ha'e a greater d for lipophilic drugs such as dia7epam9 nitra7epam9 chlordia7+epoxide and cyclosporine 0Soldin and Mattison 2//-6 chs et al! ,-.,6

1reen(latt et al! ,-.06 1reen(latt et al! ,-.56 ;o(erts et al! ,-8-6 @ahan et al!,-.B3! Increased d may translate into prolonged elimination half+life9 tissue

accumulation o'er time9 and exposure+related ad'erse reactions! Con'ersely9

%omen ha'e a smaller 'olume of distri(ution for hydrophilic drugs9 such as

propanol 0ErnstgaQrd et al! 2//3! Women are also reported to ha'e a lo%er

plasma 'olume %hen compared to men9 as %ell as a lo%er organ (lood+flo% rate

and lo%er concentrations of α+, acid glycoprotein 0Piafsky and =orga ,-886er(eeck et al! ,-.A39 a (inding protein for neutral and (asic drugs %hich may

impact the distri(ution process leading to different exposures! *s opposed toal(umin9 α+, acid glycoprotein has its expression controlled (y circulating sexhormones 0=eierle et al! ,---3! 4or+monal contracepti'es and pregnancy (oth

further decrease plasma α+, acid glyco+protein! *s a result9 the un(ound fractionof 'arious drugs that (ind toα+, acid glycoprotein is significantly higher infemales than in males9 as descri(ed for dia7epam9 chlordia7epoxide9 and

imipramine 0chs et al! ,-.,6 1reen(latt et al! ,-.06 ;o(erts et al! ,-8-6@ristensen ,-.3! 4o%e'er9 no sex differences ha'e (een found in the un(ound

fractions of 'erapamil and disopyramide or other highly (ound drugs in patients

recei'ing oral contracepti'es 0@eefe et al! ,-.,6 @ishino et al! ,--56 1leichmannet al! ,-83!

*ccording to the free drug hypothesis9 0%hich states that the pharmacological

acti'ity is correlated %ith un(ound drug concentrations in plasma3 this should

translate into more drug (eing a(le to penetrate tissues9 (ut the clinical impact of

protein (inding of drugs has not (een elucidated 0;olan ,--A3!

Meta(olism

The li'er plays an important role in the meta(olism of many drugs! 4epatic drug

meta(olism is mainly (y t%o phases+ Phase I9 %hich includes oxidation9 reduction9

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and hydrolysis %ith the maHority of Phase I meta(olism cataly7ed (y CFP

en7ymes9 and Phase II9 %hich includes conHugation9 e!g!9 glucorondination9

sulfation9 acetyl+ation9 methylation9 and glutathione conHugation!


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Moltke 2//.6 4u and $hao 2/,03

CFP2C-

Women ¼ men"lu'astatin 0Sch%art7 2//3

CFP2C,-Women ¼ menMephenytoin 0=e(ia et al! 2//A3

The CFP ‘superfamily’ has a di'erse range of en7ymes responsi(le for drugmeta(olism9 and 'arious en7ymes ha'e sex+related differences in acti'ity! Caffeine

is meta(oli7ed (y CFP,*2! This isoen7yme also meta(oli7es drugs such as the+

ophylline and clo7apine! Studies ha'e sho%n a higher acti'ity of CFP,*2 in men

than in %omen 0*nderson 2//53! In one study9 %omen had a 5 G higher concen+

tration of clo7apine compared %ith men after normali7ation for dose9 age9 and

(ody %eight 0#ane et al! ,---3! The sex differences among maHor CFP en7ymes

are summari7ed in Ta(le 2!2.

CFP2DB is the second most common en7yme in'ol'ed in therapeutic drug

(iotransformation 0"ranconi et al! 2//83! It meta(oli7es se'eral drugs including

antidepressants9 antiarrhythmics9 analgesics9 and (eta (lockers! *lthough there

ha'e (een reports sho%ing faster clearance of CFP2DB su(strates 0such as dextro+

methorphan and metoprolol3 in men than in %omen9 there ha'e (een other reports

sho%ing either no sex+(ased differences or higher CFP2DB acti'ity in %omen

0#a((eR et al! 2//06 =e(ia et al! 2//A3!

CFP* en7ymes are the most common CFPs for meta(olism9 meta(oli7ing greater

than 5/ G of commonly prescri(ed drugs! Many drugs that are su(strates for CFP*

exhi(it higher clearance in %omen leading to lo%er exposure 0"ranconi et al! 2//86

Mattison 2/,6 1reen(latt and 'on Moltke 2//.6 Chetty et al! 2/,23! "or example9

Mida7olam is a %ell+kno%n su(strate for CFP*! * meta+analysis 04u and $hao

2/,03 on sex+dependent differences in mida7olam disposition for (oth intra'enous andoral exposures sho%ed that %omen had higher clearance rates than men9 and the sex

differences %ere more pronounced for intra'enous mida7olam! There %as no

difference in oral (ioa'aila(ility (et%een the sexes! The authors concluded that %omen

exhi(ited significantly greater hepatic CFP* acti'ity than men! Similarly9 an earlierstudy that analy7ed . datasets for ,A CFP* su(strate drugs tested in healthy young

males and females sho%ed a difference in the o'erall mean ratios of female to male

%eight+normali7ed clearance of the drugs 0parenteral drugs> ,!2B _ /!/86 oral drugs>

,!,8 _ /!/839 i!e!9 %omen cleared the drugs faster than men and sex differences %ere

more pronounced for intra'enous route 01reen(latt and 'on Moltke 2//.3! They also

looked at a(solute (ioa'aila(ility of the oral drugs and identified no difference in this

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parameter


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2/,3! They are expressed in all tissues including intestine9 li'er9 kidney

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Taurocholate Co+transporting Polypeptide 0


86/106

5. E!! "adiran and #! $hang

uantification methodology sho%ed that sex %as not associated %ith transporter

protein expression of *TP,=,9 *TP,=9 *TP2=,9 and P+gp in fro7en human

li'ers 0Prasad et al! 2/,A3! There is a need for characteri7ation of sex differences in

human transporter proteins to more clearly understand any possi(le clinical effects!

4ormonal Differences

The assessment of sex+related differences is important as %omen experience a

changing internal hormonal en'ironment during the menstrual cycle 0follicular9

o'ulatory9 and luteal phases39 during pregnancy9 as %ell as during and follo%ing

menopause! "urthermore9 hormonal contracepti'es can lead to increased or

decreased drug clearance9 most likely due to induction and&or inhi(ition of CFP

isoforms in the li'er and gut!

There are numerous examples supporting the contention that female sex hor+

mones impact drug+meta(oli7ing path%ays 0Sch%art7 2//6 1andhi et al! 2//A6

@ashu(a and


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2 Effects of Sex Differences in the Pharmacokinetics of Drugs. . . 5-

What Are the %&ser'ed P( ifferences )eteen Women

and Men and Are +here ,xam-les Where Sch P( ifferences

/eslt in iffering Pharmacological /es-onses and inS&se0ent ifferent osing /ecommendations"

P@ Differences (ser'ed

*lthough P@ differences (et%een men and %omen are possi(le (ased on sex+

(ased differences in the mechanisms descri(ed a(o'e9 not all drugs exhi(it sex+

(ased P@ differences! In addition9 the magnitude of many P@ differences is often

small 0i!e! #2/ G3 and may not (e clinically rele'ant! "or example9 a sur'ey of

clinical pharmacology data contained in // ne% drug applications 0


88/106

Considerations

* fe% examples %here sex+(ased P@ differences resulted in modified pharmaco+

logical response and&or su(seuent different recommendations are highlighted here!


89/106

B/ E!! "adiran and #! $hang

%ndansetron

ndansetron9 appro'ed for the pre'ention of nausea and 'omiting resulting from

chemotherapy or in the postoperati'e setting9 has (een sho%n to display a signif+icant P@ sex difference 0ann et al! ,--.3! The "D*+appro'ed la(eling for

ondansetron states that %omen ha'e ,!5:2 times the peak drug plasma concen+

trations and a lo%er oral clearance9 (ut no sex+(ased dosage adHustment is

recommended 0$ofran$

)S "D* product la(eling3! Similar lo%er oral clearances

are reported in elderly patients and patients %ith mild+to+moderate hepatic impair+

ment and no dosage adHustment is recommended in these patients either9 possi(ly

(ased on similar exposure+response analysis for these patient populations! The

recommended adult dose of ondansetron is 2A mg administered (efore emetogenic

chemotherapy or ,B mg (efore anesthesia9 and is not dosed on an mg&kg (asis!

%lan1a-ine

lan7apine is an atypical antipsychotic appro'ed for the treatment of schi7ophrenia

and (ipolar disorder for %hich the la(el recommends a lo%er dose for patients in

%hom higher exposures are anticipated! "or schi7ophrenia9 the starting dose is 5: ,/

mg daily %ith a target dose of ,/ mg&day %ithin se'eral days 0$yprexa$ )S "D* product la(eling3! 4o%e'er9 gi'en that some treatment related ad'erse e'ents are dose

and exposure dependent9 a lo%er dose is recommended in specific populations %ho

may ha'e higher plasma concentrations! "or instance9 olan7apine clearance is lo%er in

%omen! Clearance is also lo%er in the elderly 0_B5 years39 causing higher plasma

concentrations! lan7apine is extensi'ely meta(oli7ed and CFP,*2 has (een

identified as one of the en7ymatic path%ays of meta(olism! *s noted earlier9 CFP,*2

sho%s a lo%er acti'ity in %omen9 possi(ly leading to a lo%er clearance of olan7apine

in %omen! CFP,*2 can (e induced (y cigarette smoking and as a result9 olan7apine

clearance is a(out A/ G higher in smokers than in nonsmokers!

*lthough each of these factors may not independently Hustify dosing adHustment9 the

com(ined effects of age9 smoking9 and a patient’s sex could lead to su(stantial P@differences and increase the likelihood of ad'erse effects from higher expo+sures! The

plasma concentrations in elderly nonsmoking females9 for example9 may (e higher

than those in young smoking males! The la(eling for olan7apine recom+mends a lo%er

starting dose of 5 mg daily for patients %ho exhi(it a com(ination of factors 0e!g!9

nonsmoking female patients _B5 years of age39 as higher plasma concentrations are

expected in these patients 0$yprexa$

)S "D* product la(eling3!

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2 Effects of Sex Differences in the Pharmacokinetics of Drugs. . . B,

Ta(le 2! Sex differences in the safety of amlodipine 0


91/106

Amlodi-ine

*mlodipine is a long+acting calcium channel (locker indicated for the treatment of

hypertension and coronary artery disease! The recommended adult starting dose is

5 mg once daily %ith a maximum dose of ,/ mg once daily9 ho%e'er9 a lo%er

starting dose of 2!5 mg once daily is recommended for small9 fragile9 or elderly

patients or patients %ith hepatic impairment! The la(eling contains information on

the ad'erse effects of the higher dose in %omen9 %hich is most likely related to

higher (lood le'els! "or se'eral ad'erse experiences that appear to (e drug+ anddose+related9 there %as a greater incidence in %omen than in men associated %ith

amlodipine treatment as sho%n in Ta(le 2! 0


92/106

B2 E!! "adiran and #! $hang

and for patients %ith hepatic impairment %ho meta(oli7ed the drug more slo%ly

0"arkas et al! 2/,3!

When the su(lingual formulation 0Interme77o$

)S "D* product la(eling3 %asappro'ed in 2/,,9 a sex+(ased dosage recommendation 0i!e!9 ,!8 mg for %omen and

!5 mg for men3 %as made (ased on ne% data that re'ealed a relationship (et%een

(lood 7olpidem le'el and dri'ing impairment! The data sho%ed that a (lood le'el of

7olpidem of >5/ ng&ml could impair dri'ing! With this threshold (lood le'el9 "D*retrospecti'ely assessed the safety of other dosage forms of 7olpidem (ased on the

(lood le'el of 7olpidem . h post+doing! Sex+(ased dose recommendations %ere

su(seuently made to all formulations of 7olpidem products (ased on reanalysis of P@

data! "ollo%ing administration of ,/ mg *m(ien$

ta(let 0an immediate+release

7olpidem product39 a(out ,5 G of %omen and G of men had 7olpidem concen+

trations that exceeded 5/ ng&m# approximately . h post+dosing 0"arkas et al! 2/,3!

* higher percentage of (oth men and %omen experience potentially impairing morning

7olpidem le'els after use of extended+release 7olpidem products 0*m(ien$

controlled+

released products at ,2!5 mg39 %hich is expected gi'en that approximately G of

%omen and 25 G of men had 7olpidem (lood concentrations exceeding 5/ ng&m# . h

post+dosing! In studies of 7olpidem extended+release B!25 mg9 at . h after dosing9

a(out ,5 G of adult %omen and 5 G of adult men had a 7olpidem le'el of _5/ ng&m#9

%hereas for (oth elderly men and %omen9 a(out ,/ G had such a 7olpidem le'el

0*m(ien$

C; 3! These findings are consistent %ith the sex differences o(ser'ed %ith'arious formulations of 7olpidem! In anuary 2/,9 the "D* lo%ered the

recommended dose for 7olpidem9 in particular for %omen 0 "D* drug safety

communication> "D* appro'es. . .6 "D* drug safety communication> risk of . . .3 andincluded these recommendations in the la(eling for all the 7olpidem formulations

0Interme77o$

)S "D* product la(eling6 *m(ien$

)S "D* product la(eling6

*m(ien$

C; )S "D* product la(eling3!

*lthough the la(eling of 7olpidem products also suggests that the lo%er doses

should (e considered for men9 the stronger recommendation for reduced dosage in%omen underscores the clear sex+associated differences in 7olpidem P@ o(ser'ed

in studies! * study of patients in the Tai%an


93/106

The follo%ing uestions need to (e routinely considered for sex+(ased dosing

recommendations for therapies>


94/106

2 Effects of Sex Differences in the Pharmacokinetics of Drugs. . . B

*re there differences in P@ (et%een men and %omen other than those resulting

from (ody %eight differences

What are the effects of oral contracepti'es and hormonal replacement therapy onmeta(olism of drugs What drugs affect the efficacy of oral contracepti'es 0see

Chap! 5 for more detail3

In general9 are there more ad'erse e'ent reports resulting from exposure differ+

ences in %omen as compared %ith men Is this due to a higher percentage of use9

higher reporting9 or increased sensiti'ity of certain ad'erse e'ents in %omen The

issues around %hether %omen experience more ad'erse drug reactions than men is

complex9 (ut the e'idence 0discussed more in Chap! ,A on primary care

prescri(ing3 suggests they do ha'e higher rates %hich are not Hust due to higher

rates of use and reporting!

When should drugs (e la(eled differently for %omen and men (ased on P@ sex

differences

Sex is one of many factors that can affect a drug’s P@! Tools need to (e de'elopedthat can e'aluate the effect of multiple intrinsic and extrinsic factors on P@ of an

indi'idual patient! * computational tool such as physiologically+(ased P@ 0P=P@3

modeling can integrate multiple factors in the system model to simulate the effect

from multiple intrinsic 0including sex3 and extrinsic 0including concom+itantmedications3 factors on the P@ of a drug! ;ecently9 P=P@ models ha'e (een used

in drug de'elopment to assist in clinical trial design and ans%er %hat if

uestions 0;o%land et al! 2/,,6 4uang and ;o%land 2/,23! Such models can (e

used to predict and understand %hy sex differences o(ser'ed for certain drugs (ut

not others (y considering multiple factors!

Conclusions

Women and men differ in numerous physical parameters! *mong others9 %omen

ha'e a lo%er total (ody %eight9 a higher proportion of (ody fat9 a lo%er (ody

surface area9 a lo%er muscle mass9 smaller organ si7e9 lo%er glomerular filtration

rate9 and lo%er gastric acid excretion : factors that may influence drug disposition!

Physiological differences9 such as hormonal fluctuations during the menstrual

cycle9 may also influence drug P@! Menstrual cycle 'ariations do occur in renal9

cardio'ascular9 and hematological systems9 %ith the potential to impact protein

(inding and 'olume of distri(ution! Similarly9 hormonal changes during meno+ pause9 pregnancy9 and hormonal contracepti'e therapy are likely to ha'e the same

effects! "inally9 there are molecular factors that account for sex differences in P@

0e!g!9 difference in drug+meta(oli7ing en7ymes and transporters3! These physical9

physiological9 and molecular factors may influence the processes that determine

drug disposition 0i!e!9 *DME3 0


95/106

)nderstanding the mechanisms of sex differences in drug therapy is critical for optimal

dosing in (oth sexes! E'aluation of sex differences in P@ of drugs %ill further enhance

understanding of sex+(ased differences in the safety and efficacy of


96/106

BA E!! "adiran and #! $hang

drugs and minimi7e therapeutic ad'erse e'ents! P@ differences are the most

common sex differences and early detection of these differences during drug

de'elopment can lead to clinical trial design that %ill use sex+(ased dosing and

(etter indi'iduali7ation of therapy! =ecause men and %omen may differ in specific

drug P@ it is essential to understand those sex differences in drug disposition and

response9 as in turn they may affect drug safety and effecti'eness!

In conclusion9 se'eral mechanisms rele'ant to drug a(sorption and disposition ha'e

(een sho%n to exert sex+specific acti'ity differences9 and for some drugs these ha'e

the potential to result in clinically rele'ant differences in pharmacological response!

Thus9 the importance of the e'aluation of sex+specific P@ during drug de'elopment is

to optimi7e therapy for (oth men and %omen %hich is highlighted (y the regulatory

reuirements and guidance recommendations!

Take 4ome Messages

There are sex differences in the P@ of se'eral drugs due to molecular and

physiological factors!

The molecular factors in'ol'ed in drug disposition include drug+meta(oli7ing

en7ymes and drug transporters %hile physiological factors include lo%er (ody%eight9 higher percentage of (ody fat9 lo%er glomer+ular filtration rate9 and slo%er

gastric motility in %omen!

Correction for height9 %eight9 surface area9 and (ody composition elimi+nates

some (ut not all of the sex+dependent P@ differences! nly fe% drugs ha'e sho%n

sex+related differences in P@ that ha'e resulted in different pharmacological

response 0either safety or efficacy3 and su(se+uent sex+(ased dosing

recommendation! Exposure+response data is needed to determine the clinical

implications of sex differences in P@ of drugs!

)nderstanding the science of sex differences in the P@ of drugs %ill lead to

optimal dosing for (oth men and %omen and reduce the undesira(le side effects of

pharmacotherapy!

Multiple factors in addition to sex need to (e considered to understand the clinical

conseuence of sex differences!

;eferences

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