dosing regimen determination for juvenile idiopathic arthritis: a review of studies during drug...

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Dosing Regimen Determination for Juvenile Idiopathic Arthritis:A Review of Studies During Drug Development

PING JI,1 BADRUL A. CHOWDHURY,2 SARAH YIM,2 CHANDRAHAS G. SAHAJWALLA1

1Division of Clinical Pharmacology II, Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, Maryland

2Division of Pulmonary, Allergy, and Rheumatology Products, Office of Drug Evaluation II, Center for Drug Evaluation and Research,US Food and Drug Administration, Silver Spring, Maryland

Received 2 March 2012; revised 29 March 2012; accepted 19 April 2012

Published online 31 May 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23184

ABSTRACT: Juvenile idiopathic arthritis (JIA) is the most common childhood arthritis. Inthe past 10–15 years, the medical treatment options of JIA have greatly evolved and expandeddue to a better understanding of the disease and the application of biologic agents. Regulationspertinent to pediatric clinical research have also helped provide a legal basis for investigatingthe effects of drugs and biologics in pediatrics and facilitate the pediatric drug development.The evaluation of clinical pharmacology, efficacy, and safety has provided valuable labeling in-formation for pediatric use, including comparing exposure between adult and pediatric patients,bridging different formulations and regimens, providing appropriate dose selection recommen-dation with the modeling and simulation approach, and assessing the risks and benefits. Thisreview summarizes the drugs and biologics with JIA labeling implications and discusses theapplication of clinical pharmacology, safety, and efficacy assessment in determining pediatricdosing regimens. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association JPharm Sci 101:2621–2634, 2012Keywords: juvenile idiopathic arthritis; clinical pharmacology; pediatric; clinical trials; phar-macokinetics; population pharmacokinetics; clinical pharmacokinetics; simulations

INTRODUCTION

Juvenile idiopathic arthritis (JIA), previously knownas juvenile rheumatoid arthritis (JRA), is defined bythe International League of Associations for Rheuma-tology classification system as a group of hetero-geneous arthritis that start before the age of 16years, are of unknown cause, and persist for morethan 6 weeks.1,2 It is the most common childhoodarthritis with the prevalence estimated to vary fromeight cases to as high as 400 cases per 100,000 chil-dren in developed countries.3 JIA is generally asso-ciated with significant morbidity and economic bur-den. Patients may suffer from severe debilitating anddeforming joint damage as well as extra-articular

Correspondence to: Chandrahas G. Sahajwalla (Telephone:+301-796-1599; Fax: +301-847-8719; E-mail: [email protected])

Opinions expressed in this manuscript are those of the authors’and do not reflect the views or policies of the US Food and DrugAdministration.Journal of Pharmaceutical Sciences, Vol. 101, 2621–2634 (2012)© 2012 Wiley Periodicals, Inc. and the American Pharmacists Association

manifestations.4 In the past decade, because of newtherapeutic options, better understanding of the dis-ease, and more judicious use of the traditional medica-tions, the treatment options for JIA have undergonedramatic changes and significant improvement.5 Inaddition, regulations initiated in the past 10–15 yearsrequire or encourage drug development in pediatricpopulation.6–9 As a result, many clinical studies havebeen conducted to evaluate the clinical pharmacol-ogy, efficacy, and safety in pediatric patients, deter-mine proper dosing, identify the risks and benefitsof therapies, and improve drug labeling for pediatricpatients. The role of clinical pharmacology includescomparing exposure between adult and pediatric pa-tients, bridging different formulations and regimens,providing appropriate dose selection recommenda-tions with a modeling and simulation approach, andhelping design more efficient studies. The safety andefficacy data from well-controlled trials provide risk-benefit assessment. However, information on the util-ity of this approach in pediatric drug developmenthas been limited.10 This review summarizes the drugs

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 8, AUGUST 2012 2621

2622 JI ET AL.

and biologics with JIA labeling implications and theapproaches taken for registration, focusing on theutility of pediatric clinical pharmacology, efficacy, andsafety on the pediatric dosing regimen selection in theJIA drug development. For convenience, the term JIAis used throughout this review even when we referto studies using the old JRA classification schema,and the discussion is limited to the treatments forpolyarticular types of JIA.

General Considerations on Dosing RegimenSelection in JIA

In JIA patients, the effect of age and weight onthe pharmacokinetics (PK), pharmacodynamics (PD),safety, and efficacy of drugs and biologics are the mainconsiderations for the dosing regimen selection. Ascompared with adults, young pediatric patients haverelatively larger surface area and prolonged emptyingtime of the gastrointestinal (GI) tract, higher percent-age of total body water, lower percentage of body fat,decreased amount of plasma protein, and immaturePhase I and II metabolism, etc.11 These physiologi-cal differences are attributed to the ongoing matura-tion of the body and organ function in pediatric pa-tients. Therefore, the pediatric drug absorption anddisposition process might be correlated with age and/or body size such as height, weight, or body surfacearea, the effects of which are ultimately reflected inthe pediatric dosing regimens. For JIA drugs and bio-logics (Table 1), body size-based dosing regimens arecommon.

Demonstration of the efficacy and safety of adrug/biologic to treat JIA in randomized and well-controlled clinical trials provides the key evidencefor regulatory decision making. The dose selectionin the trial design mostly utilizes the prior PK anddosing regimen information from adult rheumatoidarthritis (RA) patients. As RA is an inflammatorydisease, proinflammatory biomarkers may reflect dis-ease activity and progression. Although data are rela-tively sparse in elucidating those biomarker changesin JIA patients, many etiological factors associatedwith adult RA are also associated with JIA, includingabnormal production and regulation of cytokines andcomplement activation.12 The guidelines on the typesof studies needed for pediatric clinical trials are pro-vided in the Pediatric Decision Tree.13 Depending onthe similarity of disease progression and treatmentresponse, different study types may be selected. Forthe polyarticular JIA indication, the list of key pe-diatric clinical studies is shown in Table 2. Thesestudies have provided useful information in assess-ing the effects of drugs and biologics in JIA patients.The remainder of the review is organized according tothe drug class and individual drugs in that class, andattempted to summarize various studies conducted

for determining pediatric dosing during drug devel-opment in the treatment of JIA.

Nonselective Nonsteroid Anti-Inflammatory Drugs

Nonsteroid anti-inflammatory drugs (NSAIDs) offermainly symptomatic relief by reducing inflammationand pain. Nonselective NSAIDs inhibit both the con-stitutive form of cyclooxygenase (COX-1), which re-leases prostaglandins that protect the stomach andkidneys, and the COX-2 inducible form, which pro-duces prostaglandins involved in the inflammatoryprocess. As a Drug Efficacy Study Implementationdrug, aspirin was designated as generally recognizedas safe and effective in treating JIA. It was also fre-quently used as an active control in evaluating theefficacy and safety of many other newer NSAIDs.Other nonselective NSAIDs, specifically, naproxen,tolmetin, oxaprozin, etodolac, and meloxicam, wereapproved by US Food and Drug Administration (FDA)for the treatment of JIA. Some NSAIDs (e.g., ibupro-fen) are also frequently used off-label.34 The safetyand efficacy of sulindac and diclofenac in pediatric pa-tients have not been established. Indomethacin wasonly approved in patients over 14 years of age.

Naproxen

To assess the PK, safety, and efficacy of naproxenin JIA patients, the dosing regimen of 5 mg/kg twicedaily (b.i.d.) was selected for investigation. This dos-ing regimen is within the range of adult approved dos-ing regimen of 250–500 mg b.i.d. based on size-relatedlinear scaling, which appears to be also the basis inthe dosing regimen selection for other investigateddrugs and biologics in JIA.

Pharmacokinetics evaluation showed that themetabolic pathways of naproxen appear to be sim-ilar in pediatric and adult patients.14,35 In a studyconducted in 21 pediatric arthritis patients between5 and 16 years of age given naproxen 5 mg/kg b.i.d.,naproxen metabolite, 6-demethylated naproxen, wasexcreted mostly (70–90%) in conjugated form in urine.These results are consistent with those obtained inadult patients.14 Another study in nine children withrheumatic disorders showed that the naproxen half-life in these children (11.5 h) was also comparable tothat in adult patients (12–14 h).35

At the dosing regimen of 5 mg/kg b.i.d., the safetyand efficacy were also established. In an 8-week ran-domized, double-blind, crossover study conducted in23 children with JIA (5–16 years of age), a dailynaproxen dose of 10 mg/kg given in two divideddoses was found to be as effective as aspirin given80 mg/kg/day in four divided doses.15 The efficacy andsafety of naproxen (10 mg/kg/day) and aspirin (75 mg/kg/day) were also compared in a 24-week random-ized block, controlled, parallel, double-blind study in80 JIA patients.16 The changes in disease activity

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 8, AUGUST 2012 DOI 10.1002/jps

DOSING REGIMEN DETERMINATION FOR JIA 2623

Table 1. FDA-Approved Drugs and Biologics for Polyarticular Juvenile Idiopathic Arthritis

GenericName

Brand Name(NDA No./BLA No.)

Age Range forJIA Use (years) RA Dosing Regimen JIA Dosing Regimen

Naproxen Naprosyn (NDA017581) 2–17 250–500 mg b.i.d. 5 mg/kg b.i.d.Tolmetin Tolectin (NDA017628) 2–17 400 mg t.i.d. 20 mg/kg/day t.i.d. or q.i.d.Oxaprozina Daypro (NDA018841) 6–16 1200 mg q.d. 22–31 kg, 600 mg q.d.; 32–54 kg,

900 mg q.d.; > =55 kg, 1200 mgq.d.

Meloxicama Mobic (NDA020938) 2–17 7.5mg up to 15 mg q.d. 0.125 mg/kg up to 7.5 mg q.d.Celecoxiba Celebrex (NDA020998) 2–17 100–200 mg b.i.d. 10–25 kg, 50 mg b.i.d.; >25 kg,

100 mg b.i.d.Etodolaca Lodine XL (NDA020584) 6–16 400–1000 mg q.d. 20–30 kg, 400 mg q.d.; 31–45 kg,

600 mg q.d.; 46–60 kg, 800 mgq.d.; >60 kg, 1000 mg q.d.

Rofecoxiba,b Vioxx (NDA021042) 2–17 25 mg q.d. ≥2 to ≤11 years and ≥10 to <42 kg,0.6–25 mg q.d.; ≥2 to ≤11 yearsand ≥ 42 kg, 25 mg q.d.; ≥12 to≤17 years, 25 mg q.d.

Sulfasalazine Azulfidine EN-tabs(NDA007073)

6–16 2 g/day b.i.d. 30–50 mg/kg b.i.d. up to 2 g/day

Methotrexate Methotrexate sodium(NDA008085)

2–16 7.5mg q.w. as starting dose. Thedose is changed graduallyuntil adequate efficacy isachieved.

10 mg/m2 given q.w. as a startingdose. The dose is changedgradually until adequate efficacyis achieved.

Etanercept Enbrel (BLA103795) 2–17 50 mg SC q.w. 0.8 mg/kg up to 50 mg SC q.w.Adalimumabc Humira (BLA125057) 4–17 40 mg SC e.o.w. 15 to <30 kg, 20 mg SC e.o.w.; ≥30

kg, 40 mg SC e.o.w.Abataceptc Orencia (BLA125118) 6–17 <60 kg, 500 mg; 60–100 kg,

750 mg; >100 kg, 1000 mg.Administer as a 30-min i.v.infusion. Following initialdose, give at 2 and 4 weeks,then every 4 weeks.

<75 kg, 10 mg/kg; > =75 kg,following adult dose. Administeras a 30-min i.v. infusion.Following initial dose, give at 2and 4 weeks, then every 4 weeks.

aBest Pharmaceuticals for Children Act.bWithdrawn from market on September 30, 2004.cPediatric Research Equity Act.q.d., once a day; b.i.d., twice a day; t.i.d., three times a day; q.i.d., four times a day; q.w., once a week; e.o.w., every other week.

measurements were similar in the two treatmentgroups, whereas the safety profiles were better inthe naproxen group. Makela14 also reported in anearlier study that naproxen 6.5–10 mg/kg/day ap-peared to be at least as effective with fewer adversereactions as compared with the high-dose aspirintherapy.

Tolmetin

Safety and efficacy of tolmetin were assessed in JIApatients of 2–16 years old at the starting dosage of 15mg/kg/day with increases of 5 mg/kg of body weightat weekly intervals (maximum daily dose 30 mg/kgand 1800 mg).17 Tolmetin was shown to be equallyeffective to aspirin (starting dosage of 50 mg/kg/daywith increases of 16.7 mg/kg at weekly intervals) inanti-inflammatory and analgesic effects, with a sim-ilar incidence of clinical side effects. Therefore, therecommended starting dose of tolmetin for JIA pa-tients (2 years and older) is 20 mg/kg/day three tofour times a day with the stable dose ranging from 15to 30 mg/kg/day. No PK studies in JIA patients havebeen published.

Oxaprozin

In response to a Pediatric Written Request (PWR), thePK and safety of oxaprozin were assessed in JIA pa-tients with appropriate pediatric formulation in a 14-day PK study.18 The population PK analysis showedthat the apparent clearance of unbound oxaprozinwas comparable between adult RA (N = 40) and JIA(≥6 years, N = 44) patients after the adjustmentof body weight differences. Its antiarthritic proper-ties were reported earlier in JIA patients.36 Thusthe body weight-based dosing regimen of 10–20 mg/kg once daily (q.d.) used in the study was proposedfor oxaprozin in JIA patients.

Meloxicam

The JIA clinical program of meloxicam was conductedin response to and in accordance with a PWR. Threeclinical trials (involving 470 JIA patients) were con-ducted to evaluate the PK, safety, and efficacy ofmeloxicam in JIA patients.19,20 The PK assessmentwas conducted after both a single-dose administrationand multiple-dose administrations. In the single-dosestudy, a dose of 0.25 mg/kg meloxicam oral suspension

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 8, AUGUST 2012

2624 JI ET AL.

Tab

le2.

Key

Cli

nic

alT

rial

sU

sed

inD

eter

min

ing

JIA

Indi

cati

onan

dD

osin

gR

egim

ens

Sel

ecti

on

Dru

g/R

efer

ence

sS

tudy

Obj

ecti

ves

and

Des

ign

Nu

mbe

rof

Su

bjec

ts;

Age

Ran

geT

reat

men

tsK

eyR

esu

lts

and

Con

clu

sion

sC

omm

ents

Nap

roxe

nM

akel

a14E

ffica

cyan

dsa

fety

;ra

ndo

miz

ed,

dou

ble-

blin

d,cr

osso

ver

N=

18;7

–15

year

sN

apro

xen

:6.5

mg/

kg/d

ayb.

i.d.;

8w

eeks

.Asp

irin

:60

mg/

kg/d

ayt.

i.d.;

8w

eeks

Effi

cacy

was

base

don

phys

icia

npr

efer

ence

ofth

edr

ug.

Nap

roxe

nw

asbe

tter

inse

ven

case

s,as

piri

nin

fou

rca

ses;

in4

pati

ents

,th

edr

ug

effe

cts

wer

eeq

ual

and

3pa

tien

tsdi

scon

tin

ued

.

Effi

cacy

and

safe

tyda

tasu

ppor

tth

epe

diat

ric

use

ofn

apro

xen

at10

mg/

kg/d

ayb.

i.d.

Mor

anet

al.15

Effi

cacy

and

safe

ty;

ran

dom

ized

,do

ubl

e-bl

ind,

cros

sove

r

N=

23;5

–16

year

sN

apro

xen

:10

mg/

kg/d

ayb.

i.d.;

4w

eeks

.Asp

irin

:80

mg/

kg/d

ayq.

i.d.;

4w

eeks

Nap

roxe

nas

effe

ctiv

eas

aspi

rin

inco

ntr

olli

ng

join

tsy

mpt

oms.

Saf

ety;

open

-lab

elN

=30

Nap

roxe

n:1

0m

g/kg

/day

b.i.d

.;12

mon

ths

19pa

tien

tsco

mpl

eted

the

exte

nsi

onpe

riod

wit

hou

tu

nto

war

dad

vers

eev

ents

.K

vien

etal

.16E

ffica

cyan

dsa

fety

;ra

ndo

miz

ed,c

ontr

olle

d,do

ubl

e-bl

ind,

para

llel

N=

80;3

–16

year

sN

apro

xen

:10

mg/

kg/d

ayb.

i.d.;

N=

40;2

4w

eeks

.A

spir

in:7

5m

g/kg

/day

t.i.d

.;N

=40

;24

wee

ks

Th

ech

ange

sin

dise

ase

acti

vity

mea

sure

men

tsw

ere

sim

ilar

inth

etw

otr

eatm

ent

grou

ps,w

her

eas

the

safe

typr

ofile

sw

ere

bett

erin

the

nap

roxe

ngr

oup.

Tol

met

inL

evin

son

etal

.17E

ffica

cyan

dsa

fety

;ra

ndo

miz

ed,

dou

ble-

blin

d,pa

rall

el

N=

107;

2–16

year

sT

olm

etin

:15–

30m

g/kg

/day

;N

=53

;12

wee

ks.

Asp

irin

:50–

100

mg/

kg/d

ay;

N=

54;1

2w

eeks

Tol

met

inw

asas

effe

ctiv

eas

aspi

rin

inco

ntr

olli

ng

dise

ase

acti

vity

aspe

rcen

tim

prov

emen

tin

inde

xof

acti

vejo

ints

wit

hsi

mil

arin

cide

nce

ofA

Es.

Effi

cacy

and

safe

tyda

tasu

ppor

tth

epe

diat

ric

use

atth

edo

sin

gre

gim

enof

20m

g/kg

/day

t.i.d

.or

q.i.d

.O

xapr

ozin

Ped

iatr

icla

beli

ng

chan

ge18

PK

,saf

ety

and

tole

rabi

lity

;op

en-l

abel

N=

44;6

–17

year

sO

xapr

ozin

:10–

20m

g/kg

up

to12

00m

gq.

d.;2

wee

ksP

opu

lati

onP

Kan

alys

issh

owed

that

clea

ran

cew

asin

depe

nde

nt

ofag

eaf

ter

adju

stm

ent

ofbo

dyw

eigh

t.A

Efo

un

din

45%

ofJI

Apa

tien

ts.

PK

and

safe

tyda

tasu

ppor

tth

epe

diat

ric

use

at10

–20

mg/

kgq.

d.

(Con

tin

ued

)



Tab

le2.

Con

tin

ued

Dru

g/R

efer

ence

sS

tudy

Obj

ecti

ves

and

Des

ign

Nu

mbe

rof

Su

bjec

ts;

Age

Ran

geT

reat

men

tsK

eyR

esu

lts

and

Con

clu

sion

sC

omm

ents

Mel

oxic

amF

DA

Adv

isor

yC

omm

itte

eba

ckgr

oun

ddo

cum

ent19

Ru

pert

oet

al.20

PK

and

safe

ty;S

ingl

e-do

seop

en-l

abel

Effi

cacy

and

safe

ty;

dou

ble-

blin

d,pa

rall

el-g

rou

p

Effi

cacy

and

safe

ty;

dou

ble-

blin

d,pa

rall

el-g

rou

p

N=

18;2

–16

year

s

N=

225;

2–16

year

s

N=

209;

2–16

year

s

Mel

oxic

am:0

.25

mg/

kgu

pto

15m

g;si

ngl

edo

se

Mel

oxic

am:0

.125

mg/

kg/d

ayq.

d.;N

=73

;12

wee

ks.

Mel

oxic

am:0

.25

mg/

kg/d

ayq.

d.;N

=74

;12

wee

ks.

Nap

roxe

n:1

0m

g/kg

/day

b.i.d

.;N

=78

;12

wee

ksT

itra

tion

sch

eme

was

use

d:M

elox

icam

:0.1

25–0

.25

mg/

kg/d

ayq.

d.;N

=62

;12

wee

ks.

Mel

oxic

am:0

.25–

0.37

5m

g/kg

/day

q.d.

;N=

72;1

2w

eeks

.N

apro

xen

:10–

15m

g/kg

/day

b.i.d

.;N

=75

;12

wee

ks

PK

expo

sure

was

depe

nde

nt

onbo

dyw

eigh

t,bu

tin

depe

nde

nt

ofag

e.

AC

RP

edi3

0re

spon

seat

mon

th3

and

safe

tysi

mil

arbe

twee

ndi

ffer

ent

trea

tmen

ts.

AC

RP

edi3

0re

spon

sesi

mil

arbe

twee

ndi

ffer

ent

trea

tmen

ts.

PK

,saf

ety,

and

effi

cacy

data

supp

ort

the

low

dose

mel

oxic

am0.

125

mg/

kg/d

ay.

Eto

dola

cN

DA

revi

ew21

Saf

ety

and

effi

cacy

;op

en-l

abel

wit

h8-

wee

kex

ten

sion

N=

72;6

–16

year

sE

todo

lac:

13.3

–21.

3m

g/kg

q.d.

;12

wee

ksS

afet

ypr

ofile

sam

eas

adu

lt;s

ign

san

dsy

mpt

oms

ofJI

Aco

ntr

olle

dS

afet

y,P

K,a

nd

effi

cacy

data

supp

ort

pedi

atri

cu

se.

Cel

ecox

ibF

DA

Adv

isor

yC

omm

itte

eM

eeti

ng

Pac

kage

22

Effi

cacy

,saf

ety

and

PK

;ra

ndo

miz

ed,

dou

ble-

bin

d,ac

tive

-con

trol

led,

para

llel

-gro

up

N=

242;

2–16

year

sC

elec

oxib

:3m

g/kg

b.i.d

.;N

=77

;12

wee

ks.

Cel

ecox

ib:6

mg/

kgb.

i.d.;

N=

82;1

2w

eeks

.N

apro

xen

:7.5

mg/

kgb.

i.d.;

N=

83;1

2w

eeks

AC

RP

edi3

0re

spon

sera

tes

atw

eek

12w

ere

69%

,80%

,an

d67

%in

the

cele

coxi

b3

mg/

kgb.

i.d.,

cele

coxi

b6

mg/

kgb.

i.d.,

and

nap

roxe

n7.

5m

g/kg

b.i.d

.tre

atm

ent

grou

ps,

resp

ecti

vely

.

PK

,saf

ety,

and

effi

cacy

data

supp

ort

pedi

atri

cu

se.

Cli

nic

alfo

rmu

lati

onw

asbr

idge

dw

ith

com

mer

cial

form

ula

tion

and

apo

pula

tion

PK

mod

elin

gan

dsi

mu

lati

onap

prac

hw

asap

plie

dto

hel

pde

term

ine

the

fin

alpe

diat

ric

dosi

ng

regi

men

.

(Con

tin

ued

)


2626 JI ET AL.

Tab

le2.

Con

tin

ued

Dru

g/R

efer

ence

sS

tudy

Obj

ecti

ves

and

Des

ign

Nu

mbe

rof

Su

bjec

ts;

Age

Ran

geT

reat

men

tsK

eyR

esu

lts

and

Con

clu

sion

sC

omm

ents

Rof

ecox

ibN

DA

revi

ew23

PK

and

safe

ty;o

pen

-lab

el

PK

and

safe

ty;o

pen

-lab

el

Effi

cacy

and

safe

ty;

dou

ble-

blin

d,ac

tive

-con

trol

led,

non

-in

feri

orit

yde

sign

Saf

ety;

open

-lab

elex

ten

sion

N=

11;1

2–17

year

s

N=

38;2

–11

year

s

N=

310;

2–17

year

s

N=

227;

2–17

year

s

Rof

ecox

ib:1

2.5

mg/

day;

N=

7;14

days

.R

ofec

oxib

:25

mg/

day;

N=

4;14

days

Rof

ecox

ib:0

.7m

g/kg

/day

;N

=26

;14

days

.R

ofec

oxib

:0.3

mg/

kg/d

ay;

N=

12;1

4da

ysR

ofec

oxib

:0.3

mg/

kgu

pto

12.5

mg/

day

q.d.

;N=

109;

12w

eeks

.R

ofec

oxib

:0.6

mg/

kgu

pto

25m

g/da

yQ

D;N

=10

0;12

wee

ks.

Nap

roxe

n:1

5m

g/kg

/day

BID

;N

=101

;12

wee

ksR

ofec

oxib

:0.6

mg/

kg/d

ayu

pto

25m

g/da

y;N

=16

0;52

wee

ks.

Nap

roxe

n:1

5m

g/kg

/day

;N

=67

;52

wee

ks

Pop

ula

tion

PK

anal

ysis

show

edth

atbo

dyw

eigh

tw

asa

sign

ifica

nt

cova

riat

eof

the

appa

ren

tor

alcl

eara

nce

AC

RP

edi3

0re

spon

der

rate

was

46%

,55

%an

d55

%fo

rlo

w-d

ose

rofe

coxi

b,h

igh

-dos

ero

feco

xib,

and

nap

roxe

ngr

oups

,res

pect

ivel

y.

No

un

expe

cted

safe

tyfi

ndi

ngs

Res

ult

sfr

omth

eP

Kst

udi

esan

dpo

pula

tion

mod

elin

gsu

ppor

tth

ebo

dy-w

eigh

tba

sed

dosi

ng

regi

men

.E

ffica

cyst

udy

show

edth

atth

edo

seof

0.6

mg/

kgis

bett

erth

an0.

3m

g/kg

.

Su

lfas

alaz

ine

Van

Ros

sum

etal

.24E

ffica

cyan

dsa

fety

;ra

ndo

miz

ed,

plac

ebo-

con

trol

led,

dou

ble-

blin

d,m

ult

icen

ter

N=

69;2

–18

year

sS

ulf

asal

azin

e:50

mg/

kg/d

ay(u

pto

2000

mg/

day)

;N

=35

;24

wee

ks.

Pla

cebo

;N=

34;2

4w

eeks

Su

lfas

alaz

ine

grou

psi

gnifi

can

tly

bett

erth

anpl

aceb

ogr

oup

for

the

over

all

arti

cula

rse

veri

tysc

ore

(p=

0.02

),al

lgl

obal

asse

ssm

ents

(p=

0.01

),an

dth

ela

bora

tory

para

met

ers

(p<

0.00

1).

Adv

erse

even

tsm

ore

freq

uen

tin

the

sulf

asal

azin

egr

oup,

but

wer

etr

ansi

ent

orre

vers

ible

upo

nce

ssat

ion

oftr

eatm

ent.

Effi

cacy

and

safe

tyda

tasu

ppor

tth

epe

diat

ric

use

.N

oP

Kda

tain

JIA

pati

ents

avai

labl

e.

Imu

ndo

etal

.25E

ffica

cyan

dsa

fety

;op

en-l

abel

N=

139;

1–21

year

sS

ulf

asal

azin

e:31

mg/

kg/d

ay;

13m

onth

sS

ign

ifica

nt

impr

ovem

ent:

73%

wit

hin

12m

onth

sof

star

tin

gth

erap

y.T

reat

men

tdi

scon

tin

uat

ion

:17%

.M

eth

otre

xate

Gia

nn

inie

tal

.26E

ffica

cyan

dsa

fety

;do

ubl

e-bl

ind,

ran

dom

ized

,pl

aceb

o-co

ntr

olle

d

N=

127;

3–17

year

sM

eth

otre

xate

:10

mg/

m2

q.w

.;N

=46

;6m

onth

s.M

eth

otre

xate

:5m

g/m

2q.

w.;

N=

40;6

mon

ths.

Pla

cebo

;N=

41;6

mon

ths

Com

posi

tere

spon

sein

dex

impr

ovem

ent,

63%

for

10m

g/m

2,3

2%fo

r5

mg/

m2,

36%

for

plac

ebo.

Effi

cacy

and

safe

tyda

tasu

ppor

tth

epe

diat

ric

use

of10

mg/

m2

q.w

.

(Con

tin

ued

)



Tab

le2.

Con

tin

ued

Dru

g/R

efer

ence

sS

tudy

Obj

ecti

ves

and

Des

ign

Nu

mbe

rof

Su

bjec

ts;

Age

Ran

geT

reat

men

tsK

eyR

esu

lts

and

Con

clu

sion

sC

omm

ents

Woo

etal

.27E

ffica

cyan

dsa

fety

;ra

ndo

miz

ed,

dou

ble-

blin

d,pl

aceb

o-co

ntr

olle

d,cr

osso

ver

N=

88;2

–16

year

sM

eth

otre

xate

:15–

20m

g/m

2

q.w

.or

plac

ebo;

4m

onth

sS

ign

ifica

ntl

ycl

inic

alim

prov

emen

tob

serv

edfo

rm

eth

otre

xate

trea

tmen

t.

Eta

ner

cept

Lov

elle

tal

.28E

ffica

cyan

dsa

fety

;op

en-l

abel

lead

-in

phas

eu

pto

3m

onth

sfo

llow

edw

ith

a4-

mon

thra

ndo

miz

eddo

ubl

e-bl

ind

phas

e

N=

69;4

–17

year

s0.

4m

g/kg

up

to25

mg

SC

twic

ew

eekl

yO

pen

-lab

elph

ase:

resp

onse

rate

:74%

.D

oubl

e-bl

ind

phas

e:di

seas

efl

are

rate

was

sign

ifica

ntl

yh

igh

erfo

rpl

aceb

o(8

1%)

than

etan

erce

pttr

eate

d(2

8%).

Effi

cacy

and

safe

tyda

tasu

ppor

tth

edo

sin

gre

gim

enof

4m

g/kg

twic

ea

wee

k.T

he

choi

ceof

regi

men

sele

ctio

nof

8m

g/kg

once

wee

kly

was

base

don

the

mod

elin

gan

dsi

mu

lati

onre

sult

sth

atpr

edic

tth

eex

posu

reof

8m

g/kg

once

wee

kly

and

4m

g/kg

twic

ew

eekl

yis

over

lapp

ing.

29

Ada

lim

um

abL

ovel

let

al.30

Effi

cacy

and

safe

ty;

16-w

eek

open

-lab

elle

ad-i

nph

ase

foll

owed

wit

ha

32-w

eek

dou

ble-

blin

dw

ith

draw

alph

ase

foll

owed

wit

han

up

to13

6-w

eek

open

-lab

elex

ten

sion

phas

e,an

da

16-w

eek

open

-lab

elfi

xed

dose

phas

e

N=

171;

4–17

year

sF

irst

thre

eph

ases

:24

mg/

m2

up

to40

mg

SC

e.o.

w.F

ourt

hph

ase:

20m

gS

Ce.

o.w

.(<

30kg

);40

mg

SC

e.o.

w.

(>30

kg)

Lea

d-in

phas

e:94

%of

the

pati

ents

onm

eth

otre

xate

and

74%

ofth

epa

tien

tsw

ith

out

met

hot

rexa

tew

ere

AC

RP

edi

30re

spon

ders

.W

ith

draw

alph

ase:

sign

ifica

ntl

yfe

wer

pati

ents

wh

ore

ceiv

edad

alim

um

abex

peri

ence

ddi

seas

efl

ares

com

pare

dto

plac

ebo.

Ext

ensi

onph

ases

:AC

RP

edi

30re

spon

ses

wer

em

ain

tain

edfo

ru

pto

2ye

ars.

Effi

cacy

and

safe

tyda

tasu

ppor

tth

epe

diat

ric

use

.Dru

gin

tera

ctio

nbe

twee

nad

alim

um

aban

dm

eth

otre

xate

hel

psex

plai

nth

elo

win

cide

nce

ofan

tibo

dyde

velo

pmen

tan

dsu

ppor

tsth

eco

adm

inis

trat

ion

.

Aba

tace

ptR

upe

rto

etal

.31E

ffica

cyan

dsa

fety

;4-

mon

thop

en-l

abel

lead

-in

peri

od,f

ollo

wed

wit

ha

6-m

onth

dou

ble-

blin

d,ra

ndo

miz

edw

ith

draw

alpe

riod

,an

dan

open

-lab

elex

ten

sion

peri

od.

N=

190;

6–17

year

s10

mg/

kgu

pto

1000

mg

per

dose

intr

aven

ousl

yon

days

1,15

,29,

and

mon

thly

ther

eaft

er

Aba

tace

pt-t

reat

edpa

tien

tsex

peri

ence

dsi

gnifi

can

tly

few

erdi

seas

efl

ares

com

pare

dw

ith

plac

ebo-

trea

ted

pati

ents

(20%

vs.5

3%).

Effi

cacy

and

safe

tyda

tasu

ppor

tth

epe

diat

ric

use

. (Con

tin

ued

)


2628 JI ET AL.

Tab

le2.

Con

tin

ued

Dru

g/R

efer

ence

sS

tudy

Obj

ecti

ves

and

Des

ign

Nu

mbe

rof

Su

bjec

ts;

Age

Ran

geT

reat

men

tsK

eyR

esu

lts

and

Con

clu

sion

sC

omm

ents

Lefl

un

omid

eN

DA

Rev

iew

Pac

kage

2004

32P

K,s

afet

y,an

def

fica

cy;

open

-lab

elN

=27

;6–1

7ye

ars

Lefl

un

omid

e:L

oadi

ng

dose

for

3da

ysan

dm

ain

ten

ance

dose

wer

eba

sed

onla

bele

dad

ult

dose

adju

sted

for

body

surf

ace

area

;6m

onth

s

JIA

pati

ents

<40

kgh

adan

M1

expo

sure

low

erth

anth

atin

hea

vier

pedi

atri

cpa

tien

ts

Effi

cacy

data

did

not

supp

ort

pedi

atri

cu

se.P

Kan

alys

issh

owed

that

the

you

nge

rpe

diat

rics

may

beu

nde

rdos

ed.

Effi

cacy

,saf

ety,

and

PK

;ra

ndo

miz

ed,

dou

ble-

blin

d,pa

rall

el-a

rm,

acti

ve-c

ontr

olle

d

N=

94;3

–17

year

sL

eflu

nom

ide:

Loa

din

gdo

se:

100

mg/

day

up

to3

days

base

don

wei

ght;

Mai

nte

nan

cedo

se:1

0m

gev

ery

oth

erda

y(<

20kg

),10

mg

dail

y(2

0–40

kg),

and

20m

gda

ily

(>40

kg);

N=

47;1

6w

eeks

Met

hot

rexa

te:0

.5m

g/kg

/w

eek;

N=

47;1

6w

eeks

AC

RP

edi3

0re

spon

sera

te:8

9%fo

rm

eth

otre

xate

and

68%

for

lefl

un

omid

e.

Saf

ety,

tole

rabi

lity

,an

ddu

rabi

lity

ofef

fica

cy;

dou

ble-

blin

d,m

ult

i-ce

nte

r,ex

ten

sion

N=

70;3

–17

year

sL

eflu

nom

ide:

10m

gev

ery

oth

erda

y(<

20kg

),10

mg

dail

y(2

0–40

kg),

and

20m

gda

ily

(>40

kg);

N=

33;

8m

onth

s

Lefl

un

omid

ew

asw

ellt

oler

ated

Met

hot

rexa

te:0

.5m

g/kg

/wee

k;N

=37

;8m

onth

sIn

flix

imab

Ru

pert

oet

al.33

Effi

cacy

and

safe

ty;

14-w

eek

ran

dom

ized

,pl

aceb

o-co

ntr

olle

dan

ddo

ubl

e-bl

ind

stu

dy,

foll

owed

bya

dou

ble-

blin

d,al

l-ac

tive

trea

tmen

tex

ten

sion

N=

122;

4–17

year

sIn

flix

imab

3m

g/kg

plu

sm

eth

otre

xate

thro

ugh

wee

k44

(in

flix

imab

grou

p)or

met

hot

rexa

tepl

us

plac

ebo

for

14w

eeks

foll

owed

bym

eth

otre

xate

plu

sin

flix

imab

6m

g/kg

thro

ugh

wee

k44

(pla

cebo

grou

p).

Fail

edto

esta

blis

hst

atis

tica

lly

sign

ifica

nt

diff

eren

cebe

twee

nin

flix

imab

and

plac

ebo

grou

pat

wee

k14

.

PK

and

imm

un

ogen

icit

ypa

rtia

lly

expl

ain

edth

etr

ial

resu

lts.



was given to 18 patients of 2–16 years of age. In themultiple-dose study, 0.375 mg/kg meloxicam oral sus-pension was given to 28 patients of 2–16 years of ageq.d. for 12 weeks. The exposure of meloxicam wasfound to be dependent on body weight. After bodyweight adjustment, the exposure was independent ofage. This result was consistent with what Burgos-Vargas et al.37 had reported. Meloxicam oral suspen-sion was shown to be bioequivalent to the adult tabletformulation during the adult development program.

Each of the two efficacy studies was a 12-week,double-blind, parallel arm, active-controlled trial.Both studies had three arms: naproxen (10 mg/kg/day b.i.d.), low-dose meloxicam (0.125 mg/kg/day upto 7.5 mg q.d.), and high-dose meloxicam (0.25 mg/kg/day up to 15 mg q.d.). One study used thesedoses throughout the 12-week dosing period, whilethe other one incorporated a titration scheme after4 weeks to doses of 0.25 mg/kg/day and 0.375 mg/kg/day (22.5 mg maximum) of meloxicam and 15 mg/kg/day of naproxen. The proportion of American Collegeof Rheumatology Pediatric 30 responder rate (ACRPedi 30) at week 12, the primary efficacy endpoint,was similar for all the three treatment arms in bothstudies. The frequency of adverse events or abnormallaboratory values was also comparable between thethree arms. Because there was no additional benefitdemonstrated at doses above 0.125 mg/kg/day in theclinical trials, the lowest effective dose of 0.125 mg/kgup to 7.5 mg maximum q.d. was proposed for meloxi-cam in JIA patients.

Etodolac

Etodolac was the first approved NSAID in the treat-ment of JIA under the Best Pharmaceuticals for Chil-dren Act, under which a clinical trial of etodolac in72 pediatric JIA patients between 6 and 16 years ofage (n = 72) was conducted in response to a PWR.21

It was a 12-week, open-label study in patients withJIA, followed by an optional 8-week extension pe-riod. The primary objective of the study was to ex-amine the safety profiles for etodolac in JIA patients,and the secondary objective was to evaluate the ef-ficacy and PK. Etodolac was administered orally ata dosage based on body weight, 13.3–21.3 mg/kg q.d.The study results showed that etodolac was safe andwell tolerated, and the signs and symptoms of JIAwere improved. The population analysis based on thePK data from this study showed that the body weightwas a significant covariate of clearance. The PK ofetodolac was also reported in an open-label study,where a single body weight-based dose of etodolac(200–400 mg) was given to 11 JIA patients (8–14years of age).38 PK parameters in pediatrics were con-sistent in magnitude and degree of variability withthose from healthy adult subjects. The apparent oralclearance was independent of age. As a result, a body

weight-based dosing regimen was proposed in thispopulation.

COX-2 Selective NSAIDs

The COX-2 NSAIDs can selectively inhibit the COX-2 enzyme, thus allowing the continued production ofCOX-1, an essential enzyme involved in cytoprotec-tive and regulatory functions in GI mucosa, platelets,and renal cells. Celecoxib and rofecoxib are includedin this category.

Celecoxib

In response to a PWR, an efficacy and safety studywas undertaken in JIA patients using a clinical sus-pension formulation.22 The study included a 12-week,randomized, double-blind, active-controlled, parallelgroup, multicenter, noninferiority phase followed byan optional 12-week, open-label extension phase. Atotal of 242 JIA patients of ages 2–16 years old wererandomly given celecoxib 3 mg/kg up to 150 mg b.i.d.,celecoxib 6 mg/kg up to 300 mg b.i.d., or naproxen7.5 mg/kg up to 500 mg b.i.d. The primary efficacyendpoint, ACR Pedi 30, was assessed at week 12 andwas 69%, 80%, and 67% for the celecoxib 3 mg/kg,celecoxib 6 mg/kg, and naproxen treatment groups,respectively. The study showed that celecoxib 3 and6 mg/kg b.i.d. had similar efficacy, safety, and tolera-bility profile with the active comparator in treatingthe signs and symptoms of JIA.

Because of technical difficulties for the suspensionformulation, a capsule formulation was chosen forcommercialization instead. The population PK mod-eling and simulation approach was used to bridge thetwo formulations and to propose the final pediatricdosing regimen for the capsule formulation. The pop-ulation PK analysis showed that the oral clearance(unadjusted for body weight) of celecoxib increasesless than proportionally to weight, with 10- and 25-kgpatients predicted to have 40% and 24% lower clear-ance, respectively, compared with a 70-kg adult RApatient. The dosing regimen of 50 (≥12 to ≤25 kg)and 100 mg (>25 kg) for the capsule formulation wasselected based on a simulation approach such thatcelecoxib peak concentrations did not exceed thoseobserved with suspension formulation, while achiev-ing a similar overall exposure that was shown to beeffective from the investigational pediatric trial.

Rofecoxib

Rofecoxib was approved for JIA in 2004; however, itwas subsequently withdrawn from market becauseof the concerns of increased risk of thromboemboliccardiovascular adverse events. Nevertheless, it is in-cluded here to provide a perspective of the pedi-atric drug development for JIA. The same or bodyweight scaled dose as used in the adult RA patients of25 mg q.d. was selected in clinical trials in pediatric


2630 JI ET AL.

patients. The pediatric program focused on assessingthe PK, safety, and efficacy of rofecoxib in responseto a PWR.23 The PK studies were multiple-dose stud-ies in children with JIA between 2 and 17 years ofage. The population PK analysis showed that bodyweight was a significant covariate of the apparentoral clearance. The efficacy study was designed as a12-week, double-blind, active-controlled, noninferior-ity study in 310 JIA patients (2–17 years). Patientswere randomized to receive rofecoxib 0.3 mg/kg up to12.5 mg q.d. in children (2–11 years) or 12.5 mg q.d. inadolescent patients, rofecoxib 0.6 mg/kg up to 25 mgq.d. in children (2–11 years) or 25 mg q.d. in adoles-cent patients, or naproxen 15 mg/kg/day. The ACRPedi 30 response rate was 55% in both the rofecoxib0.6 mg/kg and naproxen groups and met the noninfe-riority criterion, whereas the 0.3 mg/kg group (46%)failed to achieve the noninferiority criterion. There-fore, the dosing regimen of 0.6 mg/kg up to 25 mg q.d.was proposed in JIA patients.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

Disease-modifying antirheumatic drugs (DMARDs)are products that are considered capable of alteringthe course of the underlying inflammatory pathologyof arthritis. DMARDs include biologic and nonbio-logic products. Approved therapies for polyarticularJIA include methotrexate, sulfasalazine, abatacept,adalimumab, and etanercept. Infliximab and lefluno-mide were also investigated but efficacy was not es-tablished in JIA patients.

Sulfasalazine

Sulfasalazine was initially approved as adjunctivetherapy in the treatment of ulcerative colitis in 1950,and only after 40–50 years was it evaluated in thetreatment of arthritis. The mechanism of action of sul-fasalazine is still not known, but is thought to involveanti-inflammatory and/or immunomodulatory prop-erties. PK studies of sulfasalazine in JIA patientshave not been reported. For ulcerative colitis, how-ever, no significant PK difference between pediatricand adult patients has been noted.39 Sulfasalazine isa conjugate of mesalazine and sulfapyridine, and issplit into these two compounds by intestinal bacte-ria after oral doses. Therefore, its oral bioavailabilityis often erratic and incomplete. Sulfapyridine is fur-ther metabolized in the liver where it is acetylatedand hydroxylated. Its acetylation is dependent uponacetylator phenotype. Slow acetylators may have alonger sulfapyridine half-life. Mesalazine is primarilyacetylated via a nonacetylation phenotype-dependentroute. Although the concentration–effect relationshipis unclear for this drug, higher total serum sulfapyri-dine concentration appears to closely relate to its tox-icity. Slow acetylators have shown more side effectsthan fast acetylators in adult patients.40 This may be

of relevance to JIA patients who are also slow acety-lators.

The safety and efficacy of sulfasalazine was eval-uated in JIA patients.24,25 The dosing regimen of50 mg/kg of body weight daily to a maximum of 2 g/day were selected in a 24-week randomized, placebo-controlled, double-blind, multicenter study.25 Sul-fasalazine group was significantly better than placebogroup for the overall articular severity score (p =0.02), all global assessments (p = 0.01), and the lab-oratory parameters (p < 0.001). Adverse events weremore frequent in the sulfasalazine group, but weretransient or reversible upon cessation of treatment.

Methotrexate

Methotrexate is recognized as a standard of carefor RA. Although six RA patients responded tomethotrexate in a small study conducted in 1951,41,42

its efficacy in treating arthritis was not widely ac-cepted until more than 30 years later. Its mechanismof action in relieving RA is unknown. Methotrexateexposure was shown to increase with age after bodyweight adjustment.43

Various dosing regimens have been evaluated formethotrexate.26,27 The recommended initial dose of10 mg/m2 q.w. in the treatment of JIA was supportedwith an efficacy and safety trial.26 In this 6-month,double-blind, placebo-controlled trial, a total of 127patients with JIA (mean age, 10.1 years) were givenmethotrexate 10 mg/m2 q.w. (n = 46), methotrexate5 mg/m2 q.w. (n = 40), or placebo (n = 41). The10 mg/m2 dose group showed significant clinical im-provement compared with placebo group as measuredby either the physician’s global assessment, or thepatient composite (25% reduction in the articular-severity score plus improvement in parent and physi-cian global assessments of disease activity). The 5 mg/m2 dose (comparable to 7.5 mg in adult RA pa-tients) group was not significantly more effective thanplacebo in this trial. Such a dose-dependent treat-ment effect for methotrexate was also seen by otherinvestigators.44,45

Etanercept

Etanercept is a dimeric fusion protein consisting ofthe extracellular domain of the human tumor necro-sis factor (TNF) receptor (75 kd) coupled to the Fcportion of the human immunoglobulin (Ig) G1. Itbinds specifically to the serum TNF-" and TNF-$,therefore blocking the binding of TNF-" and TNF-$ to the TNF receptors on the plasma membraneof the target cell and inactivating the biologic activ-ity of TNF. Etanercept is the first biologic to receiveFDA approval for JIA indication. A well-controlledwithdrawal study was conducted to evaluate its ef-ficacy and safety in JIA patients.28 The study hadtwo phases: an open-label phase and a double-blind



phase. In the open-label phase, all enrolled patients(4–17 years old) received 0.4 mg of etanercept per kilo-gram of body weight subcutaneously twice weekly forup to 3 months. In the double-blind phase, only thosewho responded to treatment were randomly assignedto receive either placebo or etanercept for 4 monthsor until a disease flare occurred. Seventy-four percentpatients responded the initial treatment entered thedouble-blind phase. As compared to the placebo group,a significantly lower percent of patients in etanercept-treated group withdrew because of disease flares (28%vs. 81%) in the double-blind phase. The frequencyof adverse events was comparable between the twogroups.

As etanercept exhibits slow absorption and elimi-nation PK profile in JIA patients, to improve patientcompliance, more convenient dosing regimens wereexplored using a Monte Carlo clinical trial simulationapproach.29 Using the population PK parameters, theconcentration–time profiles for different dosing reg-imens were simulated and compared. As comparedwith the 0.4 mg/kg twice weekly regimen, the meansteady-state peak and trough etanercept concentra-tions for 0.8 mg/kg q.w. dosing were 11% higher and18% lower, respectively. These results showed that thetwo dosing regimens yield widely overlapping concen-tration profiles at steady state and are expected toyield comparable clinical outcomes. This simulationresult supported the use of the 0.8 mg/kg q.w. regi-men in JIA patients.

Adalimumab

Adalimumab is a recombinant human IgG1 mono-clonal anti-TNF-" antibody. In response to a PediatricResearch Equity Act (PREA) requirement, the ef-fect of adalimumab was assessed in JIA patients.30,46

In this multicenter, stratified, well-controlled with-drawal trial, patients 4–17 years of age were givenfour phases of treatment after stratification basedon methotrexate use: a 16-week open-label lead-inphase, a 32-week double-blind withdrawal phase, anup to 136-week open-label extension phase, and a16-week open-label fixed dose phase. Adalimumabwas given body surface area-based dosage regimen[24 mg/m2 up to 40 mg subcutaneously every otherweek (e.o.w.)] in the first three phases followed with20 (<30 kg) or 40 mg (>30 kg) e.o.w. in the lastphase. Disease flare rate was statistically in favorof adalimumab relative to placebo in the withdrawalphase, regardless of methotrexate treatment. In thisstudy, the coadministration of methotrexate was as-sociated with higher serum adalimumab concentra-tions and lower incidence of anti-adalimumab an-tibody development. The steady-state trough serumadalimumab concentrations for subjects with con-comitant methotrexate were 23%–60% higher as com-pared with those without methotrexate. The inci-

dence of anti-adalimumab antibody development was6% in JIA patients with concomitant methotrexate ascompared with 26% in patients without methotrex-ate. These results provided evidence for the benefit ofadalimumab usage and the concomitant use of adali-mumab with methotrexate.

Abatacept

Abatacept is a selective costimulation modulator in-hibiting T cell activation, which is related to thepathogenesis of RA. The pediatric assessment of abat-acept was conducted in an efficacy and safety studyin JIA patients 6–17 years of age (n = 190) basedon the requirement of PREA. The study includedan open-label lead-in period, a double-blind random-ized withdrawal period, and an open-label extensionperiod.31 Patients received 10 mg/kg up to 1000 mgper dose intravenously (i.v.) on days 1, 15, 29, andmonthly thereafter. Patients demonstrating an ACRPedi 30 response at the end of the lead-in phasewere randomized into the double-blind phase and re-ceived either abatacept or placebo for 6 months oruntil a disease flare. Abatacept-treated patients ex-perienced significantly fewer disease flares comparedwith placebo-treated patients (20% vs. 53%). The riskof disease flares among patients continuing on abata-cept was significantly less than that for patients with-drawn from abatacept treatment.31 The mean (range)steady-state serum peak and trough concentrationsof abatacept were 217 (57–700) and 11.9 (0.15–44.6)mcg/mL, respectively. Population PK analyses of theserum concentration data estimated that clearanceof abatacept in the JIA patients has a mean (range)value of 0.4 (0.20–1.12) mL/h/kg, and this estimationwas not affected by the concomitant methotrexate,corticosteroids, or NSAIDs.47 These study results sup-port the pediatric use of abatacept in JIA patients.

Leflunomide

Leflunomide is a pyrimidine synthesis inhibitor withimmunomodulatory activity. In humans, leflunomideis extensively converted to an active metabolite, M1,during the absorption phase by first-pass metabolism.Leflunomide is mostly undetectable or measured atvery low levels. Therefore, M1 is essentially respon-sible for its antirheumatic activity in vivo.48 The ap-proved indication is for the treatment of active RA.However, leflunomide did not obtain the JIA indica-tion because of a lower response rate in JIA patientsfrom an efficacy trial conducted in response to a PWR.The PWR specified that the PK, safety, and efficacyof leflunomide should be evaluated in JIA patientages 3–17 years. Three clinical trials were thereforeconducted: an initial PK study, an efficacy trial, andan extension trial.32 Sparse PK samples were takenin the first two studies for population PK analysis.JIA patients <40 kg had an M1 exposure lower than


2632 JI ET AL.

that in heavier pediatric patients and adult RA pa-tients. The efficacy trial was a randomized, double-blind, and active-controlled study in 94 patients withJIA. Leflunomide did not perform as well as the ac-tive comparator, methotrexate, using one of the co-primary efficacy endpoints, ACR Pedi 30 at Week 16.The ACR Pedi 30 responder rate in the leflunomidegroup was 68% versus 89% in the methotrexate group,and the difference was statistically significant. Thesmaller and younger pediatric patients (≤40 kg) wereespecially less responsive to leflunomide treatmentat the administered doses. The findings of these tri-als did not support the JIA indication. However, theyprovided useful clinical information for the labelingchanges in pediatric patients with JIA.

Infliximab

Infliximab is a chimeric murine-human monoclonalanti-TNF-" antibody. It neutralizes the biological ac-tivity of TNF-" by binding to the soluble and trans-membrane forms of TNF-" with high affinity andinhibits binding of TNF-" with its receptors. Un-like etanercept, infliximab does not neutralize TNF-$, a related cytokine that utilizes the same receptorsas TNF-". It is currently indicated for use in adultRA, Crohn’s disease, ankylosing spondylitis, psori-atic arthritis, plaque psoriasis, and ulcerative col-itis. However, its efficacy in the treatment of JIAwas not established in a randomized, double-blind,placebo-controlled trial.33 In this trial, 122 JIA pa-tients (4–17 years) were randomized to receive in-fliximab 3 mg/kg plus methotrexate through week 44(infliximab group) or methotrexate plus placebo for14 weeks followed by methotrexate plus infliximab6 mg/kg through week 44 (placebo group). Although ahigher proportion of patients in the infliximab 3 mg/kg group than in the placebo group had achieved re-sponses according to the ACR Pedi 30 at week 14(63.8% and 49.2%, respectively), the between-groupdifference was not statistically significant. The safetyprofile of infliximab 3 mg/kg appeared less favorablethan that of infliximab 6 mg/kg, although infliximabwas generally well tolerated. The trial failure wasattributed to factors such as greater placebo effectand lower PK exposure. The PK analysis showed thatthe median half-life of infliximab was 9.5 days at the6 mg/kg dose versus 6.9 days at the 3 mg/kg dose.The half-life difference between the two doses mightbe the results of the difference in the incidence ofanti-infliximab antibodies. Patients who were anti-body positive were more likely to have higher clear-ance, reduced efficacy, and higher rate of infusion re-actions. The incidence of antibodies to infliximab inthe 3 mg/kg group [(20 of 53) 38%] was higher than inthe 6 mg/kg group [(6 of 49) 12%]. Among patients whohad positive test results for antibodies to infliximab,the incidence of infusion reactions was also higher in

the infliximab 3 mg/kg group [(12 of 20) 60%] than inthe infliximab 6 mg/kg group [(3 of 6) 50%].

Other Treatments

Low-dose corticosteroids (e.g., prednisone andmethylprodnisone) work either orally or parenter-ally in controlling symptoms of JIA. They have anti-inflammatory activity and are immunosuppressant.The lowest effective dose should be used to minimizeadverse effects (e.g., hyperglycemia and GI toxicity).Corticosteroids may slow joint damage; however, theyare often used as bridging therapy when patientsstart DMARDs or during the acute attack.49

SUMMARY

This review summarizes the pediatric clinical devel-opment programs of 14 drugs and biologics investi-gated for JIA indication. Five non-selective NSAIDshave been approved by FDA for the treatment ofJIA (naproxen, tolmetin, oxaprozin, meloxicam, andetodolac). As rofecoxib was withdrawn from marketsin 2004, celecoxib is the only FDA approved COX-2selective inhibitor currently on the market with JIAindication. The proposed dosing regimens were basedon the evaluation of PK, safety, and efficacy data. Twodose levels were studied in the well-controlled clini-cal trials in JIA patients for meloxicam, rofecoxib,and celecoxib. Low dose (0.125 mg/kg up to 7.5 mgmaximum a day) meloxicam was proposed in the JIAtreatment as it showed comparable effect to high dose(0.25 mg/kg up to 15 mg maximum a day) meloxicamin the clinical trial. Conversely, high dose (0.6 mg/kgq.d.) rofecoxib was proposed in the JIA treatment be-cause of its better response rate than the low dose(0.3 mg/kg q.d.) rofecoxib. Although celecoxib 3 and6 mg/kg b.i.d. were efficacious and safe as comparedwith the active control (7.5 mg/kg b.i.d. naproxen),the clinical suspension formulation was deemed notsuitable for commercialization and capsule formula-tion was therefore further assessed. The dosing reg-imen for the capsule formulation was proposed withthe population PK modeling and simulation approachsuch that the exposure for the capsule formulationwas comparable with the suspension formulation. Fornaproxen, oxaprozin, and etodolac, the dosing regi-mens were proposed based on comparable drug ex-posure between children and adults plus supportingefficacy data in JIA patients. For tolmetin, the firstFDA-approved NSAID for JIA indication, the dosingregimen was proposed based on the safety and efficacydata.

Approved DMARDs for JIA treatment includedrugs that have been on the market well over50 years (methotrexate and sulfasalazine) and bi-ologics approved in the past 10 years (abatacept,adalimumab, and etanercept). For methotrexate and



sulfasalazine, the acceptance of their JIA indicationwas the result of many years of clinical experience andseveral positive well-controlled clinical trials. Theyare also frequently used as the background therapy oras reference drugs when the newer DMARDs are eval-uated. The efficacy data plus matching systemic ex-posure support the use of abatacept, etanercept, andadalimumab in JIA patients. Leflunomide and inflix-imab were also investigated in JIA patients; however,significantly better response rate as compared withthe active control group was not established at the in-vestigated doses. Although various reasons have beenproposed to explain the inadequacy of their efficacy,further investigations need to be conducted.

In conclusion, pediatric dosing in JIA patients is de-termined by the totality of evidence, which includesfactors such as formulation, PK, safety, and efficacy.Understanding of how these factors played a role inthe past dosing regimen recommendation may facili-tate rational trial design for the future pediatric clin-ical development of new drugs or biologics in JIA orfor other disease areas.

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