John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific...
-
Upload
lizbeth-heath -
Category
Documents
-
view
214 -
download
2
Transcript of John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific...
![Page 1: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/1.jpg)
John N. van den Anker, MD, PhD
The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects
Evan and Cindy Jones Chair in Pediatric Clinical PharmacologyProfessor of Pediatrics, Pharmacology & Physiology, GWU, Washington, DCChief, Division of Pediatric Clinical Pharmacology, Children’s National, DCAdjunct Professor of Medicine, Pediatrics, Pharmacology & PhysiologyJohns Hopkins University, Baltimore, MD
![Page 2: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/2.jpg)
“ Pediatrics does not deal with miniature men and women, with reduced doses and the same class of diseases in smaller bodies, but….it has its own independent range and horizon…”
Dr. Abraham Jacobi, 1889
![Page 3: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/3.jpg)
Critical Role of Drug Disposition in Pediatric Therapeutics
The combination of absorption, distribution, metabolism & elimination determine drug exposure
drug exposure determines drug response
Knowledge of the relationship between PK and exposure dictates dose Age-dependent
PK data to guide dose/exposure
Age-dependent PD data in similar
disease processes
Safety/tolerance data with
therapeutic use
Acceptable formulations
Rational Therapeutics
![Page 4: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/4.jpg)
Absorption
Oral
Sublingual
Intramuscular
Percutaneous
Rectal
![Page 5: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/5.jpg)
Factors Influencing Oral Drug Absorption
Biliary function
Physicochemical&
Mechanical
Gastric pH
Intestinal drug
metabolism
Gastric
emptying time
Intestinal
motility
Intestinal
surface area
Splanchnic
blood flow
Microbial
colonizationIntestinal
drug transport
![Page 6: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/6.jpg)
Developmental Alterations in Gastric pH
Agunod et al. Amer J Digest Dis 1969;14:400Mozam et al. Ann Surg 1984;199:389Rodgers et al. J. Pediatr Surg 1978;13:13
% A
du
lt A
ctiv
ity
birth1 wk
2 wk3 wk
1 mos3 mos
5-10 yr adult HCl productionPepsin
Gastrin
0
50
100
150
200
250
![Page 7: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/7.jpg)
Influence of Developmental Alterations in Gastric pH
Huang et al. J Pediatr 1953;42:657
Orally Administered Penicillin (10,000 U/lb)
0
0.5
1
1.5
2
2.5
3
3.5
0 2 4 6 8
Time (hr)
Pen
icill
in c
once
ntra
tion
(U/m
L) Preterm neonate
Fullterm neonate
Infants (2 wk-2 yr)
Children (2-13 yr)
![Page 8: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/8.jpg)
Developmental Alterations in Gastric Emptying Rate
Gupta & Brans, Pediatrics 1978;62:26
Pre-term
Full term
30 minute gastric retention
0
10
20
30
40
50
60
70
4-12 hr 22-36 hr 46-60 hr
Postnatal Age
% o
f mea
l
![Page 9: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/9.jpg)
Pla
sma
Con
cent
ratio
n (n
g/m
L)
0
5
10
15
20
25
30
35
0 5 10 15 20 25Time (hr)
28-36wk (5.0 + 2.6)36-42wk (4.3 + 3.3)42-54wk (2.2 + 1.1)
PCA -- Tmax (hr)
Adult (1.8)
Kearns, van den Anker, et al. Clin Pharmacol Ther 2001;69:31
Influence of Developmental Alterations in Gastric Emptying & Intestinal Transit
Single-Dose Cisapride PK in Neonates and Young Infants
![Page 10: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/10.jpg)
Getting the drug in…
Do you have an age appropriate pediatric formulation?
solid oral
chewable
oral liquid
rectal
transdermal
parenteral
intranasal
intraocular
newborn infant preschool school-aged adolescent
![Page 11: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/11.jpg)
Developmental Alterations in Oral Drug Absorption
1st Law of Pediatric Drug Administration
Orifice rejection of drugs is the rule rather than the exception.
![Page 12: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/12.jpg)
Factors Influencing Transdermal Drug Absorption
Barrier thickness Regional blood flow Diffusional surface area Temperature Hydration Local pH Tissue binding sites Drug-vehicle interactions
![Page 13: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/13.jpg)
Developmental Alterations in Skin thickness
GA: 26 wkPNA: 1 day
GA: 26 wkPNA: 16 days
GA: 40 wkPNA: 1 day
Rutter. Clin Perinatol 1987;14:911
![Page 14: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/14.jpg)
Impact of Enhanced Skin Permeability on Cutaneous Absorption
Neonatal Case Reports
Agent Resultant ADR
silver sulfadiazene cardiorespiratory arrest
topical steroids HPA suppressioncushingoid features
pentachlorophenol(laundry detergent)
diaphoresishepatomegaly
acidosis
boric acid(talcum powder)
death
![Page 15: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/15.jpg)
Volume of Distribution
![Page 16: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/16.jpg)
EC H2O IC H2O Protein Fat
0 20 40 60 80 100
Premature
Newborn
4 mo
12 mo
24 mo
36 mo
Adult
Age Dependent Changes in Body Composition
![Page 17: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/17.jpg)
Impact of Changes in Extracellular Fluid on Drug Distribution
Siber et al. J Infect Dis 1975;132:637
0
0.5
1
1.5
2
2.5
3
3.5
0.5-5 yr 5-10 yr 10-15 yr 15-42 yr
Age
Pea
k G
enta
mic
in C
once
ntra
tion
(mg/
L pe
r m
g/kg
dos
e)
![Page 18: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/18.jpg)
Drug biotransformationDrug biotransformation
DrugDrugDrugDrugPhase IPhase I Phase IIPhase II
UGTsUGTsNATsNATs
SULTsSULTsMTsMTs
GSTsGSTs
MetaboliteMetabolite
CYPsCYPsFMOsFMOs
EsterasesEsterasesHydrolasesHydrolases
![Page 19: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/19.jpg)
Human Hepatic DME Ontogeny
Class 1
SULT1A3
CYP3A7
SULT1E1
GSTP
ADH1A
FMO1
Class 2
CYP3A5
SULT1A1
GSTA2
CYP2C19
GSTA1
Class 3
CYP2E1 UGT2B7
CYP2D6 UGT1A6
FMO3ADH1C
CYP2C9 UGT1A1
CYP1A2 SULT2A1
EPHX1
ADH1B EPHX2
CYP3A4 PON1
GSTMAOX
Hines, Pharmacol & Therap. 118:250-267, 2008
![Page 20: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/20.jpg)
Human DME OntogenyHuman DME OntogenyD
ME
(p
mol/m
g p
rote
in)
0
10
20
30
40
EGA10-26 wks
EGA>26-40 wks
PNA0-6 mo
PNA>6 mo-18 yr
SULT1E1Class 1
SULT1A1Class 2
CYP2C9Class 3
![Page 21: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/21.jpg)
Ontogeny of CYP2C19 Ontogeny of CYP2C19 In VitroIn Vitro
Koukouritaki Koukouritaki et al et al J Pharmacol Exp Ther 2004;308:965-974.J Pharmacol Exp Ther 2004;308:965-974.
EGA (Weeks)EGA (Weeks) PNA (Months)PNA (Months) PNA (Years)PNA (Years)
00 33 66 99 1212 1515 181866 1414 2222 3030 3838 11 22 33 44 55
4040
3030
2020
00
1010
00
1010
2020
3030
CY
P2C
19 P
rote
in (
pmol
/mg)
CY
P2C
19 P
rote
in (
pmol
/mg)
![Page 22: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/22.jpg)
Ontogeny of CYP2C19 Ontogeny of CYP2C19 In VivoIn Vivo
Ward Ward et al et al Eur J Clin Pharmacol 2010;66:555-561Eur J Clin Pharmacol 2010;66:555-561
rr22 = 0.35 = 0.35
Postmenstrual AgePostmenstrual Age Postnatal AgePostnatal Age
![Page 23: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/23.jpg)
APAP Biotransformation in HumansAPAP Biotransformation in Humans
APAP
APAP-G
NAPQI
APAP-S
Mercapturate
Ratio Gluc:SulfMean SE
Newborns N=4 0.340.08
3-9 yr N=7 0.750.10
12 yr N=4 1.610.21
Adults N=4 1.801.32
UGT1A6UGT1A9
SULT1A1
CYP3A4CYP3A4CYP1A2CYP1A2CYP2E1CYP2E1
Miller, et al. Clin. Pharmacol. Ther. 19:284-294, 1976
![Page 24: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/24.jpg)
Impact of Developmental Alterations in Phase II Enzymes on Drug Metabolism: Acetaminophen
12610-365 days (n=7)
210term <10 days (n=5)
265Preterm 32-36 wk (n=10)
290Preterm <32 wk (n=10)
APAP t1/2 min (IV paracetamol)
Age
Allegaert, et al. Arch Dis Child Fetal Neonatal Ed. 2004;89:25-28
![Page 25: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/25.jpg)
Term
Preterm (<2000gm)
Preterm (<1500 gm)
0
10
20
30
40
50
60
70
1-2 d 8-9 d 15-16 d
GF
R (
ml/m
in/1
.73m
2)
Postnatal Age
Developmental Alterations in Glomerular Filtration
![Page 26: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/26.jpg)
Impact of Developmental Alterations in Renal Function on Drug Elimination
< 29 wk, <14 d
q72hr
< 29 wk, >14 d
q48hr
30-36 wk, <14 d
q48hr
30-36 wk, >14 d
q24hr
clearance(ml/min/kg)
half- life(hr)
premature 1 day 0.18 88.6
premature 7 days 0.33 67.5
premature 13 days 0.52 55.2
Fluconazole
infants 19.5-25
Saxen, et al. Clin Pharmacol Ther 1993;54:269
![Page 27: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/27.jpg)
Intestinal EffluxP-gp, MRP2, MRP1,
OCT1, OATP3,NTCP
Biliary ExcretionP-gp, MRP3, MRP2, sPGP
Hepatic UptakeOATP2, OATP8, OATP-B, OCT1, NTCP,
OAT2, OAT3
Renal SecretionOAT1, OAT3, OCT1,
OCT2, OATP,P-gp, MRP1
Brain TransportP-gp, OAT3,
MRP1, MRP5,OATP1
Ritschel WA and Kearns GL. Handbook of Basic Pharmacokinetics, 7 th edition, 2009
![Page 28: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/28.jpg)
Pediatric Clinical Pharmacology FactsPediatric Clinical Pharmacology Facts
Children are not small adultsChildren are not small adults different pharmacokineticsdifferent pharmacokinetics different pharmacodynamicsdifferent pharmacodynamics
Approximately 70% of all marketed Approximately 70% of all marketed drugs not suitably labeled for drugs not suitably labeled for pediatric usepediatric use
In some instances, pediatric In some instances, pediatric patients included in studies as an patients included in studies as an “afterthought”“afterthought”
The biggest issue remains The biggest issue remains determining the effective/safe determining the effective/safe dose for pediatricsdose for pediatrics
![Page 29: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/29.jpg)
![Page 30: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/30.jpg)
The In-silico Child…….
![Page 31: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/31.jpg)
Considering protocol elements…
Are elements of the protocol nonsensical ?
Required consent language: If the patient is a female of child bearing potential, she must not be a pregnant or nursing…... If she is sexually active, she will be required to take precautions to avoid the possibility of becoming pregnant for up to 30 days past study drug ingestion. The use of oral contraceptives, ……intrauterine devices, barrier method (condom plus diaphragm, or condom plus contraceptive sponge, or condom plus intravaginal suppository) are accepted methods of birth control.. ….
A pregnancy test will be done at the start of the study
neonatal pharmacokinetic study
![Page 32: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/32.jpg)
Measuring drug concentrations…
Consider the allowable blood volume that can be drawn for the study (PK and safety labs).
ICH E11 defers to IRB/IEC
age weight circulating blood volume
max allowable q2wk
PT neonate 500 g 40 mL 1.5 mL
FT neonate 4 kg 320 mL 12
infant (3 yr) 15 kg 1.2 L 45
child (12 yr) 40 kg 3.2 L 120
Have microassays been developed & validated? Is a sparse/minimal sampling scheme appropriate?
![Page 33: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/33.jpg)
Designing a Pediatric Protocol
Selecting the population Selecting the dosing scheme Getting the drug in Measuring drug concentrations Monitoring tolerability/safety Analyzing data Considering protocol elements
![Page 34: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/34.jpg)
![Page 35: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/35.jpg)
Courtesy of Dr. Catherine Tuleu, Univ. of London, 2011
![Page 36: John N. van den Anker, MD, PhD The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects Evan and Cindy Jones Chair.](https://reader036.fdocuments.us/reader036/viewer/2022081519/56649e635503460f94b5f8dd/html5/thumbnails/36.jpg)
CONCLUSIONS
TEAM WORK TEAM WORK TEAM WORK TEAM WORK TEAM WORK