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Pediatric Drug Development

“The joint goal for industry, regulators,

practitioners and patients is to encourage

pediatric drug development in order to create a

situation where substantially more children have

access to safe and effective medication…”

Legislative incentives/mandates in place to

promote pediatric development • FDA: Pediatric Plan, BPCA, PREA

• EU: Pediatric Investigation Plan (PIP)

• WHO: Make Medicines Child Size

EFPIA 2009 Position Paper: Industry Perspectives on Pharmaceutical Development of Medicines for Pediatric Use

Pediatric Study Decision Tree • FDA guidance on exposure-response relationships

proposes extrapolation from adult to pediatric

patients for efficacy. • It does not refer

to safety and

dose adjustment.

• Some adverse

events were

observed when

using adult data in

the prediction.

FDA Guidance for Industry: Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications

Pediatric Pharmacology - History

• Some of the most disastrous therapeutic

misadventures occurred in pediatrics.

– 1957 Thalidomide

• During early pregnancy caused severe congenital

anomaly, phocomelia

• Led to the “modern era” of pharmaceutical regulation

with Kefauver-Harris Drug Amendments of 1962

– 1959 Chloramphenicol

• At the extrapolated dose caused grey baby syndrome

due to immature UDP glucuronosyltransferase

system

Dr. M. E. Blair Holbein, Clinical Pharmacologist, Presbyterian Hospital of Dallas: “Age and Pharmacokinetics: Pediatric and

Geriatric Considerations”

Pediatric pharmacology - What’s

unique?

• Continuous development from embryo to adolescent

– “Perpetual pharmacologic moving target”

– Pharmacodynamics and pharmacokinetics change with time

• The most profound differences occur in the first weeks through first year of life.

Dr. M. E. Blair Holbein, Clinical Pharmacologist, Presbyterian Hospital of Dallas:

“Age and Pharmacokinetics: Pediatric and Geriatric Considerations”

Kearns, G. L. et al. N Engl J Med 2003;349:1157-1167

Pediatric pharmacology - What’s

unique?

• Descriptive pharmacology (especially for new drugs) in pediatric patients is often lacking

– Children are not “miniature adults” • Dosing based on scaling (by body weight or body

surface area) not always predictable for a given drug.

– Animal studies not always predictive.

– Clinical studies in children fraught with ethical and financial hurdles.

– Administration of drug can also be problematic.

Dr. M. E. Blair Holbein, Clinical Pharmacologist, Presbyterian Hospital of

Dallas: “Age and Pharmacokinetics: Pediatric and Geriatric Considerations”

Pediatric Drug Development Initiatives • FDA:

– Best pharmaceuticals for Children Act (BPCA) provides 6 month patent incentive

– Pediatric Research Equity Act (PREA) mandates that clinical trials in pediatric populations for NDAs of drugs with potential pediatric indications

• EFPIA – European Federation of Pharmaceutical Industries and Associations:

– Pediatric Investigation Plan (PIP) states pediatric trials have to begin when clinical testing begins

• WHO:

– Encourages everyone to Make Medicines Child Size

Best Pharmaceuticals for Children Act (BPCA)

Best Pharmaceuticals in

Children Act Testing drugs in children presents considerable

scientific, clinical, ethical, technical, and logistical

challenges. Over the years, several practical

challenges have discouraged the testing of drugs

in pediatric populations. These include:

– Lack of incentives for companies to study drugs in

neonates, infants, and children

– Lack of necessary technology to monitor patients and

assay very small amounts of blood

– Lack of suitable infrastructure for conducting pediatric

pharmacology drug trials.

Taken verbatim from: http://bpca.nichd.nih.gov/about/index.cfm

Pediatric Research Equity Act

(PREA)

Impetus for Pediatric Development • > 8,000,000 deaths in children under 5 in 2008 • Scant / absent guidance for pediatric dosing • Unexpected results from off-label preparations • Children do not swallow pills

Blake et al. PIDJ 2006; 25:405 Notterman. Pediatrics 1986; 77:850

Pediatric Formulations

• Differences between EMA’s and FDA's view on pediatric trials now exist.

• EMA will not allow a products release, including adult formulation, if their Pediatric Investigation Plan (PIP) isn't satisfactory. – Encourages more pediatric formulation applications

– May be hindering excellent products from release to the market for mitigating many diseases, possibly with limited pediatric potential.

– We hypothesize that pediatric preclinical animal studies may provide support for release and enable some harmonization.

Pediatric Drug Development Initiatives • Paradigm shift for industry:

– Traditional views over the last couple of decades have been to protect children from clinical research.

– However, the current regulatory paradigm shift is to now

protect children through clinical research.

• New challenges based on the Paradigm shift – Children are not minature adults

– Pediatric patients need to be age classified

– Pediatric patients require age appropriate formulations that used to be primarily made through compounding

– First in child safety and efficacy preclinical models are lacking

Pediatric Drug Development Initiatives

• 42% failure rates possibly

due to not having the right

drug-patient, dose and

trial design.

• Institute for Advanced

Clinical Trials for Children

in 2017 to foster public-

private collaboration.

Robert M. Ward et al. The Need for Pediatric Drug Development. J Pediatr. 2018; 192:13 – 21.

FDA Voice. Nov 9, 2017. https://blogs.fda.gov/fdavoice/index.php/tag/iact-for-children/

Challenges with Pediatrics

• Biological Challenges • Ontogenic Changes

• Compositional Changes

• Clinical Challenges • Clinical Trials

• Caregiver Requirements

• Formulation Challenges • Dosage Form Selection

• Flexibility in Dosing

• Excipient Selection

• Taste Masking

Atkinson et al. Principles of Clinical Pharmacology 2006 Schirm et al. Acta Paediatr. 2003; 92:1486

• Tablets/Capsules ◦ Oral Solutions

Age (yr)

Pediatric Pharmacology - Challenges • Developmental changes are occurring from

conception to adulthood (moving target): – Organ development – Drug transporter (largely unknown for humans)

and metabolizing enzyme ontogeny – Pharmacodynamics and Toxicokinetics

• Preclinical animal models are poorly defined and lack proper scaling approaches.

• Human data is sparse: to date no healthy pediatric PK/PD clinical trials.

• Pharmacogenetic/Pharmacogenomic effects

Relationship between DOSE and Toxic

Response

Time

Blood/

Plasma

Level

Toxic Response

Safe and Efficacious

Not Efficacious

Therapeutic Window

The blood/plasma concentration vs. time plot is how we

measure pharmacokinetics (PK).

The effect on the body is called pharmacodynamics (PD)

CMAX. TMAX

Other Pediatric Pharmacology Issues

• Historical cases with drugs like thalidomide in the 1950’s induced in utero malformations.

• Animal models have differing sensitivity to xenobiotic exposure than humans

• Xenobiotic exposure can lead to changes in developmental PK/PD.

• The target moves even further due to the environment!

Pediatric Biopharmaceutics Classification System (PBCS)

• The BCS has been widely used to expedite generic and drug

repurposing formulations for industry.

• Classification is based on three factors that influence the

drug’s bioavailability from a peroral formulation:

– Solubility (in vitro, biorelevancy?)

– Intestinal permeation across the intestinal barrier (in vitro vs. in

vivo, regional?)

– Dissolution rate (in vitro, biorelevancy?)

• There is a urgent need to expedite the development of

pediatric formulations.

S. Abdel-Rahman, G.L. Amidon, A. Kaul, V. Lukacova, A.A. Vinks, G.T. Knipp. Summary of the

NICHD-BPCA Pediatric Formulation Initiatives Workshop-Pediatric Biopharmaceutics

Classification System (PBCS) Working Group. Clin. Ther. 34(11S):S11-S24 (2012).

Pediatric Biopharmaceutics Classification System (PBCS)

• Our joint NICHD-FDA Task Force tentatively proposed the

following BCS classification:

– Class 1: (pediatric, volume = 25 ml): rapid dissolution (t50= 15

min.) for immediate release

– Class 2: (Subclasses a,b,c for acidic, basic and neutral drugs);

Dissolution criteria are critically needed

– BCS Class 3: very rapid dissolution.

– BCS Class 4: Same as BCS Class 2.

• Disposition drives safety and efficacy, there is a need for

consideration of distribution, metabolism and elimination

in the system-BDDCS. S. Abdel-Rahman, G.L. Amidon, A. Kaul, V. Lukacova, A.A. Vinks, G.T. Knipp. Summary of the

NICHD-BPCA Pediatric Formulation Initiatives Workshop-Pediatric Biopharmaceutics

Classification System (PBCS) Working Group. Clin. Ther. 34(11S):S11-S24 (2012).

Pediatric Formulations • The Safety and Toxicology of Excipients for Pediatrics

Database – Collaboration between EMA and NICHD

– Draws considerable attention to use of traditional excipients, particularly co-solvents for pediatrics vs. adults

– Encouraging greater use of solid dosage forms

International Journal of Pharmaceutics 457 (2013) 310–322

International Journal of Pharmaceutics 435 (2012) 101–111

Excipients in Pediatric Formulation • Generally Regarded As Safe (GRAS) status does not consider

the population specific aspects and lacks validation in pediatric

patients.

Robert M. Ward et al. The Need for Pediatric Drug Development. J Pediatr. 2018; 192:13 – 21.

Verica Ivanovska et al. Pediatric Drug Formulations. Pediatrics 2014; 2013-3225.

Karel Allegaert. Neonates need tailored drug formulations. World J Clin Pediatr. 2013; 2(1): 1–5.

• 10 prioritized excipients for pilot STEP development

Propylene glycol (PG) Ethanol

Polysorbate 80 Benzyl alcohol

Parabens Benzlkonium chloride

Aspartame Sorbitol

Benzoic acid Sodium benzoate

• Ethanol/ PG toxicity in premature newborns administered with

Kaletra (lopinavir/ritonavir) oral solution led to FDA safety

communication and label change.

Propylene Glycol • Largely considered as a solubility enhancer, with a

negligible effect on P-gp for substrates.

• Appeared to have a slight, but not statistically different effect on small intestinal transit times (SITT) that may be linked to absorption in humans.

• There was no effect on SITT in dogs.

• Hypertonic effect is larger than most co-solvents.

• PEG 400 does increase small intestinal transit times.

• Commonly used as a co-solvent with other P-gp inhibitors.

J.D. Schulze, et al. Impact of formulation excipients on human intestinal transit. J Pharm

Pharmacol. 58:821-825 (2006).; J.D. Schulze, et al. Excipient effects on gastrointestinal transit and

drug absorption in beagle dogs. Int J Pharm. 300:67-75 (2005).

Proof of Concept Study

Hypothesis: Juvenile porcine of similar body weight can serve as a surrogate for human pediatric patients during preclinical PK/PD allowing for more accurate predictions of PK data during pediatric drug development.

Specific Aims

– Establish the extent of rifampicin uptake into the body of juvenile pigs and compare with published pediatric literature

– Determine ontogenic changes in rifampicin uptake in pigs

– Develop novel dosage forms of rifampicin and establish their performance parameters in juvenile pigs (globalization)

W.J. Roth, et al., 2013, Assessment of Juvenile Pigs to Serve as Human Pediatric

Surrogates for Preclinical Formulation Pharmacokinetic Testing. AAPS J. Pediatric

Theme Issue 15(3):763-774.

Approaches to Enhance Development • Fundamental

research to understand how can we change doses and administer medicines at safe and efficacious levels in pediatrics

• Improve preclinical performance assessment and utility with better characterized animal models

H. Musther et al. Quantitative prediction of human oral bioavailability from animal bioavailability

data: Comprehensive analysis of literature data. Eur. J. Pharm. Sci. 2014; 57:280

Pediatric Formulation Preclinical Testing

• The minipig and porcine models are the preferred safety pharmacology species in Europe.

R Forster, G Bode, L Ellegaard, JW van der Laan. The RETHINK project on minipigs in the toxicity

testing of new medicines and chemicals: Conclusions and recommendations. J Pharmacol Toxicol

Meth 62:236-242, 2010

Human – Porcine Comparison • High similarity to humans with respect to the liver,

GI tract, lungs, skin, cardiovascular, and immune systems

• Best non-primate model for safety and pharmacology testing (J.Phamacol. Toxicol. Met, Dec. 2010)

• Potential to develop disease states (e.g. diabetes)

DeSesso et al. Ann. Rep. Med. Chem 2008; 43:353

Anatomical and cell maturation is largely complete by term, with a few

changes in integrity occurring postnatally in fetal pigs and humans.

Gestation is 114 days in the pig, 9 months in humans, and 21 days in the rat.

C.M. DeKaney, F.W. Bazer, L.A. Jaeger. Mucosal Morphogenesis and

Cytodifferentiation in Fetal Porcine Small Intestine. Anat Record. 249:517–523, 1997.

Dr. Jaeger is a collaborator at Purdue in the Animal Sciences Department.

Gastrointestinal Developmental Similarities

Human – Porcine CYP and Transporter Comparison

• Specificity of porcine CYPs is similar to man1

• Expression levels of porcine CYPs are similar to man2

• Porcine CYP3A metabolism is closest to man3

Human

Orthologue

Porcine

Orthologue

mRNA

% Identity

Protein

% Identity

CYP1A2 CYP1A2 85% 81%

CYP2A6 CYP2A6 87% 87%

CYP2B6 CYP2B22 80% 74%

CYP2C9 CYP2C49 83% 78%

CYP2C18

CYP2C19

CYP2C49 85%

83%

80%

78%

CYP2D6 CYP2D21

CYP2D25

83%

77%

78%

77%

CYP3A4 CYP3A22

CYP3A29

82%

83%

75%

77%

SLC15A1 pPepT1 89% 83%

MRP1 MRP1 63% 62%

MRP2 MRP2 87% 82%

MDR1 (P-gp) MDR1 (P-gp) 90%

87%

89%

BCRP BCRP 85% 84% 3Bogaards et al. Xenobiot. (2000) 30:1131

2Swindle et al. Pharm. Pathobiol. (2012) 49:344

1Bode et al. J. Pharmacol. Toxicol. Meth (2010) 62:196

•Human liver transcriptome

•Age: 0-81

•Pig liver transcriptome •Pig 1: fetal

•Pig 2: postnatal day 1

•Pig 3: Postnatal day 28

•Pig 4: postnatal day 188

•Focusing on 248 PK (Phase I, II, III) genes

•Similarity between expression pattern of PK

genes were found between pig 3 and human

aged 1-8, and between pig 4 and human aged

•It is our goal to collect more pig samples to make

a high-resolution match of PK gene patterns

between pig and human

•This will establish a genome-based pig selection

for pediatric pharmacological analysis. age

D e

v e

lo p m

e n ta

l s ta

g e

pig human

A network-based comparison of PK gene

expression profile in the liver tissue between

human and pig

Courtesy of Dr. Wanqing Liu, Purdue University

Blood Perfusion Comparison

Percent of Cardiac Output

Organ/Tissue Pigs Human Dog

Brain 5 12 9

GI Total 18 15 10

Stomach & Esophagus 2 1 2

Small Intestine 11 10 6

Large Intestine 5 4 2

Heart 4 4 6

Kidneys 17 19 20

Liver 26 25 30

CYP mRNA Species Comparisons

Human Mouse Rat Rabbit Dog Pig Monkey

1A2 1A2 (73%) 1A2 (75%) 1A2 (78%) 1A2 (82%) 1A2 (81%) 1A2 (94%)

2A6 2A4 (84%) 2A1 (69%) 2A10 (85%) 2A7 (86%) 2A6 (87%) 2A23 (92%)

2B6 2B9 (72%) 2B1 (76%) 2B4 (78%) 2B11 (77%) 2B22 (75%) 2B6 (91%)

2C9 2C37 (73%) 2C11 (76%) 2C1 (74%) 2C21 (69%) 2C49 (78%) 2C43 (92%)

2D6 2D9 (71%) 2D1 (72%) 2D24 (79%) 2D15 (75%) 2D21 (79%) 2D6 (94%)

2E1 2E1 (78%) 2E1 (79%) 2E1 (79%) 2E1 (77%) 2E1 (80%) 2E1 (95%)

3A4 3A11 (73%) 3A1 (72%) 3A6 (76%) 3A26 (77%) 3A29 (78%) 3A64 (92%)

Rifampin

• First-line antibiotic used for treating tuberculosis

• Included in WHO 2011 list of Essential Medicines for Children

• Adult dose: 10 – 20 mg/kg

• Children’s dose*: 5 – 10 mg/kg

Molecular Formula C43H58N4O12

Molecular Weight 823.0

Aqueous Solubility 1-2 mg/ml

Melting Point 183° C

Log P 3.7

Adult Pig Rifampin Enterohepatic Recycling

 Pharmacokinetics of a 14 mg/Kg dose of Rifampin in the porcine model (50 kg)

determined with two 300 mg capsules in pigs.

 3-5 characteristic enterohepatic recycling peaks

 AUC0-∞= 235754 ng-hr/ml, t1/2=4.7 hours and Tmax= 1.3 hrs after initial dose.

 Results similar to those observed in human adults.

Pharmacokinetic Summary

• Juvenile porcine PK parameters may be predictive of human pediatrics

• Porcine ontogenic changes in PK are similar to humans

• Higher exposure may be necessary to produce minimum desired Cmax concentration (8 µg/ml)

• Adult dosage forms may need to be administered extemporaneously-compromised dosing

• Alternative dosage forms are needed to increase compliance and compatibility for pediatric use.

Infant and Toddler Formulations

Exposure

• Current Practice Off Label Adult Dosing

• Concerns: Safety and Efficacy

Critical Need

• Alternative Dosage Forms

• Compliance

Our Efforts

• Oral Disintegrating Films (ODFs)

• Oral Disintegrating Tablets (ODTs)

Figure 4. (Left) Representative ODFs containing 25 mg of Rifampin prepared using

three different particle size distributions of API (d50 = 60, 25, and 10 µm, respectively).

(Right) Representative ODTs containing 50 mg of Rifampin.

ODF Shortcomings • Limited drug loading (24 mg)

• Moisture sensitive

• Difficult to manufacture

• Focus shifted to development of orally disintegrating tablets (ODTs)

0 20 40 60 80 100

P e

rc e

n t

W e

ig h

t G

a in

Relative Humidity

ODT Formulation Development

• Objective: Utilize commercially available excipients to formulate 50 mg ODTs of Rifampin for pediatric use

– Optimize with respect to disintegration time & shipping conditions (powdering)

– Determine juvenile pig pharmacokinetic parameters of ODT and compare with capsule formulation

Orally Disintegrating Tablets (ODTs)

• ODTs as defined by the U.S. Center for Drug Evaluation and Research (CDER)

A solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue.

• Recommendations/Guidance from the FDA NOT enforceable rules – Disintegration in 30 seconds or less

– Tablet weight of 500 mg or less

• Example: Oprapred prednisone ODT for asthma.

Pharmacokinetic Results in Juvenile Pigs Marketed 300 mg Capsule

2 4 6 8 10 12 14 16 18 20 22 24 -2

Sampling Time Post Dose (h)P la

s m

a C

o n

c e n

tr a ti

o n

( 

g /m

CMAX. TMAX

Area Under the Curve

(AUC)

Comparative Porcine-Pediatric Absorption

• No statistical difference between juvenile pigs and children in Tmax or dose normalized Cmax

Parameter Porcine TB/HIV Infected

Childrenǂ TB Infected

Childrenǂ

Weight (kg)

Dose (mg/kg)

Cmax (µg/ml)

Dose Norm Cmax (g/ml)

Tmax (h)

Ka (h -1)

20.90 (2.05)

14.46 (1.40)

8.34 (1.98)

0.58 (0.13)

1.88 (0.75)

1.51 (0.85)

12.26 (5.18)

9.61 (1.69)

4.91 (2.03)

0.51 (0.23)

1.80 (0.87)

1.02*

13.97 (6.94)

9.61 (1.69)

6.92 (5.88)

0.72 (0.62)

1.67 (0.93)

1.45*

ǂSchaaf et al. BMC Medicine 2009; 7:19

Comparative Porcine-Pediatric Elimination

• No statistical difference for dose normalized AUC; Ke and T1/2 were extrapolated from the data reported

Parameter Porcine TB/HIV Infected

Children

TB Infected

Children

Weight (kg)

Dose (mg/kg)

AUC0-t (µg*h/ml)

Dose Norm AUC0-t (g*h/ml)

Ke (h -1)

T1/2 (h)

22.79 (0.47)

13.17 (0.28)

28.80 (8.51)

2.19 (0.67)

0.21 (0.06)

3.54 (1.03)

12.26 (5.18)

9.61 (1.69)

14.88 (7.43)

1.54 (0.82)

0.30*

2.31*

13.97 (6.94)

9.61 (1.69)

18.07 (12.52)

1.88 (1.34)

0.24*

2.95*

ǂSchaaf et al. BMC Medicine 2009; 7:19

Comparative Rifampin PK Across Species

Modified from: W.J. Roth, et al., 2013,

Assessment of Juvenile Pigs to Serve as

Human Pediatric Surrogates for Preclinical

Formulation Pharmacokinetic Testing.

AAPS J. Pediatric Theme Issue 15(3):763-

774.

Juvenile Porcine Dose Comparison

• No statistical difference in absorption parameters

• Statistical differences AUC and elimination rates (Ke and T1/2)

Parameter 50 mg ODT 300 mg Capsule

Weight (kg)

Dose (mg/kg)

Cmax (µg/ml)

Dose Norm Cmax (g/ml)

Tmax (h)

Ka (h -1)

AUC (µg*h/ml)

Dose Norm AUC0-t (g*h/ml)

Ke (h -1)

T1/2 (h)

20.73 (0.06)

2.41 (0.01)

1.10 (0.30)

0.46 (0.12)

1.17 (0.29)

2.33 (1.13)

3.73 (1.14)

1.55 (0.48)

0.44 (0.04)

1.57 (0.14)

22.79 (0.47)

13.17 (0.28)

7.01 (2.18)

0.53 (0.17)

1.95 (0.84)

1.55 (0.80)

28.80 (8.51)

2.19 (0.67)

0.21 (0.06)

3.54 (1.03)

Juvenile-Adult Porcine Comparison

• Age-based changes in PK parameters in the porcine model are similar to those reported for humans

Parameter Juvenile Porcine Adult Porcine

Weight (kg)

Dose (mg/kg)

Cmax (µg/ml)

Dose Norm Cmax (g/ml)

Tmax (h)

Ka (h -1)

Dose Norm AUC0-t (g*h/ml)

Ke (h -1)

T1/2 (h)

V/F (L)

22.79 (0.47)

13.17 (0.28)

7.01 (2.18)

0.53 (0.17)

1.95 (0.84)

1.55 (0.80)

2.19 (0.67)

0.21 (0.06)

3.54 (1.03)

63.29 (26.70)

40.56 (1.55)

14.80 (0.54)

20.90 (11.68)

1.42 (0.78)

1.81 (0.80)

0.68 (0.38)

11.08 (7.81)

0.18 (0.04)

3.93 (0.74)

31.92 (24.71)

Mini-Tablet Platform Formulation

• Ability to incorporate BCS Class I and III

– Less effect of formulation

– Likely more beneficial for testing of medications already on the market

• Easy translation to market formulation

– Pediatric compliance

– Flexible dosing

– Protected from degradation of vehicle or stomach

– Can make ODTs

Mini-Tablet Platform Formulation

• Minimal excipients – Single filler, disintegrant, lubricant with functional coatings

• Same or similar manufacturing conditions – Size is constant, number can fluctuate

• Fractional factorial DOE approach – Many process and formulation variables

49 In cm.

Pharmaceutical Film Considerations Advantages

• Acceptable for patients with dysphagia

• Ease and accuracy of dosing

• Increased stability compared to solutions/suspensions

• Faster onset of action

• Life cycle management

Disadvantages

• Difficult to manufacture

• Moisture sensitive

• Limited dosing capacity

• Increased packaging costs

http://www.zuplenz.com/zuplenz_about-

zuplenz.php

Conclusions and Future Directions • Juvenile porcine model appears to be fairly

predictive for Rifampin pediatric PK.

• Other studies demonstrated similar porcine- human PK relationships with Itraconazole, Kaletra, and other drugs.

• Complete ongoing FDA funded studies on the effects of taste masking and controlled release on PK in the juvenile porcine model

• Develop more fascile, flexible dosage forms that enable age-appropriate dosing.

Pediatric Pharmacology – Challenges Remain

• Age based dosage form selection

• Need for descriptive pharmacology (especially for new drugs) in pediatric patients – Children are not “miniature adults”

• Dosing based on scaling needs to better incorporate age based ontogenic changes.

– Animal models need to be refined for prediction.

– Enable clinical studies in children by tackling some of the ethical and financial hurdles.

– Better means of drug administration are needed.

Adapted from :Dr. M. E. Blair Holbein, Clinical Pharmacologist, Presbyterian Hospital

of Dallas: “Age and Pharmacokinetics: Pediatric and Geriatric Considerations”

Acknowledgements • Dr. Wyatt Roth

• Mrs. Candice Kissinger

• Dr. Rachael Vreeman

• Dr. Bruce Cooper

• Dr. Peter Kissinger

• Dr. Laurie Jaeger

• Dr. Chris Kulczar

• Mrs. Robyn McCain

• Dr. Carmen Popescu

• Dr. Rodolfo Pinal

• Dr. Wanqing Liu

• Dr. Alan Qi

Funding and Research Support •Dane O. Kildsig Center for Pharmaceutical Processing Research

•Indiana Clinical and Translational Sciences Institute

•Food and Drug Administration-Current and Future studies.

•Department of Industrial and Physical Pharmacy

•Ronald W. Dollens Graduate Scholarship in Life Sciences

•Lilly Endowment Graduate Fellowship

•NICHD-BPCA support for Pediatric Research

Pediatric Drug Development Initiatives • The “Therapeutic Orphan” label was first used by Dr. Harry

Shirkey in 1962 to describe pediatric patients.

• The 1962 Kefauver-Harris Drug Amendments were drafted to address pediatric drug development by requiring efficacy and safety demonstration for FDA approval and marketing.

• Recently legislative incentives and mandates promote pediatric formulation development for product release.

• These incentives/mandates have led to an increased need for pediatric clinical testing and and have lead to label changes for at least 115 meds

Pediatric pharmacology - Approved drugs • Children are “therapeutic orphans” • Only 20-30% of approved drugs have pediatric labeling • FDA has encouraged pediatric studies

– Financial incentive to conduct studies • Orphan and off-patent drugs - no incentive to do studies

– Increased studies resulted in new labeling for 40 drugs. – For approval of selective number of new drugs pediatric

studies have been required.

• Resources – Center for Drug Evaluation and Research at FDA -

www.fda.gov/cder/pediatric/ – Pediatric Drug Labeling: Improving the Safety and Efficacy of

Pediatric Therapies. JAMA. 2003;290:905-911.

Dr. M. E. Blair Holbein, Clinical Pharmacologist, Presbyterian Hospital of Dallas: “Age and Pharmacokinetics: Pediatric and Geriatric Considerations”

http://www.fda.gov/cder/pediatric/

Tonicity • Osmolarity is the number of osmoles of a solute present in

1 L of solution, and is influenced by charge.

• Osmolality accounts for mass density of the solution, the media density may change from polymers

• Tonicity is defined by the osmolality in the extracellular compartment in comparison to the osmolality in the intracellular cytoplasm.

• Permeability assays are often conducted in media that is isotonic with the cytoplasm. – Hypertonic extracellular solutions can cause cell shrinkage

– Hypotonic extracellular solutions can cause cell swelling and membrane damage

• Based on my knowledge, most excipient studies revealing transporter/enzyme effects do not highlight tonicity.

• Tonicity may affect predominant route of permeation.

Hyperosmosis and Paracellular Permeability in Caco-2 Cells.

H. Inokuchi, et al. The effect of hyperosmosis on paracellular permeability in Caco-2 cell

monolayers. Biosci Biotechnol Biochem. 73:328-334 (2009).

Increasing

osmotic pressure

reduces TEER

values, increases

the paracellular

marker

permeation and

alters

permeability of

substrates.

Care needs to be

taken when

working with

higher

concentrations of

polymers in

Caco-2 cells.

Polyamidoamine (PAMAM) Polymers Anionic and

cationic PAMAMs

appear to more

dramatically

disrupt the tight

junctions in Caco-2

cells.

PAMAMs can bind

to the lipid bilayer

in in vitro Caco-2

cells.

Questions:

1) Is isotonicity

maintained in

culture

systems?

2) How would the

glycocalyx and

mucus

influence

binding-in vivo

relevance?

K.M. Kitchens, R.B. Kolhatkar, P.W. Swaan, N.D. Eddington, H. Ghandehari. Transport

of Poly(Amidoamine) Dendrimers across Caco-2 Cell Monolayers: Influence of Size,

Charge and Fluorescent Labeling. Pharm Res. 23:2818-2826 (2006).

PAMAM Dendrimer Conjugates and Pgp

• Propranolol conjugated to PAMAM dendrimers increased solubility and blocked Pgp?, increasing Caco-2 permeability

• Propranolol conjugated to lauroyl-PAMAM dendrimers also had a similar effect with reduced dendrimer cytotoxicity.

• Paracellular markers increased with dendrimers

• Conjugates proposed to be endocytosed, however Caco-2 cells have very low endocytosis.

A. D’Emanuele, R. Jevprasesphant, J. Penny, D.

Attwood. The use of a dendrimer-propranolol

prodrug to bypass efflux transporters and enhance

oral bioavailability. J Contr Rel. 95:447– 453

(2004).

Proposed Mechanisms for Surfactants

• Most believe that the mechanism is membrane disruption or fluidization to alter P-gp and other ABC transporters like BCRP. – TPGS is thought to rigidize membranes

– Cremophor EL and Tween 80 fluidize

• Off target effects can occur, e.g. drug targets or other transporters being effected (e.g. MRP2)

• Lipid membranes differ in phospholipid composition, so cell types may behave differently.

G. Cornaire, J. Woodley, et al. Impact of excipients on the absorption of P-

glycoprotein

substrates in vitro and in vivo. Int J Pharm. 278:119–131 (2004).

TransActiveTransActiveTransPassiveParaBarrier nPPPPP ,,,

...1 

Passive Paracellular Permeation • Hydrophilicity. • Molecular Size and Shape • pKa of the ionizable groups • Linear increase in permeability with increasing

concentration

• Adjuvants can open tight junctions and increase transport

Facilitative/Active Transcellular Permeation

• Affinity (Km), Capacity (Vmax/Jmax)

• Concentration dependent saturation

• Expression level (constitutive, induced).

• Function (drug-drug & drug-nutrient interactions, competitive inhibition.)

• Excipients like surfactants can limit the effects of efflux by Pgp or BCRP.

Passive Transcellular Permeation • Lipophilicity

-Hydrogen Bonding Potential -Hydrophobicity

• Molecular Size and Shape • pKa of the ionizable groups • Linear increase in permeability with increasing

concentration

• Dissolution/Solubility limited with high lipophilicity

Efflux and metabolism can affect the net absorption of

drug

G. Zografi, G. Knipp, A. Newman. J Pharm Sci. 101:1355–1377 (2012)

Outline • Introduction

– Pediatric Pharmacokinetic Challenges – Issues with Formulation

• Brief Overview of NICHD Working Groups and Initiatives – Academic Research- Needs to Address Pediatric Formulation

Challenges

• Safety testing considerations – Safety and Efficacy-moving targets – Excipient issues

• Preclinical animal models – How do we assess first in pediatric patient

• Discussion Points