John N. van den Anker, MD, PhD

1. The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects John N. van den Anker, MD, PhD Evan and Cindy Jones Chair in Pediatric Clinical Pharmacology Professor of Pediatrics, Pharmacology & Physiology, GWU, Washington, DC Chief, Division of Pediatric Clinical Pharmacology, Children’s National, DC Adjunct Professor of Medicine, Pediatrics, Pharmacology & Physiology Johns Hopkins University, Baltimore, MD

2. “ 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

3. Critical Role of Drug Disposition in Pediatric Therapeutics Age-dependent PD data in similar disease processes • 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 Safety/tolerance data with therapeutic use Rational Therapeutics Acceptable formulations Age-dependent PK data to guide dose/exposure

4. Absorption Oral Sublingual Intramuscular Percutaneous Rectal

5. Factors Influencing Oral Drug Absorption Splanchnic blood flow Biliary function Gastric pH Intestinal drug metabolism Gastric emptying time Physicochemical & Mechanical Intestinal surface area Intestinal motility Microbial colonization Intestinal drug transport

6. 250 200 % Adult Activity 150 100 50 0 birth 1 wk 2 wk Gastrin 3 wk 1 mos Pepsin 3 mos 5-10 yr HCl production adult Developmental Alterations in Gastric pH Agunod et al. Amer J Digest Dis 1969;14:400 Mozam et al. Ann Surg 1984;199:389 Rodgers et al. J. Pediatr Surg 1978;13:13

7. Orally Administered Penicillin (10,000 U/lb) 3.5 Preterm neonate Fullterm neonate 3 Infants (2 wk-2 yr) 2.5 Children (2-13 yr) 2 Penicillin concentration (U/mL) 1.5 1 0.5 0 0 2 4 6 8 Time (hr) Influence of Developmental Alterations in Gastric pH Huang et al. J Pediatr 1953;42:657

8. 30 minute gastric retention 70 60 Pre-term 50 Full term 40 % of meal 30 20 10 0 4-12 hr 22-36 hr 46-60 hr Postnatal Age Developmental Alterations in Gastric Emptying Rate Gupta & Brans, Pediatrics 1978;62:26

9. 35 PCA -- Tmax (hr) 30 28-36wk (5.0 + 2.6) 36-42wk (4.3 + 3.3) 25 42-54wk (2.2 + 1.1) Adult (1.8) 20 Plasma Concentration (ng/mL) 15 10 5 0 0 5 10 15 20 25 Time (hr) Influence of Developmental Alterations in Gastric Emptying & Intestinal Transit Single-Dose Cisapride PK in Neonates and Young Infants Kearns, van den Anker, et al. Clin Pharmacol Ther 2001;69:31

10. Getting the drug in… Do you have an age appropriate pediatric formulation?

11. Developmental Alterations in Oral Drug Absorption 1st Law of Pediatric Drug Administration • Orifice rejection of drugs is the rule rather than the exception.

12. Factors Influencing Transdermal Drug Absorption • Barrier thickness • Regional blood flow • Diffusional surface area • Temperature • Hydration • Local pH • Tissue binding sites • Drug-vehicle interactions

13. Developmental Alterations in Skin thickness GA: 26 wk PNA: 1 day GA: 26 wk PNA: 16 days GA: 40 wk PNA: 1 day Rutter. Clin Perinatol 1987;14:911

14. Neonatal Case Reports Agent Resultant ADR silver sulfadiazene cardiorespiratory arrest topical steroids HPA suppression cushingoid features pentachlorophenol diaphoresis (laundry detergent) hepatomegaly acidosis death boric acid (talcum powder) Impact of Enhanced Skin Permeability on Cutaneous Absorption

15. Volume of Distribution

16. EC H2O IC H2O Protein Fat Premature Newborn 4 mo 12 mo 24 mo 36 mo Adult 0 20 40 60 80 100 Age Dependent Changes in Body Composition

17. Impact of Changes in Extracellular Fluid on Drug Distribution 3.5 3 2.5 2 (mg/L per mg/kg dose) Peak Gentamicin Concentration 1.5 1 0.5 0 0.5-5 yr 5-10 yr 10-15 yr 15-42 yr Age Siber et al. J Infect Dis 1975;132:637

18. Drug biotransformation Metabolite Phase I Phase II Drug Metabolite UGTs NATs SULTs MTs GSTs CYPs FMOs Esterases Hydrolases

19. Human Hepatic DME Ontogeny Class 1 Class 2 Class 3 ADH1A CYP2C19 ADH1B EPHX2 CYP3A5 ADH1C CYP3A7 FMO3 AOX GSTA1 GSTM FMO1 GSTA2 CYP1A2 SULT2A1 GSTP CYP2C9 UGT1A1 SULT1A1 SULT1E1 CYP2D6 UGT1A6 SULT1A3 CYP2E1 UGT2B7 CYP3A4 PON1 EPHX1 Hines, Pharmacol & Therap. 118:250-267, 2008

20. 40 SULT1E1 Class 1 30 SULT1A1 Class 2 20 DME (pmol/mg protein) CYP2C9 Class 3 10 0 PNA 0-6 mo PNA >6 mo-18 yr EGA 10-26 wks EGA >26-40 wks Human DME Ontogeny

21. Ontogeny of CYP2C19 In Vitro 30 40 30 20 20 CYP2C19 Protein (pmol/mg) 10 10 0 0 6 14 22 30 38 1 2 3 4 5 0 3 6 9 12 15 18 EGA (Weeks) PNA (Months) PNA (Years) Koukouritaki et al J Pharmacol Exp Ther 2004;308:965-974.

22. Ontogeny of CYP2C19 In Vivo Postmenstrual Age Postnatal Age r2 = 0.35 Ward et al Eur J Clin Pharmacol 2010;66:555-561

23. APAP Biotransformation in Humans APAP-G UGT1A6 UGT1A9 SULT1A1 APAP APAP-S CYP3A4 CYP1A2 CYP2E1 NAPQI Mercapturate Miller, et al. Clin. Pharmacol. Ther. 19:284-294, 1976

24. Age APAP t1/2 min (IV paracetamol) Preterm <32 wk (n=10) 290 Preterm 32-36 wk (n=10) 265 term <10 days (n=5) 210 10-365 days (n=7) 126 Impact of Developmental Alterations in Phase II Enzymes on Drug Metabolism: Acetaminophen Allegaert, et al. Arch Dis Child Fetal Neonatal Ed. 2004;89:25-28

25. 70 60 Term Preterm (<2000gm) 50 Preterm (<1500 gm) 40 GFR (ml/min/1.73m2) 30 20 10 0 1-2 d 8-9 d 15-16 d Postnatal Age Developmental Alterations in Glomerular Filtration

26. Fluconazole clearance half- life (ml/min/kg) (hr) premature 1 day 0.18 88.6 premature 7 days 0.33 67.5 premature 13 days 0.52 55.2 infants 19.5-25 < 29 wk, <14 d < 29 wk, >14 d 30-36 wk, <14 d 30-36 wk, >14 d q72hr q48hr q48hr q24hr Impact of Developmental Alterations in Renal Function on Drug Elimination Saxen, et al. Clin Pharmacol Ther1993;54:269

27. Biliary Excretion P-gp, MRP3, MRP2, sPGP Hepatic Uptake OATP2, OATP8, OATP-B, OCT1, NTCP, OAT2, OAT3 Intestinal Efflux P-gp, MRP2, MRP1, OCT1, OATP3, NTCP Brain Transport P-gp, OAT3, MRP1, MRP5, OATP1 Renal Secretion OAT1, OAT3, OCT1, OCT2, OATP, P-gp, MRP1 Ritschel WA and Kearns GL. Handbook of Basic Pharmacokinetics, 7th edition, 2009

28. Pediatric Clinical Pharmacology Facts • Children are not small adults • different pharmacokinetics • different pharmacodynamics • Approximately 70% of all marketed drugs not suitably labeled for pediatric use • In some instances, pediatric patients included in studies as an “afterthought” • The biggest issue remains determining the effective/safe dose for pediatrics

30. The In-silico Child…….

31. 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

32. 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 • Have microassays been developed & validated? • Is a sparse/minimal sampling scheme appropriate?

33. 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

35. Courtesy of Dr. Catherine Tuleu, Univ. of London, 2011

36. CONCLUSIONS TEAM WORK TEAM WORK TEAM WORK TEAM WORK TEAM WORK