Off-Label and Unlicensed Medicines in Children: Evidence-Based Treatments

3. Off-label and unlicensed medicines in children – a population approach to evidence based treatments James C. McElnay School of Pharmacy Queen’s UniversityBelfast

4. Unlicensed and off-label drug use in paediatrics 50% in general hospitals 60% in specialist centres 90% in seriously ill neonates Approx. 10% in primary care?

5. Press coverage

6. Treatment dilemma Not desirable to treat children with medicines which have only been tested and licensed for adult use Not appropriate to withhold potentially effective treatments from children because the manufacturer has not obtained a license for their use in children

7. Adults compared with children Testing of drugs in adults involves a series of blood samples taken to measure plasma drug concentrations (large number of samples from a small number of volunteers or patients) Reluctance to subject children to repeated blood sampling (particularly in neonates) At present children’s doses often based on adult information Children are not simply small adults – differences in kinetics (ADME) and dynamics

8. The problem solved? Opportunistic drug levels measured in routine blood samples in hospitalised children who have been prescribed off-label medicines Small number of samples from large number of children – not large number of samples from small number of children Close monitoring of children to record beneficial outcomes and side-effects Specialist statistical analysis (sparse data analysis) performed to provide required information for safe and effective drug use

9. 18 16 14 12 Cp (mg/L) 10 8 6 4 2 0 0 2 4 6 8 10 12 Time (hours) Plasma concentration vs time curve

10. 18 16 14 12 Cp (mg/L) 10 8 6 4 2 0 0 2 4 6 8 10 12 Time (hours) Plasma concentration vs time curve

11. Diclofenac initial data Concentration (mg/Litre) Time

12. The team • School of Pharmacy, Queen’s • James McElnay • Paul Collier • Jeff Millership • Shirish Yakkundi • Shu Chaw • Joanne Smyth • Godwill Iheagwaram • Ahmed Hawwa • Maysa Suyah • Paul Westwood • Aileen Hamilton

13. The team • Royal Victoria Hospital Belfast • Mike Shields • Dennis Carson • Henry Halliday • Rhona Fair • Muriel Millar • Gillian Thurley • Research links • Alder Hey Hospital, Liverpool (Tony Nunn) • University of Missouri (Greg Kearns) • Keio University, Tokyo (Ken Kosaki) • Royal Hospital for Sick Children, Glasgow (Neil Morton)

14. Research process (1) Select drugs to be studied Obtain ethical approval for study Develop range of pharmacodynamic outcome measurement tools and proformas Develop drug assays for small volume samples Having obtained parental consent (+ assent of child if 10 years or over) commence collection of blood samples (outpatient clinics, day hospital, inpatients) Each time a blood sample is collected, pharmacodynamic measurements are undertaken by research nurse

15. Research process (2) Blood sample centrifuged and separated plasma frozen (transported to lab on dry ice) Plasma sample analysed (HPLC) Patient data entered into study database: - Demographic and clinical data (patient chart) - Dosing regimen and drug formulation - Time of sample from last dose - Measured drug concentration - Pharmacodynamic data (desired effects and side-effects) Data analysed using NONMEM

16. Pharmacodynamic monitoring in children Diclofenac: Pain relief scale administered at blood sampling times - CRIES (neonatal pain score) - CHEOPS (1-3 year old) - FACES (3 - 7 years) - Visual analogue scale (7 years +) Antiplatelet activity Increased bleeding post surgery

17. Faces pain rating scale Explain to the person that each face is for a person who feels happy because he has no pain or sad because he has a lot of pain. Face 0 is very happy because he doesn’t hurt at all…. Face 5 hurts as much as you can imagine, although you don’t have to be crying to feel this bad. Wong and Baker (1988)

18. Pain experienced in children receiving diclofenac

19. Pharmacodynamic monitoring in children Enalapril: Heart rate / BP Respiratory rate Liver size Side-effects - cough - raised K+ - creatinine - urea

20. Drugs of interest to the group • Indometacin (patent ductus arteriosis)* • Diclofenac (0-12 y): post-op analgesia • Enalapril (0-12y): hypertension / heart failure • Cisapride (0-12y): GORD;stress ulceration • Ranitidine (0-7y): stress ulceration* • Omeprazole (0-12 years): ICU stress ulceration • Codeine (0-1y; rectal - all ages): post-op pain • Spironolactone (0-12y): heart failure • Midazolam (oral 0-12y; all routes 0-7y): day clinic procedures • Spironolactone (neonates): chronic pulmonary dysplasia • Metronidazole (neonates): necrotising enterocolitis*

21. Exemplars of kinetic analysis • Indometacin • Ranitidine • Metronidazole

22. Indometacin

23. Indometacin 35 neonates: 1-6 doses of indometacin for patent ductus arteriosus Age: 25-34 weeks gestational age (GA) 1-77 days post natal age (PNA) Weight: 0.57 – 2.19 kg Dose: 0.1 – 0.2 mg / kg i.v. 185 plasma concentrations of indometacin Cp: 0.01 – 2.37 mg / litre Closure of ductus in 75% of infants with Cp of >0.4mg / L 24 hours post last dose

24. 2.5 2 1.5 Individual predicted indometacin concentration (mg l-1) 1 0.5 0 0 0.5 1 1.5 2 2.5 Measured indometacin concentration (mg l-1) Indometacin

25. Indometacin predictions

26. Ranitidine

27. Ranitidine 60 children Age: 1 month – 12 years Weight: 2.5 – 45 kg Dose: 0.77 – 2 mg / kg (iv) & oral /NG (0.7 – 7.6 mg / kg) 152 plasma samples Cp: 9 – 1250 ng / ml

28. Preliminary results for ranitidine Mean pharmacokinetic parameter estimates - CL 0.68 Litres / hour / kg - V 3.31 Litres / kg - ka 0.33 / hour CL and V linearly related to weight Ka and F lower than reported adult values; CL within normal adult range, V and t1/2 are larger

29. Metronidazole

30. Dried Blood Spots • Dried Blood Spots (DBS) - Guthrie Cards (quality controlled absorbent paper) • Inborn errors of metabolism • Other applications – e.g. antimalarials at bush clinics; drugs in sport • Applications in drug level determinations in paediatric patients – e.g. Oliveira et al. (2002); Millership et al. (2003)

32. DBS methodology • Blood spots from a heel prick or indwelling catheter are spotted onto a “Guthrie Card” and the spots are allowed to dry • Once dried the cards are placed in a wallet and transported to the lab for analysis • Drug concentrations in DBS determined by HPLC (with range of detection systems e.g. UV, fluorescence and MS/MS)

33. Advantages of the DBS approach • Consent may be easier since the volume of blood required is much smaller (particularly in neonates) • Purposive sampling throughout dosing interval will be facilitated if patient is not catheterised • Can use technique to collect samples at outpatient clinics and in patients’ homes (since venipuncture not required) • Transportation facilitated since drugs and metabolites more stable in dried form

34. Diclofenac (HPLC in DBS using UV detection)

35. Necrotising enterocolitis (NEC) and metronidazole • Analysis of metronidazole in DBS

36. Metronidazole in neonates • Initial pharmacokinetic study of 6 patients • Prescribed 7.5mg/kg IV metronidazole tds • Bloodspot samples taken on Guthrie cards at random times- 2 per dose interval • 44 bloodspots collected and analysed • NONMEM used to calculate population and individual CL and Vd

38. Metronidazole in neonates In the final preliminary model • Clearance • Related to corrected gestational age, vancomycin therapy and weight 0.75 • Volume of distribution • Related to frusemide therapy • Need more patients to provide a better assessment of covariate effects

39. The future

40. Future developments • Laboratory facilities upgraded to GCP standards (including LCMSMS) • New funding achieved from HPSS R&D Office and Department of Trade and Industry (KTP) (developmental work funded by Action Research) • Extend the number of centres involved in studies and become LRN within UK Medicines for Children Research Network (UKCRN) • Increasingly use of dried blood spots (DBSs) rather than plasma samples (incl. primary care) • Add a pharmacogenetics aspect to ongoing research • Children’s Mercy Hospital and Clinics, Kansas City, USA (Greg Kearns) • Keio University, Tokyo, Japan (Ken Kosaki)

41. Pharmacogenetic analyses Diclofenac (USA) Omeprazole (Japan)

42. Metabolism of diclofenac Substantial first pass effect (50%) CYP2C9 - Major Metabolite 4’-hydroxydiclofenac - Minor Metabolites 3’-hydroxydiclofenac 3’-hydroxy-4’-methoxydiclofenac CYP3A4 - 5-hydroxydiclofenac

43. CYP2C9 polymorphism CYP2C9*1 wild type, homozygous CYP2C9*2 CYP2C9*3 8-12% 3-8% Caucasian 0% 2-3% Oriental 1-4% 0.5-2% Black Conflicting reports that CYP2C9*3 is associated with decreased metabolic activity Metabolism of diclofenac dependent on genetic makeup

44. Omeprazole Metabolism - CYP2C19 5-hydroxyomeprazole Poly morphism - CYP2C19*1 (wild type) Extensive metabolisers - CYP2C19*2  CYP2C19*6 Poor metabolisers (2-5% Caucasians, 13-23% Orientals)

45. Conclusions Much more work required, however, using innovative research methodologies, and via government support to industry and research networks, the next 5-10 years will see a major increase in evidence available for the safe and effective use of medicines in children.

46. Off-label and unlicensed medicines in children – a population approach to evidence based treatments James C. McElnay School of Pharmacy Queen’s UniversityBelfast