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Paediatric Antiretroviral PK

Paediatric Antiretroviral PK. David Back University of Liverpool, UK. Pediatric Developmental Pharmacology. PK in Paediatric Populations. Developmental changes can significantly affect ADME Majority of PK data in paediatric patients obtained in older children

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Paediatric Antiretroviral PK

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  1. Paediatric Antiretroviral PK David Back University of Liverpool, UK

  2. Pediatric Developmental Pharmacology

  3. PK in Paediatric Populations • Developmental changes can significantly affect ADME • Majority of PK data in paediatric patients obtained in older children • Substantial intra and inter patient variability

  4. Issues for dosing of ART in children • Large variability in pharmacokinetic (PK) parameters • age (and PK data by age-group often sparse) • effect of nutritional status • ethnicity • Methods of dose calculation (per m2 or per kg) • Ability to give with/without food (ddI, NFV)

  5. Impact of Nutrition on PK(Can have a profound effect) • Diminished protein status in malnourished children results in lower plasma proteins Increasing concentrations of ‘free’ drug • Severely malnourished children have decreased CYP450 metabolism Reduced hepatic clearance • Severely malnourished children have decreased GFR Reduced renal clearance Murry et al Int J Cancer 1998; 11: 48-51 Jorquera F et al Nutrition 1996; 12: 442-447

  6. Mechanism of Genetic Variability in Drug Response Same dose but different plasma concentrations Drug A AUC 1 10 Concentration GCCCCGCCTC P 450 1 wild type Time Drug B AUC 20 10 Concentration GCCCCACCTC 1 P450 mutation Time ME3012.PPT

  7. Slide #7 A Common CYP2B6 Variant Associated with EFV PK and CNS Side Effects • A CYP2B6 polymorphism. • More common in African-Americans than European-Americans. • Associated with higher EFV levels, and increased CNS AE’s. • Additional studies needed.

  8. Resistance WT at wk 6 S. Taylor et al. 11th CROI Abs 131

  9. S. Taylor et al. 11th CROI Abs 131

  10. 10000 Plasma Abacavir 1000 t1/2 2.59 h Intracellular Carbovir-TP t1/2 20.64h 100 10 1 0 5 10 15 20 25 Time (hours) Note: Difference between plasma and intracellular half life Intracellular CBV-TP, fmol/million cell Plasma Abacavir, ng/mL Piliero P, et al. 43rd ICAAC 2003, Abstr. A-1797

  11. NRTI (intracellular) and NNRTI half lives ZDVTP 7 h NVP 25-30 h d4TTP 7 h EFV 35 h 3TCTP 16 h CBVTP 20 h ddATP 25 h TDFDP 60 h FTCTP 39 h

  12. MONOTHERAPY Balancing drugs with different half lives Last Dose Day 1 Day 2 Drug concentration IC90 Zone of potential replication IC50 12 0 24 36 48 S. Taylor et al. 11th CROI Abs 131 Time (hours)

  13. 3TC Clearance in Children Sokol E, et al. AAC 2000, 44:590-97

  14. 22500 20000 17500 15000 12500 NVP Concentration (ng/ml) 10000 7500 5000 2500 0 < 2 years 2-8 years > 8 years NVP Concentrations in Children by Age

  15. 26.0% (20/77) below target Paediatric Nevirapine Concentrations(twice daily regimens) 3400 ng/ml

  16. 23.4% (18/77) above target Paediatric Nevirapine Concentrations(twice daily regimens) 8000 ng/ml

  17. Nelfinavir PK in Children Children <2 y at risk of subtherapeutic NFV levels Bergshoeff et al, 2002

  18. Nelfinavir Troughs with TID and BID Dosing • NFV PK were evaluated in 35 children (8.1 ± 3.5 yrs) receiving 20-30 mg/kg q8h or 50 mg/kg q12 h with food. • Trough values were: • 1.55 mg/L (0.13-5.22 mg/L) for TID dosing • 1.11 mg/L (nd-6.08 mg/L) with BID. • 1/11 (9%) in TID group vs. 7/14 (50%) in BID group had values < 1 mg/L (p=0.042). * Gatti G, et al. Clin Infect Dis, 2003;36:1476-82.

  19. Nelfinavir Use in Children • The proportion of children 2-13 years of age achieving an HIV RNA level < 400 cpm through 48 wks ranged from 26-42%. • Response rates in children < 2 years of age appeared to be poorer than those ≥ 2 years. • Highly variable exposure remains a significant problem in the use of nelfinavir in pediatric patients. Viracept Package Insert, March 29, 2004

  20. LPV Concentrations in Children by Age 50000 40000 30000 LPV Concentration (ng/ml) 20000 10000 0 < 2 years 2-8 years > 8 years

  21. Lopinavir/r (300/75 mg/m2 BID) Pharmacokinetics in Children X. Saez-Llorens et al. Ped Infect Dis J 2003;22:216-23.

  22. Reduced Lopinavir Plasma Concentrations in Pregnancy 10 9 8 7 6 Median (± SE) Lopinavir (μg/mL) 5 4 3 2 Protein-adjusted IC50 for LPV 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Time Post Dose (hours) Pregnancy (n = 17) Postpartum (n = 8) Nonpregnant historical controls • Note also abstract 4644 – NVP plasma exposure reduced in pregnant vs nonpregnant women Stek et al. Abstract LBOrB08.

  23. Key Points • Incomplete knowledge of pharmacology • Marked Inter individual variability • Nutritional status & PK • Age group & PK • Ethnicity & PK • Dosing according to weight or BSA seems arbitary. • Equivalence – Pharmaceutic & Bioequivalence • Bd vs qd • The future of PIs in children • 1st line to ?????

  24. Nelfinavir Pharmacokinetics in Children vs. Adults

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