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Paediatric Antiretroviral PK David Back University of Liverpool, UK.

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Presentation on theme: "Paediatric Antiretroviral PK David Back University of Liverpool, UK."— Presentation transcript:

1 Paediatric Antiretroviral PK David Back University of Liverpool, UK

2 Slide #2 Pediatric Developmental Pharmacology

3 Slide #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 Slide #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 m 2 or per kg) Ability to give with/without food (ddI, NFV)

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

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 AEs. Additional studies needed. Slide #7

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

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

10 Slide #10 Note: Difference between plasma and intracellular half life Plasma Abacavir, ng/mL Intracellular CBV-TP, fmol/million cell Piliero P, et al. 43 rd ICAAC 2003, Abstr. A-1797

11 Slide #11 ZDVTP7 hNVP25-30 h d4TTP7 hEFV35 h 3TCTP16 h CBVTP20 h ddATP25 h TDFDP60 h FTCTP39 h NRTI (intracellular) and NNRTI half lives

12 Slide #12 Balancing drugs with different half lives 0244836 12 Time (hours) Drug concentration Zone of potential replication IC 90 IC 50 Last Dose Day 1 Day 2 MONOTHERAPY S. Taylor et al. 11th CROI Abs 131

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

14 Slide #14 NVP Concentrations in Children by Age

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

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

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

18 Slide #18 Nelfinavir Troughs with TID and BID Dosing * Gatti G, et al. Clin Infect Dis, 2003;36:1476-82. 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).

19 Slide #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 Slide #20 LPV Concentrations in Children by Age < 2 years2-8 years> 8 years 0 10000 20000 30000 40000 50000 LPV Concentration (ng/ml)

21 Slide #21 Lopinavir/r (300/75 mg/m 2 BID) Pharmacokinetics in Children All Subjects (N=27) No NVP (5 2 yrs) With NVP (2 2 yrs) T max (h) 4 ± 2.14 ± 24 ± 2.3 C max (mg/L) 11.4 ± 4.912.5 ± 5.810.0 ± 3.3 C min (mg/L) 5.2 ± 4.36.53 ± 4.63.6 ± 3.5 C pre (mg/L) 6.9 ± 4.17.9 ± 4.55.6 ± 3.3 AUC 12 (mgh/L) 102.8 ± 50.7116.4 ± 57.185.8 ± 36.9 T 1 / 2 (h) 6.1 ± 5.27.6 ± 5.14.7 ± 4.5 X. Saez-Llorens et al. Ped Infect Dis J 2003;22:216-23.

22 Slide #22 Reduced Lopinavir Plasma Concentrations in Pregnancy Stek et al. Abstract LBOrB08. 0 1 2 3 4 5 6 7 8 9 10 0123456789 1112 Time Post Dose (hours) Median (± SE) Lopinavir (μg/mL) 13 Pregnancy (n = 17)Postpartum (n = 8) Nonpregnant historical controls Note also abstract 4644 – NVP plasma exposure reduced in pregnant vs nonpregnant women Protein-adjusted IC 50 for LPV

23 Slide #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 1 st line to ?????

24 Slide #24

25 Slide #25 Nelfinavir Pharmacokinetics in Children vs. Adults


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