1. Paediatric Antiretroviral PK University of Liverpool, UK
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)
High within and between individual variability and PK
Age a very important facros – high doses required in infants in particular for most drugs esp PI and NNRTIs
Bioequivalence varies by formulationi – eg efv need to give higher dose of lquid

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: Jorquera F et al Nutrition 1996; 12:

6. Same dose but different plasma concentrations
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
GCCCCACCTC
Concentration
P450 1
mutation
Time
ME3012.PPT

7. A Common CYP2B6 Variant Associated with EFV PK and CNS Side Effects
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. Left Hand Y Axis EFV concentration on a log scale
Resistance WT at wk 6
Left Hand Y Axis EFV concentration on a log scale
Orientation slide, blue points EFV conc
Second right hand y axis plasma viral load log scale represented by green tiangles
viral load over time
Vertical arrows 1,2 and 3 weeks
Lower Horizontal red lines protein corrected EC95 for EFV 92
Upper red line lower end of therapeutic range
Horizontal bar drugs patient continued to take
0 patient stopped EFV
S. Taylor et al. 11th CROI Abs 131

9. Finally T1/2 > 200 hours although LFTs not deranged
This is the 3rd African woman with therapeutic levels at week 2 +/- week 3
Intersetingly she also developed toxicty with NVP data on nvp levels to be added
Viral load and NVP data needs adding
S. Taylor et al. 11th CROI Abs 131

10. Note: Difference between plasma and intracellular half life
Time (hours) 5 10 15 20 25 1
100
1000
10000
Intracellular
Carbovir-TP
t1/ h
Plasma Abacavir
t1/ h
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 h
d4TTP 7 h EFV 35 h
3TCTP 16 h
CBVTP 20 h
ddATP 25 h
TDFDP 60 h
FTCTP 39 h

12. Balancing drugs with different half lives
Last Dose
Day 1
Day 2
MONOTHERAPY
Drug concentration
Key Points
Considerations of forgiveness are critical for ensuring “coverage” if a dose is missed
IC90
Zone of potential replication
IC50 12 24 36 48
Time (hours)
S. Taylor et al. 11th CROI Abs 131

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

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

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

16. Paediatric Nevirapine Concentrations (twice daily regimens)
23.4% (18/77) above target
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 mg/kg q8h or 50 mg/kg q12 h with food.
Trough values were:
1.55 mg/L ( 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:

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
< 2 years
2-8 years
> 8 years

21. Lopinavir/r (300/75 mg/m2 BID) Pharmacokinetics in Children
All Subjects (N=27)
No NVP (5 ≤ 2 yrs)
With NVP (2 ≤ 2 yrs)
Tmax (h)
4 ± 2.1
4 ± 2
4 ± 2.3
Cmax (mg/L)
11.4 ± 4.9
12.5 ± 5.8
10.0 ± 3.3
Cmin (mg/L)
5.2 ± 4.3
6.53 ± 4.6
3.6 ± 3.5
Cpre (mg/L)
6.9 ± 4.1
7.9 ± 4.5
5.6 ± 3.3
AUC12 (mg•h/L)
102.8 ± 50.7
116.4 ± 57.1
85.8 ± 36.9
T1/2 (h)
6.1 ± 5.2
7.6 ± 5.1
4.7 ± 4.5
X. Saez-Llorens et al. Ped Infect Dis J 2003;22:

22. Reduced Lopinavir Plasma Concentrations in Pregnancy10 9 8 7 6
Median (± SE) Lopinavir (μg/mL) 5 4 3 2
Protein-adjusted IC50 for LPV 1
One of the more important issues that has emerged in pharmacology relates to the use of antiretroviral drugs in pregnancy. Previous data had suggested that pregnancy—particularly in the third trimester—might be associated with lower protease inhibitor exposures, although not necessarily to a clinically significant degree. The Pediatric ACTG examined boosted lopinavir in a cohort of patients between 30 and 36 weeks of pregnancy, and also examined the same patients 6 to 12 weeks after delivery. The study was designed to compare the drug exposures in these women to the expected levels derived from nonpregnant women. As shown in the slide, during pregnancy (shown in orange) the concentrations of lopinavir were markedly lower than one would expect in a nonpregnant woman. Postpartum, the lopinavir concentrations rose, but not to the levels that one would anticipate in nonpregnant women. The implications of these findings are unclear. The majority of women in this study maintained virologic suppression while receiving lopinavir/ritonavir with 2 NRTIs. However, the reduction in plasma concentrations is a concern, and has led the Pediatric ACTG to amend this study to examine higher doses of boosted lopinavir during the third trimester of pregnancy to see if one can consistently achieve acceptable drug levels. Another study at the meeting evaluated nevirapine and showed that concentrations of nevirapine were reduced in pregnancy compared with nonpregnant women, but in that study, the degree of reduction was unlikely to be clinically relevant.
For more information, please go online to: 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 ?????

25. Nelfinavir Pharmacokinetics in Children vs. Adults