Paediatric Antiretroviral PK David Back University of Liverpool, UK Pediatric Developmental Pharmacology Slide #2
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Transcript Paediatric Antiretroviral PK David Back University of Liverpool, UK Pediatric Developmental Pharmacology Slide #2
Paediatric Antiretroviral PK
David Back
University of Liverpool, UK
Pediatric Developmental Pharmacology
Slide #2
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
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 m2 or per kg)
Ability to give with/without food (ddI, NFV)
Impact of Nutrition on PK
(Can have a profound effect)
Slide #5
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
Slide #6
Mechanism of Genetic Variability in Drug Response
Same dose but different plasma concentrations
Drug
A
GCCCCGCCTC
wild type
P 450
Concentration
10
AUC 1
1
Time
Drug
B
GCCCCACCTC
mutation
ME3012.PPT
P450
Concentration
10
AUC
20
1
Time
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.
Slide #8
Patient 6: 40 yrs cauc man primary infection
10000
100000
10000
1000
1000
T1/2 50.7 h
100
100
1 wk
2 wk
viral load copies/ml log scale
EFV conc ng/ml (log scale)
Resistance WT at wk 6
3 wk
CBV
10
0
100
200
300
400
500
10
600
Time after stopping EFV (h)
S. Taylor et al. 11th CROI Abs 131
Slide #9
Patient 9: 32 yrs African woman Toxicity
100000
efv conc ng/ml( (log scale)
T1/2 228.6 h
10000
1000
1000
100
100
1 wk
10
3 wk
2 wk
CBV + NVP 10
days
0
100
200
300
400
Time after stopping EFV (h)
S. Taylor et al. 11th CROI Abs 131
500
10
600
Viral load copies/ml (log scale)
10000
Note: Difference between plasma and Slide #10
intracellular half life
10000
Plasma Abacavir
t1/2 2.59 h
1000
Intracellular CBV-TP,
fmol/million cell
100
Intracellular
Carbovir-TP
t1/2 20.64h
Plasma Abacavir,
ng/mL
10
1
0
5
10
15
Time (hours)
20
25
Piliero P, et al. 43rd ICAAC 2003, Abstr. A-1797
Slide #11
NRTI (intracellular) and NNRTI half lives
ZDVTP
7h
NVP
25-30 h
d4TTP
7h
EFV
35 h
3TCTP
16 h
CBVTP
20 h
ddATP
25 h
TDFDP
60 h
FTCTP
39 h
Slide #12
Balancing drugs with different half lives
Last Dose
Day 1
Drug concentration
Day 2
MONOTHERAPY
IC90
Zone of potential replication
IC50
0
12
24
Time (hours)
36
48
S. Taylor et al. 11th CROI Abs 131
Slide #13
3TC Clearance in Children
Sokol E, et al. AAC 2000, 44:590-97
Slide #14
NVP Concentrations in Children by Age
22500
20000
NVP Concentration (ng/ml)
17500
15000
12500
10000
7500
5000
2500
0
< 2 years
2-8 years
> 8 years
Slide #15
Paediatric Nevirapine Concentrations
(twice daily regimens)
Plasma Nevirapine (ng/ml)
100000
10000
3400 ng/ml
1000
26.0% (20/77)
below target
100
10
0
4
8
12
16
Time post dose (h)
20
24
Slide #16
Paediatric Nevirapine Concentrations
(twice daily regimens)
Plasma Nevirapine (ng/ml)
100000
23.4% (18/77)
above target
10000
8000 ng/ml
1000
100
10
0
4
8
12
16
Time post dose (h)
20
24
Slide #17
Nelfinavir PK in Children
Age
<2 y
(n=7)
>2 y
(n=17)
Cmax (µg/ml)
2.2
3.6
Cmin (µg/ml)
0.43
0.69
AUC (µg/ml.h)
11.2
15.0
Children <2 y at risk of subtherapeutic NFV levels
Bergshoeff et al, 2002
Slide #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.
* Gatti G, et al. Clin Infect Dis, 2003;36:1476-82.
1/11 (9%) in TID group
vs. 7/14 (50%) in BID
group had values < 1
mg/L (p=0.042).
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
Slide #20
LPV Concentrations in Children by Age
50000
LPV Concentration (ng/ml)
40000
30000
20000
10000
0
< 2 years
2-8 years
> 8 years
mg/m2
Lopinavir/r (300/75
BID)
Pharmacokinetics in Children
All Subjects
(N=27)
No NVP
(5 ≤ 2 yrs)
With NVP
(2 ≤ 2 yrs)
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
Tmax (h)
AUC12
(mg•h/L)
T1/2 (h)
102.8 ± 50.7 116.4 ± 57.1
6.1 ± 5.2
7.6 ± 5.1
X. Saez-Llorens et al. Ped Infect Dis J 2003;22:216-23.
Slide #21
85.8 ± 36.9
4.7 ± 4.5
Slide #22
Median (± SE) Lopinavir
(μg/mL)
Reduced Lopinavir Plasma
Concentrations in Pregnancy
10
9
8
7
6
5
4
3
2
1
0
Protein-adjusted
IC50 for LPV
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.
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 ?????
Slide #23
Slide #24
Slide #25
Nelfinavir Pharmacokinetics in Children
vs. Adults