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