paediatric antiretroviral pk david back university of liverpool, uk
TRANSCRIPT
Paediatric Antiretroviral PK Paediatric Antiretroviral PK
David BackUniversity of Liverpool, UK
Slide #2Pediatric Developmental Pharmacology
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)
Slide #5Impact 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
Slide #6
Drug
ME3012.PPT
10
1
Time
Con
cent
ratio
n
Time
10
1C
once
ntra
tion
Drug
GCCCCACCTC
GCCCCGCCTC
A
B
P 450
P450
mutation
wild type
Mechanism of Genetic Variability in Drug ResponseSame dose but different plasma concentrations
AUC 1
AUC 20
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 #7
Slide #8Patient 6: 40 yrs cauc man primary infection
10
100
1000
10000
0 100 200 300 400 500 600
Time after stopping EFV (h)
EF
V c
on
c n
g/m
l (l
og
sca
le)
10
100
1000
10000
100000
vira
l lo
ad c
op
ies/
ml l
og
sca
le
T1/2 50.7 h
CBV
1 w k 2 w k 3 w k
Resistance WT at wk 6
S. Taylor et al. 11th CROI Abs 131
Slide #9Patient 9: 32 yrs African woman Toxicity
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10000
0 100 200 300 400 500 600
Time after stopping EFV (h)
efv
con
c n
g/m
l( (
log
sca
le)
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100
1000
10000
100000
Vir
al l
oad
co
pie
s/m
l (l
og
sca
le)
CBV + NVP 10 days
T1/2 228.6 h
1 wk 2 wk 3 wk
S. Taylor et al. 11th CROI Abs 131
Slide #10Note: Difference between plasma and intracellular half life
Time (hours)
0 5 10 15 20 251
10
100
1000
10000
IntracellularCarbovir-TPt1/2 20.64h
Plasma Abacavirt1/2 2.59 h
Plasma Abacavir, ng/mL
Intracellular CBV-TP, fmol/million cell
Piliero P, et al. 43rd ICAAC 2003, Abstr. A-1797
Slide #11
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
NRTI (intracellular) and NNRTI half lives
Slide #12
Balancing drugs with different half lives
0 24 483612
Time (hours)
Dru
g c
on
cen
trat
ion
Zone of potential replication
IC90
IC50
Last Dose
Day 1 Day 2
MONOTHERAPY
S. Taylor et al. 11th CROI Abs 131
Slide #13
3TC Clearance in Children
Sokol E, et al. AAC 2000, 44:590-97Sokol E, et al. AAC 2000, 44:590-97
Slide #14
NVP Concentrations in Children by Age
< 2 years 2-8 years > 8 years0
2500
5000
7500
10000
12500
15000
17500
20000
22500N
VP
Co
nce
ntr
atio
n (
ng
/ml)
Slide #15Paediatric Nevirapine Concentrations(twice daily regimens)
10
100
1000
10000
100000
0 4 8 12 16 20 24
Time post dose (h)
Pla
sma
Nev
irap
ine
(ng
/ml)
3400 ng/ml
26.0% (20/77) below target
Slide #16Paediatric Nevirapine Concentrations(twice daily regimens)
10
100
1000
10000
100000
0 4 8 12 16 20 24
Time post dose (h)
Pla
sma
Nev
irap
ine
(ng
/ml)
8000 ng/ml
23.4% (18/77) 23.4% (18/77) above targetabove target
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 #18Nelfinavir Troughs with TID and BID Dosing
* Gatti G, et al. Clin Infect Dis, 2003;36:1476-82.* 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).
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, 2004Viracept Package Insert, March 29, 2004
Slide #20
LPV Concentrations in Children by Age
< 2 years 2-8 years > 8 years0
10000
20000
30000
40000
50000
LP
V C
on
cen
trat
ion
(n
g/m
l)
Slide #21Lopinavir/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;22:216-23.
Slide #22Reduced Lopinavir Plasma Concentrations in Pregnancy
Stek et al. Abstract LBOrB08.
0123456789
10
0 1 2 3 4 5 6 7 8 9 10 11 12Time Post Dose (hours)
Med
ian
(±
SE
) L
op
inav
ir (
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 IC50 for LPV
Slide #23Key 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 #24
Slide #25
Nelfinavir Pharmacokinetics in Children vs. Adults