pediatric arv working group dosing recommendationsaccepted higher dosing for children < 3 years...
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Pediatric ARV Working Group Dosing Recommendations
Overall Goals
• To develop pediatric weight band dosing for ARVs that would simplify dosing and produce therapeutic drug exposure
• Recommend dosing strengths for manufacturers for individual agents and FDCs
Guiding Principles• Attempted to avoid dosing any single
ARV component below 90% of intended delivered dose and not more than 25 % above intended dose. Better to give a bit too much than too little.
• For nevirapine, the group sought to avoid dosing below (150mg/m2).
• Each individual drug considered was assessed for a range of tablet strengths using the same tool and principles.
General Criteria
• Maximum number of tablets at any one dose should be no more than three.
• Minimum dose is one half tablet of products that are scored
• Limit the number of dosing forms for each single ARV or FDC required for prevention and treatment of HIV in adults and children.
• Harmonize dosing schedules and weight-based dose switching points for all products wherever possible – Facilitate FDC switches
Challenge• Various drug clearance and distribution
pathways have different age dependency –ideal dosing changes vary by age and drug
• Consequences – Expected to result in non approved doses.– FDCs not limited to same ratio as adult
formulation– While aimed a achieving a target dose done with
consideration that are actually shooting for a target exposure (labeled doses are not always optimal)
– Some compromising needed
Sizing Issues and Harmonization
• Although FDA approved dosing is often weight based, CL and exposure (AUC) correlates more closely with BSA –
• True for drugs that are dosed based on weight
• Focused on most critical agent (narrow therapeutic range) and linked dosing for other agents
NRTIs with Weight Based Dosing
8 10 12 14 16 18 20 22 24 26
Age (y)
0
10
20
30
40
50
60
AB
C C
L/F
(mL/
min
/kg)
ABC Age Effects
Accepted higher dosing for children < 3 years based on PK: Nevirapine, Lamivudine, Stavudine, Abacavir, Lopinavir.
3TC Age Effects
Approach to Challenge• In FDC priority placed on achieving target
NVP doses due to correlation with Cmin (>3) and treatment success.
• FDCs dosing established first to harmonize mg doses between FDCs and non-FDC.– The doses for individual components should be
the same.• Established BSA based targets for all drugs• Quadratic BSA estimator from Weight
Weight Bands• 3-3.9kg*• 4-4.9kg*• 5-5.9 kg• 6-9.9 kg• 10-13.9kg• 14-19.9kg• 20-24.9kg
*some differences based on age
Dose Assessments
• Developed Excel Template to provide visual guidance of proposed tablet strength and dose weight bands – (Tony Nunn)
• Additional assessment performed applying recommended to existing PK data for NVP from CHAPAS, PACTG-US, IMPAACT-Thailand. (Observed * WTBND/Actual)
• Monte Carlo simulations on population model
Dose Tables - NRTIs & NVP
Number of Tablets by Weight Band (Twice Daily)
5-5.9 kg 6-9.9 kg 10-13.9 kg 14-19.9 kg 20-24.9 kg Adult 25-34.9 kgAZT 60 1 1.5 2 2.5 3 300 1
AZT/3TC 60/30 1 1.5 2 2.5 3 300/150 1AZT/3TC/NVP 60/30/50 1 1.5 2 2.5 3 300/150/200 1
ABC 60 1 1.5 2 2.5 3 300 1ABC/3TC 60/30 1 1.5 2 2.5 3 300/150 1
ABC/AZT/3TC 60/60/30 1 1.5 2 2.5 3 300/300/150 13TC 30 1 1.5 2 2.5 3 150 1d4T 6 1 1.5 2 2.5 3 30 1
d4T/3TC 6/30 1 1.5 2 2.5 3 30/150 1d4T/3TC/NVP 6/30/50 1 1.5 2 2.5 3 30/150/200 1
NVP 50 1 1.5 2 2.5 3 200 1
Drug Strength of Child Tab (mg)
WHO Weight Band Dosing
0 4 8 12 16 20 24 28 32
Weight (kg)
120
140
160
180
200
220
240
NVP
dos
e (m
g/m
2 )
Predicted Exposure if WHO dosing vs FDA
C FDA0
20
40
60
80
100
Per
cent
age
of S
ubje
cts
Exc
eedi
ng T
hres
hold
Figure 4. Varying NVP Tablet Strength vs FDA Dosing (Liquid)
AUC > 48 Cmin > 3.0 AUC > 120
NVP MC Exposure by Age Group
<2 yr 2-6 yr 6-12 yr >12yr
Age Groups
0
20
40
60
80
100
120
140
160
NV
P A
UC
(mcg
*h/m
L)WHO 2007 Dosing
75th
50th
25th
5th
Adult Ave
Percentiles
Dose Tables (<6kg)
3-3.9 kg 4-4.9 kg 5-5.9 kgAZT 60 1* 1* 1
AZT/3TC 60/30 1* 1* 1AZT/3TC/NVP 60/30/50 1* 1* 1
ABC 60 0.5 0.75 1ABC/3TC 60/30 0.5 0.75 1
ABC/AZT/3TC 60/60/30 0.5 0.75 13TC 30 1 1 1d4T 6 1 1 1
d4T/3TC 6/30 1 1 1d4T/3TC/NVP 6/30/50 1 1 1
NVP 50 1 1 1* Except in the infant < 6m of age where 3-3.9 kg 0.5/0.5 and 4-4.9 kg 1/0.5 is recommended.
Strength of Child Tab (mg)DrugNumber of Tablets by Weight Band (Twice Daily)
WHO Weight Band Dosing
0 4 8 12 16 20 24 28 32
Weight (kg)
120
140
160
180
200
220
240
NVP
dos
e (m
g/m
2 )
NVP NVP withZDV in FDC
Future Plans
• Approval of simple tables• New drugs• Population modeling for NVP, 3TC and
d4T• Evaluate each ARV and incorporate
new data
Dosing Tables – LPV/RTV
5-5.9 kg 6-6.9 kg 7-8.9 kg 9-11.9 kg 12-13.9 kg 14-16.9 kg 17-19.9 kg 20-24.9 kgAdult
Strength 25-29.9 kg 30-34.9 kgLop/Rit 100/25 1 1 1.5 1.5 2 2 2.5 3 200/50 1.5 2
Rit (boost) 25 0.75 1 1 1.5 1.5 2 2 2.5 100 0.75 1
DrugStrength of
Child Tab (mg)
Number of Tablets by Weight Band (Twice Daily)
WHO Weight Band Dosing for LPV
0 4 8 12 16 20 24 28 32
Weight (kg)
200
250
300
350
400
450
LPV
dose
(mg/
m2 )
Modified W Original WT FDA Liq Do
d4T
0 2 4 6 8 10 12 14 16 18
Age (yr)
0
10
20
30
40
50
60
70
80
90
100
d4T
CL/
F (L
/h/m
2)
CHAPAS d4T CL/F by Age
0 2 4 6 8 10 12 14 16 18
Age (yr)
0.00
0.50
1.00
1.50
2.00
2.50
3.00
d4T
AU
C
CHAPAS d4T AUC by Age
d4T
6mg 7mgDose Formulation
0.40
0.60
0.80
1.00
1.20
1.40
1.60
1.80
2.00A
UC
(mcg
*hr/m
L)
d4T Exposure from CHAPAS
10th
25th
50th
75th
90th
Adult Mean Target 1.28
3TC
0 2 4 6 8 10 12 14 16 18
Age (yr)
0
2
4
6
8
10
12
3TC
AU
C
CHAPAS 3TC AUC by Age
3TC
30mgDose Formulation
2
3
4
5
6
7
8
9
10A
UC
(mcg
*hr/m
L)
3TC Exposure from CHAPAS
10th
25th
50th
75th
90th
Adult Mean Target 4.7