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