Pediatric ARV Working Group Dosing Recommendations

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/m 2 ). 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 weightbased 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 ABC Age Effects 3TC Age Effects 60 ABC CL/F (ml/min/kg) 50 40 30 20 10 0 8 10 12 14 16 18 20 22 24 26 Age (y) Accepted higher dosing for children < 3 years based on PK: Nevirapine, Lamivudine, Stavudine, Abacavir, Lopinavir.

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) Drug Strength of Child Tab (mg) 5-5.9 kg 6-9.9 kg 10-13.9 kg 14-19.9 kg 20-24.9 kg Adult 25-34.9 kg AZT 60 1 1.5 2 2.5 3 300 1 AZT/3TC 60/30 1 1.5 2 2.5 3 300/150 1 AZT/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 1 ABC/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 1 3TC 30 1 1.5 2 2.5 3 150 1 d4t 6 1 1.5 2 2.5 3 30 1 d4t/3tc 6/30 1 1.5 2 2.5 3 30/150 1 d4t/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

WHO Weight Band Dosing 240 220 NVP dose (mg/m 2 ) 200 180 160 140 120 0 4 8 12 16 20 24 28 32 Weight (kg)

Predicted Exposure if WHO dosing vs FDA Figure 4. Varying NVP Tablet Strength vs FDA Dosing (Liquid) 100 Percentage of Subjects Exceeding Threshold 80 60 40 20 0 C FDA AUC > 48 Cmin > 3.0 AUC > 120

NVP MC Exposure by Age Group WHO 2007 Dosing NVP AUC (mcg*h/ml) 160 140 120 100 80 60 40 Percentiles 75th 50th 25th 5th Adult Ave 20 0 <2 yr 2-6 yr 6-12 yr >12yr Age Groups

Dose Tables (<6kg) Number of Tablets by Weight Band (Twice Daily) Drug Strength of Child Tab (mg) 3-3.9 kg 4-4.9 kg 5-5.9 kg AZT 60 1* 1* 1 AZT/3TC 60/30 1* 1* 1 AZT/3TC/NVP 60/30/50 1* 1* 1 ABC 60 0.5 0.75 1 ABC/3TC 60/30 0.5 0.75 1 ABC/AZT/3TC 60/60/30 0.5 0.75 1 3TC 30 1 1 1 d4t 6 1 1 1 d4t/3tc 6/30 1 1 1 d4t/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.

WHO Weight Band Dosing 240 NVP dose (mg/m 2 ) 220 200 180 160 140 120 0 4 8 12 16 20 24 28 32 Weight (kg) NVP NVP with ZDV 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 Number of Tablets by Weight Band (Twice Daily) Drug Strength of Child Tab (mg) 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 kg Adult Strength 25-29.9 kg 30-34.9 kg Lop/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

WHO Weight Band Dosing for LPV 450 LPV dose (mg/m 2 ) 400 350 300 250 200 0 4 8 12 16 20 24 28 32 Weight (kg) Modified W Original WT FDA Liq Do

d4t CHAPAS d4t CL/F by Age CHAPAS d4t AUC by Age 100 3.00 90 80 2.50 d4t CL/F (L/h/m2) 70 60 50 40 30 d4t AUC 2.00 1.50 1.00 20 10 0.50 0 0 2 4 6 8 10 12 14 16 18 Age (yr) 0.00 0 2 4 6 8 10 12 14 16 18 Age (yr)

d4t d4t Exposure from CHAPAS 2.00 1.80 1.60 10th AUC (mcg*hr/ml) 1.40 1.20 1.00 Adult Mean Target 1.28 25th 50th 75th 0.80 90th 0.60 0.40 6mg 7mg Dose Formulation

3TC CHAPAS 3TC AUC by Age 12 10 8 3TC AUC 6 4 2 0 0 2 4 6 8 10 12 14 16 18 Age (yr)

3TC 3TC Exposure from CHAPAS 10 9 8 10th AUC (mcg*hr/ml) 7 6 5 Adult Mean Target 4.7 25th 50th 75th 4 90th 3 2 30mg Dose Formulation