Development of ARV FDC for Pediatric use

1. Development of ARV FDC for Pediatric use Alan Parr, Pharm.D., Ph.D. GlaxoSmithKline Research Triangle Park, NC

2. Presentation Outline • Introduction • Physical/Chemical considerations • Formulation consideration • Packaging considerations • Conclusions E://presentations/WHO110304a

3. Introduction • Development of formulations for pediatric population is very challenging for the following reasons: • Requires a wide range of doses (not achievable using solid dosage forms) • Limited patient populations to evaluate efficacy of compound/product • Difficulty in doing studies in this patient population • Potential biological differences (e.g., metabolic differences) between pediatric patients and adult patients E://presentations/WHO110304a

4. Overall Formulation considerations for Pediatric Formulations • Need to be aware of taste preference which differ significantly around the world • Need to be aware of sweetness preferences which differ from around the world • Need to be aware of the limit of inactive ingredients administered per the dosing regimen E://presentations/WHO110304a

5. Physical/Chemical considerations for Pediatric formulations • Solubility of drug substance • Stability of the drug substance in solution • Compatibility of drug substance with excipients (e.g., flavors, sweeteners, preservatives) • Stability of multiple drug substances in a given formulation E://presentations/WHO110304a

6. Formulation consideration for Pediatric formulations (Chemical basis) • Chemical stability of the drug substance • Chemical stability of the preservative system • Chemical stability of flavor and sweetening system • Impact of the buffering system on drug substance stability E://presentations/WHO110304a

7. Formulation consideration for Pediatric formulations (Physical basis) • Loss of taste (e.g., sweetness and flavor) • pH of the product • Viscosity of the product • Change of color of the product • Mouth feel E://presentations/WHO110304a

8. Packaging considerations for Pediatric formulations • Compatibility of packaging components with: • The drug substance • The preservatives • The flavors and sweeteners • The pH and buffering system • Absorption or adsorption of drug and inactive ingredients • Amount and type of leachables • Headspace in the container E://presentations/WHO110304a

9. Conclusions • Development of a pediatric formulation is very challenging and complex • It requires a balance between a number of different variables to ensure a consistent product with appropriate stability, preservative system, and acceptable taste E://presentations/WHO110304a

10. Back-up Slides E://presentations/WHO110304a

11. Available Formulations that could be used in Pediatric Patients • Abacavir (Ziagen®) Pediatric Oral Solution (GSK) • Didanosine (Videx®) Pediatric Powder (BMS) • Lamivudine (Epivir®) Oral Solution (GSK) • Stavudine (Zerit®) Oral Solution (BMS) • Zidovudine (Retrovir®) Syrup (GSK) • Nevirapine (Viramune®) Suspension (BI) • Amprenavir (Agenerase®) Pediatric Oral Solution (GSK) • Fosamprenavir (Lexiva®) Suspension* (GSK) • Lopinavir/Ritonavir (Kaletra®) Pediatric Oral Solution (Abbott) • Nelfinavir (Viracept®) Powder for Oral Suspension (Agouron/Pfizer) • Ritonavir (Norvir®) Oral Solution (Abbott) * Under development E://presentations/WHO110304a

12. Formulation Options for Pediatric patients • Oral solutions • Oral suspensions • Sachets • Note: need to re-constitute with a specific volume of liquid to dose on a mg/kg or mg/m2 E://presentations/WHO110304a