Development of ARV FDC for Pediatric use Alan

Development of ARV FDC for Pediatric use Alan Parr, Pharm. D. , Ph. D. Glaxo. Smith. Kline Research Triangle Park, NC WHO Meeting 03 NOV 2004 E: //presentations/WHO 110304 a

Presentation Outline • • • Introduction Physical/Chemical considerations Formulation consideration Packaging considerations Conclusions WHO Meeting 03 NOV 2004 E: //presentations/WHO 110304 a 2

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 WHO Meeting 03 NOV 2004 E: //presentations/WHO 110304 a 3

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 WHO Meeting 03 NOV 2004 E: //presentations/WHO 110304 a 4

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 WHO Meeting 03 NOV 2004 E: //presentations/WHO 110304 a 5

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 WHO Meeting 03 NOV 2004 E: //presentations/WHO 110304 a 6

Formulation consideration for Pediatric formulations (Physical basis) • • • Loss of taste (e. g. , sweetness and flavor) p. H of the product Viscosity of the product Change of color of the product Mouth feel WHO Meeting 03 NOV 2004 E: //presentations/WHO 110304 a 7

Packaging considerations for Pediatric formulations • Compatibility of packaging components with: – – The drug substance The preservatives The flavors and sweeteners The p. H and buffering system • Absorption or adsorption of drug and inactive ingredients • Amount and type of leachables • Headspace in the container WHO Meeting 03 NOV 2004 E: //presentations/WHO 110304 a 8

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 WHO Meeting 03 NOV 2004 E: //presentations/WHO 110304 a 9

Back-up Slides WHO Meeting 03 NOV 2004 E: //presentations/WHO 110304 a 10

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 WHO Meeting 03 NOV 2004 E: //presentations/WHO 110304 a 11

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/m 2 WHO Meeting 03 NOV 2004 E: //presentations/WHO 110304 a 12