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

WHO Meeting 03NOV2004 E://presentations/WHO110304aSlide 2 Presentation Outline Introduction Physical/Chemical considerations Formulation consideration Packaging considerations Conclusions

WHO Meeting 03NOV2004 E://presentations/WHO110304aSlide 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

WHO Meeting 03NOV2004 E://presentations/WHO110304aSlide 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

WHO Meeting 03NOV2004 E://presentations/WHO110304aSlide 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

WHO Meeting 03NOV2004 E://presentations/WHO110304aSlide 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

WHO Meeting 03NOV2004 E://presentations/WHO110304aSlide 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

WHO Meeting 03NOV2004 E://presentations/WHO110304aSlide 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

WHO Meeting 03NOV2004 E://presentations/WHO110304aSlide 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

WHO Meeting 03NOV2004 E://presentations/WHO110304aSlide 10 Back-up Slides

WHO Meeting 03NOV2004 E://presentations/WHO110304aSlide 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

WHO Meeting 03NOV2004 E://presentations/WHO110304aSlide 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/m 2