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1、Development of ARV FDC for Pediatric useAlan Parr, Pharm.D., Ph.D. GlaxoSmithKline Research Triangle Park, NC1E:/presentations/WHO110304aPresentation Outline Introduction Physical/Chemical considerations Formulation consideration Packaging considerations Conclusions2E:/presentations/WHO110304aIntrod
2、uction 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 populat
3、ion Potential biological differences (e.g., metabolic differences) between pediatric patients and adult patients3E:/presentations/WHO110304aOverall Formulation considerations for Pediatric Formulations Need to be aware of taste preference which differ significantly around the world Need to be aware
4、of sweetness preferences which differ from around the world Need to be aware of the limit of inactive ingredients administered per the dosing regimen4E:/presentations/WHO110304aPhysical/Chemical considerations for Pediatric formulations Solubility of drug substance Stability of the drug substance in
5、 solution Compatibility of drug substance with excipients (e.g., flavors, sweeteners, preservatives) Stability of multiple drug substances in a given formulation5E:/presentations/WHO110304aFormulation consideration for Pediatric formulations (Chemical basis) Chemical stability of the drug substance
6、Chemical stability of the preservative system Chemical stability of flavor and sweetening system Impact of the buffering system on drug substance stability6E:/presentations/WHO110304aFormulation consideration for Pediatric formulations (Physical basis) Loss of taste (e.g., sweetness and flavor) pH o
7、f the product Viscosity of the product Change of color of the product Mouth feel7E:/presentations/WHO110304aPackaging considerations for Pediatric formulations Compatibility of packaging components with: The drug substance The preservatives The flavors and sweeteners The pH and buffering system Abso
8、rption or adsorption of drug and inactive ingredients Amount and type of leachables Headspace in the container8E:/presentations/WHO110304aConclusions Development of a pediatric formulation is very challenging and complex It requires a balance between a number of different variables to ensure a consi
9、stent product with appropriate stability, preservative system, and acceptable taste 9E:/presentations/WHO110304aBack-up Slides10E:/presentations/WHO110304aAvailable Formulations that could be used in Pediatric PatientsAbacavir (Ziagen) Pediatric Oral Solution (GSK) Didanosine (Videx) Pediatric Powde
10、r (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 Sol
11、ution (Abbott) Nelfinavir (Viracept) Powder for Oral Suspension (Agouron/Pfizer) Ritonavir (Norvir) Oral Solution (Abbott)* Under development11E:/presentations/WHO110304aFormulation Options forPediatric 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/m212E:/presentations/WHO110304a
