Developing child-appropriate formulations: what is in the research pipeline for paediatric ARVS?

1. Developing child-appropriate formulations: what is in the research pipeline for paediatric ARVS? July 17, 2011 Challenges in the Development & Procurement of Paediatric ARV Formulations Elaine Abrams

2. Challenges in Development of Pediatric Antiretroviral Formulations • HIV lasts a lifetime • Each therapeutic decision has long-term implications • ‘Pediatrics’ spans a broad spectrum, from infancy through adolescence • Evolving physical, psychological and social status • The vast majority of children with HIV are poor and live in poor countries • Limited funds for health (medications, laboratory services, health care workers, infrastructure) • Limited access to transportation, clean water • Multiple competing health threats (malnutrition, TB, malaria)

3. Long term consequences of perinatal and postnatal ARV exposure • Resistance acquired with exposure to ARVs for PMTCT

4. Physical growth and development • Periods of rapid growth • End organ maturation: renal, hepatic, bone, brain • Environmental and genetic influences

5. Dependence upon an adult caretaker for drug administration Ability to tolerate tastes and formulations varies with age and size

6. Adolescence Rapid physical growth, organ maturation Psychological maturation and individuation Cope with the legacy of lifetime ART

7. Limited pediatric ART formulary • Nevirapine + 2 NRTI - fixed dose combination pediatric tablets • Nevirapine liquid, tablets • Efavirenz tablets, capsules, solution • Liquid formulations of zidovudine, lamivudine, stavudine, abacavir • Lopinavir/ritonavir liquid, pediatric tabs

8. What’s in the pipeline?

9. What’s in the pipeline?

10. DNDi: Drugs for Neglected Disease Initiative • Collaborative, patients; needs-driven, virtual non-profit drug R&D organization to develop new treatments against the most neglected diseases • Expansion of portfolio to include pediatric HIV • A first-line combination therapy for use in infants and children less than 3 years of age • develop a drug that is safe, well-tolerated, easy to administer, forgiving of missed doses, with a high threshold to resistance and minimal drug-drug interactions in next 3-5 years • RTV pro-drug • Second-line treatment for children

11. Short term optimization priorities for first-line ART in children • LPV/r reformulation (sprinkles and heat stable solid formulations suitable for infants) • AZT/3TC and ABC/3TC dispersible formulations • Pediatric heat-stable RTV formulations (25 mg) • Pediatric TDF tabs and powder • Scored adult-strength dispersible fixed dose formulations of TDF/3TC/EFV Adapted from WHO 2010, DNDi, expert consultation

12. Medium term priorities for ART for children • In the next five years likely to have an emerging large population of children failing PI-based therapy (first or second line) with MDR HIV • NOW is the time to address future treatment needs for these children • Darunavir, dolutegravir, etravirine, ‘the quad’ to name a few…. • Optimize dosing and regimens for HIV-TB co-treatment Adapted from WHO 2010, DNDi, expert consultation

13. Long term priorities for ART for children • Once daily dosing • Age-weight appropriate heat stable formulations (sprinkles, dispersible tablets, breakable tablets) • Fixed dose combination • Low toxicity profile • High genetic barrier • Highly potent • No drug-drug interactions • Low cost