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

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)

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

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

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

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

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

What’s in the pipeline? Drug/FormulationAge Efavirenz : open capsules with and without rifampin PK, safety, pharmacogenetics 3 mos – 3 yrs Efavirenz oral solution and sprinkle PK, safety3 mo-6 yr EtravirenePK and safety2 mo- 6 yr yr Rilpiverine (TMC 278) (Once daily) PK and safety in adolescents Lopinavir/ritonavir liquid and pediatric tabs PK of WHO weight band dosing Weight bands ; kg Lopinavir/ritonavir sprinkles PK and safetyTrial to begin in Uganda: infants, young children AtazanavirPRINCE I & II3 mo – 8 yr Darunavir (Requires boosting) PK, safety, efficacy3 yrs – 6 yr yr

What’s in the pipeline? Drug/formulationAge Ritonavir sprinklesUnder development Raltegravir (Twice daily) PK and safety6 mo-19 yr Pediatric formulations: chewable & solution Dolutegravir: GSK (once daily, no boost) PK and safety6 wks – 19 yr Pediatric formulation in development Elvitegravir (Once daily, needs boosting) PK and safetyAdolescents; Pediatric development planned Maraviroc CCR5 antagonist PK and safety2-18 yr Tenofovir powderApplication to US FDA 2-5 yr Tenofovir tablets 150mg, 200 mg, 250 mg Application to US FDA 2-12 yr

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

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

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

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