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 administrationAbility 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/Formulation Age

Efavirenz : open capsules with and without rifampin

PK , safety, pharmacogenetics

3 mos – 3 yrs

Efavirenz oral solution and sprinkle

PK, safety 3 mo-6 yr

Etravirene PK and safety 2 mo- 6 yr6 -18 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 ; 3 -25 kg

Lopinavir/ritonavir sprinkles

PK and safety Trial to begin in Uganda: infants, young children

Atazanavir PRINCE I & II 3 mo – 8 yr

Darunavir(Requires boosting)

PK, safety, efficacy 3 yrs – 6 yr12 -18 yr

What’s in the pipeline?Drug/formulation Age

Ritonavir sprinkles Under development

Raltegravir(Twice daily)

PK and safety 6 mo-19 yrPediatric formulations: chewable & solution

Dolutegravir: GSK1349572 (once daily, no boost)

PK and safety 6 wks – 19 yrPediatric formulation in development

Elvitegravir(Once daily, needs boosting)

PK and safety Adolescents;Pediatric development planned

Maraviroc CCR5 antagonist

PK and safety 2-18 yr

Tenofovir powder Application to US FDA2-5 yr

Tenofovir tablets150mg, 200 mg, 250 mg

Application to US FDA2-12 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