Transcript Developing child-appropriate formulations: what is in the

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
Adolescence
Rapid physical growth,
organ maturation
Psychological
maturation and
individuation
Cope with the legacy
of lifetime ART
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 yr
6 -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 yr
12 -18 yr
What’s in the pipeline?
Drug/formulation
Age
Ritonavir sprinkles
Under development
Raltegravir
(Twice daily)
PK and safety
6 mo-19 yr
Pediatric formulations: chewable &
solution
Dolutegravir: GSK1349572
(once daily, no boost)
PK and safety
6 wks – 19 yr
Pediatric 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 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 nonprofit 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 cotreatment
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