new and improved lpv/r based formulations for infants and young children
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New and improved LPV/r based formulations for infants and young children. Marc Lallemant - IAS July 1 st 2013. DNDi : R&D to Respond to the Needs of Patients Suffering from Neglected Diseases…. Malaria. Leishmaniasis. Paediatric HIV. Chagas Disease. - PowerPoint PPT PresentationTRANSCRIPT
New and improved LPV/r based formulations for infants and young children
Marc Lallemant - IAS July 1st 2013
Malaria Leishmaniasis
Sleeping Sickness (HAT) Chagas Disease
Paediatric HIV
Helminth infections
DNDi: R&D to Respond to the Needs of Patients Suffering from Neglected Diseases…
Easy to Use Affordable Field-Adapted Non-Patented
6 New Treatments Developed Since 2007
From NVP to LPV/r based first-lines!
NVP based ART LPV/r + 2 NRTIs
FDCs availableBaby and junior dosingScored tabletsCan be crushed/dispersedEasy dosing
Liquid only currentlyBitter tasteNeurotoxic excipients
• 42% ethanol• 15% propylene glycol
Needs cold chainHeavy to carry, hard to hideDifficult dosingNeed for RTV super-boosting in TB/HIV co-infection
DNDi Paediatric HIV Program Objectives
Develop two solid first-line LPV/r-based fixed-dose combinations (FDC) with two NRTIs, 3TC plus ABC or AZT.
Well taste masked Heat-stable without refrigeration, long shelf life single strength for dosing throughout weight bands
Develop complementary granule of RTV to be added to the 4-in-1 LPV/r based FDCs during HIV and tuberculosis treatment
4:1 1:1 LPV/RTV ratio when on RIF
Formulation Challenges of Lopinavir and Ritonavir
High solubility Low solubilityHigh permeability ZDV, FTC
Low permeability 3TC, ABC RTV, LPV
LPV RTV
DNDi Initial Explorations Original LPV and RTV formulations were alcohol based oral
solutions and soft gel capsules (Abbott) Replaced for adults and older children with LPV/r tablets
(Abbott) Soluble polymer (copovidone)
Tablets cannot be used in young children as crushed they loose up to 50% bioavailability
Alternative options Prodrugs (eg. RTV)
o Nano particleso Nano dispersions
Encouraging PK in animalsPoor taste; 5 years minimum time line (NCE)
The Concept of 4-in-1 Granules
The DNDi-Cipla partnership
5 10 15 20 25
020
4060
8010
0
Bodyweight (kg)
Per
cent
age
of c
hild
ren
with
LP
V C
min
abo
ve 3
mg/
L
FDAWHOOur recommendation
4
% of patients with Cmin > 3mg/L
5 10 15 20 25
020
4060
8010
0
Bodyweight (kg)
Per
cent
age
of c
hild
ren
with
LP
V C
min
abo
ve 1
mg/
L
FDAWHOOur recommendation
4
WHO 2010FDAWHO 2010 modified
% of patients with Cmin > 1mg/L
WHO 2010FDAWHO 2010 modified
Weight band Dosing accepted by WHOTo be included in 2013 guidelines
US and European paediatric ARV PK databases merge; Developmental PK modelling; Exposure simulations:• New LPV/r dosing harmonizes WHO
weight band table for LPV/r and accompanying NRTIs.
New dosage of 4-in-1 FDC included in WHO urgently needed fomulations
am pm am pm am pm am pm am pm
ABC/3TC/LPV/r 30/15/40/10mg 2 2 3 3 4 4 5 5 6 6
AZT/3TC/LPV/r 30/15/40/10mg 2 2 3 3 4 4 5 5 6 6
DrugStrength of tab or
sprinkle sachet/capsule (mg)
Number of tablets by weight-band morning and evening
3–5.9 kg 6–9.9 kg 10–13.9 kg 14–19.9 kg 20–24.9 kg
4-in-1 Granules Development Timeline
LPV/R
Assemble 4-in-1 Registration stability
LPV/r granules vs. Liquid comparative bioavailability in healthy adult volunteers
Clinical batch 4-in-1
Accelerated stability
Bioequivalence in healthy adult volunteers (4-in-1)
Paediatric phase 2 LPV/r granules vs. liquid cross-over PK
Phase 2/3 paediatric pop PK, safety, efficacy study (4-in-1)
Dossier submission to FDA
2014 20152013
Industrial scale up
Cipla pharma
DNDi Clinical
Superboosting PK Study in South Africa
PK
PK
PK
6 months RIF based TB therapy
PI based antiretroviral therapy
6 months RIF based TB therapy
PI based antiretroviral therapy
PK
>= 1 month after RIF discontinuation
>1 month after RIF initiation
>1 month after RIF initiation
>= 1 month after RIF discontinuation
3 months after RIF discontinuation
RIF based TB therapy initiated first
Antiretroviral therapy initiated first
PK
PK
Limited data on pharmacokinetics, safety and efficacy of superboosted LPV/r 1:1 in young children
More data is needed to support superboosting in children of various ages and clinical conditions using the new rifampicin doses.
RTV Booster Development Timeline
Taste masked granulesRegistration stability
RTV granules vs. Liquid comparative bioavailability in healthy adult volunteers
Pivotal Bioequivalence HAV in healthy adult volunteers
Superboosting PK, safety, efficacy of newly developed RTV
Dossier submission to FDA
2014 20152013
Industrial scale up
2x2 PK
Superboosting PK, safety, efficacy of RTV liquid formulationCipla
pharma
DNDi Clinical
Registration – Feasibility - Access
Implementation studies to: Assess
Field effectiveness Safety Acceptability Instructions for use
Facilitate in country registration Facilitate program adoption
2012 2013 2014
SYRUPS TODAY
CHAPAS-2LPV/r
sprinkles
Registration of LPV/r sprinkles
Dual NRTIs dispersible
tablets
LPV/r +2NRTIs granules clinical batch FINAL 4-in-1
Brooklyn Chest Hospital – Cape Town
Thank you18
Photo: Anne Detjen
The DNDi pediatric HIV teamJanice LeeGwenaelle CarnJean René KiechelMarc Lallemant
DNDi teams in Geneva, New York, NairobiPenang, Tokyo, Delhi, Rio de Janeiro
PartnersCipla ltd, MSF, MRC, International Pediatric HIV networks
UNITAID, AFD, MSF International & Norway