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New and improved LPV/r based formulations for infants and young children

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.

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New and improved LPV/r based formulations for infants and young children

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  1. New and improved LPV/r based formulations for infants and young children Marc Lallemant - IAS July 1st 2013

  2. DNDi: R&D to Respond to the Needs of Patients Suffering from Neglected Diseases… Malaria Leishmaniasis Paediatric HIV Chagas Disease Helminth infections Sleeping Sickness (HAT)

  3. 6 New Treatments Developed Since 2007 • Easy to Use  Affordable  Field-Adapted  Non-Patented

  4. From NVP to LPV/r based first-lines! LPV/r + 2 NRTIs NVP based ART FDCs available Baby and junior dosing Scored tablets Can be crushed/dispersed Easy dosing • Liquid only currently • Bitter taste • Neurotoxic excipients • 42% ethanol • 15% propylene glycol • Needs cold chain • Heavy to carry, hard to hide • Difficult dosing • Need for RTV super-boosting in TB/HIV co-infection

  5. 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

  6. Formulation Challenges of Lopinavir and Ritonavir LPV RTV

  7. DNDi Initial Explorations • Nano particles • Nano dispersions • Encouraging PK in animals • Poor taste; 5 years minimum time line (NCE) 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)

  8. The Concept of 4-in-1 Granules

  9. The DNDi-Cipla partnership

  10. Weight band Dosing accepted by WHO To be included in 2013 guidelines % of patients with Cmin > 1mg/L 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. WHO 2010 FDA WHO 2010 modified % of patients with Cmin > 3mg/L WHO 2010 FDA WHO 2010 modified

  11. New dosage of 4-in-1 FDC included in WHO urgentlyneededfomulations

  12. 4-in-1 Granules Development Timeline 2013 2014 2015 Assemble 4-in-1 Registration stability Ciplapharma LPV/r granules vs. Liquid comparative bioavailability in healthy adult volunteers LPV/R DNDi Clinical 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 Industrial scale up

  13. SuperboostingPK Study in South Africa • 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. PK PK PK RIF based TB therapy initiated first >1 month after RIF initiation >= 1 month after RIF discontinuation 6 months RIF based TB therapy PI based antiretroviral therapy 3 months after RIF discontinuation Antiretroviral therapy initiated first 6 months RIF based TB therapy PI based antiretroviral therapy >= 1 month after RIF discontinuation >1 month after RIF initiation PK PK PK

  14. RTV Booster Development Timeline 2013 2014 2015 Ciplapharma Superboosting PK, safety, efficacy of RTV liquid formulation Taste masked granules Registration stability DNDi Clinical RTV granules vs. Liquid comparative bioavailability in healthy adult volunteers 2x2 PK Pivotal Bioequivalence HAV in healthy adult volunteers Dossier submission to FDA Industrial scale up Superboosting PK, safety, efficacy of newly developed RTV

  15. Registration – Feasibility - Access Implementation studies to: • Assess • Field effectiveness • Safety • Acceptability • Instructions for use • Facilitate in country registration • Facilitate program adoption

  16. CHAPAS-2 LPV/r sprinkles Dual NRTIs dispersible tablets Registration of LPV/r sprinkles SYRUPS TODAY LPV/r +2NRTIs granules clinical batch FINAL 4-in-1 2012 2014 2013

  17. Brooklyn Chest Hospital – Cape Town Thank you The DNDi pediatric HIV team Janice Lee GwenaelleCarn Jean RenéKiechel Marc Lallemant DNDiteams in Geneva, New York, Nairobi Penang, Tokyo, Delhi, Rio de Janeiro Partners Cipla ltd, MSF, MRC, International Pediatric HIV networks UNITAID, AFD, MSF International & Norway Photo: Anne Detjen

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