R&D MODEL & PORTFOLIO
Two ‘4-in-1’ LPV/r based FDC granules
PROJECT START: 2012 OVERALL OBJECTIVE: Develop and register two solid tastemasked first-line LPV/r-based fixed-dose formulations with two NRTIs, 3TC plus ABC or AZT 2015 OBJECTIVES:
Superbooster therapy for paediatric HIV/TB co-infection
PROJECT START: 2012 OVERALL OBJECTIVE: Evaluate the pharmacokinetic enhancer/
booster formulation to be added to any PI-based paediatric ARV regimen
• Perform pilot comparative bioavailability studies of the most promising taste-masked LPV/r granule or pellet formulations in adult volunteers • Perform as-needed bioequivalence studies in healthy human volunteers using all components of the ‘4-in-1’ FDC
Pharmacokinetic modelling was carried out to determine drug dosages within potential ‘4-in-1’ formulations, and the proposed dosing for the two ‘4-in-1’ LPV/r based FDCs and RTV booster were incorporated into Annex 7 of the WHO’s new Consolidated Guidelines on The Use of Antiretroviral Drugs for Treating and Preventing HIV Infection, under ‘urgently needed ARV drugs for children recommended by the Paediatric ARV Working Group’ in 2013. New formulations of LPV/r pellets are required to optimize bioavailability and taste-masking, but this has proved to be very challenging. In 2015, three of the most promising formulations tested in previous in vivo studies were assessed, and were found to be highly bioavailable in Phase I studies in man. Additional bioavailability studies and standardized electronic tongue taste-testing (e-tongue) of granules with modified coatings and different polymers will be performed in 2016.
MAIN PARTNERS: Cipla Ltd., India; Department of Health, South
• Finish recruitment of the RTV superboosting study performed in South Africa (using LPV/r and RTV originator’s liquid formulations) • Ensure guideline change • Prepare for the evaluation of superboosting with solid formulations (LPV/r granules/pellets plus RTV solid booster)
In Africa, a large proportion of recruited at 5 sites HIV-positive infants and children are co-infected with tuberculosis (TB). Rifampicin is commonly used to treat TB in children, however it has negative interactions with protease inhibitors (PIs) included in treatments used to combat HIV infection: concomitant administration of rifampicin leads to a decrease in LPV/r exposure of up to 90%. To counteract this effect, the amount of ritonavir (RTV) in the LPV/r combination must be quadrupled in a procedure known as superboosting. A stand-alone RTV booster formulation is needed that can be added to any PI-based paediatric ARV regimen. Like LPV/r, RTV has a high alcohol content, is unstable, and completely unpalatable.
Africa; UNITAID; President’s Emergency Plan for AIDS Relief (PEPFAR), USA; Médecins Sans Frontières; Necker Institute, Paris; various academic partners in South Africa and Kenya; AbbVie, USA; WuXi AppTech, China
A pharmacokinetic study has been carried out in infants and young children co-infected with TB and HIV at five sites in South Africa to supplement existing information and evaluate the effect of the ‘super-boosting’ strategy. At the end of November 2015 all 96 patients had been included. Interim results show that LPV exposure during TB/HIV cotreatment using the superboosting approach is as good as that when children return to standard LPV/r based therapy. Superboosting was safe and well tolerated. This study is being extended to include all solid formulations. Results were shared with the South African government and WHO to support a change in guidelines for the management of TB/ HIV co-infections in children. The South African government changed its guidelines in December 2015 and WHO is expected to do so by summer 2016.
MAIN PARTNERS: Department of Health and Department of