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Double dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based antitubercular treatment . H McIlleron*, Y Ren, J Nuttall, A Riddick , L Kleynhans, H Rabie, M Cotton, B Eley, C Merry, G Maartens
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Double dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based antitubercular treatment H McIlleron*, Y Ren, J Nuttall, A Riddick, L Kleynhans, H Rabie, M Cotton, B Eley, C Merry, G Maartens University of Cape Town, South Africa; University of the Witswatersrand, Johannesburg, South Africa; University of Stellenbosch, South Africa; Trinity College, Dublin, Ireland
background • Rifampicin (RIF)-based TB treatment is recommended for TB/HIV co-infected children (no rifabutin pediatric formulation) • RIF reduces trough lopinavir (LPV) concentrations (>90%) • Super-boosted LPV (LPV/RTV ratio=1:1) during TB treatment achieved adequate concentrations in 13/15 children • Super-boosting of LPV with RTV is complex with oral solutions • An alternative approach is to double the dose of LPV/RTV (ratio=4:1), which achieved adequate concentrations in adult healthy normal volunteers, but has not been studied in children Ren et al. J Acquir Immune Defic Syndr 2008; 47:566-9; La Porte et al. Antimicrob Agents Chemother 2004; 48:1553–60.
methods • Steady state plasma pharmacokinetics (PK) of LPV in South African children > 6-months old • TB/HIV group: double dose LPV/RTV (460/115 mg/m2) + 2NRTIs once established on rifampicin-based TB treatment • controls without TB: standard doses of LPV/RTV (230/57.5 mg/m2) + 2NRTIs • PK • Sampling: pre-dose, 2, 4, 8 h(+ 12 h) • LC-MS/MS analysis • TDM approach: LPV concentration results were available in real-time • Interim analysis and DSMB review after 15 children with TB/HIV had undergone PK sampling Study stopped
LPV concentration vs. time controls TB/HIV
LPV trough concentrations 4.25 mg/L 0.76 mg/L
trough concentrations of LPV reported in the literature ‘230’ mg/m2 adult studies LPV/RTV = 400/100 mg 2 x/day 265 mg/m2 234 mg/m2 227 mg/m2 Super-boosted LPV (LPV/RTV = 292/292 mg/m2) during TB Rx pediatric studies ♦ median LPV trough median LPV dose/BSA 276 mg/m2 Double dose LPV/RTV = 486/122 mg/m2 during TB Rx Chadwick et al., AIDS 2008; Eron et al., J Infect Dis 2004; La Porte et al., Antimicrob Agent Chemother 2004; Micheli et al., Ther Drug Monit 2008; Murphy et al., AIDS 2001; Ren et al. J Acquir Immune Defic Syndr. 2008; Rosso et al., J Antimicrob Chemother 2006; Verweel et al., Antivir Ther 2007
Serious adverse events • SAEs possibly or probably related to study treatment were reported in 3 children with TB: • 2 children had DAIDS grade 3/4 ↑ALT • One child HAV + • ALT returned to normal without treatment interruption • 1 child had grade 4 neutropenia • Resolved without treatment interruption
conclusions • LPV concentrations were highly variable within both groups. Median LPV Cpre, Cmax, and AUC0-8h were reduced by 82%, 44% and 51%, respectively, in children receiving twice the standard dose of LPV/RTV together with rifampicin-based TB treatment • The approach of doubling the dose of LPV/RTV during rifampicin-based TB treatment should not be recommended in young children • There is an urgent need to establish safe, effective and feasible co-treatment for young children with HIV associated tuberculosis
acknowledgements • European and Developing Countries Clinical Trial Partnership (EDCTP) • Research programme for the comprehensive HIV and AIDS care, management, and treatment plan for South Africa (SA DoH) • The clinic teams at Chris Hani Baragwanath Hospital, Red Cross Hospital and Tygerberg Hospital • Marque Venter, Pete Smith and laboratory staff in the Division of Clinical Pharmacology, UCT declarations HM and GM received speaker’s honoraria from Abbott Laboratories, South Africa.