BACKGROUND: Lopinavir/ritonavir (LPV/r) is available in a liquid formulation that is far from ideal for treatment of children in resource-poor settings. Flexible, low-cost, solid, oral fixed-dose combinations (FDC) of LPV/r with nucleoside reverse transcriptase inhibitors (LPV/r/abacavir [ABC]/lamivudine [3TC] and LPV/r/zidovudine [ZDV]/3TC) are needed to improve both management and adherence of children. This work aimed to develop appropriate drug ratios and dosing for each FDC. METHODS: Data from 25 combined datasets included therapeutic drug monitoring and clinical studies from IMPAACT and PENTA. Population pharmacokinetic analyses were performed using Monolix. Monte-Carlo simulations of WHO and FDA dosing recommendations were performed to assess their ability to provide optimal exposure in children weighing 4 to 25 kg based on consensus plasma targets. The LPV/r:3TC:ZDV(ABC) dose ratios were 2.67:1:2(2), respectively. RESULTS: Using WHO dosage, LPV efficacy target was reached in all weight bands. Given the recommended drug ratios, the dosage for the 4-5.9 kg weight band (LPV/ZDV: 120/90 mg twice daily [bid]) showed more than 20% of subjects had ZDV levels at high risk of neutropenia. Reducing the LPV/ZDV dose to 80/60 mg bid decreased frequency of high ZDV concentrations but retained the LPV efficacy criteria. CONCLUSIONS: This defined a flexible and simple FDC containing 40 mg LPV, 10 mg ritonavir, 15 mg 3TC and 30 mg ABC or ZDV. According to the weight bands defined by WHO, 4-5.9 kg, 6-9.9 kg, 10-13.9 kg, 14-19.9 kg, 20-24.9 kg, therapeutic doses would be 2, 3, 4, 5 or 6 individual units administered by oral route bid.
BACKGROUND:Lopinavir/ritonavir (LPV/r) is available in a liquid formulation that is far from ideal for treatment of children in resource-poor settings. Flexible, low-cost, solid, oral fixed-dose combinations (FDC) of LPV/r with nucleoside reverse transcriptase inhibitors (LPV/r/abacavir [ABC]/lamivudine [3TC] and LPV/r/zidovudine [ZDV]/3TC) are needed to improve both management and adherence of children. This work aimed to develop appropriate drug ratios and dosing for each FDC. METHODS: Data from 25 combined datasets included therapeutic drug monitoring and clinical studies from IMPAACT and PENTA. Population pharmacokinetic analyses were performed using Monolix. Monte-Carlo simulations of WHO and FDA dosing recommendations were performed to assess their ability to provide optimal exposure in children weighing 4 to 25 kg based on consensus plasma targets. The LPV/r:3TC:ZDV(ABC) dose ratios were 2.67:1:2(2), respectively. RESULTS: Using WHO dosage, LPV efficacy target was reached in all weight bands. Given the recommended drug ratios, the dosage for the 4-5.9 kg weight band (LPV/ZDV: 120/90 mg twice daily [bid]) showed more than 20% of subjects had ZDV levels at high risk of neutropenia. Reducing the LPV/ZDV dose to 80/60 mg bid decreased frequency of high ZDV concentrations but retained the LPV efficacy criteria. CONCLUSIONS: This defined a flexible and simple FDC containing 40 mg LPV, 10 mg ritonavir, 15 mg 3TC and 30 mg ABC or ZDV. According to the weight bands defined by WHO, 4-5.9 kg, 6-9.9 kg, 10-13.9 kg, 14-19.9 kg, 20-24.9 kg, therapeutic doses would be 2, 3, 4, 5 or 6 individual units administered by oral route bid.
Authors: Paolo Denti; Anneke C Hesseling; Louvina E van der Laan; Anthony J Garcia-Prats; H Simon Schaaf; Tjokosela Tikiso; Lubbe Wiesner; Mine de Kock; Jana Winckler; Jennifer Norman; Helen McIlleron Journal: Antimicrob Agents Chemother Date: 2018-01-25 Impact factor: 5.191
Authors: Esther J H Janssen; Diane E T Bastiaans; Pyry A J Välitalo; Annemarie M C van Rossum; Evelyne Jacqz-Aigrain; Hermione Lyall; Catherijne A J Knibbe; David M Burger Journal: Br J Clin Pharmacol Date: 2017-02-14 Impact factor: 4.335
Authors: Frantz Foissac; Jörn Blume; Jean-Marc Tréluyer; Thorkild Tylleskär; Chipepo Kankasa; Nicolas Meda; James K Tumwine; Mandisa Singata-Madliki; Kim Harper; Silvia M Illamola; Naïm Bouazza; Nicolas Nagot; Philippe Van de Perre; Stéphane Blanche; Déborah Hirt Journal: Antimicrob Agents Chemother Date: 2017-01-24 Impact factor: 5.191
Authors: Rajith K R Rajoli; David J Back; Steve Rannard; Caren Freel Meyers; Charles Flexner; Andrew Owen; Marco Siccardi Journal: Clin Pharmacokinet Date: 2018-02 Impact factor: 6.447
Authors: James G Carlucci; Meridith Blevins Peratikos; Aaron M Kipp; Mary L Lindegren; Quy T Du; Lorna Renner; Gary Reubenson; John Ssali; Marcel Yotebieng; Anna M Mandalakas; Mary-Ann Davies; Marie Ballif; Lukas Fenner; April C Pettit Journal: J Acquir Immune Defic Syndr Date: 2017-06-01 Impact factor: 3.731
Authors: Elin M Svensson; Gunnar Yngman; Paolo Denti; Helen McIlleron; Maria C Kjellsson; Mats O Karlsson Journal: Clin Pharmacokinet Date: 2018-05 Impact factor: 6.447
Authors: Adrie Bekker; Helena Rabie; Nicolas Salvadori; Samantha du Toit; Kanchana Than-In-At; Marisa Groenewald; Isabelle Andrieux-Meyer; Mukesh Kumar; Ratchada Cressey; James Nielsen; Edmund Capparelli; Marc Lallemant; Mark F Cotton; Tim R Cressey Journal: J Acquir Immune Defic Syndr Date: 2022-03-01 Impact factor: 3.771