Wael A Alghamdi1,2, Sampson Antwi3,4, Anthony Enimil3,4, Hongmei Yang5, Albert Dompreh3, Lubbe Wiesner6, Taimour Langaee1, Charles A Peloquin1, Awewura Kwara7. 1. Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA. 2. Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha, Saudi Arabia. 3. Directorate of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana. 4. Department of Child Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana. 5. Department of Biostatistics and Computational Biology, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA. 6. Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. 7. College of Medicine and Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA.
Abstract
OBJECTIVES: The current WHO weight-based dosing recommendations for efavirenz result in a wide variability of drug exposure in children. Our objectives are to characterize the effects of rifampicin- and isoniazid-containing anti-TB therapy and CYP2B6 activity on efavirenz concentrations in children, using non-linear mixed-effects modelling. METHODS: This is a pharmacokinetic (PK) substudy of a prospective study that examined the interactions between anti-TB therapy and efavirenz in HIV-infected children with and without TB. PK samples were obtained 4 weeks after starting efavirenz (PK1) and repeated 4 weeks after completing TB therapy (PK2) in TB/HIV coinfected patients. Drug concentrations were measured using LC-MS/MS. Composite CYP2B6 516/983/15582 genotype was determined. Population PK modelling was performed in Monolix. Simulations were performed to obtain the predicted mid-dose concentrations (C12). RESULTS: One hundred and five HIV-infected Ghanaian children (46 with TB/HIV) were included. The median age and weight were 7 years and 19 kg. The efavirenz concentrations over time were adequately described using a one-compartment model. Weight, composite CYP2B6 genotype and PK visit had a significant influence on the PK parameters, while TB therapy had no significant effect. Simulations showed adequate C12 for intermediate composite CYP2B6 metabolizers only. CONCLUSIONS: Our model showed that rifampicin- and isoniazid-containing anti-TB therapy does not influence efavirenz PK parameters. On the other hand, it describes the effect of efavirenz autoinduction after completing TB treatment. In addition, dosing efavirenz in children based only on weight results in a large variability in drug exposure. We propose dose adjustments for slow and extensive composite CYP2B6 metabolizers.
OBJECTIVES: The current WHO weight-based dosing recommendations for efavirenz result in a wide variability of drug exposure in children. Our objectives are to characterize the effects of rifampicin- and isoniazid-containing anti-TB therapy and CYP2B6 activity on efavirenz concentrations in children, using non-linear mixed-effects modelling. METHODS: This is a pharmacokinetic (PK) substudy of a prospective study that examined the interactions between anti-TB therapy and efavirenz in HIV-infectedchildren with and without TB. PK samples were obtained 4 weeks after starting efavirenz (PK1) and repeated 4 weeks after completing TB therapy (PK2) in TB/HIV coinfectedpatients. Drug concentrations were measured using LC-MS/MS. Composite CYP2B6 516/983/15582 genotype was determined. Population PK modelling was performed in Monolix. Simulations were performed to obtain the predicted mid-dose concentrations (C12). RESULTS: One hundred and five HIV-infected Ghanaian children (46 with TB/HIV) were included. The median age and weight were 7 years and 19 kg. The efavirenz concentrations over time were adequately described using a one-compartment model. Weight, composite CYP2B6 genotype and PK visit had a significant influence on the PK parameters, while TB therapy had no significant effect. Simulations showed adequate C12 for intermediate composite CYP2B6 metabolizers only. CONCLUSIONS: Our model showed that rifampicin- and isoniazid-containing anti-TB therapy does not influence efavirenz PK parameters. On the other hand, it describes the effect of efavirenz autoinduction after completing TB treatment. In addition, dosing efavirenz in children based only on weight results in a large variability in drug exposure. We propose dose adjustments for slow and extensive composite CYP2B6 metabolizers.
Authors: David W Haas; Heather J Ribaudo; Richard B Kim; Camlin Tierney; Grant R Wilkinson; Roy M Gulick; David B Clifford; Todd Hulgan; Catia Marzolini; Edward P Acosta Journal: AIDS Date: 2004-12-03 Impact factor: 4.177
Authors: David Burger; Ilse van der Heiden; Charles la Porte; Marchina van der Ende; Paul Groeneveld; Clemens Richter; Peter Koopmans; Frank Kroon; Herman Sprenger; Jan Lindemans; Paul Schenk; Ron van Schaik Journal: Br J Clin Pharmacol Date: 2006-02 Impact factor: 4.335
Authors: Christoph Wyen; Heidy Hendra; Martin Vogel; Christian Hoffmann; Heribert Knechten; Norbert H Brockmeyer; Johannes R Bogner; Jürgen Rockstroh; Stefan Esser; Hans Jaeger; Thomas Harrer; Stefan Mauss; Jan van Lunzen; Nicole Skoetz; Alexander Jetter; Christiane Groneuer; Gerd Fätkenheuer; Saye H Khoo; Deirdre Egan; David J Back; Andrew Owen Journal: J Antimicrob Chemother Date: 2008-02-14 Impact factor: 5.790
Authors: Marc Pfister; Line Labbé; Scott M Hammer; John Mellors; Kara K Bennett; Susan Rosenkranz; Lewis B Sheiner Journal: Antimicrob Agents Chemother Date: 2003-01 Impact factor: 5.191
Authors: Alberto Matteelli; Mario Regazzi; Paola Villani; Giuseppina De Iaco; Maria Cusato; Anna Cristina C Carvalho; Silvio Caligaris; Lina Tomasoni; Maria Manfrin; Susanna Capone; Giampiero Carosi Journal: Curr HIV Res Date: 2007-05 Impact factor: 1.581
Authors: Mina Nikanjam; Lana Tran; Ellen G Chadwick; Mutsa Bwakura-Dangarembizi; Carolyn Bolton Moore; Pearl Samson; Stephen A Spector; Nahida Chakhtoura; Patrick Jean-Philippe; Lisa Frenkel; Bonnie Zimmer; Alex Benns; Jennifer Libous; Edmund V Capparelli Journal: AIDS Date: 2022-03-15 Impact factor: 4.632
Authors: Marieke G G Sturkenboom; Anne-Grete Märtson; Elin M Svensson; Derek J Sloan; Kelly E Dooley; Simone H J van den Elsen; Paolo Denti; Charles A Peloquin; Rob E Aarnoutse; Jan-Willem C Alffenaar Journal: Clin Pharmacokinet Date: 2021-03-06 Impact factor: 6.447
Authors: Tom G Jacobs; Elin M Svensson; Victor Musiime; Pablo Rojo; Kelly E Dooley; Helen McIlleron; Rob E Aarnoutse; David M Burger; Anna Turkova; Angela Colbers Journal: J Antimicrob Chemother Date: 2020-12-01 Impact factor: 5.790