Mina Nikanjam1, Lana Tran2, Ellen G Chadwick3, Mutsa Bwakura-Dangarembizi4, Carolyn Bolton Moore5,6, Pearl Samson7, Stephen A Spector1, Nahida Chakhtoura8, Patrick Jean-Philippe9, Lisa Frenkel10, Bonnie Zimmer11, Alex Benns11, Jennifer Libous12, Edmund V Capparelli1. 1. Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California. 2. Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina. 3. Department of Pediatrics, Northwestern University's Feinberg School of Medicine, Chicago, Illinois, USA. 4. Department of Paediatrics and Child Health, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe. 5. Centre for Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama. 6. Centre for Infectious Disease Research in Zambia, Lusaka, Zambia. 7. Statistical and Data Management Center (SDMC) Harvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research/Frontier Science Foundation, Boston, Massachusetts. 8. Maternal and Pediatric Infectious Disease Branch (MPIDB), Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health. 9. Division of AIDS, National Institutes of Allergy and Infectious Diseases, Bethesda, Maryland, USA. 10. Department of Pediatrics, University of Washington, Seattle, Washington. 11. Frontier Science and Technology Research Foundation, Amherst, New York. 12. IMPAACT Operations Center, FHI360, Durham, North Carolina, USA.
Abstract
OBJECTIVE: Dosing efavirenz (EFV) in children less than 3 years of age is challenging due to large variability in drug levels. This study evaluated differences in pharmacokinetics with tuberculosis (TB) therapy, formulation, age, and CYP2B6 genotype. DESIGN: Pharmacokinetic data from three IMPAACT/PACTG studies (P382, P1021, and P1070) for children initiating therapy less than 40 months of age were evaluated. METHODS: Pharmacokinetic data were combined in a population pharmacokinetic model. Exposure from the 2-week pharmacokinetic visit was compared with changes in viral RNA between the Week 0 and Week 4 visits. RESULTS: The model included 103 participants (19 on TB therapy). CYP2B6 516 genotype information was available for 82 participants (TT: 15, GT: 28, GG: 39). Median age at the first pharmacokinetic visit was 17.0 months (range: 2.0-39.0 months). Liquid formulation led to a 42% decrease in bioavailability compared with opened capsules. TB therapy (isoniazid and rifampin) led to a 29% decreased clearance, however Monte Carlo simulations demonstrated the majority of participants on TB therapy receiving standard EFV dosing to be in the target area under the curve range. Clearance was 5.3-fold higher for GG than TT genotype and 3.3-fold higher for GT than TT genotype. Age did not have a significant effect on clearance in the final model. Initial viral RNA decay was lower for patients in the lowest quartile of exposures (area under the curves) than for higher quartiles (P = 0.013). CONCLUSION: EFV dosing should account for CYP2B6 516 genotype and formulation, but does not require adjustment for concurrent TB therapy.
OBJECTIVE: Dosing efavirenz (EFV) in children less than 3 years of age is challenging due to large variability in drug levels. This study evaluated differences in pharmacokinetics with tuberculosis (TB) therapy, formulation, age, and CYP2B6 genotype. DESIGN: Pharmacokinetic data from three IMPAACT/PACTG studies (P382, P1021, and P1070) for children initiating therapy less than 40 months of age were evaluated. METHODS: Pharmacokinetic data were combined in a population pharmacokinetic model. Exposure from the 2-week pharmacokinetic visit was compared with changes in viral RNA between the Week 0 and Week 4 visits. RESULTS: The model included 103 participants (19 on TB therapy). CYP2B6 516 genotype information was available for 82 participants (TT: 15, GT: 28, GG: 39). Median age at the first pharmacokinetic visit was 17.0 months (range: 2.0-39.0 months). Liquid formulation led to a 42% decrease in bioavailability compared with opened capsules. TB therapy (isoniazid and rifampin) led to a 29% decreased clearance, however Monte Carlo simulations demonstrated the majority of participants on TB therapy receiving standard EFV dosing to be in the target area under the curve range. Clearance was 5.3-fold higher for GG than TT genotype and 3.3-fold higher for GT than TT genotype. Age did not have a significant effect on clearance in the final model. Initial viral RNA decay was lower for patients in the lowest quartile of exposures (area under the curves) than for higher quartiles (P = 0.013). CONCLUSION: EFV dosing should account for CYP2B6 516 genotype and formulation, but does not require adjustment for concurrent TB therapy.
Authors: Tanuja N Gengiah; Nicholas H G Holford; Julia H Botha; Andrew L Gray; Kogieleum Naidoo; Salim S Abdool Karim Journal: Eur J Clin Pharmacol Date: 2011-11-23 Impact factor: 2.953
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Authors: M Arab-Alameddine; J Di Iulio; T Buclin; M Rotger; R Lubomirov; M Cavassini; A Fayet; L A Décosterd; C B Eap; J Biollaz; A Telenti; C Csajka Journal: Clin Pharmacol Ther Date: 2009-02-18 Impact factor: 6.875
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Authors: Awewura Kwara; Hongmei Yang; Sampson Antwi; Anthony Enimil; Fizza S Gillani; Albert Dompreh; Antoinette Ortsin; Theresa Opoku; Dennis Bosomtwe; Anima Sarfo; Lubbe Wiesner; Jennifer Norman; Wael A Alghamdi; Taimour Langaee; Charles A Peloquin; Michael H Court; David J Greenblatt Journal: Antimicrob Agents Chemother Date: 2018-12-21 Impact factor: 5.191