Stefanie Hennig1, Elin M Svensson2, Ronald Niebecker2, P Bernard Fourie3, Marc H Weiner4, Stefano Bonora5, Charles A Peloquin6, Keith Gallicano7, Charles Flexner8, Alex Pym9, Peter Vis10, Piero L Olliaro11, Helen McIlleron12, Mats O Karlsson2. 1. School of Pharmacy, University of Queensland, Brisbane, Australia Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden s.hennig@uq.edu.au. 2. Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden. 3. Department of Medical Microbiology, University of Pretoria, Pretoria, South Africa. 4. Department of Medicine, University of Texas Health Science Center and Veterans Administration Medical Center, San Antonio, TX, USA. 5. Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy. 6. College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA. 7. Novum Pharmaceutical Research Services, Murrieta, CA, USA. 8. Johns Hopkins Adult AIDS Clinical Trials Unit, Division of Clinical Pharmacology, Baltimore, MD, USA. 9. Tuberculosis Research Unit, Medical Research Council and KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa. 10. Janssen Infectious Diseases BVBA, Beerse, Belgium. 11. Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization (WHO), Geneva, Switzerland. 12. Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Abstract
OBJECTIVES: Extensive but fragmented data from existing studies were used to describe the drug-drug interaction between rifabutin and HIV PIs and predict doses achieving recommended therapeutic exposure for rifabutin in patients with HIV-associated TB, with concurrently administered PIs. METHODS: Individual-level data from 13 published studies were pooled and a population analysis approach was used to develop a pharmacokinetic model for rifabutin, its main active metabolite 25-O-desacetyl rifabutin (des-rifabutin) and drug-drug interaction with PIs in healthy volunteers and patients who had HIV and TB (TB/HIV). RESULTS: Key parameters of rifabutin affected by drug-drug interaction in TB/HIV were clearance to routes other than des-rifabutin (reduced by 76%-100%), formation of the metabolite (increased by 224% in patients), volume of distribution (increased by 606%) and distribution to the peripheral compartment (reduced by 47%). For des-rifabutin, clearance was reduced by 35%-76% and volume of distribution increased by 67%-240% in TB/HIV. These changes resulted in overall increased exposure to rifabutin in TB/HIV patients by 210% because of the effects of PIs and 280% with ritonavir-boosted PIs. CONCLUSIONS: Given together with non-boosted or ritonavir-boosted PIs, rifabutin at 150 mg once daily results in similar or higher exposure compared with rifabutin at 300 mg once daily without concomitant PIs and may achieve peak concentrations within an acceptable therapeutic range. Although 300 mg of rifabutin every 3 days with boosted PI achieves an average equivalent exposure, intermittent doses of rifamycins are not supported by current guidelines.
OBJECTIVES: Extensive but fragmented data from existing studies were used to describe the drug-drug interaction between rifabutin and HIV PIs and predict doses achieving recommended therapeutic exposure for rifabutin in patients with HIV-associated TB, with concurrently administered PIs. METHODS: Individual-level data from 13 published studies were pooled and a population analysis approach was used to develop a pharmacokinetic model for rifabutin, its main active metabolite 25-O-desacetyl rifabutin (des-rifabutin) and drug-drug interaction with PIs in healthy volunteers and patients who had HIV and TB (TB/HIV). RESULTS: Key parameters of rifabutin affected by drug-drug interaction in TB/HIV were clearance to routes other than des-rifabutin (reduced by 76%-100%), formation of the metabolite (increased by 224% in patients), volume of distribution (increased by 606%) and distribution to the peripheral compartment (reduced by 47%). For des-rifabutin, clearance was reduced by 35%-76% and volume of distribution increased by 67%-240% in TB/HIV. These changes resulted in overall increased exposure to rifabutin in TB/HIV patients by 210% because of the effects of PIs and 280% with ritonavir-boosted PIs. CONCLUSIONS: Given together with non-boosted or ritonavir-boosted PIs, rifabutin at 150 mg once daily results in similar or higher exposure compared with rifabutin at 300 mg once daily without concomitant PIs and may achieve peak concentrations within an acceptable therapeutic range. Although 300 mg of rifabutin every 3 days with boosted PI achieves an average equivalent exposure, intermittent doses of rifamycins are not supported by current guidelines.
Authors: M Ghannad; M Dennehy; C la Porte; I Seguin; D Tardiff; R Mallick; E Sabri; G Zhang; S Kanji; D W Cameron Journal: PLoS One Date: 2019-10-24 Impact factor: 3.240