Pharmacokinetics of oral antimycobacterials and dosing guidance for Mycobacterium avium complex treatment in cystic fibrosis |
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| Affiliation: | 1. Department of Pediatrics, Children''s Hospital Colorado, University of Colorado Anschutz Medical Campus, 13123 E. 16th Ave. B-395 Aurora, CO 80045, United States;2. Department of Biostatistics and Informatics, University of Colorado School of Public Health, Aurora, CO 80045, United States;3. Department of Pharmacy, Children''s Hospital Colorado, Aurora, CO 80045, United States;4. Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045, United States;5. Department of Medicine, National Jewish Health, Denver, CO and University of Colorado School of Medicine, Aurora, CO 80206, United States;1. Division of Pulmonary Medicine, Nationwide Children’s Hospital, Columbus, OH, USA;2. Biostatistics Resource at Nationwide Children’s Hospital, Columbus, OH, USA;3. Center for Biostatistics, The Ohio State University, Columbus, OH, USA;1. Department of Physiology, McGill University, Montréal, Canada;2. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.;3. Department of Biochemistry, McGill University, Montréal, Canada.;1. Department of Translational Research NTMS, University of Pisa Medical School, Pisa, Italy;2. Department of Pathology, University of Pisa Medical School, Pisa, Italy;3. Children''s Hospital, Ludwig-Maximilians-University Munich, German Center for Lung Research (DZL), Munich, Germany;4. University of Tübingen Children''s Hospital, Section of Pediatric Infectiology and Immunology, Tübingen, Germany;5. Department of Medicine, General Pathology Division, University of Verona, Verona, Italy;1. Cystic Fibrosis Regional Reference Center, Department of Paediatric Medicine, Anna Meyer Children''s University, Florence, Italy;2. Cystic Fibrosis Regional Reference Center, Fondazione IRCCS Ca'' Granda Ospedale Maggiore Policlinico, University of Milan, Department of Pathophysiology and Transplantation, Milan, Italy;3. Paediatric Unit, Department of Translational Medical Sciences, Cystic Fibrosis Regional Reference Center, University of Naples Federico II, Naples, Italy;4. Cystic Fibrosis Regional Reference Center, Mother - Child Department, United Hospitals, Ancona, Italy;5. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy;6. Pasteur Institute Cenci Bolognetti Foundation, Rome, Italy;7. Cystic Fibrosis Regional Reference Center, A.O.U. Policlinico Umberto I, Rome, Italy;8. Cystic Fibrosis Regional Support Center, Department of Pediatrics, University of Brescia, ASST Spedali Civili Brescia, Brescia, Italy;9. Department of Health Sciences, University of Florence, Florence, Italy;12. Freelance Statistician, Bergamo, Italy;13. Freelance Statistician, Milan, Italy;14. Department of Women''s and Children''s Health, University of Liverpool, Institute in the Park, Alder Hey Children''s Hospital, Liverpool, United Kingdom |
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| Abstract: | ![]()
BackgroundTreatment failure of Mycobacterium avium complex (MAC) pulmonary disease occurs in about 30% of people with cystic fibrosis (CF) and may be a result of abnormal drug concentrations.MethodsProspective, cross-over, single-dose PK study of 20 pancreatic insufficient individuals with CF and 10 healthy controls (HC). CF subjects received simultaneous doses of oral azithromycin, ethambutol, and rifampin in the fasting state and with food and pancreatic enzymes, separated by two weeks. HC received fasting doses only. A non-compartmental model was used to estimate PK parameters of drugs and metabolites.ResultsAzithromycin maximum concentration (Cmax ) was higher and rifampin Cmax was lower in fasting CF subjects compared to HC, while other PK measures, including those for ethambutol, were similar. Addition of food and enzymes did not improve the Cmax of the antimycobacterial drugs. Nineteen of 20 CF subjects had one or more abnormal Cmax z-scores in either the fasting or fed state (or both), when compared to HC.ConclusionPK profiles of azithromycin and ethambutol were similar between CF and HC, except azithromycin Cmax was slightly higher in people with CF after a single dose. Rifampin PK parameters were altered in persons with CF. Addition of food and enzymes in CF subjects did not improve PK parameters. Standard dosing guidelines should be used as a starting point for people with CF initiating MAC therapy and therapeutic drug monitoring should be routinely performed to prevent the possibility of treatment failure due to abnormal drug concentrations.Clinical trial registrationClinicalTrials.gov Identifier: NCT02372383Prior abstract publication:1. Martiniano S, Wagner B, Brennan L, Wempe M, Anderson P, Nick J, Sagel S. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. Am J Resp Crit Care Med A4842-A4842, 2017.2. Martiniano SL, Wagner BD, Brennan L, Wempe MF, Anderson PL, Nick JA, Sagel SD. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. J Cyst Fibros 16: S52–53, 2017. |
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