Stacey L Martiniano1, Brandie D Wagner2, Laney Brennan3, Michael F Wempe4, Peter L Anderson4, Charles L Daley5, Meg Anthony3, Jerry A Nick5, Scott D Sagel6. 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. Electronic address: stacey.martiniano@childrenscolorado.org. 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. 6. Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, 13123 E. 16th Ave. B-395 Aurora, CO 80045, United States.
Abstract
BACKGROUND: Treatment 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. METHODS: Prospective, 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. RESULTS: Azithromycin 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. CONCLUSION: PK 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 REGISTRATION: ClinicalTrials.gov Identifier: NCT02372383 Prior 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.
BACKGROUND: Treatment 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. METHODS: Prospective, 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. RESULTS: Azithromycin 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. CONCLUSION: PK 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 REGISTRATION: ClinicalTrials.gov Identifier: NCT02372383 Prior 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.
Authors: Paul Beringer; Kitty My Tu Huynh; Jane Kriengkauykiat; Luke Bi; Nils Hoem; Stan Louie; Emily Han; Thao Nguyen; Donald Hsu; Purush A Rao; Bertrand Shapiro; Mark Gill Journal: Antimicrob Agents Chemother Date: 2005-12 Impact factor: 5.191
Authors: M C Nahata; K I Koranyi; S D Gadgil; D M Hilligoss; H G Fouda; M J Gardner Journal: Antimicrob Agents Chemother Date: 1993-02 Impact factor: 5.191
Authors: K E Stott; H Pertinez; M G G Sturkenboom; M J Boeree; R Aarnoutse; G Ramachandran; A Requena-Méndez; C Peloquin; C F N Koegelenberg; J W C Alffenaar; R Ruslami; A Tostmann; S Swaminathan; H McIlleron; G Davies Journal: J Antimicrob Chemother Date: 2018-09-01 Impact factor: 5.790