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. 2021 Sep;20(5):772-778.
doi: 10.1016/j.jcf.2021.04.011. Epub 2021 May 21.

Pharmacokinetics of oral antimycobacterials and dosing guidance for Mycobacterium avium complex treatment in cystic fibrosis

Stacey L Martiniano  1 , Brandie D Wagner  2 , Laney Brennan  3 , Michael F Wempe  4 , Peter L Anderson  4 , Charles L Daley  5 , Meg Anthony  3 , Jerry A Nick  5 , Scott D Sagel  6
Affiliations

Pharmacokinetics of oral antimycobacterials and dosing guidance for Mycobacterium avium complex treatment in cystic fibrosis

Stacey L Martiniano et al. J Cyst Fibros. 2021 Sep.

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.

Keywords: Cystic fibrosis; Mycobacterium avium; Nontuberculous mycobacteria; Pharmacokinetics; Therapeutic drug monitoring.

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Conflict of interest statement

Declaration of Competing Interest SM: Dr. Martiniano reports receipt of grants from the Cystic Fibrosis Foundation (CFF) and National Institutes of Health (NIH) for this project. Generally related to nontuberculous mycobacteria, she serves on the advisory board for Beyond Air.; BW: No conflicts of interest to report related to the subject of the manuscript.; LB: No conflicts of interest to report related to the subject of the manuscript.; MW: No conflicts of interest to report related to the subject of the manuscript.; PA: Dr. Anderson reports no conflicts of interest directly related to the manuscript under consideration but reports personal fees and research support from Gilead Sciences for other investigations.; CD: Dr. Daley reports no conflicts of interest directly related to the subject of the manuscript. Generally related to nontuberculous mycobacteria, he reports receipt of research grants from Insmed and Spero. He also serves on the advisory board or as a consultant for Insmed, Spero, Paratek, Cipla, Matinas, AN2, Johnson and Johnson, and Meiji.; MA: No conflicts of interest to report related to the subject of the manuscript.; JA: Dr. Nick reports no conflicts of interest directly related to the subject of the manuscript. More broadly, he reports research support from the NIH, CFF, Gates Foundation, Department of Defense, State of Colorado, Genentech, Vertex, and Gilead. Also he has served on the advisory board or as a consultant for the CFF, Gilead, Novartis, Vertex, Pharmaxis, Genentech, Savara, and pH Pharma.; SS: Dr. Sagel reports no conflicts of interest directly related to the manuscript under consideration, but reports grants from the CFF and NIH funding other studies and investigations.

Figures

Figure 1:
Figure 1:. Summary of CF subjects (fasting and fed) Cmax z-scores for azithromycin, ethambutol, and rifampin compared to HC.
Each line represents the Cmax z-scores from one CF subjects across all drugs and fasting and fed states. The shades area represents the typical Cmax z-scores from HC subjects (within +/− 2 standard deviations (SD) from the mean). Overall, 16 CF subjects had at least one high Cmax z-score greater than +2SD and 6 CF subjects had at least one low Cmax z-score below −2SD. In total, 19 of 20 CF subjects had one or more abnormal Cmax z-scores (outside +/− 2SD) when compared to HC.
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