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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacokinetics
  • Antibiotics, Antitubercular / pharmacokinetics
  • Antitubercular Agents / administration & dosage
  • Antitubercular Agents / pharmacokinetics
  • Azithromycin / administration & dosage
  • Azithromycin / pharmacokinetics*
  • Cross-Over Studies
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / microbiology
  • Ethambutol / administration & dosage
  • Ethambutol / pharmacokinetics*
  • Humans
  • Mycobacterium avium Complex
  • Mycobacterium avium-intracellulare Infection / drug therapy*
  • Prospective Studies
  • Rifampin / administration & dosage
  • Rifampin / pharmacokinetics*

Substances

  • Anti-Bacterial Agents
  • Antibiotics, Antitubercular
  • Antitubercular Agents
  • Azithromycin
  • Ethambutol
  • Rifampin

Associated data

  • ClinicalTrials.gov/NCT02372383