title: Pharmacokinetics and relative bioavailability of clofazimine in relation to food, orange juice and antacid.
abstract: BACKGROUND
  Clofazimine is potentially useful for the treatment of disease due to multidrug resistant Mycobacterium tuberculosis, as well as leprosy and certain chronic skin diseases. Its pharmacokinetics have been incompletely characterized. This study was conducted to explore issues relating to bioavailability in the presence of food, orange juice, and antacid.
  
  
  METHODS
  A 5 drug regimen consisting of clofazimine, cycloserine, ethionamide, para-aminosalicyclic acid, and pyridoxime was administered to healthy subjects four times using a four period cross-over design with two weeks washout between treatments. Subjects also received orange juice, a high fat meal, aluminum/magnesium antacid, or only water in random order with the drug regimen. The pharmacokinetics of clofazimine were assessed using individual- and population-based methods and relative bioavailability compared to fasting administration was determined.
  
  
  RESULTS
  Clofazimine exhibited a sometimes prolonged and variable lag-time and considerable variability in plasma concentrations. From the population analysis (one-compartment model), the mean oral clearance was 76.7 l/h (CV=74.2%) and mean apparent volume of distribution was 1470 l (CV=36.3%). The first-order absorption rate constant ranged from 0.716 to 1.33 h(-1) (pooled CV=61.7%). Residual (proportional) error was 49.1%. Estimates of bioavailability compared to fasting administration were 145% (90% CI, 107-183%) for administration with high fat food, 82.0% (63.2-101%) for administration with orange juice, and 78.5% (55.1-102%) for administration with antacid.
  
  
  CONCLUSIONS
  Administration of clofazimine with a high fat meal provides the greatest bioavailability, however, bioavailability is associated with high inter- and intra-subject variability. Both orange juice and aluminum-magnesium antacid produced a reduction in mean bioavailability of clofazimine.
authors.affiliation: University of Arizona College of Pharmacy, P.O. Box 210-207, Tucson, AZ 85721-0207, USA. nix@pharmacy.arizona.edu
authors.forename: D E David E
authors.initials: DE
authors.lastname: Nix
authors.forename: R D Rodney D
authors.initials: RD
authors.lastname: Adam
authors.forename: Barbara
authors.initials: B
authors.lastname: Auclair
authors.forename: T S Todd S
authors.initials: TS
authors.lastname: Krueger
authors.forename: P G Paul G
authors.initials: PG
authors.lastname: Godo
authors.forename: C A Charles A
authors.initials: CA
authors.lastname: Peloquin
mesh_terms: D000284:Administration, Oral; D000328:Adult; D010131:Aminosalicylic Acid / Q000008:administration & dosage; D000863:Antacids / Q000378:metabolism*; D000995:Antitubercular Agents / Q000008:administration & dosage; D001628:Beverages; D001682:Biological Availability; D032084:Citrus sinensis; D002991:Clofazimine / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003523:Cycloserine / Q000008:administration & dosage; D004041:Dietary Fats; D004338:Drug Combinations; D004347:Drug Interactions; D005000:Ethionamide / Q000008:administration & dosage; D005502:Food; D018565:Food-Drug Interactions; D006801:Humans; D007917:Leprostatic Agents / Q000097:blood / Q000493:pharmacokinetics*; D011736:Pyridoxine / Q000008:administration & dosage
chemical_list: D000863:Antacids; D000995:Antitubercular Agents; D004041:Dietary Fats; D004338:Drug Combinations; D007917:Leprostatic Agents; D010131:Aminosalicylic Acid; D003523:Cycloserine; D002991:Clofazimine; D011736:Pyridoxine; D005000:Ethionamide