Evaluation of the pharmacokinetics of posaconazole and rifabutin following co-administration to healthy men

Abstract

Based on the reduced exposure to posaconazole observed in the limited number of subjects in this study and the increased risk for adverse events associated with elevated rifabutin concentrations, concomitant use of rifabutin and posaconazole should be avoided unless the benefit outweighs the risk.

Multicenter Study of Posaconazole Therapeutic Drug Monitoring: Exposure-Response Relationship and Factors Affecting Concentration

“…While posaconazole is excreted primarily unchanged in feces and is not metabolized by CYP450 enzymes, approximately 20 to 30% is known to be glucuronidated via the phase 2 enzyme UDP glucuronosyltransferase 1A4 (UGT1A4) (12,26). Both phenytoin and rifamycins have been shown to significantly reduce posaconazole exposure (21,22), although less information is available for rifampin (15). Posaconazole is also a substrate of P glycoprotein, although the importance of this pathway to posaconazole disposition appears to be limited (36).…”

Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis

“…3). Both phenytoin and rifabutin have been associated with a reduction in the posaconazole area under the concentration-time curve of approximately 50% in studies of healthy volunteers (33,34), with a case study demonstrating a similar interaction with rifampin (35). Approximately 20 to 30% of a posaconazole dose is known to be glucuronidated via the phase 2 enzyme UDP-glucuronosyltransferase 1A4 (UGT1A4) in the liver (36,37).…”

Posaconazole Exposure-Response Relationship: Evaluating the Utility of Therapeutic Drug Monitoring

“…This interaction is especially problematic due to the high incidence of gastroesophageal reflux in certain patient populations where posaconazole is indicated, such as lung transplant recipients (28). Agents that increase gastrointestinal motility, such as metoclopramide, have also been shown to reduce posaconazole concentrations after concomitant oral administration (39), as have inducers of UDP-glucuronosyltransferases such as rifabutin (40) and phenytoin (41), although the exact mechanism of these interactions is not known.…”