Garg and colleagues studied interactions involving tezacaftor and ivacaftor in healthy participants. In one set of comparisons, midazolam served as a probe for CYP3A metabolism and digoxin served as a probe for the transporter P-glycoprotein. The researchers measured systemic exposure to see whether the combination affected each probe.
The combination did not meaningfully change measured midazolam exposure under the study conditions. Digoxin’s area under the concentration–time curve increased by about 30%. A result for the CYP3A probe describes the pathway tested by that comparison. It cannot exclude an effect on a transporter substrate or on a different drug under different conditions.
A separate study arm found that itraconazole increased exposure to tezacaftor and ivacaftor. That comparison reversed the direction of the question. It examined how another drug affected the combination, while the midazolam comparison examined how the combination affected the probe. In a toxicology review, identify which drug’s concentration changed, which pathway was tested and what dosing conditions produced the result.
Garg et al., Clinical and Translational Science (2019) · Full text