A drug-drug interaction study and physiologically based pharmacokinetic modelling to assess the effect of an oral 5-lipoxygenase activating protein inhibitor on the pharmacokinetics of oral midazolam.

AIMS

Early clinical studies have indicated that the pharmacokinetics of Atuliflapon (AZD5718) are time and dose dependent. The reason(s) for these findings is(are) not fully understood, but pre-clinical profiling suggests that time-dependent CYP3A4 inhibition cannot be excluded. In clinical practice, Atuliflapon will be co-administered with CYP3A4 substrates; thus, it is important to determine the impact of Atuliflapon on the pharmacokinetics (PK) of CYP3A4 substrates. The aim of this study was to evaluate the effect of Atuliflapon on the pharmacokinetics of a sensitive CYP3A4 substrate, midazolam, and to explore if the time-/dose-dependent effect seen after repeated dosing could be an effect of change in CYP3A4 activity.

METHODS

Open-label, fixed-sequence study in healthy volunteers to assess the PK of midazolam alone and in combination with Atuliflapon. Fourteen healthy male subjects received single oral dose of midazolam 2 mg on days 1 and 7 and single oral doses of Atuliflapon (125 mg) from days 2 to 7. A physiologically based pharmacokinetic (PBPK) model was developed to assess this drug-drug interaction.

RESULTS

Mean midazolam values of maximum plasma concentration (C) and area under the curve (AUC) to infinity were increased by 39% and 56%, respectively, when co-administered with Atuliflapon vs. midazolam alone. The PBPK model predicted a 27% and 44% increase in AUC and a 23% and 35% increase in C of midazolam following its co-administrations with two predicted therapeutically relevant doses of Atuliflapon.

CONCLUSIONS

Atuliflapon is a weak inhibitor of CYP3A4; this was confirmed by the validated PBPK model. This weak inhibition is predicted to have a minor PK effect on CYP3A4 metabolized drugs.