Physiologically based pharmacokinetic modeling to understand the observed drug–drug interaction of LY2623091 with CYP3A inhibitors itraconazole and diltiazem

Aims: Drug–drug interaction studies were used to estimate CYP3A4-dependent clearance of LY2623091. Methods: in a cross-over design, healthy adults received a single 6-mg dose of LY2623091 at baseline. Itraconazole (200 mg twice on day 1 then daily × 19 days; n = 16) and diltiazem (240 mg Extended Release daily × 13 days; n = 16) were given. On days 6 and 4, respectively, LY2623091 was dosed 1 h after itraconazole/diltiazem. Pharmacokinetic samples were obtained and static and dynamic models were used to assess interaction. Results: Area under the concentration–time curve for LY2623091 increased 2.2-fold with itraconazole and 1.4-fold with diltiazem. Maximum plasma concentration did not change. The physiologically based pharmacokinetic model overpredicted itraconazole and hydroxy–itraconazole concentrations. Extraction by CYP3A4 was ∼0.5; gut wall extraction was negligible. Conclusion: Interaction risk requires early clinical assessment to quantify the candidate drug. (Clinical trial registration number: N...