Quantitative prediction of OATP1B-mediated drug-drug interactions using endogenous biomarker coproporphyrin I.

Evaluation of the organic anion transporting polypeptide (OATP) 1B-mediated drug-drug interaction (DDI) potential is important for drug development. The focus of this study was coproporphyrin I (CP-I), an endogenous OATP1B biomarker.We investigated a new approach to OATP1B-mediated DDI prediction based on the mechanistic static pharmacokinetics (MSPK) model.The ratio of the area under the plasma concentration-time curve (AUCR) with and without co-administration of rifampicin (a typical OATP1B inhibitor) was found for CP-I and OATP1B substrate, respectively, and was then used to derive the correlation curve equation. The AUCR with and without co-administration of another OATP1B inhibitor than rifampicin was then predicted for the OATP1B substrates by substituting the AUCR of CP-I in the correlation curve equation to verify the predictability of the AUCR of the OATP1B substrates.The derived correlation curve equation between CP-I and the OATP1B substrates of the AUCRs with and without co-administration of rifampicin matched the observed AUCRs well. Regarding pitavastatin, rosuvastatin, and pravastatin, 92.9% of the predicted AUCR values were within a two-fold range of the observed values, indicating that this approach may be a good way to quantitatively predict DDI potential.

Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial.

Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation.Objectives: To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis.Methods: This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90.Measurements and Main Results: Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa, n = 40; placebo, n = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%; P = 0.0863). In the safety population (n = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%).Conclusions: Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).