Pharmacokinetic Drug–Drug Interaction Studies Between Trilaciclib and Midazolam, Metformin, Rifampin, Itraconazole, and Topotecan in Healthy Volunteers and Patients with Extensive-Stage Small-Cell Lung Cancer

Background and Objective Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor indicated to decrease the incidence of chemotherapy-induced myelosuppression in patients with extensive-stage small-cell lung cancer. Trilaciclib is a substrate and time-dependent inhibitor of cytochrome P450 3A4 and an inhibitor of multidrug and toxin extrusion 1, multidrug and toxin extrusion 2-K, organic cation transporter 1, and organic cation transporter 2. Here, we investigate the pharmacokinetic drug–drug interaction potential of trilaciclib. Methods Two phase I studies were conducted as prospective, open-label, fixed-sequence drug–drug interaction studies in healthy subjects ( n = 57, n = 20) to investigate potential interactions between intravenously administered trilaciclib (200 or 240 mg/m 2 ) and orally administered midazolam (5 mg), metformin (1000 mg), itraconazole (200 mg), and rifampin (600 mg). A population pharmacokinetic model was fit to phase Ib/IIa data in patients with extensive-stage small-cell lung cancer ( n = 114) to assess the impact of trilaciclib dose and exposure (area under the plasma concentration–time curve) on topotecan clearance. Results Coadministration with trilaciclib had minimal effects on the exposure (area under the plasma concentration–time curve from time 0 to infinity) of midazolam (geometric least-square mean ratio [GMR] vs midazolam alone 1.065; 90% confidence interval [CI] 0.984–1.154) but statistically significantly increased plasma exposure (GMR 1.654; 90% CI 1.472–1.858) and decreased renal clearance (GMR 0.633; 90% CI 0.572–0.701) of metformin. Coadministration of trilaciclib with rifampin or itraconazole decreased trilaciclib area under the plasma concentration–time curve from time 0 to infinity by 17.3% (GMR 0.827; 90% CI 0.785–0.871) and 14.0% (GMR 0.860; 0.820–0.902), respectively, vs trilaciclib alone. Population pharmacokinetic modeling showed no significant effect of trilaciclib on topotecan clearance. Conclusions Overall, the drug–drug interaction and safety profiles of trilaciclib in these studies support its continued use in patients with extensive-stage small-cell lung cancer. Clinical Trial Registration Study 106: EudraCT number: 2019-002303-18; Study 114: not applicable; Study 03: Clinicaltrials.org: NCT02514447; August 2015.