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

Abstract

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/m2) 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.