Trial results for a study (NCT05072106) evaluating the effect of bosentan on the pharmacokinetics of lurbinectedin in patients with advanced solid tumors were posted on ClinicalTrials.gov on 2025-09-16. The study found that co-administration with bosentan decreased the dose-normalized area under the plasma concentration-time profile from time zero to extrapolated infinity (AUC0-∞) of lurbinectedin by approximately 20%, with a least-squares geometric mean ratio of 79.81% (90.0% CI: 64.78 to 98.32) compared to lurbinectedin alone.
Background
The study, titled "Study to Evaluate the Effect of Bosentan on the Pharmacokinetics of Lurbinectedin in Patients With Advanced Solid Tumors," investigated potential drug-drug interactions between lurbinectedin and bosentan. Lurbinectedin (Zepzelca) is used in the treatment of advanced solid tumors, and understanding its pharmacokinetic profile when co-administered with other medications like bosentan is crucial for patient management.
Trial design
The study (NCT05072106) was a Phase 1, prospective, open-label, two-way crossover drug-drug interaction study. It enrolled 11 patients diagnosed with advanced solid tumors. The trial design included two cycles of lurbinectedin administration: one cycle in combination with bosentan and one cycle as a single agent. The order of these cycles varied depending on the study sequence. An additional third cycle of lurbinectedin as a single agent was offered to patients who met continuation criteria and showed clinical benefit after the first two cycles.
Key results
The trial evaluated the pharmacokinetic parameters of lurbinectedin when administered alone and in combination with bosentan. The least-squares geometric mean ratios (Bosentan co-administration vs. Single agent lurbinectedin) and their 90.0% confidence intervals were:
- For dose-normalized maximum observed plasma concentration (Cmax) of total lurbinectedin: 96.83% (90.0% CI: 81.09 to 115.62). The geometric mean Cmax was 20.71 µg/L/mg with bosentan and 21.39 µg/L/mg without.
- For dose-normalized area under the plasma concentration-time profile from time zero to extrapolated infinity (AUC0-∞) of total lurbinectedin: 79.81% (90.0% CI: 64.78 to 98.32). The geometric mean AUC0-∞ was 58.83 µg·h/L/mg with bosentan and 73.71 µg·h/L/mg without.
- For dose-normalized area under the plasma concentration-time profile from time zero to last quantifiable concentration (AUC0-t) of total lurbinectedin: 79.2% (90.0% CI: 64.12 to 97.82). The geometric mean AUC0-t was 56.33 µg·h/L/mg with bosentan and 71.13 µg·h/L/mg without.
- For plasma clearance (CL) of total lurbinectedin: 125.3% (90.0% CI: 101.71 to 154.36). The geometric mean CL was 17.00 L/h with bosentan and 13.57 L/h without.
- For plasma volume of distribution at steady-state (Vss) of total lurbinectedin: 106.79% (90.0% CI: 74.63 to 152.8). The geometric mean Vss was 412.94 L with bosentan and 386.69 L without.
- For terminal elimination half-life (t1/2) in plasma of total lurbinectedin: 104.93% (90.0% CI: 69.49 to 158.44). The geometric mean t1/2 was 35.51 h with bosentan and 33.84 h without.
What this means
The results of this Phase 1 drug-drug interaction study indicate that co-administration of bosentan with lurbinectedin leads to a reduction in lurbinectedin systemic exposure. Specifically, the dose-normalized AUC0-∞ and AUC0-t were approximately 20% lower when lurbinectedin was given with bosentan compared to lurbinectedin alone, as evidenced by the least-squares geometric mean ratios of 79.81% and 79.2%, respectively, with their 90.0% confidence intervals not including 100%. Concurrently, the plasma clearance (CL) of lurbinectedin increased by approximately 25% when co-administered with bosentan. These findings suggest that bosentan may induce the metabolism or increase the clearance of lurbinectedin, potentially leading to sub-optimal therapeutic levels of lurbinectedin. Clinicians should consider these pharmacokinetic interactions when prescribing lurbinectedin to patients also receiving bosentan.
Source
The information regarding these trial results was obtained from ClinicalTrials.gov, a public database of clinical studies. The results for study NCT05072106, titled "Study to Evaluate the Effect of Bosentan on the Pharmacokinetics of Lurbinectedin in Patients With Advanced Solid Tumors," were posted on 2025-09-16 on clinicaltrials.gov.