Zibotentan Can Be Co-administered with Contraceptives Containing Ethinyl Estradiol and Levonorgestrel: A Pharmacokinetic Drug-Drug Interaction Study.

The endothelin A receptor antagonist zibotentan, combined with the sodium-glucose co-transporter-2 inhibitor dapagliflozin, is being investigated for the treatment of chronic kidney disease with high proteinuria. To allow women of childbearing potential access to this treatment, highly effective contraception is required and drug interactions compromising contraception reliability must be avoided. This study investigated the risk of pharmacokinetic (PK) interaction between zibotentan and the contraceptives ethinyl estradiol and levonorgestrel. A single-sequence, within-participant comparison study was conducted in 24 healthy women of non-childbearing potential, comparing the PK of ethinyl estradiol/levonorgestrel alone and with zibotentan. Single oral doses of 0.06 mg ethinyl estradiol/0.3 mg levonorgestrel were administered on Days 1 and 15; zibotentan 10 mg was dosed orally, once-daily through Days 6-19. PK profiles were determined and ethinyl estradiol/levonorgestrel PK was compared between Day 1 and 15 based on geometric least-squares mean ratios of PK parameters, including maximum observed concentration (Cmax) and area under the plasma concentration-time curve from zero to infinity (AUCinf). Co-administration with zibotentan did not affect ethinyl estradiol PK (geometric mean ratio [90% confidence interval] Cmax 1.05 [0.99-1.11], AUCinf 1.00 [0.96-1.05]), while a weak interaction (increased exposure) was observed for levonorgestrel (Cmax 1.12 [1.02-1.23], AUCinf 1.30 [1.21-1.39]), which was regarded as without clinical relevance. Plasma exposure of ethinyl estradiol/levonorgestrel was not reduced by multiple-dose zibotentan. In conclusion, contraception containing ethinyl estradiol/levonorgestrel is regarded possible under zibotentan-containing treatments. This expands choices for women of childbearing potential, supporting diversity in the ZENITH High Proteinuria trial.

Phase II Efficacy and Safety of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer (BLOSSOM).

PURPOSE: Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs. MATERIALS AND METHODS: In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6. RESULTS: A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set-T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2. CONCLUSION: The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.