In silico evaluation of the interaction of P-gp and 3A4 substrates with the WEE1 inhibitor Debio 0123 and clinical application in the Debio 0123-104 combination trial with carboplatin and etoposide.

Abstract

e15127 Background: Debio 0123 is an oral, brain-penetrant, highly selective WEE1 kinase inhibitor currently being investigated in several clinical trials in patients with advanced solid tumors both as monotherapy and in combination. In vitro , Debio 0123 can inhibit and induce cytochrome P450 (CYP) 3A4 and inhibit P-gp. Methods: A physiologically-based pharmacokinetic (PBPK) model using Simcyp Population Based Simulator was developed for Debio 0123 to evaluate its perpetrator effect on sensitive substrates of CYP3A4 and P-gp. A second model was developed for etoposide as victim drug. Both were combined to assess the risk of clinical drug-drug interaction (DDI) between Debio 0123 and etoposide. Plasma etoposide concentrations were simulated following single and three daily doses of etoposide 100 mg/m 2 IV administered concomitantly with, or without, 520 mg oral (PO) Debio 0123. The Debio 0123 model was developed using in vitro and clinical data from previous Debio 0123 clinical trials. Results: No clinically significant DDIs were predicted between Debio 0123 given for 3 consecutive days and the CYP3A4 probe substrate, midazolam. When PO or IV administration of midazolam was simulated, the 90%CI of the geometric mean ratio (GMR) for AUC inf and C max , alone versus in combination with Debio 0123, entirely fell within 0.9 and 1.3. A weak DDI was predicted towards the P-gp probe substrate dabigatran etexilate. When given orally, AUC inf and C max GMR of dabigatran with, or without, Debio 0123 were 1.87 and 1.93, respectively. Administration, for 3 consecutive days, of Debio 0123 combined with IV etoposide was predicted to have no effect on etoposide exposure (90%CI of GMR for both AUC and C max within 0.80-1.25). Accordingly, the design of Debio 0123-SCLC-104 trial with Debio 0123 administered in combination with carboplatin and etoposide (NCT05815160 - ASCO 2025 # 495064) was developed with standard doses of IV etoposide. To confirm the absence of DDI, PK samples were collected in the trial. No major changes were noted in the observed etoposide exposure across Debio 0123 dose levels (200 to 400 mg) after one or three days of co-administration in adult SCLC participants that recurred or progressed after previous platinum treatment. Etoposide PK observed in the study was also in line with literature data (US label Etopophos 2011). Debio 0123 PK was consistent with data previously reported for monotherapy (Abstract #3120 ASCO 2024). Conclusions: Overall, these results indicate that there is no relevant PK interaction between Debio 0123 and IV etoposide. For concomitant medications that are P-gp substrates, only a weak DDI is expected with Debio 0123. Furthermore, the absence of significant DDIs predicted with CYP3A4 substrates suggests that Debio 0123 can be combined with a wide range of therapies. Clinical trial information: NCT05815160 .