PII-100 - PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELLING FOR PREDICTING DRUG-DRUG INTERACTIONS (DDI) OF SHR2554

X. Wang¹, Z. Zhu², S. Li², K. Shen², N. DJEBLI³; ¹Jiangsu Hengrui Pharmaceuticals, Shanghai, China, Jiangsu Hengrui Pharmaceuticals - Shanghai,, China, ²Jiangsu Hengrui Pharmaceuticals, Shanghai, China, Jiangsu Hengrui Pharmaceuticals, Shanghai, China, ³Luzsana / Hengrui, Luzsana Biotechnology (subsidiary of Jiangsu Hengrui Pharmaceutical), Basel, Switzerland.

Background: SHR2554 is a novel, highly potent, selective oral EZH2 inhibitor. It is intended for the treatment of malignant tumors including recurrent/refractory mature lymphoid neoplasms. SHR2554 is extensively metabolized, primarily via CYP3A. Therefore, the present analysis used mechanistic modelling to simulate the pharmacokinetic (PK) of SHR2554 in clinical scenarios and to evaluate its DDI potential.

Methods: A PBPK model for SHR2554 was developed in PK-Sim (V11.2). The initial model was optimized and validated using clinical PK data either as monotherapy or in combination with the strong CYP3A4 inhibitor itraconazole or the strong CYP3A4 inducer rifampicin and finally went through sensitivity analysis. The final model was used to simulate the impact of other (weak to strong) CYP3A4 inhibitors and inducers on the PK of SHR2554.

Results: The final model demonstrated good predictive performance for SHR2554. In cancer patients (CP), 24/24 exposures (i.e. AUC, Cmax) from different scenarios had fold errors within the range of 0.5-2, while it was 83.3% (15/18) of the exposures (i.e. AUC, Cmax, AUCR, CmaxR) in healthy volunteers (HV). The predictions suggested that the strong CYP3A4 inhibitor clarithromycin significantly increases the SHR2554 exposure (CmaxR: 1.79 - 2.78, AUCR: 6.37 - 19.70) at therapeutic dose (350 mg) in CP. The strong CYP3A4 inducer carbamazepine significantly reduces SHR2554 exposures (CmaxR: 0.34 - 0.47, AUCR: 0.27 - 0.35) at same dose in CP. When co-administered with the moderate CYP3A4 inhibitors erythromycin or verapamil, SHR2554 AUC increases more than 2-fold. The moderate competitive CYP3A4 inhibitor fluvoxamine and weak CYP3A inhibitor cimetidine have limited impact on SHR2554 exposure. When co-administered with strong CYP3A4 inhibitors or inducers, the impact was different in CP vs. HV. When 50 mg of SHR2554 was co-administered with the strong CYP3A4 inhibitor clarithromycin, Cmax change in HV was twice that observed in CP (6.21 vs 3.36). When 350 mg of SHR2554 was co-administered with the strong CYP3A4 inducer carbamazepine, Cmax and AUC changes were 1.5 times greater in HV than in CP (0.20 vs 0.31).

Conclusion: PBPK model provided insights for SHR2554 dosage adjustments when co-administered with CYP3A4 inhibitors or inducers and has been used as an alternative to clinical studies to assist in regulatory decision-making.