Abstract MBQ-167 is a first-in-class dual inhibitor of Rac and Cdc42 GTPases with potent preclinical anti-metastatic activity and is currently under evaluation in a Phase 1 clinical trial (NCT06075810) in patients with advanced breast cancer. This study aimed to characterize the pharmacokinetic (PK) profile of MBQ-167 and its active metabolite M6 in patients treated with 20 mg, 40 mg and 80 mg BID doses (cohorts 0, 1 and 2, respectively). Plasma concentration-time data were analyzed from eight patients using non-compartmental analysis. MBQ-167 was rapidly absorbed with a median Tmax of 1–4 hours and a Cmax ranging from 139 to 573 ng/mL (20 mg BID), 520 to 843 ng/mL (40 mg BID) and 578 to 688 ng/mL (80 mg BID). The elimination half-life (t½) of MBQ-167 was approximately 3–4.5 hours, and the mean residence time (MRT) was 7 hours. Dose-normalized systemic exposure (AUC/D) did not increase proportionally with dose, suggesting a possible reduction in bioavailability at higher doses, potentially due to enterohepatic recycling or saturation of absorption. Importantly, there was no evidence of systemic overexposure or meaningful accumulation (Rac 2.0) of MBQ-167 or M6, indicating a favorable safety margin. Volume of distribution (Vdss) exceeded 30L for both compounds, reflecting extensive tissue distribution consistent with their lipophilicity. M6 demonstrated rapid formation and elimination with t½ values ranging from 3.1 to 4.4 hours, further supporting efficient metabolic conversion. These findings confirm that MBQ-167 exhibits linear PK at clinically relevant doses with manageable exposure and clearance. The observed pharmacokinetics support continued clinical development and provided essential dosing guidance for Phase 2 trials. Further analyses with additional cohorts will be presented up to 400 mg BID. Citation Format: J. F. Rodriguez-Orengo, J. Duconge, M. Acosta, J. Wang, D. Yardley, S. Dharmawardhane, N. Sankar. Pharmacokinetic Evaluation of MBQ-167 a Dual Rac/Cdc42 Inhibitor in Advanced Breast Cancer Patients abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-06-13.
Rodriguez-Orengo et al. (2026) studied this question.