PII-141 - PILOT FEASIBILITY STUDY OF AN ORAL CYP3A4/2C19 PROBE COCKTAIL TO PREDICT BORTEZOMIB CLEARANCE IN MULTIPLE MYELOMA PATIENTS

M. Hai¹, B. Dangi², J. Johnson², P. Patel², M. Phelps¹, K. Sweiss²; ¹The Ohio State University, ²University of Illinois at Chicago.

Background: Bortezomib (BTZ) is a first-in-class drug in multiple myeloma that reversibly binds to the chymotrypsin-like subunit of the 26S proteasome, resulting in its inhibition and preventing the degradation of various pro-apoptotic factors. The dose-limiting toxicity of BTZ is peripheral neuropathy (PN), which can be long-term and debilitating in many patients and requires dose modification or discontinuation. Few studies have identified risk factors for BTZ PN, but data suggest BTZ exposure may predict PN. BTZ exhibits dose-dependent PK and is oxidatively metabolized via cytochrome P450 (CYP) enzymes 3A4 (~80%) and CYP2C19 (~20%). We hypothesize inter-patient and within-patient variability in CYP activity could impact BTZ clearance and risk for PN. Identification of those patients up front could be a strategy for reducing PN toxicity for myeloma patients.

Methods: We piloted a single-center PK study implementing a probe cocktail for phenotypic analysis of CYP3A4 and 2C19 activity and analysis of BTZ clearance in myeloma patients undergoing two cycles of a BTZ-containing regimen. Probe drugs, buspirone (BUS, for CYP3A4) and omeprazole (OMEP, for CYP2C19), were orally administered immediately prior to subcutaneous BTZ, and blood was sampled up to 8 hours after dosing. BTZ, BUS, OMEP, and probe metabolites were quantified via LC-MS/MS.

Results: Ten patients have been enrolled with 182 blood samples collected. Sampling times adequately cover the absorption and distribution phases of the BTZ PK profile, though portions of probe/metabolite profiles are not captured with 30%-60% of concentrations below the limit of quantification (BLQ). Probe drug PK estimates may be partially salvageable by applying various approaches to handle the BLQ data, though BTZ PK can be adequately estimated with the current sampling scheme.

Conclusion: Within the confines of the allowable sampling window, PK estimation of all analytes will be challenging, thus reducing the utility of the probe cocktail for BTZ PK prediction. Further sampling design options are being explored within the allowable sampling window and within alternative sampling windows to provide recommendations for sampling scheme revision to enable adequate probe drug PK estimation.