Pharmacokinetics and safety of carfilzomib in patients with relapsed multiple myeloma and end-stage renal disease (ESRD): an open-label, single-arm, phase I study

Hang Quach,Darrell White,Sandeep Inamdar,Mike White,Ying Ou,Andrew Spencer,Martin Gyger,P Joy Ho,Chris Morris,Divaya Bhutani

doi:10.1007/s00280-017-3287-8

Abstract

PurposeThe pharmacokinetics (PK) of carfilzomib have been previously studied in multiple myeloma patients with varying degrees of renal impairment (normal, mild, moderate, severe, and end-stage renal disease [ESRD]) at doses of 15 and 20 mg/m2. This study evaluated carfilzomib PK at higher doses of 27 and 56 mg/m2 in normal renal function and ESRD patients.MethodsPatients received carfilzomib on two consecutive days/week for 3 weeks every 28-day cycle: 20 mg/m2 (cycle 1 day 1–2), escalated to 27 mg/m2 on cycle 1 day 8; if tolerated, 56 mg/m2 starting cycle 2 day 1. The primary objective was PK assessment with safety/tolerability and response rate as secondary and exploratory objectives, respectively.Results26 patients were enrolled (15 normal, 11 ESRD). There was a trend toward higher area under the concentration time curve (AUC) and maximum concentration in ESRD versus normal renal function patients; however, high interpatient PK variability was discerned. Relative to patients with normal renal function, ESRD patients showed 33% higher AUC. Overall response rate was 43% for the normal renal function and 60% for the ESRD groups. Safety findings were generally similar between the two groups and consistent with the known safety profile of carfilzomib in multiple myeloma patients.ConclusionThere were no meaningful differences in PK between patients with normal renal function and ESRD in light of carfilzomib exposure–response relationships. These results continue to support dosing recommendation that no starting dose adjustment of carfilzomib appears warranted in patients with baseline renal impairment.

Highlights

Renal insufficiency is a common and often severe complication in multiple myeloma [1, 2]
The results show no apparent differences in carfilzomib (15 or 20 mg/m2) clearance, area under the concentration time curve (AUC), and maximum plasma concentration (Cmax) between patients with normal versus those with mild, moderate, or severe renal impairment, including patients with end-stage renal disease (ESRD) on hemodialysis [11]
The other 4 deaths (n = 2 per cohort) were due to disease progression. In this phase I trial, trends toward higher exposure (AUC and Cmax), longer t1/2, and slower clearance for carfilzomib 27- and 56-mg/m2 doses were observed in patients with ESRD relative to those with normal renal function without an apparent increase in adverse events (AEs)

Summary

Introduction

Renal insufficiency is a common and often severe complication in multiple myeloma [1, 2]. Several factors can contribute to renal insufficiency in multiple myeloma, including hypercalcemia and myeloma cast nephropathy. Two demographic studies evaluating a combined 2380 patients with newly diagnosed multiple myeloma found that nearly. 50% of patients had impaired renal function as determined by estimated creatinine clearance (CrCL) at presentation, approximately 15% of whom had severe renal insufficiency with serum creatinine levels of >2.3 mg/dL [5, 6]. The presence of renal impairment can limit treatment options or complicate dosing of drugs, leading in some cases to higher incidence or exacerbation of adverse events (AEs) [7]

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Results

Conclusion