Pharmacokinetics of Plerixafor (AMD3100) in Volunteers with Renal Impairment.
Authors: MacFarland Ronald , Ewesuedo Reginal B. , Badel Karin , Calandra Gary 
Published: October 2019

Introduction: Plerixafor (AMD3100) is a first-in-class, small molecule inhibitor of the CXCR4 chemokine receptor that blocks binding of its cognate ligand, SDF-1α. In clinical studies conducted in non-Hodgkin’s lymphoma and multiple myeloma patients, plerixafor when used with G-CSF was shown to be safe and effective in mobilizing CD34+ cells for autologous hematopoietic stem cell transplantation. Non-clinical studies conducted using radiolabeled plerixafor have shown 60-70% recovery of total radioactivity in urine within 24 hours after subcutaneous (SQ) administration. Based on this observation, we hypothesized that plerixafor clearance from plasma is likely to be reduced in patients with impaired renal function, which is commonly observed in multiple myeloma patients. The purpose of this study was to determine the pharmacokinetic parameters of plerixafor in subjects with renal impairment.

Methods: This open-label study examined the pharmacokinetics of a single 240 mcg/kg SQ dose of plerixafor in subjects with varying degrees of renal impairment. Otherwise healthy subjects of normal weight and liver function, not requiring kidney dialysis, were classified into 4 groups of varying renal function, based on 24 hour creatinine clearance collected within 2 weeks prior to plerixafor administration. Approximately 6 subjects are to be enrolled into each group. Serial blood and urine samples were collected over a 24 hour period for analysis of plerixafor concentration using a validated LC-MS method. Plerixafor pharmacokinetics were characterized using noncompartmental methods.

Results: Data were available from 18 subjects (aged 36–74 years) at the time this abstract was prepared. Pharmacokinetic parameters from available subjects are summarized in Table 1.

Plerixafor clearance was dependent upon renal function. A statistically significant correlation between decreasing renal function, as determined by creatinine clearance, and reduced plerixafor clearance was observed, p < 0.001. Median clearance values were reduced from 3.96 L/hr in control subjects to 1.65 L/hr in subjects with severe renal impairment. A corresponding increase in half-life was observed from 4.7 hours in control subjects to 12.5 hours in subjects with severe renal impairment. No significant change in Cmax was observed across the groups, with time to Cmax observed at the 0.5 or 1 hour sampling time points in all subjects.

Conclusions: These preliminary findings indicate a correlation between decreasing renal function and reduced plerixafor clearance from plasma. While peak exposures to plerixafor were apparently independent of renal function, total drug exposure over time was dependent on renal function. Preliminary review of the available results suggests that dose reduction of plerixafor may be warranted in patients with moderately to severely impaired renal function.

Pharmacokinetic Parameters1 Cohort CrCl (mL/min) Cmax(ng/mL) AUC0-24h(ng*hr/mL) t1/2(hr) CLCR(L/hr) 1values shown are median (range) Control (n=6) 136 (107-455) 895 (812-1260) 5089 (3886-6218) 4.7 (4.3-5.7) 3.96 (3.65-5.63) Mild (n=2) 73 (71-74) 738 (705-770) 5563 (4580-6545) 7.1 (6.0-8.2) 3.09 (2.51-3.66) Moderate (n=6) 41 (31-51) 964 (559-1270) 7096 (4661-8388) 11.1 (8.8-15.0) 2.03 (1.67-4.74) Severe (n=4) 11 (9-14) 781 (609-1140) 7840 (5807-8010) 12.5 (12.1-22.0) 1.65 (1.59-1.80)