Population pharmacokinetics of pomalidomide in patients with relapsed or refractory multiple myeloma with various degrees of impaired renal function

Yan Li, Xiaomin Wang, Edward O'Mara, Meletios A Dimopoulos, Pieter Sonneveld, Katja C Weisel, Jeffrey Matous, David S Siegel, Jatin J Shah, Elisabeth Kueenburg, Lars Sternas, Chloe Cavanaugh, Mohamed Zaki, Maria Palmisano, Simon Zhou, Yan Li, Xiaomin Wang, Edward O'Mara, Meletios A Dimopoulos, Pieter Sonneveld, Katja C Weisel, Jeffrey Matous, David S Siegel, Jatin J Shah, Elisabeth Kueenburg, Lars Sternas, Chloe Cavanaugh, Mohamed Zaki, Maria Palmisano, Simon Zhou

Abstract

Pomalidomide is an immunomodulatory drug for treatment of relapsed or refractory multiple myeloma (rrMM) in patients who often have comorbid renal conditions. To assess the impact of renal impairment on pomalidomide exposure, a population pharmacokinetics (PPK) model of pomalidomide in rrMM patients with various degrees of impaired renal function was developed. Intensive and sparse pomalidomide concentration data collected from two clinical studies in rrMM patients with normal renal function, moderately impaired renal function, severely impaired renal function not requiring dialysis, and with severely impaired renal function requiring dialysis were pooled over the dose range of 2 to 4 mg, to assess specifically the influence of the impaired renal function as a categorical variable and a continuous variable on pomalidomide clearance and plasma exposure. In addition, pomalidomide concentration data collected on dialysis days from both the withdrawal (arterial) side and from the returning (venous) side of the dialyzer, from rrMM patients with severely impaired renal function requiring dialysis, were used to assess the extent to which dialysis contributes to the removal of pomalidomide from blood circulation. PPK analyses demonstrated that moderate to severe renal impairment not requiring dialysis has no influence on pomalidomide clearance or plasma exposure, as compared to those patients with normal renal function, while pomalidomide exposure increased approximately 35% in patients with severe renal impairment requiring dialysis on nondialysis days. In addition, dialysis increased total body pomalidomide clearance from 5 L/h to 12 L/h, indicating that dialysis will significantly remove pomalidomide from the blood circulation. Thus, pomalidomide should be administered post-dialysis on the days of dialysis.

Keywords: hemodialysis; pomalidomide; population pharmacokinetics; renal impairment.

Conflict of interest statement

Disclosure Yan Li, Xiaomin Wang, Edward O’Mara, Elisabeth Kueen-burg, Lars Sternas, Chloe Cavanaugh, Mohamed Zaki, Maria Palmisano, and Simon Zhou are employees of and hold equity ownership in Celgene Corporation; Meletios A Dimopoulos has received honoraria and consulting/advisory fees from Amgen, Celgene, Janssen, and Takeda; Pieter Sonneveld has received advisory/consultancy fees from Celgene, Amgen, Janssen, Karyopharm, and Skyline, and honoraria from Celgene, Amgen, Janssen, and Karyopharm; Katja C Weisel has received research funding from Celgene and Janssen and honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, Onyx, and Takeda, and has held advisory board membership for Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, Onyx, and Takeda; Jeffrey Matous has received advisory/consultancy fees from Celgene and served on their speaker’s bureau; David S Siegel has served on speaker’s bureaus for Celgene, Amgen, Takeda, Merck, and Novartis; Jatin J Shah has received research funding from Bristol-Myers Squibb, Celgene, Amgen, Novartis, and Array, consulting fees from Bristol-Myers Squibb, Celgene, Takeda, and Novartis, and served on speaker’s bureaus for Bristol-Myers Squibb, Amgen, and Janssen. The authors report no other conflicts of interest.

Figures

Figure 1
Figure 1
Average dose-normalized pomalidomide concentration vs time profiles by renal function group.
Figure 2
Figure 2
Visual predictive checks for time profiles of pomalidomide concentrations by group. Notes: Group 1: patients with normal renal function; Group 2: patients with moderately impaired renal function; Group 3: patients with severely impaired renal function not requiring hemodialysis; Group 4: patients with severely impaired renal function requiring hemodialysis. Circles represent observed data. Lines represent the 50th (solid) percentiles of the observed data. Shaded areas represent nonparametric 95% CI about the 50th (pink) percentiles for the corresponding model-predicted percentiles. Abbeviations: LCONC, logarithm-transformed concentration; NTIME, nominal time.
Figure 3
Figure 3
Median values of the plasma concentration profiles with 90% CI from 200 Monte Carlo simulations based on the final population pharmacokinetic model with renal function treated as a categorical variable.
Figure 4
Figure 4
Relationship between pomalidomide apparent clearance (CL/F) and CrCl (A) or eGFR (B). Note: Red lines represent the locally weighted scatterplot smoothing line. Abbreviations: CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate.
Figure 5
Figure 5
Simulated plasma concentration vs time profiles under different starting times of the hemodialysis procedure after pomalidomide administration.
Figure 6
Figure 6
Simulated plasma concentration vs time profiles when the hemodialysis procedure is completed before pomalidomide administration. Notes: Red line represents the mean of the simulated concentration vs time profile. Light blue shaded area represents the 90% CI of the simulated concentration vs time profile. Blue arrows represent pomalidomide dosing time. Bold green lines represent hemodialysis procedure (lasting for 4 h).

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