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

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

doi:10.2147/cpaa.s144606

Cited by 13 publications

(15 citation statements)

References 23 publications

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“…13 The pharmacokinetics (PK) of pomalidomide after a single oral dose of 4 mg in plasma was characterized by rapid absorption (median time to peak plasma drug concentration [t max ] 2.50-3.25 hours post dose) and rapid elimination (mean terminal half-life [t 1/2 ] range of 8.90-11.21 hours). Consistently, several studies showed that the PK of pomalidomide was not remarkably affected in renally impaired patients, 17,18 and the liver plays the predominant role in eliminating pomalidomide in vivo. Human [ 14 C]pomalidomide absorption, metabolism, and excretion study showed that the recovery of total [ 14 C]radioactivity was approximately 88% of the administered dose, with 72.8% and 15.5% recovered in urine and feces, respectively.…”

supporting

confidence: 54%

“…In addition to pomalidomide, 4 metabolites were detected in fecal extracts. Consistently, several studies showed that the PK of pomalidomide was not remarkably affected in renally impaired patients, 17,18 and the liver plays the predominant role in eliminating pomalidomide in vivo.…”

supporting

confidence: 54%

“…In addition, a meta-analysis pooling data from patients with relapsed and refractory multiple myeloma with normal renal function, moderately impaired renal function, and severely impaired renal function showed there was no remarkable difference in pomalidomide exposure among different renal function groups, suggesting pomalidomide is cleared predominately via nonrenal routes, accounting for approximately 70% of pomalidomide total body clearance. 18 Both studies suggest that the liver plays the predominant role in eliminating pomalidomide in vivo.…”

Section: Discussionmentioning

confidence: 99%

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An Open‐Label, Phase 1 Study to Assess the Effects of Hepatic Impairment on Pomalidomide Pharmacokinetics

Li¹,

Wang²,

Liu³

et al. 2018

Clinical Pharm in Drug Dev

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Pomalidomide is an immunomodulatory drug and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and United States to treat patients with relapsed/refractory multiple myeloma. Because pomalidomide is extensively metabolized prior to excretion, a total of 32 subjects (8 healthy subjects in group 1; 8 subjects with severe hepatic impairment in group 2; 8 subjects with moderate hepatic impairment in group 3; and 8 subjects with mild hepatic impairment in group 4) were enrolled in a multicenter, open-label, single-dose study to assess the impact of hepatic impairment on pomalidomide exposure. Following administration of a single oral dose of 4-mg pomalidomide, the geometric mean ratios of pomalidomide total plasma exposures (AUC) were 171.5%, 157.5%, and 151.2% and the geometric mean ratios of pomalidomide plasma peak exposures (C ) were 75.8%, 94.8%, and 94.2% for subjects with severe, moderate, or mild hepatic impairment, respectively, versus healthy subjects. Pomalidomide administered as a single oral 4-mg dose was safe and well tolerated by healthy subjects and subjects with severe, moderate, or mild hepatic impairment. Based on the pharmacokinetic results from this study, the pomalidomide prescribing information approved by the US Food and Drug Administration recommends for patients with mild or moderate hepatic impairment (Child-Pugh classes A or B), a 3-mg starting daily dose (25% dose reduction) and for patients with severe hepatic impairment (Child-Pugh class C), a 2-mg starting daily dose (50% dose reduction).

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supporting

confidence: 54%

supporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

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An Open‐Label, Phase 1 Study to Assess the Effects of Hepatic Impairment on Pomalidomide Pharmacokinetics

Li¹,

Wang²,

Liu³

et al. 2018

Clinical Pharm in Drug Dev

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“…Pomalidomide pharmacokinetics have been well characterized both in healthy subjects and in subjects with relapsed and refractory MM . Pomalidomide was absorbed with a maximum plasma concentration (C max ) at a median time (t max ) between 2.0 and 3.0 hours.…”

mentioning

confidence: 99%

“…11 Pomalidomide pharmacokinetics have been well characterized both in healthy subjects and in subjects with relapsed and refractory MM. [16][17][18][19][20][21][22] Pomalidomide was absorbed with a maximum plasma concentration (C max ) at a median time (t max ) between 2.0 and 3.0 hours. Systemic exposure to a single dose of pomalidomide as determined from the area under the concentration-time curve (AUC) increased in an approximately dose-proportional manner up to 50 mg.…”

mentioning

confidence: 99%

In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects

Li¹,

Liu²,

Wang³

et al. 2018

The Journal of Clinical Pharma

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Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1‐21 of repeated 28‐day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open‐label, single‐dose studies. Following administration of a single oral dose of 4 mg pomalidomide, the plasma exposure when coadministered with fluvoxamine was 225.1% and 123.7% of that when administered alone for the total plasma exposure (AUC0‐inf) and the plasma peak exposure (Cmax), respectively. In smokers with elevated CYP1A2 activity demonstrated by high caffeine clearance (a marker of CYP1A2 induction), the AUC0‐inf was 32.3% lower, whereas the Cmax was 14.4% higher than that in nonsmokers. In addition, pomalidomide was safe and well tolerated as a single oral dose of 4 mg in healthy male smokers and nonsmokers ≥ 40 to ≤ 80 years old, and a single oral dose of 4 mg pomalidomide coadministered with multiple oral 50‐mg doses of the CYP1A2 inhibitor fluvoxamine compared with pomalidomide alone was safe and well tolerated by the healthy male subjects.

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Bioequivalence of Pomalidomide Capsules in Fasting and Fed States in Healthy Male Volunteers: A Randomized, Open, Single‐Dose, Biperiodic, Double‐Crossover Study

Wang

Lin

Wang

et al. 2022

Clinical Pharm in Drug Dev

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This study evaluated the safety, pharmacokinetic parameters, and bioequivalence (BE) of pomalidomide (POM) capsules (specification: 4 mg) acquired from 2 sponsors (test [T] and reference [R]), under fasting and fed conditions. A single‐center, randomized, open‐label, 2‐cycle, self‐crossover, single‐dose clinical trial was conducted. Subjects were divided into fasting (n = 28) and fed (n = 28) groups and assigned randomized treatment sequences (T‐R or R‐T). Blood samples for pharmacokinetic evaluation were collected within 48 hours of administration, and safety was assessed throughout. Exposure to POM was similar following single‐oral‐dose administrations of T or R between the fasting and fed states. T and R exhibited BE, as demonstrated by statistical analysis; the 90%CIs of the geometric mean ratios of maximum plasma concentration, area under the plasma concentration–time curve (AUC)from time 0 to the last measurable concentration, and AUC from time 0 to infinity were within the acceptable BE range (80%–125%). Administering POM capsules with high‐fat meals resulted in a 2.5‐hour delay in time to maximum concentration and an ≈20.4% reduction in maximum plasma concentration. However, AUCs were comparable after dose administrations with and without food. The fast and fed groups revealed that POM capsules were tolerated in healthy Chinese male subjects, and so were orally bioavailable in healthy subjects under fasting and fed states.

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

Cited by 13 publications

References 23 publications

An Open‐Label, Phase 1 Study to Assess the Effects of Hepatic Impairment on Pomalidomide Pharmacokinetics

An Open‐Label, Phase 1 Study to Assess the Effects of Hepatic Impairment on Pomalidomide Pharmacokinetics

In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects

Bioequivalence of Pomalidomide Capsules in Fasting and Fed States in Healthy Male Volunteers: A Randomized, Open, Single‐Dose, Biperiodic, Double‐Crossover Study

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