Pharmacokinetics, safety, and efficacy of lenalidomide plus dexamethasone in patients with multiple myeloma and renal impairment

Bridoux, Frank; Chen, Nianhang; Moreau, Stéphane; Arnulf, Bertrand; Moumas, Eric; Abraham, Julie; Desport, Éstelle; Jaccard, Arnaud; Fermand, Jean Paul

doi:10.1007/s00280-016-3068-9

Cited by 18 publications

(27 citation statements)

References 23 publications

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“…The lenalidomide starting dose followed the dosing guidelines derived in that study [30]: 25 mg once daily for normal renal function and mild RI, 10 mg once daily for moderate RI, 15 mg once every other day for severe RI, and 5 mg once daily for ESRD. The study showed a highly significant linear relationship between lenalidomide clearance and CrCl in patients with MM [46]. This relationship was almost identical to that observed in patients with RI due to non-malignant conditions (Fig.…”

Section: Pharmacokinetics In Special Populationssupporting

confidence: 64%

“…To further assess whether the condition of MM may affect lenalidomide exposure, a phase II study was prospectively conducted and validated lenalidomide dose adjustments by evaluating the pharmacokinetics, safety, and efficacy of lenalidomide given with dexamethasone 40 mg weekly in patients with MM and various degrees of stable RI [46]. The study enrolled 38 patients (median age 65 years) with symptomatic MM.…”

Section: Pharmacokinetics In Special Populationsmentioning

confidence: 99%

“…2). Thus, MM disease itself does not affect the relationship between lenalidomide clearance (or plasma exposure) and renal function [46]. The mean AUC of each renal function group was within ±25 % of the mean AUC at the maximum tolerated dose [30], suggesting that the starting doses achieved the appropriate plasma exposure.…”

Section: Pharmacokinetics In Special Populationsmentioning

confidence: 99%

“…The solid line indicates the best fit line of linear regression, and the interval between the two dotted lines indicates the 90 % prediction interval of the best fit line for patients without cancer. MM multiple myeloma.Based on data from the literature reviewed in the text [30, 46] …”

Section: Pharmacokinetics In Special Populationsmentioning

confidence: 99%

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Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Chen¹,

Zhou²,

Palmisano³

2016

Clin Pharmacokinet

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Lenalidomide is a lead therapeutic in multiple myeloma and deletion 5q myelodysplastic syndromes and shows promising activities in other hematologic malignancies. This article presents a comprehensive review of the clinical pharmacokinetics and pharmacodynamics of lenalidomide. Oral lenalidomide is rapidly and highly absorbed (>90 % of dose) under fasting conditions. Food affects oral absorption, reducing area under the concentration–time curve (AUC) by 20 % and maximum concentration (C max) by 50 %. The increase in AUC and C max is dose proportional, and interindividual variability in plasma exposure is low to moderate. Lenalidomide distributes into semen but is undetectable 3 days after stopping treatment. Biotransformation of lenalidomide in humans includes chiral inversion, trivial hydroxylation, and slow non-enzymatic hydrolysis. Approximately 82 % of an oral dose is excreted as lenalidomide in urine within 24 h. Lenalidomide has a short half-life (3–4 h) and does not accumulate in plasma upon repeated dosing. Its pharmacokinetics are consistent across patient populations, regardless of the type of hematologic malignancy. Renal function is the only important factor affecting lenalidomide plasma exposure. Lenalidomide has no QT prolongation risk at approved doses, and higher plasma exposure to lenalidomide is associated with increased risk of neutropenia and thrombocytopenia. Despite being a weak substrate of P-glycoprotein (P-gp) in vitro, lenalidomide does not have clinically significant pharmacokinetic interactions with P-gp substrates/inhibitors in controlled studies. The AUC-matched dose adjustment is recommended for patients with renal impairment at the start of therapy. No dose adjustment for lenalidomide is needed on the basis of age, ethnicity, mild hepatic impairment, or drug–drug interactions.

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Section: Pharmacokinetics In Special Populationssupporting

confidence: 64%

Section: Pharmacokinetics In Special Populationsmentioning

confidence: 99%

Section: Pharmacokinetics In Special Populationsmentioning

confidence: 99%

Section: Pharmacokinetics In Special Populationsmentioning

confidence: 99%

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Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Chen¹,

Zhou²,

Palmisano³

2016

Clin Pharmacokinet

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“…On the other hand, it is controversy and debatable whether lenalidomide can be used to control solid tumors (14,16), although lenalidomide significantly inhibited growth of the chronic lymphocytic leukemia cells (19). In the present study, we further confirmed that lenalidomide alone had only a minimal effect on MDA-MB-231 cell viability, even at a very high dose of 320 µM, far beyond the clinically achievable concentration in humans (20). Thus, it is suggested that lenalidomide alone does not have much anti-proliferative activity in solid tumors, especially in TNBC cells.…”

Section: Discussionsupporting

confidence: 74%

Lenalidomide improvement of cisplatin antitumor efficacy on triple-negative breast cancer cells inï¿½vitro

et al. 2018

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Abstract.Lenalidomide is an immunomodulatory drug and possesses anti-angiogenic and immunomodulatory activities against multiple myeloma. The present study assessed the in vitro effect of lenalidomide combined with cisplatin on MDA-MB-231, a triple-negative breast cancer (TNBC) cell line and explored the underlying molecular mechanism of this combination. Cell viability, apoptosis and the protein expression of phosphorylated (p) and total extracellular signal-regulated kinase (ERK), B-cell lymphoma-2 (Bcl-2), caspase-3, cleaved poly-adenosine diphosphate-ribose polymerase (cPARP), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were measured in MDA-MB-231 cells treated with different concentrations of lenalidomide, cisplatin and their combination using different biochemical assays. Lenalidomide demonstrated no significant effect on the cell viability of MDA-MB-231 cells, even at high concentrations, whereas lenalidomide in combination with cisplatin, significantly reduced cisplatin IC 50 from 7.8 to 3.0 µM in MDA-MB-231 cells. In addition, lenalidomide and cisplatin in combination significantly induced cell apoptosis by 1.6-and 1.38-fold, respectively compared with lenalidomide and cisplatin alone (P<0.05). The expression levels of VEGF, bFGF and Bcl-2 proteins were significantly reduced (P<0.01), whereas caspase-3 and cleaved PARP expression were significantly increased in MDA-MB-231 cells treated with the combination compared to those treated with single agents (P<0.01). Lenalidomide treatment alone significantly reduced the p-ERK level compared with the control (P<0.05) and cisplatin treatment alone significantly increased it (P<0.01), however treatment with them in combination significantly reduced the p-ERK level in MDA-MB-231 cells compared with cisplatin treatment alone (P<0.05). In conclusion, the present study provides the basis for using lenalidomide in combination with cisplatin in TNBC therapy.

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Population Pharmacokinetics of Lenalidomide in Healthy Volunteers and Patients With Hematologic Malignancies

Connarn¹,

Hwang²,

Gao³

et al. 2017

Clinical Pharm in Drug Dev

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A population pharmacokinetic (PopPK) model of lenalidomide was developed using data pooled from 13 clinical studies (dose range, 5-400 mg) in participants who were considered to have adequate capability for renal excretion of lenalidomide (creatinine clearance [CrCl] > 50 mL/min). The analysis population included 305 healthy volunteers and 83 patients with multiple myeloma or myelodysplastic syndromes. A 1-compartment model with linear absorption and elimination described well the observed data for both healthy volunteers and patients. Covariate analysis suggested lenalidomide apparent clearance was positively correlated with CrCl, and lenalidomide volume of distribution was positively correlated with body weight. Both pharmacokinetic parameters were reduced by 29% in patients, independent of the effect of CrCl or body weight. Despite their statistical significance, effects of study population and body weight are considered clinically unimportant in adult patients with CrCl > 50 mL. After accounting for the above effects, body weight had no significant effect on CL/F, whereas age, sex, race, and mild hepatic impairment had no significant effect on either lenalidomide parameter. The PopPK model should be useful for future modeling of lenalidomide pharmacokinetics in the pediatric population and for further comparison of pharmacokinetic properties among structurally similar immunomodulatory drugs.

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Pharmacokinetics, safety, and efficacy of lenalidomide plus dexamethasone in patients with multiple myeloma and renal impairment

Abstract: In patients with stable renal function, the recommended dose adjustments achieved proper plasma exposure and similar safety and efficacy across renal groups.

Cited by 18 publications

References 23 publications

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Lenalidomide improvement of cisplatin antitumor efficacy on triple-negative breast cancer cells inï¿½vitro

Population Pharmacokinetics of Lenalidomide in Healthy Volunteers and Patients With Hematologic Malignancies

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