Lenalidomide at Therapeutic and Supratherapeutic Doses Does Not Prolong <scp>QT</scp>c Intervals in the Thorough <scp>QT</scp>c Study Conducted in Healthy Men

Chen, Nianhang; Ye, Ying; Liu, Liangang; Reyes, Josephine; Assaf, Mahmoud; Kasserra, Claudia; Zhou, Simon; Palmisano, Maria

doi:10.1111/bcpt.12081

Cited by 19 publications

(19 citation statements)

References 27 publications

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“…As observed in healthy volunteers, lenalidomide displayed rapid absorption and elimination in patients, often with a median T max of 1 h under fasting conditions and a mean half-life of 3–4 h. The median T max was longer in studies in which food, which delays drug absorption, was not restricted prior to dosing [38, 41, 42]. As demonstrated in Table 2, the dose–exposure relationship remained linear across studies, with plasma AUC and C max proportional to dose from 5 to 50 mg. Dose-proportional increases in AUC and C max were also demonstrated in a study evaluating dose ranges in patients with MM [29]. …”

Section: Pharmacokinetics In Patients With Hematologic Malignanciesmentioning

confidence: 96%

“…As demonstrated in Table 2, the dose–exposure relationship remained linear across studies, with plasma AUC and C max proportional to dose from 5 to 50 mg. Dose-proportional increases in AUC and C max were also demonstrated in a study evaluating dose ranges in patients with MM [29]. …”

Section: Pharmacokinetics In Patients With Hematologic Malignanciesmentioning

confidence: 96%

“…An assessment of the effect of lenalidomide on corrected QT (QTc) intervals was conducted in healthy males who each received a single oral dose of 10 mg lenalidomide, 50 mg lenalidomide, 400 mg moxifloxacin (positive control), and placebo, in a randomized order [29]. Moxifloxacin significantly prolonged QTc, as expected.…”

Section: Pharmacodynamics and Exposure Responsementioning

confidence: 99%

“…Lenalidomide C max and AUC increase proportionally with increases in dose from 5 to 400 mg [27]. The interindividual variability for lenalidomide plasma exposure parameters is low to moderate in well-controlled studies in healthy volunteers: approximately 20 % for AUC and 30 % for C max [29]. Coadministration with a high-fat meal reduces the extent and rate of lenalidomide oral absorption, resulting in an approximate 20 % decrease in AUC, 50 % decrease in C max , and 1.6-h delay in the time to reach C max ( T max ) [27].…”

Section: Pharmacokinetics In Healthy Adultsmentioning

confidence: 99%

“…There were no differences in lenalidomide pharmacokinetics between patients of varying hematologic malignancies and healthy volunteers if they were of advanced age and had similar renal function (Tables 1, 2), except for a slightly high interindividual variability for AUC (25–60 %) [29]. Compared with young healthy volunteers, patients consistently showed lower lenalidomide clearance and thus higher AUC (+50 % or more) for the same dose (Tables 1, 2).…”

Section: Pharmacokinetics In Patients With Hematologic Malignanciesmentioning

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 Patients With Hematologic Malignanciesmentioning

confidence: 96%

Section: Pharmacokinetics In Patients With Hematologic Malignanciesmentioning

confidence: 96%

Section: Pharmacodynamics and Exposure Responsementioning

confidence: 99%

Section: Pharmacokinetics In Healthy Adultsmentioning

confidence: 99%

Section: Pharmacokinetics In Patients With Hematologic Malignanciesmentioning

confidence: 99%

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Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Chen¹,

Zhou²,

Palmisano³

2016

Clin Pharmacokinet

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Exposure‐Response Analysis to Assess the Concentration‐QTc Relationship of Iberdomide

Cheng

Gaudy

Liu

et al. 2023

Clinical Pharm in Drug Dev

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Iberdomide is an orally available cereblon‐modulating agent being developed for the treatment of hematologic malignancies and autoimmune‐mediated diseases. To assess the potential concentration‐QTc relationship in humans and to ascertain or exclude a potential QT effect by iberdomide, a plasma concentration and ΔQTcF (change from baseline of corrected QT interval using the Fridericia formula) model of iberdomide was developed. Iberdomide concentration and paired high‐quality, intensive electrocardiogram signal from a single‐ascending‐dose study in healthy subjects (N = 56) were included in the analysis. The primary analysis was based on a linear mixed‐effect model with ΔQTcF as the dependent variable; iberdomide plasma concentration and baseline QTcF as continuous covariates; treatment (active or placebo) and time as a categorical factor; and a random intercept per subject. The predicted change from baseline and placebo corrected (ΔΔQTcF) at the observed geometric mean maximum plasma concentration and 2‐sided 90% confidence intervals at different dose levels were calculated. The upper bound of the 90% confidence interval of the model‐predicted ΔΔQTcF effect at maximum concentration from the supratherapeutic dose of 6 mg (2.54 milliseconds) is <10‐millisecond threshold, suggesting that iberdomide does not have a clinically relevant QT prolongation liability.

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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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Lenalidomide at Therapeutic and Supratherapeutic Doses Does Not Prolong QTc Intervals in the Thorough QTc Study Conducted in Healthy Men

Cited by 19 publications

References 27 publications

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide

Exposure‐Response Analysis to Assess the Concentration‐QTc Relationship of Iberdomide

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

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