Single-Dose Comparative Pharmacokinetics of Two Formulations of Lenalidomide 25 mg in Healthy Subjects: A Randomized Crossover Study
TL;DR: The PKs of the two formulation of lenalidomide 25 mg were similar and the test formulation met the regulatory criteria for assuming bioequivalence with the reference formulation, and the tolerability profile was not significantly different between the two formulations.
Abstract: Lenalidomide is used for the treatment of multiple myeloma in combination with dexamethasone. The purpose of this study was to compare the pharmacokinetics (PKs) and assess the bioequivalence of two formulations of lenalidomide 25 mg: Lenalid® 25 mg tablet (test formulation) and Revlimid® 25 mg capsule (reference formulation). A randomized, single-dose, two-treatment, two-period, two-sequence crossover study was conducted in 42 healthy subjects. All subjects were randomly assigned to one of the two sequences, and they received a single dose of test or reference formulation in the first period and the alternative formulation during the next period under fasting conditions. Serial blood samples for PK evaluation were collected up to 24 h post-dose and the PK parameters were estimated by non-compartmental methods. Throughout the study, tolerability was assessed on the basis of adverse events, vital signs, and clinical laboratory tests. The test formulation showed similar PK profiles to those of the reference formulation. The geometric mean ratio and 90% confidence interval (CI) of the test formulation to the reference formulation for maximum plasma concentration (Cmax) was 0.9995 (0.9250–1.0799) and the corresponding value for the area under the concentration–time curve from time zero to time of last quantifiable concentration (AUCt) was 0.9648 (0.9451–0.9850). Both CIs were within the conventional bioequivalence range of 0.8–1.25. The tolerability profile was not significantly different between the two formulations. This study found that the PKs of the two formulations of lenalidomide 25 mg were similar and the test formulation met the regulatory criteria for assuming bioequivalence with the reference formulation. Samyang Biopharmaceutical Corp.
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TL;DR: Cereblon downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities, and may also provide a biomarker to predict IMid response and resistance.
Abstract: Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance.
218 citations
"Single-Dose Comparative Pharmacokin..." refers background in this paper
...Lenalidomide, an amino-substituted analogue of thalidomide, has immunomodulatory, antiangiogenic, and antineoplastic properties [2, 3]....
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TL;DR: Following oral administration, lenalidomide is highly absorbed and bioavailable, metabolized minimally, and eliminated predominantly via urinary excretion in the unchanged form in humans.
Abstract: Purpose
Assessment of the absorption, metabolism and excretion of [14C]-lenalidomide in healthy male subjects following a single oral dose.
77 citations
"Single-Dose Comparative Pharmacokin..." refers background in this paper
...Although many clinical studies of lenalidomide have been conducted in healthy subjects without safety concerns [5, 6, 10], and regulatory agencies recommend studies with healthy volunteers, some concerns about con-...
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...0%), although any consistent pattern of AEs across the studies was not observed [5, 6, 10]....
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TL;DR: Lenalidomide (REVLIMID™), an immunomodulatory compound targeting both cancer cells and their microenvironment, has substantial activity in several difficult‐to‐manage hematological malignancies and its oral formulation reduces the burden on patients.
Abstract: Lenalidomide (REVLIMID), an immunomodulatory compound targeting both cancer cells and their microenvironment, has substantial activity in several difficult-to-manage hematological malignancies. In previously treated multiple myeloma, lenalidomide produces high-quality responses combined with sustained disease control. Recently, several randomized studies have demonstrated a clinical benefit of continuous lenalidomide treatment in newly diagnosed multiple myeloma. In many patients with refractory anemia associated with lower risk myelodysplastic syndromes and a 5q chromosome deletion, lenalidomide leads to transfusion independence, considerably improving quality of life. It has a manageable safety profile, and its oral formulation reduces the burden on patients. Several phase III trials are ongoing in other indications currently underserved by conventional therapy, such as chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and prostate cancer. Several early-stage studies are exploring lenalidomide alone and in combination across different hematological malignancies, solid tumors, and immune-related disorders.
67 citations
"Single-Dose Comparative Pharmacokin..." refers background in this paper
...Lenalidomide, an amino-substituted analogue of thalidomide, has immunomodulatory, antiangiogenic, and antineoplastic properties [2, 3]....
[...]
TL;DR: Lenalidomide is a lead therapeutic in multiple myeloma and deletion 5q myelodysplastic syndromes and shows promising activities in other hematologic malignancies and its pharmacokinetics are consistent across patient populations, regardless of the type of hematological malignancy.
Abstract: 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.
60 citations
TL;DR: Lenalidomide displayed linear pharmacokinetics from doses 5–400 mg in healthy subjects and was generally well tolerated in both ethnic groups.
Abstract: Lenalidomide is an immunomodulatory drug with efficacy in various hematological malignancies. The purpose of these studies was to evaluate the single-dose pharmacokinetics of lenalidomide, including dose proportionality, food effect, and racial sensitivity. Three studies were conducted including a total of 58 healthy subjects: a randomized, single-blind, alternating group, single-ascending dose study; a randomized, two-way crossover food effect study; and a randomized, double-blind, two-group, within-subject, single-ascending dose study. Oral absorption of lenalidomide was rapid and the maximum plasma concentration (C
max) was observed approximately 1 h post-dose. Co-administration with a high-fat meal reduced the area under the concentration–time curve (AUC) and C
max by approximately 20 and 50 %, respectively, and delayed time to C
max (t
max) by 1.63 h. However, phase III trials were dosed without regard to food; therefore, clinical relevance of the food effect was minimal. The terminal elimination half-life (t
½) was 3–4 h at doses up to 50 mg and was not affected by food. The AUC and C
max were proportional to lenalidomide single doses (5–400 mg), and total and renal clearance were dose-independent. The R- to S-lenalidomide ratio in plasma was stable over time, approximately 45–55 % of total drug. There were no differences in pharmacokinetic parameters, dose–exposure relationship, or enantiomeric ratio, between Japanese and Caucasian subjects. Lenalidomide displayed linear pharmacokinetics from doses 5–400 mg in healthy subjects. Although food reduced bioavailability, this was not considered clinically relevant. Lenalidomide was generally well tolerated in both ethnic groups.
35 citations
"Single-Dose Comparative Pharmacokin..." refers background in this paper
...Although many clinical studies of lenalidomide have been conducted in healthy subjects without safety concerns [5, 6, 10], and regulatory agencies recommend studies with healthy volunteers, some concerns about con-...
[...]
...0%), although any consistent pattern of AEs across the studies was not observed [5, 6, 10]....
[...]