Toxicity profile of the immunomodulatory thalidomide analogue, lenalidomide: Phase I clinical trial of three dosing schedules in patients with solid malignancies

Sharma, Ricky A.; Steward, W.P.; Daines, C.A.; Knight, Robert D.; O’Byrne, Kenneth J.; Dalgleish, Angus

doi:10.1016/j.ejca.2006.05.018

Cited by 48 publications

(37 citation statements)

References 37 publications

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“…Similarly, we report lenalidomide brain exposures following 5 and 10 mg/kg in mice are approximately 0.9% and 2.3% of that observed in plasma. These results may explain why clinical neurotoxicities are minimal and reported in few patients relative to thalidomide (57,58). While studies are being pursued to evaluate lenalidomide efficacy in cancers of the CNS and other neurological disorders, the relatively low lenalidomide CNS penetration may become an important factor.…”

Section: Discussionmentioning

confidence: 98%

Pharmacokinetics and Tissue Disposition of Lenalidomide in Mice

Rozewski

Herman²,

Towns³

et al. 2012

AAPS J

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Abstract. Lenalidomide is a synthetic derivative of thalidomide exhibiting multiple immunomodulatory activities beneficial in the treatment of several hematological malignancies. Murine pharmacokinetic characterization necessary for translational and further preclinical investigations has not been published. Studies herein define mouse plasma pharmacokinetics and tissue distribution after intravenous (IV) bolus administration and bioavailability after oral and intraperitoneal delivery. Range finding studies used lenalidomide concentrations up to 15 mg/kg IV, 22.5 mg/kg intraperitoneal injections (IP), and 45 mg/kg oral gavage (PO). Pharmacokinetic studies evaluated doses of 0.5, 1.5, 5, and 10 mg/kg IV and 0.5 and 10 mg/kg doses for IP and oral routes. Liquid chromatography-tandem mass spectrometry was used to quantify lenalidomide in plasma, brain, lung, liver, heart, kidney, spleen, and muscle. Pharmacokinetic parameters were estimated using noncompartmental and compartmental methods. Doses of 15 mg/kg IV, 22.5 mg/kg IP, and 45 mg/kg PO lenalidomide caused no observable toxicity up to 24 h postdose. We observed dose-dependent kinetics over the evaluated dosing range. Administration of 0.5 and 10 mg/kg resulted in systemic bioavailability ranges of 90-105% and 60-75% via IP and oral routes, respectively. Lenalidomide was detectable in the brain only after IV dosing of 5 and 10 mg/kg. Dose-dependent distribution was also observed in some tissues. High oral bioavailability of lenalidomide in mice is consistent with oral bioavailability in humans. Atypical lenalidomide tissue distribution was observed in spleen and brain. The observed dose-dependent pharmacokinetics should be taken into consideration in translational and preclinical mouse studies.

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Section: Discussionmentioning

confidence: 98%

Pharmacokinetics and Tissue Disposition of Lenalidomide in Mice

Rozewski

Herman²,

Towns³

et al. 2012

AAPS J

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“…At present, lenalidomide is approved by the US Food and Drug Administration for use in patients with myelodysplastic syndromes (associated with no or 5q-deletions), and in combination with dexamethasone in patients with multiple myeloma who have received one previous therapy (Dimopoulos et al, 2007;Weber et al, 2007). However, there is a growing list of other cancers, including non-small-cell lung cancer, pancreatic, thymic, rectal apocrine carcinomas and angiosarcoma, in which objective responses have been observed in monotherapy or in combination with other therapies (Sharma et al, 2006;Kalmadi et al, 2007;Liu et al, 2009a).…”

mentioning

confidence: 99%

Inhibition of metastatic potential in colorectal carcinoma in vivo and in vitro using immunomodulatory drugs (IMiDs)

et al. 2009

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BACKGROUND: Thalidomide and lenalidomide are FDA approved for the treatment of multiple myeloma and, along with pomalidomide, are being investigated in various other cancers. Although these agents display immunomodulatory, anti-angiogenic and anti-apoptotic effects, little is known about their primary mode of therapeutic action in patients with cancer. METHODS: As part of a continuing research effort, we have investigated the effects of these agents on the metastatic capacity of murine colorectal cancer cell lines both in vivo and in vitro. Allied to these, we have studied their effects on the molecular pathways associated with metastasis. RESULTS: Results indicate that thalidomide, lenalidomide and pomalidomide significantly inhibit the metastatic capability of colorectal carcinoma cells. Anchorage-independent growth, used as a coarse indicator of transformation, was significantly reduced, as were migratory capacity and invasive competence. In addition, an in vivo experimental metastasis model also showed that treatment with the drugs resulted in a significantly lower number of metastatic pulmonary nodules relative to control mice. Allied to these cellular and phenotypic changes were alterations in molecular markers of metastasis and in intracellular signalling competency. CONCLUSIONS: These results provide evidence that in addition to their immunomodulatory effects, thalidomide, lenalidomide and pomalidomide can impair the metastatic capacity of tumours, and that this mechanism may involve alterations to cell signalling functionality.

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“…Overall, in phase I studies of single-agent lenalidomide in patients with pancreatic cancer, no responses were noted [32,33,40].…”

Section: Pancreatic Cancermentioning

confidence: 91%

“…Phase I studies included patients with sarcoma treated with lenalidomide alone (n = 1) or in combination with docetaxel (n = 7) [33,46]. No antitumor activity was reported.…”

Section: Sarcomamentioning

confidence: 99%