Phase I Trial of Lenalidomide and CCI-779 in Patients With Relapsed Multiple Myeloma: Evidence for Lenalidomide–CCI-779 Interaction via P-Glycoprotein

Hofmeister, Craig C.; Yang, Xiaoxia; Chen, Ping; Rozewski, Darlene M.; Johnson, Amy J.; Lee, Seungsoo; Liu, Zhongfa; Garr, Celia; Hade, Erinn M.; Jia, Jinping; Schaaf, Larry J.; Benson, Don M.; Kraut, Eric H.; Hicks, William; Chan, Kenneth K.; Chen, Ching Shih; Farag, Sherif; Grever, Michael R.; Byrd, John C.; Phelps, Mitch A.

doi:10.1200/jco.2010.32.4962

Cited by 79 publications

(58 citation statements)

References 39 publications

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“…While passive diffusion likely plays a role in its absorption, the high bioavailability and absorption of protonated lenalidomide may also be facilitated by transporter-mediated pathways. Approximately 90% of lenalidomide clearance occurs primarily by renal excretion, and a portion of this is believed to be transporter mediated (21,23). Renal reabsorption has not been directly studied for lenalidomide, and it is therefore unknown if this contributes to its overall disposition.…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 99%

“…The authors evaluated a Michaelis-Menten function to describe this perceived nonlinearity, but ultimately utilized a dose-proportional model which fit the data equally well. In addition to humans (21,23,24,28), pharmacokinetic studies of lenalidomide have been reported in rats and monkeys (3,29).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Tissue Disposition of Lenalidomide in Mice

Rozewski

Herman²,

Towns³

et al. 2012

AAPS J

Self Cite

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“…The in vitro studies proved that lenalidomide is actively transported by P-gp and this effect was reversed by CCI-779 and verapamil. In addition, ABCB1 silencing RNA or short interfering RNA (siRNA) knockdown studies in vitro also showed more lenalidomide uptake, supporting lenalidomide and P-gp drug-drug interaction (154).…”

Section: Discussionmentioning

confidence: 99%

“…In light of emerging studies that these novel drugs that have been incorporated to MM therapeutic management are substrates of ABC transporters, the situation warrants a re-evaluation of the manipulative power of MM cells (154). It is evident that opting for more aggressive chemotherapy has brought some promise of prolonging remission and survival in MM.…”

Section: Discussionmentioning

confidence: 99%

“…Although there is no current evidence to suggest that thalidomide itself is a substrate of the these drug efflux pumps, the drugs used in combination as part of the recommended regimens are themselves substrates of one or more of these efflux transporters (Table II) (151)(152)(153)(154)(155)(156)(157)(158)(159)(160)(161)(162)(163)(164)(165)(166). This contributes to compromised therapeutic effects, reduced rates of response and overall survival of the tumor.…”

Section: Cam-drmentioning

confidence: 99%

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