Pharmacokinetics, metabolism and excretion of [14C]-lenalidomide following oral administration in healthy male subjects

Abstract

PurposeAssessment of the absorption, metabolism and excretion of [14C]-lenalidomide in healthy male subjects following a single oral dose.MethodsSix healthy male subjects were administered a single 25 mg oral suspension dose of [14C]-lenalidomide. Blood (plasma), semen and excreta were collected. Mass balance assessments were done by radioactivity measurements. Metabolite profiling and quantitation were accomplished using liquid chromatography with mass spectrometric and radiochemical detection.Results[14C]-Lenalidomide was rapidly absorbed (Tmax 0.77–1.0 h), and the levels declined with a terminal half-life of approximately 3 h, with similar profiles for total blood and plasma radioactivity as well as plasma lenalidomide. The whole blood to plasma radioactivity exposure levels were comparable, suggesting equal distribution between plasma and blood cells. On average, 94% of the administered radioactivity was recovered within 10 days, with >88% recovered within 24 h. Urinary excretion was the primary route of elimination (90% of radioactive dose), with minor amounts excreted in feces (4%). Semen contained a small amount of the radioactive dose (0.0062%). Lenalidomide was the primary radioactive component in plasma (92% of the [14C]-area under the concentration–time curve) and urine (>90% of the radioactivity in urine). The remaining radioactivity was composed of primarily two metabolites: 5-hydroxy-lenalidomide and N-acetyl-lenalidomide, each accounting for less than 5% of the total radioactivity as well as lenalidomide levels in plasma and excreta.ConclusionsIn summary, following oral administration, lenalidomide is highly absorbed and bioavailable, metabolized minimally, and eliminated predominantly via urinary excretion in the unchanged form in humans.

Pharmacokinetics and Tissue Disposition of Lenalidomide in Mice

“…Plasma protein binding in patients is between 35% and 45%, does not vary significantly in patients with renal impairment, and is constant over physiological concentrations (24). Hydroxylated and acetylated metabolites (21) are formed at a low abundance less than 5% of dose (21). Hydrolysis products of lenalidomide have also been observed (21,25); however, to our knowledge, their structures and activities have not been reported.…”

“…Hydroxylated and acetylated metabolites (21) are formed at a low abundance less than 5% of dose (21). Hydrolysis products of lenalidomide have also been observed (21,25); however, to our knowledge, their structures and activities have not been reported. The contributing effects of these properties on lenalidomide linearity and differential tissue distribution need to be further characterized.…”

“…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.…”

“…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).…”

“…Lenalidomide is orally administered with rapid absorption and bioavailability greater than 80% in healthy individuals (21). It is a small molecule (molecular weight=259) with moderate solubility at physiological pH where it is not ionized.…”