Phase I Study Of P-Glycoprotein (P-gp) Mediated Drug Interactions Between Lenalidomide (LEN) and Quinidine Or Temsirolimus

Lenalidomide (LEN) is a weak substrate of P-glycoprotein (P-gp) in vitro and renal excretion of LEN is the primary elimination route following oral administration.  A P-gp inhibitor may have the potential to increase systemic exposure to LEN by reducing renal elimination at the tubular level and enhancing oral absorption at the gut level. Recently, a single uncontrolled phase 1 study (Hofmeister, 2011) and a case report (Takahashi, 2012) described that plasma exposure to LEN and temsirolimus was increased in multiple myeloma patients when lenalidomide was co-administered with a P-gp inhibitor (temsirolimus and intraconazole, respectively).  This clinical study assessed LEN-drug interactions via P-gp using two probe drugs under controlled conditions.  Quinidine, a P-gp inhibitor with high in vivo inhibition potential and proven effect on plasma exposure of the prototype P-gp substrate digoxin in humans, was used to maximize the likelihood of detecting drug-drug interactions via P-gp.  Temsirolimus, a P-gp inhibitor/substrate, was used to evaluate P-gp mediated interactions on either drug in comparison with the results reported in literature.