No clinically significant drug interactions between lenalidomide and P-glycoprotein substrates and inhibitors: results from controlled phase I studies in healthy volunteers

• Published in: Cancer chemotherapy and pharmacology Vol. 73; no. 5; pp. 1031 - 1039
• Main Authors: Chen, Nianhang, Weiss, Daniel, Reyes, Josephine, Liu, Liangang, Kasserra, Claudia, Wang, Xiaomin, Zhou, Simon, Kumar, Gondi, Weiss, Lilia, Palmisano, Maria
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2014; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Antineoplastic agents; ATP Binding Cassette Transporter, Sub-Family B; Biological and medical sciences; Cancer Research; Cross-Over Studies; Double-Blind Method; Drug Interactions; Female; Healthy Volunteers; Humans; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Oncology; Original; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Thalidomide - administration & dosage; Thalidomide - analogs & derivatives; Thalidomide - pharmacology; Thalidomide - therapeutic use; Young Adult; P-glycoprotein; Temsirolimus; Lenalidomide; Digoxin; Quinidine; Drug–drug interactions; Antineoplastic agent; Human; Healthy subject; Toxicity; P Glycoprotein; Drug―drug interactions; Result; Substrate; Treatment; Phase I trial; Glycoside; Drug interaction; Pharmacokinetics; Digitalis drug
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-014-2438-4

Purpose Lenalidomide, a weak substrate of P-glycoprotein (P-gp) in vitro, is an oral anticancer drug eliminated predominantly via renal excretion as unchanged compound. The role of P-gp in lenalidomide disposition and the associated clinical relevance were evaluated. Methods Two phase I, crossover studies were conducted in healthy volunteers. In Study 1, subjects received lenalidomide (10 mg × 7 days) alone or with the P-gp substrate digoxin (0.5 mg on Day 5). In Study 2, subjects received lenalidomide (a single 25 mg dose) alone, the P-gp inhibitor quinidine (300–600 mg twice-daily × 5 days) plus lenalidomide (on Day 4), the P-gp inhibitor/substrate temsirolimus (a single 25 mg dose) alone, or lenalidomide plus temsirolimus. Pharmacokinetic and safety data were collected for lenalidomide and the co-administrated drugs. Results There were no significant changes in the maximum concentration ( C max ) and area under the plasma concentration–time curve (AUC) of lenalidomide when co-administered with quinidine, digoxin, or temsirolimus. Neither the rate nor the capacity of lenalidomide renal excretion was affected by quinidine or temsirolimus, in addition lenalidomide absorption rate and bioavailability remained unchanged. Furthermore, lenalidomide had no significant effect on blood C max and AUC of temsirolimus and its active metabolite sirolimus (also a P-gp inhibitor/substrate). The C max of digoxin was slightly higher (+14 %) when administered with lenalidomide versus placebo. There were no other changes in digoxin pharmacokinetics upon co-administration with lenalidomide. No remarkable safety findings were observed. Conclusions There are no clinically significant pharmacokinetic interactions between lenalidomide and substrates or inhibitors of P-gp.