Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide
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- 作者：Nianhang Chen ; Simon Zhou ; Maria Palmisano
- 刊名：Clinical Pharmacokinetics
- 出版年：2017
- 出版时间：February 2017
- 年：2017
- 卷：56
- 期：2
- 页码：139-152
- 全文大小：1136KB
- 刊物主题：Pharmacotherapy; Pharmacology/Toxicology; Internal Medicine;
- 出版者：Springer International Publishing
- ISSN：1179-1926
- 卷排序：56
文摘
Lenalidomide is a lead therapeutic in multiple myeloma and deletion 5q myelodysplastic syndromes and shows promising activities in other hematologic malignancies. This article presents a comprehensive review of the clinical pharmacokinetics and pharmacodynamics of lenalidomide. Oral lenalidomide is rapidly and highly absorbed (>90 % of dose) under fasting conditions. Food affects oral absorption, reducing area under the concentration–time curve (AUC) by 20 % and maximum concentration (Cmax) by 50 %. The increase in AUC and Cmax is dose proportional, and interindividual variability in plasma exposure is low to moderate. Lenalidomide distributes into semen but is undetectable 3 days after stopping treatment. Biotransformation of lenalidomide in humans includes chiral inversion, trivial hydroxylation, and slow non-enzymatic hydrolysis. Approximately 82 % of an oral dose is excreted as lenalidomide in urine within 24 h. Lenalidomide has a short half-life (3–4 h) and does not accumulate in plasma upon repeated dosing. Its pharmacokinetics are consistent across patient populations, regardless of the type of hematologic malignancy. Renal function is the only important factor affecting lenalidomide plasma exposure. Lenalidomide has no QT prolongation risk at approved doses, and higher plasma exposure to lenalidomide is associated with increased risk of neutropenia and thrombocytopenia. Despite being a weak substrate of P-glycoprotein (P-gp) in vitro, lenalidomide does not have clinically significant pharmacokinetic interactions with P-gp substrates/inhibitors in controlled studies. The AUC-matched dose adjustment is recommended for patients with renal impairment at the start of therapy. No dose adjustment for lenalidomide is needed on the basis of age, ethnicity, mild hepatic impairment, or drug–drug interactions.