Title: Drug interaction between lenalidomide and itraconazole
Abstract: American Journal of HematologyVolume 87, Issue 3 p. 338-339 CorrespondenceFree Access Drug interaction between lenalidomide and itraconazole† Naoto Takahashi, Corresponding Author Naoto Takahashi [email protected] Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, JapanNaoto Takahashi, Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita city, Akita, 010-8543, Japan. Tel.: +81-18-884-6116. Fax: +81-18-836-2613Search for more papers by this authorMasatomo Miura, Masatomo Miura Department of Pharmacy, Akita University Hospital, Akita, JapanSearch for more papers by this authorYoshihiro Kameoka, Yoshihiro Kameoka Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, JapanSearch for more papers by this authorMaiko Abumiya, Maiko Abumiya Department of Pharmacy, Akita University Hospital, Akita, JapanSearch for more papers by this authorKenichi Sawada, Kenichi Sawada Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, JapanSearch for more papers by this author Naoto Takahashi, Corresponding Author Naoto Takahashi [email protected] Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, JapanNaoto Takahashi, Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita city, Akita, 010-8543, Japan. Tel.: +81-18-884-6116. Fax: +81-18-836-2613Search for more papers by this authorMasatomo Miura, Masatomo Miura Department of Pharmacy, Akita University Hospital, Akita, JapanSearch for more papers by this authorYoshihiro Kameoka, Yoshihiro Kameoka Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, JapanSearch for more papers by this authorMaiko Abumiya, Maiko Abumiya Department of Pharmacy, Akita University Hospital, Akita, JapanSearch for more papers by this authorKenichi Sawada, Kenichi Sawada Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, JapanSearch for more papers by this author First published: 23 November 2011 https://doi.org/10.1002/ajh.22260Citations: 16 † Conflict of interest: Nothing to report. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat To the Editor: In July 2010, a 53-year-old woman was diagnosed with multiple myeloma, IgG-lambda stage 2, and was initially administered chemotherapy with melphalan and prednisone. Because of continued disease progression, however, in October 2010 she was administered lenalidomide 25 mg plus low-dose dexamethasone (Rd). Although she achieved partial response after one course of Rd (IgG declined from 6,977 to 1,200 mg/dL), she began suffering from febrile neutropenia, which persisted for 10 days. Following the recommendation of Dimopoulos et al. [1], in November 2010, we reduced the patient's lenalidomide dosage to 15 mg and added 100 mg/day itraconazole and 400 mg/day–80 mg/day sulfamethoxazole–trimethoprim for infection prophylaxis. Nevertheless, she suffered repeated infections associated withneutropenia, even after further reducing her lenalidomide to 10 mg. We therefore began monitoring the patient's plasma lenalidomide concentrations using high-performance liquid chromatography (Fig. 1, closed circles). Lenalidomide was separated using a mobile phase of 0.5% KH2PO4 (pH 2.5)–acetonitrile (87.5:12.5, v/v) on a Capcell Pak C18 MG II column at a flow rateof 0.5 mL/min and UV absorbance at 220 nm. The lenalidomide and itraconazole were then stopped because the AUC0–24 and maximum plasma lenalidomide concentration (Cmax) after intake of 10 mg with prophylaxis using itraconazole were 33,249 ng hr/mL and 2,757 ng/mL, respectively. After 10 days, lenalidomide was restarted at a dosage of 5 mg, without itraconazole, and its plasma concentrations were monitored (Fig. 1, open circles). The AUC0–24 and lenalidomide Cmax after intake of 5 mg were 283 ng hr/mL and 38 ng/mL, respectively; however, there was no difference in the terminal elimination half-life (t1/2) of lenalidomide, with or without itraconazole (5.5 hr vs. 5.6 hr). By comparison, the mean (±SD) AUC0–24, Cmax, and elimination t1/2 in four other myeloma patients taking 25 mg of lenalidomide were 2,763 ± 917 ng hr/mL, 400 ± 172 ng/mL and 6.7 ± 1.3 hr, respectively (Fig. 1). Figure 1Open in figure viewerPowerPoint Plasma concentration-time profiles after administration of 10 mg of lenalidomide with itraconazole (closed circles), 5 mg of lenalidomide without itraconazole (open circles), and 25 mg of lenalidomide without itraconazole (mean values from four patients, open triangles). Pharmacokinetic analysis of lenalidomide was done using the standard non-compartmental method with WinNonlin software (Pharsight Co., Mountain View, CA, version 4.0.1). An estimated creatinine clearance for each patient was calculated using Cockcroft and Gault formulas from the initially analyzed serum creatinine concentration. This is the first report showing a drug interaction between lenalidomide and itraconazole, which is a potent inhibitor of CYP3A4 and P-glycoprotein activity [2]. Hofmeister et al. recently reported an in vitro study indicating that P-glycoprotein is involved in the lenalidomide pharmacokinetics, and drug-interactions via P-glycoprotein between lenalidomide and CCI-779 (temsirolimus) as substrates of P-glycoprotein [3]. Because lenalidomide isscarcely metabolized by cytochrome P450s (CYP), the activity of drug-transporters such as P-glycoprotein may be a key determinant of lenalidomide pharmacokinetics. In the present case, the AUC0–24 and Cmax for lenalidomide were markedly increased by itraconazole, though its elimination t1/2 was unaffected. This suggests that the drug interaction between lenalidomide and itraconazole occurs via P-glycoprotein during absorption from the small intestine. This patient exhibited neutropenia when administered a combination of 10 mg of lenalidomide plus itraconazole, and gave a dose-adjusted AUC0–24 for lenalidomide of 3,324.9 ng hr/mL/mg, which is much higher than in four other patients who did not show drug toxicity. This suggests that lenalidomide exposure could contribute to its toxicity [4], and careful monitoring of lenalidomide as well as creatinine clearance may be appropriate to avoid the risk of toxicity. References References 1 Dimopoulos MA,Palumbo A,Attal M, et al. Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: Consensus statement. Leukemia 2011; 25: 749– 760. CrossrefCASPubMedWeb of Science®Google Scholar 2 Saad AH,DePestel DD,Carver PL. Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants. Pharmacotherapy 2006; 26: 1730– 1744. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 3 Hofmeister CC,Yang X,Pichiorri F, et al. Phase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: Evidence for lenalidomide-CCI-779 interaction via P-glycoprotein. J Clin Oncol 2011; 29: 3427– 3234. CrossrefCASPubMedWeb of Science®Google Scholar 4 Bonkowski J,Vermeulen LC,Kolesar JM. The clinical utility of lenalidomide in multiple myeloma and myelodysplastic syndromes. J Oncol Pharm Pract 2010; 16: 223– 232. CrossrefCASGoogle Scholar Naoto Takahashi*, Masatomo Miura , Yoshihiro Kameoka*, Maiko Abumiya , Kenichi Sawada*, * Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan, Department of Pharmacy, Akita University Hospital, Akita, Japan. Citing Literature Volume87, Issue3March 2012Pages 338-339 FiguresReferencesRelatedInformation
Publication Year: 2011
Publication Date: 2011-11-23
Language: en
Type: letter
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 25
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