LAUSR

Dear Editor, Clarithromycin (CAM), lenalidomide (Len), and dexamethasone (Dex) combination therapy (BiRd) is highly effective in multiple myeloma (MM) treatment [1]. The addition of CAM to Len and Dex (Ld) therapy is thought to enhance the corticosteroid effect by increasing the area under the concentration-time curve (AUC) and the maximum concentration of corticosteroids [2, 3]. Hofmeister et al. has reported that Len is a substrate of P-glycoprotein (P-gp); we also have reported that the absorption of Len from the small intestine is increased when combined with itraconazole due to the drug interaction via P-gp [4, 5]. Until now, however, in BiRd therapy, no information about the effect of CAM on Len pharmacokinetics has been published; CAM is a known potent inhibitor of P-gp and cytochrome P450 (CYP) 3A. Hence, we expected that the real role of CAM addition to Ld therapy would be explained by the enhanced Len function through the increased absorption of Len from the small intestine via P-gp. In vitro, we examined whether Len was a substrate of P-gp by using cell monolayers of human colon adenocarcinoma cells, Caco-2, as we had previously reported [6]. After treating the cells with verapamil (control A) and CAM (B), the basalto-apical and not apical-to-basal apparent permeability of Len was changed, suggesting that P-gp was involved in the intestinal absorption of Len (Fig. 1). We confirmed clinically that Len was a substrate of Pgp by comparing the plasma concentration of Len in a patient with MM treated with Ld and thereafter BiRd therapy. Plasma concentrations of Len were analyzed using liquid chromatography-tandem mass spectrometry and AUC0–24 was estimated, as we had previously reported [7]. A 72-year-old man with IgD MM was treated with Ld therapy and achieved very good partial response; however, subsequently, he became refractory to Ld therapy and received BiRd therapy by adding CAM. Before the addition of CAM, he was treated with Ld therapy and the doses of Len and Dex were 15 mg/day and 20 mg/week, respectively; the plasma concentrations of Len at 2 h (C2) and 4 h (C4) after intake were 20.3 and 29.8 ng/ml, respectively (Table 1). After the addition of CAM 400 mg/day to Ld therapy with no dose modification of Len, he achieved stable disease (SD) and the plasma concentration of Len: C2 and C4 increased to 283 and 114 ng/ml, respectively (Table 1). The estimated AUC0–24 of Len was also increased after the addition of CAM. These data suggest that CAM increases the absorption of Len through Pgp inhibition because Len is mostly not metabolized by CYPs. This is the first report revealing the drug interaction between Len and CAM. These data show that the addition of * Naoto Takahashi [email protected]