Maiko Abumiya

Drug interaction between lenalidomide and itraconazole

are present at high frequencies in patients with hypereosinophilic syndrome. Haematologica 2009;94:1236–1241. 3. Ghia P, Prato G, Stella S, et al. Age-dependent accumulation of monoclonal CD41CD81 double positive T lymphocytes in the peripheral blood of the elderly. Br J Haematol 2007;139:780–790. 4. Morice WG, Kimlinger T, Katzmann JA, et al. Flow cytometric assessment of TCR-Vbeta expression in the evaluation of peripheral blood involvement by T-cell lymphoproliferative disorders: A comparison with conventional T-cell immunophenotyping and molecular genetic techniques. Am J Clin Pathol 2004; 121:373–383. 5. Helbig G, Wichary R, Razny M, et al. The proportion of CD3CD41 T-cell population remained unaffected after corticosteroids treatment for lymphocytic variant hypereosinophilic syndrome (L-HES). Scand J Immunol 2010;72: 372–373. 6. Verstovsek S, Tefferi A, Kantarjian H, et al. Alemtuzumab therapy for hypereosinophilic syndrome and chronic eosinophilic leukemia. Clin Cancer Res 2009;15: 368–373.

Influence of UGT1A1 *6, *27, and *28 Polymorphisms on Nilotinib-induced Hyperbilirubinemia in Japanese Patients with Chronic Myeloid Leukemia

Nilotinib potently inhibits human uridine diphosphate-glucuronosyltransferase (UGT1A1) activity, causing hyperbilirubinemia. We investigated the influence of UGT1A1 polymorphisms and nilotinib plasma trough concentrations (C0) on nilotinib-induced hyperbilirubinemia in 34 Japanese patients with chronic myeloid leukemia (CML). The proportion of patients with hyperbilirubinemia was significantly higher among patients with the UGT1A1*6/*6 and *6/*28 genotypes (poor metabolizers) than among those with other genotypes (p = 0.004). The median time to elevation of bilirubin levels in UGT1A1 poor metabolizers was 2.0 weeks (hazard ratio, 6.11). The median time to reduction in nilotinib dose in UGT1A1 poor metabolizers was 4.0 weeks (hazard ratio, 7.52; p = 0.002). Consequently, in the maintenance phase 3 months following the initiation of nilotinib therapy, the median daily dose and C0 of nilotinib were 350 mg/day and 372 ng/mL, respectively, in UGT1A1 poor metabolizers, and 600 mg/day and 804 ng/mL, respectively, in the other patients. Patients at increased hyperbilirubinemia risk could be identified by prospective UGT1A1 genotyping prior to nilotinib therapy. To avoid an interruption of CML treatment due to nilotinib-induced hyperbilirubinemia, it may be beneficial to reduce the initial nilotinib dose to 300-400 mg/day for UGT1A1 poor metabolizers.

A limited sampling model to estimate exposure to lenalidomide in multiple myeloma patients.

Background: The aim of this study was to develop a model able to predict the area under the lenalidomide plasma concentration–time curve (AUC) in multiple myeloma (MM) patients using a limited sampling strategy. Methods: Forty-six hospitalized Japanese MM patients (25 men and 21 women) participated in this study. On days 3–10 of lenalidomide therapy, whole-blood samples were collected just before oral lenalidomide administration, and 1, 2, 4, 8, 12, and 24 hours thereafter. Plasma concentrations of lenalidomide were analyzed using liquid chromatography–tandem mass spectrometry. Results: The AUC0–24 predicted from a single lenalidomide plasma concentration measured 8 hours after the administration (C8h) showed the highest correlation with the measured AUC0–24 of lenalidomide (AUC0–24 = 13.0 × C8h + 1305.0; r2 = 0.832). To enhance the correlation between the predicted and the actual AUC0–24 of lenalidomide, we included information regarding lenalidomide elimination by entering creatinine clearance (CCr) data in the predictive formula of lenalidomide AUC0–24. Predicting the AUC0–24 of lenalidomide using data from 2 time points, C0h and C4h, along with CCr data further strengthened the correlation with the measured AUC0–24 of lenalidomide [AUC0–24 = 37.1 × C0h + 6.4 × C4h − 32.1 × CCr + 3265.6; r2 = 0.842]. Conclusions: The AUC0–24 of lenalidomide can be predicted using plasma concentrations measured at only 2 time points, C0h and C4h, in combination with CCr. Our study also suggests that the limited sampling strategy approach might help to identify patients with renal function impairment and who, despite dose adjustments, accumulate the drug, leading to a high AUC.

Therapeutic drug monitoring of ponatinib using a simple high-performance liquid chromatography method in Japanese patients

A simple and highly sensitive high-performance liquid chromatography (HPLC) method was developed for the quantification of ponatinib in human plasma. The developed HPLC method was validated based on International D.S. Food and Drug Administration guidelines. This technique utilized a solid-phase extraction step and required only 200μL plasma for a single analysis. The lower limit of quantification for ponatinib was 1.0ng/mL. Coefficients of variation and accuracies for intra- and interday assays were less than 10.8% and within 13.7%, respectively. The precision and accuracy of our HPLC assay was suitable for pharmacokinetic studies of ponatinib. On day 8 after beginning ponatinib therapy with an initial dose of 15mg, patients having a ponatinib C0 of less than 23ng/mL by HPLC may require a dose adjustment to 30mg to obtain a C0 of 23ng/mL of more. The median ponatinib C0 in 6 Japanese patients taking a 15mg daily dose was 24.6ng/mL, which was greater than the target concentration of 23ng/mL, and that of patients taking 30mg increased to a plasma concentration of 48.0ng/mL. This novel treatment strategy using the HPLC method developed herein may be useful for routine ponatinib therapy.

The potential role of clarithromycin addition to lenalidomide and dexamethasone therapy (BiRd) in multiple myeloma

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 naotot@doc.med.akita-u.ac.jp