Postmarketing safety experience with edoxaban in Japan for thromboprophylaxis following major orthopedic surgery.

PURPOSE: Edoxaban is an oral, once-daily, selective, direct factor Xa inhibitor approved in Japan for the prevention of venous thromboembolism following major orthopedic surgery. Currently, edoxaban is in Phase III clinical development for the prevention of stroke and systemic embolic events in patients with atrial fibrillation, and for the treatment and prevention of recurrences of venous thromboembolism. This report describes the adverse drug reactions (ADRs) spontaneously reported during early postmarketing phase vigilance from the time of its commercial launch in Japan. MATERIALS AND METHODS: All spontaneously reported ADRs following edoxaban use received by Daiichi Sankyo during early postmarketing phase vigilance from July 19, 2011, to January 18, 2012, were entered into the safety database and included in this review. Approximately 20,000 patients were estimated to have been treated with edoxaban. RESULTS: The mean age of patients was 74.2 years, their mean weight was 59.4 kg, and approximately 70% were female. A total of 67 ADRs were reported in 56 patients, of which the majority included bleeding events (51 ADRs in 42 patients). Of these, 15 ADRs (in 14 patients) were serious, including cerebral hemorrhage (n = 1), gastric hemorrhage (n = 2; gastric hemorrhage [n = 1] and gastric ulcer hemorrhage [n = 1]), and surgical-site hemorrhage (n = 12; hemorrhage [n = 6], subcutaneous hemorrhage [n = 3], wound hemorrhage [n = 2], and wound hematoma [n = 1]). Most ADRs occurred within the first week of treatment and there were no fatalities. Nonserious ADRs associated with bleeding that occurred in >1 patient included subcutaneous hemorrhage (n = 9), wound hemorrhage (n = 5), postprocedural hematoma (n = 4), anemia (n = 4), and hemarthrosis (n = 3). Other nonserious ADRs not associated with bleeding and occurring in >1 patient included abnormal hepatic function (n = 4) and diarrhea (n = 2). CONCLUSION: Safety data from the first 6 months of postmarketing experience with edoxaban did not identify any unforeseen safety signals, consistent with the known safety profile of edoxaban.

Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia.

This study explored the association of 14 single nucleotide polymorphisms in three genes coding for influx transporters (SLC22A1, SLCO1B1, and SLCO1B3), two genes coding for efflux transporters (ABCB1 and ABCG2), and four genes coding for enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A5) with the pharmacokinetics of imatinib in Japanese patients with chronic myeloid leukemia. Pharmacokinetic parameters were estimated by a population pharmacokinetic analysis based on 622 plasma samples from 34 patients at steady state. Approximately 4.6-fold variability in individual clearance was observed (range, 3.4-15.5 L/hr). The individual estimated clearance was significantly increased in patients with the SLCO1B3 334GG genotype (median value ± standard deviation, 9.5 ± 3.1 L/hr; n = 19) compared with SLCO1B3 334TT and TG genotypes (7.0 ± 3.1 L/hr; n = 15) (P = 0.019). Patients with the ABCB1 3435CC genotype had significantly higher imatinib clearance (12.7 ± 3.0 L/hr; n = 7) compared with patients with ABCB1 3435CT and TT genotypes (7.9 ± 2.7 L/hr; n = 27) (P = 0.035). In conclusion, the present study suggests that single nucleotide polymorphisms of the influx transporter SLCO1B3 and the efflux transporter ABCB1 were functionally associated with individual variability of imatinib pharmacokinetics in Japanese patients with chronic myeloid leukemia.

Relationship between an effective dose of imatinib, body surface area, and trough drug levels in patients with chronic myeloid leukemia.

The standard dose of imatinib for the treatment of chronic-phase chronic myeloid leukemia (CML) is 400 mg/day. Some patients receive reduced doses of imatinib because of serious adverse effects. Recently, the effective plasma threshold for trough imatinib levels was demonstrated to be 1,002 ng/mL. In this study, we evaluated the association of an imatinib dose with trough plasma concentrations and clinical outcomes in 31 patients with chronic-phase CML who were treated at Kumamoto University Hospital. Twenty-seven patients were optimally treated with various doses of imatinib. The mean (+/-SD) trough plasma concentrations of imatinib were 1.40 +/- 0.57 microg/mL in 13 patients receiving 400 mg/day and 1.15 +/- 0.44 microg/mL in 9 patients receiving 300 mg/day as an effective dose. Mean trough levels of the two groups were not significantly different and exceeded the effective plasma threshold. Body surface area (BSA) was significantly smaller in patients receiving the reduced dose compared with those receiving the standard dose (p = 0.001). The effective imatinib dose was associated with age and gender as well as BSA. A reduced dose of 300 mg/day of imatinib may be sufficient for the treatment of CML patients with smaller body size, particularly when intolerability arises.

Constitutive overexpression of P-glycoprotein, rather than breast cancer resistance protein or organic cation transporter 1, contributes to acquisition of imatinib-resistance in K562 cells.

PURPOSE: The purpose of this study was to investigate the contribution of drug transporters in acquired imatinib-resistance. Specifically, we focused on the efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), and an influx transporter, organic cation transporter 1 (OCT1). MATERIALS AND METHODS: We established imatinib-resistant K562 cells (K562/IM). Real-time PCR or Western blot analyses were performed to examine the mRNA or protein levels. Alamar blue method was used in the cytotoxicity assay. The transport activities and intracellular imatinib levels were measured by flow cytometry and HPLC, respectively. RESULTS: K562/IM displayed a 47-fold increase in resistance to imatinib over the parent K562 cells. Both P-gp and BCRP were overexpressed in K562/IM relative to K562. Furthermore, the intracellular imatinib level was markedly reduced in K562/IM. Interestingly, cyclosporin A, a P-gp inhibitor, but not fumitremorgin C, a BCRP inhibitor, restored both imatinib-sensitivity and the intracellular imatinib level. By contrast, no significant difference in the expression and function of OCT1 was observed between K562/IM and K562. CONCLUSIONS: P-gp, rather than BCRP or OCT1, is partially responsible for the development of imatinib-resistance due to constitutive and functional overexpression, leading to reduced intracellular accumulation of imatinib in K562/IM.