Immunoglobulin light-chain (AL) amyloidosis is a rare and potentially fatal disease characterized by clonal plasma cells in the bone marrow that produce abnormal κ or λ light chains (1). The mechanisms of outbreak, which arise from abnormal plasma cells in the bone marrow, are known to be similar to that of multiple myeloma (MM). The pathogenesis of MM is characterized primarily by the overproduction of interleukin-6 (IL-6) (2), the major growth and survival (anti-apoptotic) factor, which may also be expressed in AL amyloidosis (3).

Currently, there is no standard treatment for AL amyloidosis. However, lenalidomide (one of the more potent immunomodulatory drugs) and low-dose dexamethasone therapy has been approved for the treatment of AL amyloidosis (4) as this treatment has been demonstrated to be effective against MM (5), a condition with a similar pathology as AL amyloidosis. In addition, a common cause of mortality of patients with AL amyloidosis is cardiac dysfunction (6), including atrial fibrillation, a condition where warfarin is used to lower the risk of stroke.

Lenalidomide is excreted by the kidney, and the drug-metabolizing enzyme cytochrome P450 (CYP) is not involved in this metabolizing process (7,8). Lenalidomide is known to be a poor substrate of P-glycoprotein (P-gp), but no clinically significant drug interactions between lenalidomide and P-gp substrates and inhibitors have been observed (9). Warfarin interacts with numerous drugs demonstrating pharmacokinetic or pharmacodynamic drug interactions (10–12). The pharmacokinetic interaction of warfarin is mediated by the inhibition of CYP2C9 or displacement of plasma protein binding. The pharmacodynamic interactions are primarily attributed to the additive or antagonistic effects on vitamin K-dependent cycle of blood coagulation (13). Dexamethasone is an inducer of CYP3A4, an enzyme that metabolizes dexamethasone. The interaction between anticoagulant agents and corticosteroids including dexamethasone has been reported (14–16). It has been demonstrated that a high-dose of dexamethasone (40 mg/day for 4 days) is able to increase the international normalized ratio (INR) values in patients that take warfarin (14) and corticosteroids accelerated or inhibited anticoagulant activity (15,16). In the case of low-dose dexamethasone, increase in INR elevation was not observed (17).

Recently, Weiss et al (18) demonstrated that co-administration of lenalidomide with a single dose of warfarin did not alter the plasma exposure or anticoagulant effect of warfarin or the plasma exposure of lenalidomide in healthy volunteers, but this was not the case for patients with overproduction of IL-6. However, it remains unclear whether there are interactions between multiple doses of warfarin and the combination of lenalidomide and low-dose dexamethasone.

The present study focused on evaluating the association of drug interactions between warfarin and the combination of lenalidomide and low-dose dexamethasone in patients with AL amyloidosis.

In the present analysis, the additional use of warfarin with lenalidomide and low-dose dexamethasone combination therapy significantly increased the INR values. Therefore, this indicates a drug interaction between warfarin and the combination of lenalidomide and low-dose dexamethasone, which is of clinically importance.

The mechanism of the interaction between warfarin and combination therapy with lenalidomide and low-dose dexamethasone remains unclear, but a number of concepts were considered. With regards to the combination of warfarin and dexamethasone, it was reported that the high-dose of corticosteroids potentiated the effects of warfarin, resulting in increased INR values (14,15). By contrast, Yano et al (17) reported that the increase in INR values was not observed with concomitant use of low-dose (6.6 mg) dexamethasone, which is comparable to the results of the present analysis. The extent of interaction between warfarin and dexamethasone was poor, even though low-dose dexamethasone may increase INR values.

Lenalidomide is not metabolized by cytochrome P450 enzymes in the liver (8), and the ratio of binding to plasma protein was ~40% (7). By contrast, warfarin is metabolized by CYP2C9 and has a high plasma protein binding ratio of ~99% (10–12). Therefore, there is unlikely to be a pharmacokinetic interaction between lenalidomide and warfarin. This was supported by the observation that concomitant use of multiple-dose lenalidomide with a single-dose warfarin had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin in healthy volunteers (18). However, the alteration of INR values was time-dependent and reproducible for lenalidomide in the present analysis (Fig. 1). In addition, the increase in INR values continued, even though treatment with lenalidomide was discontinued (Fig. 1B), and increased markedly when lenalidomide was re-administered in the next cycle. The Horn's Drug Interaction Probability Scale (19) indicated that the interaction between warfarin and lenalidomide was a possibility. By contrast, patients exhibited no marked alterations in hepatic function and serum albumin concentration prior and subsequent to combination chemotherapy. Furthermore, and no additional administration of CYP2C9 inhibitors or vitamin K supplements was observed. In addition, chemotherapy-induced nausea or appetite loss, which may alter vitamin K absorption and serum albumin concentration, was not observed in any patients. These findings suggest that the total clearance or protein binding of warfarin remained unchanged. Accordingly, the combination of warfarin and lenalidomide was considered to result in pharmacodynamic interactions.

The mechanism of pharmacodynamic interaction between warfarin and lenalidomide was considered. Lenalidomide is known to have immunomodulatory effects, which alters the production of Th2-type cytokines, including IL-6 and tumor necrosis factor α and is primarily modulated by a decrease in IL-6 levels (20,21). IL-6 has been demonstrated to be associated with extrinsic blood coagulation cascades, which produces a tissue factor in macrophages (22). Lenalidomide may decrease the synthesis of a tissue factor by inhibiting the production of IL-6 and thus resulting in an increase of anticoagulant activity of warfarin, as shown in Fig. 2. The mechanism proposed by the authors of the present study was supported by a study into the drug interaction of capecitabine and warfarin, which demonstrated that capecitabine effects the factor VII activity and contributes to the increase in INR values (23). Collectively, the interaction between lenalidomide and warfarin may have occurred due to pharmacodynamic interaction by inhibiting the production of IL-6 but not pharmacokinetic interaction. Analysis of levels of IL-6 and tissue factors may provide further insights into the precise mechanism of this interaction.

Clinically important interactions between warfarin and combination therapy with lenalidomide and low-dose dexamethasone were observed in AL amyloidosis, where there was a significant increase in INR values. Therefore, patients taking warfarin should be monitored closely and regularly for alterations in INR values during lenalidomide and low-dose dexamethasone combination therapy, and the dose of warfarin should be reduced if necessary.