Dose-dependent artificial prolongation of prothrombin time by interaction between daptomycin and test reagents in patients receiving warfarin: a prospective in vivo clinical study.

BACKGROUND: Daptomycin has been reported to cause artificial prolongation of prothrombin time (PT) by interacting with some test reagents of PT. This prolongation was particularly prominent with high concentrations of daptomycin in vitro. However, whether this prolongation is important in clinical settings and the optimal timing to assess PT remain unclear. METHODS: A prospective clinical study was conducted with patients who received daptomycin for confirmed or suspected drug-resistant, gram-positive bacterial infection at a university hospital in Japan. PT at the peak and trough of daptomycin was tested using nine PT reagents. Linear regression analyses were used to examine the difference in daptomycin concentration and the relative change of PT-international normalized ratios (PT-INR). RESULTS: Thirty-five patients received daptomycin (6 mg/kg). The mean ± standard deviation of the trough and peak concentrations of daptomycin were 13.5 ± 6.3 and 55.1 ± 16.9 µg/mL, respectively. Twelve patients (34%) received warfarin. With five PT reagents, a significant proportion of participants experienced prolongation of PT-INR at the daptomycin peak concentration compared to the PT-INR at the trough, although the mean relative change was less than 10%. None of the participants clinically showed any signs of bleeding. A linear, dose-dependent prolongation of PT was observed for one reagent [unadjusted coefficient ß 3.1 × 10-3/µg/mL; 95% confidence interval (CI) 2.3 × 10-5-6.3 × 10-3; p = 0.048]. When patients were stratified based on warfarin use, this significant linear relationship was observed in warfarin users for two PT reagents (adjusted coefficient ß, 6.4 × 10-3/µg/mL; 95% CI 3.5 × 10-3-9.3 × 10-3; p < 0.001; and adjusted coefficient ß, 8.3 × 10-3/µg/mL; 95% CI 4.4 × 10-3-1.2 × 10-2; p < 0.001). In non-warfarin users, this linear relationship was not observed for any PT reagents. CONCLUSIONS: We found that a higher concentration of daptomycin could lead to artificial prolongation of PT-INR by interacting with some PT reagents. This change may not be clinically negligible, especially in warfarin users receiving a high dose of daptomycin. It may be better to measure PT at the trough rather than at the peak daptomycin concentration.

NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy.

Vitamin K (VK) is a micronutrient that facilitates blood coagulation. VK antagonists, such as warfarin, are used in the clinic to prevent thromboembolism. Because VK is not synthesized in the body, its intestinal absorption is crucial for maintaining whole-body VK levels. However, the molecular mechanism of this absorption is unclear. We demonstrate that Niemann-Pick C1-like 1 (NPC1L1) protein, a cholesterol transporter, plays a central role in intestinal VK uptake and modulates the anticoagulant effect of warfarin. In vitro studies using NPC1L1-overexpressing intestinal cells and in vivo studies with Npc1l1-knockout mice revealed that intestinal VK absorption is NPC1L1-dependent and inhibited by ezetimibe, an NPC1L1-selective inhibitor clinically used for dyslipidemia. In addition, in vivo pharmacological studies demonstrated that the coadministration of ezetimibe and warfarin caused a reduction in hepatic VK levels and enhanced the pharmacological effect of warfarin. Adverse events caused by the coadministration of ezetimibe and warfarin were rescued by oral VK supplementation, suggesting that the drug-drug interaction effects observed were the consequence of ezetimibe-mediated VK malabsorption. This mechanism was supported by a retrospective evaluation of clinical data showing that, in more than 85% of warfarin-treated patients, the anticoagulant activity was enhanced by cotreatment with ezetimibe. Our findings provide insight into the molecular mechanism of VK absorption. This new drug-drug interaction mechanism between ezetimibe (a cholesterol transport inhibitor) and warfarin (a VK antagonist and anticoagulant) could inform clinical care of patients on these medications, such as by altering the kinetics of essential, fat-soluble vitamins.

Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information.

The aim of the present paper was to present an overview of the current status of the methods used to predict the magnitude of pharmacokinetic drug-drug interactions (DDIs) which are caused by apparent changes in cytochrome P450 (CYP) activity with an emphasis on a method using in vivo information. In addition, more than a hundred representative CYP substrates, inhibitor and inducer drugs involved in significant pharmacokinetic DDIs were selected from the literature and are listed. Although the magnitude of DDIs has been conventionally predicted based on in vitro experiments, their predictability is restricted occasionally due to several difficulties, including a precise determination of the unbound inhibitor concentrations at the enzyme site and a reliable in vitro measurement of the inhibition constant (K(i)). Alternatively, a simple method has been recently proposed for the prediction of the magnitude of DDIs based on information fully available from in vivo clinical studies. The new in vivo-based method would be applicable to the adjustment of dose regimens in actual pharmacotherapy situations although it requires a prior clinical study for the prediction. In this review, theoretical and quantitative relationships between the in vivo- and the in vitro-based prediction methods are considered. One of the interesting outcomes of the consideration is that the K(i)-normalized dose (dose/in vitro K(i)) of larger than approximately 20L (2-200L, when variability is considered) may be a pragmatic index which predicts significant in vivo DDIs. In the last part of the article, the relevance of the inclusion of the in vivo-based method into the process of new drug development is discussed for good prediction of in vivo DDIs.