Pharmacokinetic Interaction Between Tacrolimus and Fentanyl in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND Tacrolimus and fentanyl are well-known cytochrome P450 (CYP) 3A4 substrates with a narrow therapeutic range. However, the pharmacokinetic interaction between tacrolimus and fentanyl is unclear. The aim of this study was to determine whether drug interaction exists between tacrolimus and fentanyl. MATERIAL AND METHODS A retrospective study was performed in 6 patients who had received allogeneic hematopoietic stem cell transplantation between April 2010 and March 2015. The patients received continuous intravenous infusion of fentanyl with concomitant use of tacrolimus, and the blood concentrations of tacrolimus were evaluated using fluorescence polarization immunoassay. RESULTS The clearance (CL) of tacrolimus decreased significantly from 1.28 to 0.68 mL/min/kg with concomitant use of fentanyl. The CL changed with time and dose of fentanyl administration. In addition, the CL of tacrolimus was reverted by stopping fentanyl infusion. Horn's drug interaction probability scale indicated a probable category or possible category, suggesting a drug interaction between tacrolimus and fentanyl. No patient showed a difference in hepatic or renal function before and after fentanyl administration. No additional administration of other CYP3A4 inhibitors was observed, suggesting that the drug interaction was mediated by CYP3A4. CONCLUSIONS The influence of fentanyl on the pharmacokinetics of tacrolimus was demonstrated to be of clinical importance. It is proposed that the dose of tacrolimus be reduced by 40% when used in combination with fentanyl.

Combination of lenalidomide and low-dose dexamethasone therapy promotes the anticoagulant activity of warfarin in patients with immunoglobulin light-chain amyloidosis.

The present study aimed to evaluate the drug interactions between warfarin and combination chemotherapy with lenalidomide and low-dose dexamethasone in immunoglobulin light-chain (AL) amyloidosis patients with unstable international normalized ratios (INR). The changes to INR values over time in 3 AL amyloidosis patients treated with warfarin and a combination of lenalidomide and low-dose dexamethasone between March 2011 and February 2015 were analyzed retrospectively. The mean INR value was 1.52 prior to the combination chemotherapy, and the value increased 1.7-fold during treatment. The median time to reach maximum values was 17 days. Horn's drug Interaction Probability Scale indicated a possible interaction between lenalidomide and warfarin. These patients exhibited no marked alterations in hepatic function or serum albumin concentrations prior to and following combination chemotherapy and no additional administration of CYP2C9 inhibitors or vitamin K supplements was conducted. In addition, no patient experienced chemotherapy-induced nausea or appetite loss. These findings suggest that the total clearance or protein binding of warfarin remained unchanged. Therefore, the combination of warfarin and lenalidomide may cause a pharmacodynamic interaction, more likely by inhibiting the production of interleukin-6. In conclusion, clinically important interactions between warfarin and lenalidomide and low-dose dexamethasone therapy were observed in AL amyloidosis patients, where INR values signi ficantly increased. Therefore, close and regular monitoring of patients during the course of treatment is important, and the dose of warfarin should be reduced if required.

The interaction between oral melphalan and gastric antisecretory drugs: Impact on clinical efficacy and toxicity.

The aim of the present study was to clarify whether gastric antisecretory drugs affect the clinical efficacy and toxicity of orally administered melphalan in patients with multiple myeloma. A total of 10 patients receiving bortezomib plus oral melphalan and prednisolone (VMP) therapy between December 2011 and November 2014 were analyzed retrospectively. The patients were divided into a control group (seven patients) and a concomitant group (three patients, who were also administered with gastric antisecretory drugs). The gastric antisecretory drugs included rabeprazole sodium (two patients) and famotidine (one patient). No significant differences between the groups were observed in either the characteristics of the patients or the VMP regimen. The levels of monoclonal protein (M protein) in the control group tended to decrease (with a VMP cycle-dependency), although they were primarily stable in the concomitant group. During the second and third VMP cycles, the levels of M protein were markedly lower in the control group compared with the concomitant group. All the patients in the control group achieved a partial response, whereas those in the concomitant group exhibited stable disease. Hematological toxicity levels were revealed to be comparable between the two groups, whereas gastrointestinal toxicity was more prevalent in the control group. In conclusion, the results of the present study suggested that the clinical efficacy of melphalan may be reduced by the co-administration of gastric antisecretory drugs. This interaction may result in decreased toxicity and clinical efficacy of melphalan.

Pharmacokinetics and tolerance of linezolid for meticillin-resistant Staphylococcus aureus mediastinitis in paediatric patients.

Here we report our experience with four paediatric patients with mediastinitis due to meticillin-resistant Staphylococcus aureus (MRSA) following cardiac surgery refractory to glycopeptide treatment and treated by linezolid. The pharmacokinetics and tolerance of linezolid administered orally or intravenously were analysed. Linezolid was administered intravenously at a dosage of 10 mg/kg every 8 h and then orally. In oral administration, 10 mg/kg or 15 mg/kg was given every 8 h as a powder made by crushing tablets. The linezolid serum trough concentration was >or=3.5 mg/L in patients treated by intravenous administration. However, with oral administration lower trough levels were detected, including patients with an undetectable level (<0.1 mg/L). No significant intolerance or drug-related haematological events were reported. We conclude that linezolid, with a switch from intravenous to oral administration, could be an effective and safe option in paediatric mediastinitis refractory to conventional glycopeptides, whilst care must be taken to maintain an adequate dose by monitoring the trough concentration.

Glycopeptide pharmacokinetics in current paediatric cardiac surgery practice.

OBJECTIVE: To examine the evolution of serum concentrations of prophylactic glycopeptides administered during state-of-the-art cardiopulmonary bypass (CPB) and vigorous haemodiafiltration in paediatric patients undergoing cardiac surgery. METHODS: We enrolled infants and children <3 years of age who, based on the preoperative microbiological screening, age and surgical complexity, were at high risk of methicillin-resistant Staphylococcus aureus (MRSA) infection. Antimicrobial prophylaxis with glycopeptides was administered to 22 patients, randomly assigned to vancomycin (VAN; n=11) versus teicoplanin (TEC; n=11). Fixed doses of each drug (15 mg/kg for VAN and 8 mg/kg for TEC) were administered immediately before the operation, at the time of priming of the extracorporeal circuit, upon admission to the intensive care unit and for 48 h thereafter, q. 8 h for VAN, and once daily for TEC. Vigorous haemodiafiltration was applied during and briefly after CPB. RESULTS: The second dose of drug added to the prime prevented a fall in serum drug concentrations at the onset of CPB in both groups. A 77% decrease in VAN, versus 53% in TEC concentrations, was observed after the conclusion of CPB. Serum concentrations of TEC>10 microg/ml were observed throughout the treatment period in 91% of patients, while 55% of patients assigned to VAN had serum concentrations consistently >5 microg/ml (p=0.08). Therapeutic serum concentrations were maintained throughout the intraoperative period, particularly with TEC, administered before the first surgical incision, followed by a supplemental bolus in the priming fluid of CPB. Postoperative surgical wound infections occurred in neither group. CONCLUSIONS: The prophylactic use of glycopeptides in paediatric patients at high risk of MRSA infection undergoing cardiac surgery was safe and effective. TEC might be the drug of choice, since stable, therapeutic serum concentrations were easily maintained throughout the treatment period.