Simplified dosing regimens of teicoplanin for patient groups stratified by renal function and weight using Monte Carlo simulation.

The purpose of this study was (i) to determine the optimal dosage of teicoplanin for each patient group stratified by renal function and weight based on a population pharmacokinetic model and observed distribution of patient characteristics and (ii) to develop new simplified dosing regimens designed to achieve 15-30 µg/mL. Patient data were collected retrospectively from routine therapeutic drug monitoring files of adult patients who were given the standard loading dose regimen of teicoplanin (400 mg twice on Day 1, followed by 400 mg once daily for 2 days) and whose trough concentration was measured just before administration on Day 4. Monte Carlo simulation was conducted to estimate the trough concentration at 72 h after the initial loading dose (C(min)(72 h)) and at steady state (C(ss)(min)). The percentage of observed C(min)(72 h) in patients who received the standard loading dose regimen outside the non-parametric 90% prediction interval (from 5th to 95th percentile) of the simulated C(min)(72 h) was <10%. Simplified loading dose and maintenance dose regimens for each group stratified by renal function and weight were created to achieve C(min)(72 h) and C(ss)(min) of 15 µg/mL and 20-25 µg/mL, respectively. The percentage of C(min)(72 h) and C(ss)(min) in the range 15-30 µg/mL was 43-65% and 61-82% across each renal function and weight strata, respectively. These new simplified dosing regimens of teicoplanin could be helpful in individual adjustment of the loading and maintenance doses to achieve 15-30 µg/mL.

Decrease in the vinorelbine-induced venous irritation by pharmaceutical intervention.

PURPOSE: The intravenous injection of vinorelbine often causes venous irritation such as erythema, injection site pain, and phlebitis. The purpose of the present study was to investigate the risk factor associated with the vinorelbine-induced venous irritation and to establish a suitable administration method of vinorelbine. METHODS: We analyzed the risk factor associated with venous irritation in 63 patients administered vinorelbine from April 2006 to September 2008. We subsequently changed the regimen of vinorelbine and examined the incidence of venous irritation in 24 patients administered vinorelbine from October 2008 to March 2010. RESULTS: A multivariate logistic regression analysis revealed that the dose of vinorelbine (≥ 40 mg) was a significant predictor for venous irritation (adjusted odds ratio = 4.39; 95% confidence intervals, 1.33-14.49; p = 0.015). Moreover, the grade of venous irritation in patients administered vinorelbine at the doses of ≥ 40 mg was significantly higher than that in patients administered vinorelbine at the doses of <40 mg (p = 0.011). Based on this result, we altered the volume of normal saline for vinorelbine dissolution from 50 to 100 mL. After the change of regimen, the grade of venous irritation induce by vinorelbine was significantly decreased (p = 0.034), although the incidence was not significantly changed (46.0% versus 33.3%). CONCLUSIONS: The change of regimen of vinorelbine based on the analysis significantly decreased the grade of venous irritation. Pharmacists can contribute to the management for the vinorelbine-induced venous irritation.

Timing of expression of blood coagulation abnormality in patients treated with warfarin and s-1 concomitantly.

Although S-1 is frequently used in cancer chemotherapy, the drug interaction with warfarin, an anticoagulant agent, is not fully paid attention. In the present study, we investigated retrospectively the timing of expression of blood coagulation abnormality in nine patients treated with warfarin and S-1 concomitantly. In five patients, the dose of warfarin was reduced or interrupted after concomitant use of S-1. The International Normalized Ratio (INR) was significantly increased after combination with S-1 compared with the former value. In all patients, the INR was increased in three weeks after combination with S-1. On the other hand, serum creatinine, aspartate aminotransferase, alanine aminotransferase or serum albumin was not different before and after combination with S-1. These results suggest that the careful monitoring of the blood coagulation ability is necessary in all patients receiving warfarin and S-1 concomitantly.

Pharmacoepidemiologic investigation of clonazepam relative clearance by mixed-effect modeling using routine clinical pharmacokinetic data in Japanese patients.

The effects of drug-drug interactions on clonazepam clearance were examined through a retrospective analysis of serum concentration data from pediatric and adult epileptic patients. Patients received clonazepam as monotherapy or in combination with other antiepileptic drugs. A total of 259 serum clonazepam concentrations gathered from 137 patients were used in a population analysis of drug-drug interactions on clonazepam clearance. Data were analyzed using a nonlinear mixed-effects modeling (NONMEM) technique. The final model describing clonazepam clearance was CL = 152 x TBW(-0.181) x DIF, where CL is clearance (ml/kg/h), TBWis total body weight (kg), and DIF (drug interaction factor) is a scaling factor for concomitant medication with a value of 1 for patients on clonazepam monotherapy, 1.18 for those patients receiving concomitant administration of clonazepam and one antiepileptic drug (carbamazepine or valproic acid), and 2.12 x TBW(-0.119) for those patients receiving concomitant administration of clonazepam and more than two antiepileptic drugs. Clonazepam clearance decreased in a weight-related fashion in children, with minimal changes observed in adults. Concomitant administration of clonazepam and carbamazepine resulted in a 22% increase in clonazepam clearance. Concomitant administration of clonazepam and valproic acid resulted in a 12% increase in clonazepam clearance. Concomitant administration of clonazepam with two or more antiepileptic drugs resulted in a 23% to 75% increase in clonazepam clearance.