Dennis Mungall

Population pharmacokinetics of racemic warfarin in adult patients

The population pharmacokinetics of racemic warfarin was evaluated using 613 measured warfarin plasma concentrations from 32 adult hospitalized patients and 131 adult outpatients. Warfarin concentrations were measured in duplicate using a high-performance liquid chromatographic procedure. The pharmacokinetic model used was a one-compartment open model with first-order absorption (absorption rate constant set equal to 47 day−1) and first-order elimination. The extent of availability was assumed to be one. A linear regression model was used to evaluate the influence of various demographic factors on warfarin oral clearance. Age appeared to be an important determinant of warfarin clearance in this adult population. There was about a 1%/year decrease in oral clearance over the age range of 20–70 years. Smoking appeared to result in a 10% increase in warfarin clearance, while coadministration of the inducers phenytoin or phenobarbital yielded about a 30% increase in clearance. This study has yielded a predictive model that, when combined with appropriate pharmacological response data, may be useful in the design and adjustment of warfarin regimens.

Initiation of warfarin therapy - Comparison of physician dosing with computer-assisted dosing

In a prospective, randomized study at two university hospitals, the authors examined how effectively housestaff physicians (n=36) managed the initiation of warfarin therapy compared with a computer-assisted dosing regimen (n=39) using the software program Warfcalc, which was managed by one of the authors. Target prothrombin time ratios were selected by the physicians. Study endpoints included: the time to reach a therapeutic prothrombin ratio, the time to reach a stable therapeutic dose, the number of patients transiently overanticoagulated, the number of bleeding complications, and the accuracy of the predicted maintenance dose, which was assessed at steady-state 10–14 days later. Computer-assisted dosing consistently outperformed the physicians: a stable therapeutic dose was achieved 3.7 days earlier (p=0.002), fewer patients were overanticoagulated (10% versus 41%), and the predicted maintenance dose was in the therapeutic range in 85% of the computer-dosed patients versus 42% of the physician group (p<0.002). For physicians who did not routinely manage warfarin therapy, computer-assisted dosing improved the accuracy of dosing and shortened the time required to achieve a stable therapeutic dose.

Effects of Quinidine on Serum Digoxin Concentration: A Prospective Study

Results of studies of 15 adults placed on quinidine therapy after their serum digoxin concentrations were stabilized showed significantly increased digoxin concentrations. The average digoxin concentration before quinidine therapy was 0.75 +/- 0.28 ng/mL and after 4 days of quinidine therapy was 1.41 +/- 0.43 ng/mL. During this period, the renal clearance of digoxin decreased from 53.4 +/- 21 mL/min . 1.73 m to 35.3 +/- 12.6 mL/ min . 1.73 m. No significant correlation was found between the individual rise in serum digoxin concentrations and the rise in serum quinidine concentrations. These results suggest that serum digoxin concentration should be monitored closely for at least the first 4 days of quinidine therapy.

Individualizing theophylline therapy: the impact of clinical pharmacokinetics on patient outcomes.

We have studied 19 male patients whose theophylline therapy was individualized by a clinical pharmacokinetics service and 34 male patients with empirically derived dosages. All patients were admitted to the medical intensive care unit. Patients in the pharmacokinetics group had fewer adverse reactions (15.7 vs. 50%), shorter intensive care unit stay (6.6 +/- 5.5 vs. 12.4 +/- 16.3 days), shorter hospital stay (15.4 +/- 10 vs. 22.3 +/- 14.1 days), and a shorter period of time to be placed on oral therapy (5.2 +/- 3.1 vs. 8.6 +/- 7.2 days) than the group with empirically derived regimens. The pharmacokinetic method used to individualize theophylline therapy offered an accurate and efficient method of achieving therapeutic concentrations. We conclude that the use of clinical pharmacokinetics to individualize theophylline therapy offers substantial benefits over empirical assessments.

Bayesian pharmacokinetic/pharmacodynamic forecasting of prothrombin response to warfarin therapy: preliminary evaluation.

The ability of a pharmacokinetic/pharmacodynamic Bayesian forecasting computer program to predict prothrombin response to warfarin therapy was investigated. The performance of the program was evaluated retrospectively in an inpatient study population of 45 subjects. Predictions of prothrombin response at discharge, based on zero to five serially measured prothrombin ratios, were compared. Precision of prediction was measured by root mean squared error (rmse), bias was measured by average prediction error, and significance (p less than 0.05) was determined by 95% confidence intervals and correlation coefficients. Eleven (3.8%) predictions exceeded established limitations of the pharmacokinetic/pharmacodynamic model and were excluded from data analysis. Correlations between measured and predicted prothrombin ratios for all methods were significant. The five prothrombin ratio feedbacks provided the most accurate predictions (rmse 0.219). These predictions were significantly better than the population parameter (rmse 0.418), one (rmse 0.401), and two (rmse 0.459) prothrombin ratio feedback predictions. The predictions based on population parameters and one prothrombin ratio feedback were significantly biased. When provided with sufficient feedback, the bias was not apparent and the predictive performance improved with each additional prothrombin ratio. The predictive performance of the four and five prothrombin ratio feedbacks is sufficient to provide clinically useful dosage guidelines early in the course of warfarin therapy. The population parameter estimates require further delineation in order to improve the performance of limited prothrombin ratio feedback predictions.

Sucralfate and Warfarin

Excerpt To the editor: Sucralfate has recently been introduced for the treatment of duodenal peptic ulcer disease (1). Little information is available on the interaction in humans of sucralfate and...

Pharmacodynamics of Warfarin at Steady State

W studied the pharmacodynamics of warfarin in chronically treated patients. Two methods were used to estimate the pharmacodynamic parameters M/Kd and Cmax (mg/L). In Method 1 the prothrombin time response was modeled directly without use of warfarin concentrations and Method 2 used warfarin concentrations and prothrombin time response to estimate M/Kd and Cmax. The mean Cmax and M/Kd for Method 1 (n = 88) were 5.5 ± 2.3 mg/L and 51 ± 46 and for Method 2 (n = 27) 6.3 ± 2.8 mg/L and 35.4 ± 13. When Method 1 was applied to the same 27 patients in Method 2, the mean Cmax and M/Kd were 5.7 ± 3.3 mg/L and 36.1 ± 14.9. These differences were not significant. Multiple regression analysis revealed that the value of Cmax and M/Kd varied between medical centers. No other patient characteristics were found to be significant. We conclude that modeling steady-state prothrombin time response directly adequately describes pharmacodynamic response to warfarin.

Predicting the daily prothrombin time response to warfarin.

Our objective was to evaluate the effectiveness of a computer program to predict daily prothrombin time (PT) response to warfarin therapy using prospectively collected data. The programs predictive performance (precision) and accuracy (bias) were evaluated using fraction mean absolute error and fraction mean error, respectively. We analyzed data from 40 patients using from zero to nine PT feedbacks. The fraction mean absolute error varied from 0.058 to 0.13. The program utilized a pharamocokinetic/pharmacodynamic Bayesian forecasting system to predict prothrombin response.

Effect of Diltiazem on Warfarin Plasma Protein Binding

Previous work by Bloedow et al. evaluated the effect of warfarin on diltiazem binding. Unbound diltiazem remained constant (22.5 +/- 3.6 per cent) in the presence of warfarin. We studied 10 patients, 51 to 72 years old, who were receiving warfarin as an anticoagulant for valvular replacement, thrombosis, or embolus. Our study demonstrates that a single 120-mg oral diltiazem dose, sufficient to cause hemodynamic changes, does not displace warfarin from plasma binding sites.

Treatment of Proximal Deep-Vein Thrombosis Using Subcutaneously Administered Calcium Heparin: Comparison with Intravenous Sodium Heparin

In a prospective, randomized clinical trial we compared the efficacy of subcutaneously (SC) administered (every 8 h) calcium heparin to intravenous (IV) sodium heparin in the treatment of proximal deep-vein thrombosis (DVT). A secondary objective was to give enough heparin to achieve a therapeutic anticoagulant effect by the end of the first 24 h. Five of 36 patients (14%) in the SC heparin group failed to achieve a therapeutic anticoagulant effect by the end of the first 24 h compared to 2 of 23 patients (9%) in the IV group (p = NS; 95% CI for true difference = -11.7% to 22.1%). Two of 31 patients (6.5%) in the SC group had venographic evidence of clot propagation compared to 1 of 19 patients (5.3%) in the IV group (p = NS; 95% CI for true difference = -12.4% to 14.8%). The rate of major hemorrhagic complications was similar in each group (approximately 15%). We conclude: (1) using a large initial dose of SC heparin, a therapeutic anticoagulant effect can be readily achieved within 24 h, and (2) combining the results of this trial with previous studies, the efficacy of SC administered calcium appears to be comparable to IV sodium heparin.