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NCT01176968.

A 47-year-old patient suffering from coronary artery disease was admitted to the CCU in shock with III. AV block, severe hypotension, and impairment of ventricular function. One week prior to admission a therapy with standard doses of metoprolol (100 mg t.i.d. and then 100 mg b.i.d.) had been initiated. Two days before admission diltiazem (60 mg b.i.d.) was prescribed in addition. Analyses of a blood sample revealed unusually high plasma concentrations of metoprolol (greater than 3000 ng/ml) and diltiazem (526 ng/ml). The patient recovered within 1 week following discontinuation of antianginal therapy. Three months later the patient was exposed to a single dose of metoprolol, diltiazem, propafenone (since he had received this drug in the past), and sparteine (as a probe for the debrisoquine/sparteine type polymorphism of oxidative drug metabolism). It was found that he was a poor metabolizer of all four drugs, indicating that their metabolism is under the same genetic control. Therefore, patients belonging to the poor-metabolizer phenotype of sparteine/debrisoquine polymorphism in drug metabolism, which constitutes 6.4% of the German population, may experience adverse drug reactions when treated with standard doses of one of these drugs alone. Moreover, the coadministration of these frequently used drugs is expected to be especially harmful in this subgroup of patients.

The prediction performance of the Bayesian feedback method was evaluated with respect to accuracy and precision, and efficacy and safety (width of the prediction interval) on the basis of 90 predictions in 30 patients treated with lidocaine. The mean of the prediction error (PE) and the root mean squared error (RMSE) served as a measure of accuracy and precision. The variance of the standardized prediction error (SPE) was used to evaluate the estimate of the standard deviation of the prediction error. SPE was defined as PE divided by the standard deviation of the predicted concentration. The standard error of RMSE and of the variance of SPE was determined by bootstrap. The results indicate that the lidocaine serum concentration at 12 hr (C2) after starting continuous infusion can be predicted with high accuracy and precision with a single feedback measurement obtained 2-4 hr (C1) after commencement of treatment: RMSE = 20.6%. Prediction at 24 hr (C3) was less accurate: RMSE = 31.4%. Using both C1 and C2 to predict C3 improved precision (RMSE = 23.4%). The evaluation of the prediction interval revealed that the current algorithm produces an upward biased estimate, probably due to a positive bias in the estimate of the covariance matrix of the parameter estimates. It is suggested that evaluation of prediction performance should include the estimate of the prediction interval.

No abstract