Samuel Vozeh

Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d‐tubocurarine

We propose a model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time‐independent sensitivity component. The total model can accommodate extremes of effect. It allows fitting of simultaneous plasma concentration (Cp) and effect data from the initial distribution phase of drug administration, or from any non‐equilibrium phase. The model postulates a hypothetical effect compartment, the dynamics of which are adjusted to reflect the temporal dynamics of drug effect. The effect compartment is modeled as an additional compartment linked to the plasma compartment by a first‐order process, but whose exponential does not enter into the pharmacokinetic solution for the mass of drug in the body. The hypothetical amount of drug in the effect compartment is then related to the observed effect by the Hill equation, a nonlinear sigmoid form. Nonlinear least‐squares data fitting is used for parameter estimation. The model is demonstrated on two different sets of Cp and effect data for the drug d‐tubocurarine (dTC). In 7 normal subjects, the (mean ± SD) rate constant for equilibration of dTC effect (paralysis) and Cp is 0.13 ± 0.04 min−1 and the (mean ± SD) steady‐state Cp required to produce 50% paralysis is 0.37 ± 0.05 µg/ml.

Population pharmacokinetics of alfentanil: the average dose-plasma concentration relationship and interindividual variability in patients

The population pharmacokinetic parameters describing the plasma concentration versus time profile of alfentanil in patients undergoing general anesthesia were determined from 614 plasma concentration measurements collected in four previously reported studies with a total of 45 patients. A nonlinear regression analysis evaluating the effect of six concomitant variables revealed a significant influence of body weight on the volume of the central compartment (Vc), and a decrease with age of total body clearance (CL) and of redistribution rate from the deep compartment (k31). A small but significant effect of sex on the Vc was also observed. The duration of anesthesia and the concomitant administration of inhalational anesthetics had no effect on alfentanil pharmacokinetic parameters. The mean CL and Vc for alfentanil in a 70-kg male, aged less than 40 yr, were estimated as 0.356 l/min and 7.77 l, respectively. After correction for age, body weight, and sex, the remaining interindividual variability of alfentanil kinetics (expressed as coefficient of variation) was 48% for CL and 33% for Vc. These population pharmacokinetic parameter estimates should increase the accuracy of predicting concentration-time profiles for intravenous alfentanil infusions. A computer program is presented that allows prediction of the alfentanil plasma concentration and the 68% interval limits of the prediction from the study data analysis.

Predicting individual phenytoin dosage

Most previously suggested methods for predicting phenytoin dosage from steady-state drug levels (Cpss)measured in the clinical setting fail to fully exploit all relevant (population) information. A Bayesian prediction method, applicable to any drug, is available. It appropriately combines all types of information. In this paper, we compare the Bayesian method as applied to phenytoin to two other prediction methods (and a baseline, nonfeedback one). Actual doses are compared to predictions in 49 patients. Each method is optimized, as far as possible, for the test data. The comparison favors the Bayesian method. Since each of the other prediction methods for phenytoin can be shown to be a theoretically suboptimal special case of the Bayesian one, the superiority of the latter may be a general phenomenon. Because the pharmacokinetic model linking steady-state phenytoin levels and dosage is so simple, a good approximation of the general Bayesian method can be implemented as a graphical device, or as a program for a programmable calculator. We present and describe both of these approximations.

Intravenous cyclosporine kinetics in renal failure

Kinetics of the novel immunosuppressive cyclosporine were determined in four patients with terminal renal failure. After a short intravenous infusion (2.05 to 3.5 mg/kg in 4 hr), blood and plasma concentrations were measured (HPLC and radioimmunoassay [RIA]) up to 36 hr. After infusion, concentration curves of the drug were characterized by a rapid initial fall (t½α 0.10 ± 0.03 hr), followed by a biphasic elimination phase with corresponding t½s of 1.08 ± 0.25 hr (t½β) and 15.8 ± 8.4 hr (t½γ). The volumes of distribution, calculated from whole blood concentrations (HPLC), were 0.140 ± 0.48 l/kg (volume of the central compartment) and 3.49 ± 2.65 l/kg (volume of distribution at steady state), whereas systemic clearances were 0.369 ± 0.08 l/hr/kg. Blood levels measured by RIA exceeded the HPLC values after the fourth hour by up to 100%, indicating the production of cross‐reacting cyclosporine metabolites. Plasma concentrations were considerably lower than in whole blood. Elimination of unchanged cyclosporine in patients with renal failure appears to be of the same order as in those with normal kidney function. Modification of the initial dosage regimens is therefore probably not required.

Evaluation of population (NONMEM) pharmacokinetic parameter estimates

The application of population pharmacokinetic analysis has received increasing attention in the last few years. The main goal of this report is to make investigators aware of the necessity of independent evaluation of the results obtained from a population analysis based on observational studies. We also describe with the help of a specific example (a new synthetic opiate Alfentanil) how such evaluation can be performed for parameter estimates obtained with the software system NONMEM. The method differs depending on the type of serum concentration data that are used for the evaluation. A general method is described, based on the regression model used in NONMEM, that can test for bias in the estimates af fixed and random effects independent of the number of observations per patient and dosing. Since the procedure for testing for statistically significant bias in the prediction of the average concentration and its variability can be relatively complex, we propose that generally available program packages performing estimation of the pharmacokinetic parameters from observational data should contain the necessary software to evaluate the reliability of the parameter estimates on a second data set.

Serum level monitoring of antibacterial drugs. A review.

SummarySerum concentration measurements of antibacterial agents are increasingly used to optimise drug dosage regimens. However, this approach is only justified for drugs with a low therapeutic index and poor predictability of serum concentrations, such as the aminoglycosides, chloramphenicol and vancomycin, whereas the penicillins and cephalosporins can safely be applied well above their minimum inhibitory concentrations.Wide interpatient variation in distribution and elimination are the main reasons for the unpredictability of aminoglycoside serum concentrations. It has been shown that in patients with normal creatinine clearance, the apparent elimination half-life of gentamicin varies from 0.4 to 7.6 hours. The pharmacokinetics of the atninoglycosides are most adequately described by a 3-compartment open model where the slow terminal half-life reflects elimination from the deep tissue compartment. The accumulation of the aminoglycosides in this compartment, which includes the kidneys and inner ear, is probably an important factor in their potential toxicity in these organs. Careful serum level monitoring may reduce, but cannot totally avoid, the risk of side effects. However, maintenance of effective drug levels appears to be at least an equally important goal of aminoglycoside serum level monitoring.Chloramphenicol is also a potentially toxic antibacterial agent. Its therapeutic range is usually considered to be 15 to 25 mg/L. The most important side effects are the ‘grey baby syndrome’ and bone marrow toxicity. Chloramphenicol is metabolised to several microbiologically inactive products. It also shows wide interpatient variability of its pharmacokinetics, especially in young children, and serum levels should therefore be followed in these patients.Vancomycin, a highly effective agent for staphylococcal and enterococcal infections, may also exhibit nephrotoxic and ototoxic side effects. A well-defined therapeutic range has not yet been established but in view of its minimum inhibitory concentrations it seems reasonable to maintain vancomycin serum concentrations between 15 and 50 mg/L. Since this drug is excreted unchanged in the urine, serum levels should particularly be monitored in patients with impaired renal function.The advances in routine therapeutic drug monitoring are directly related to rapid developments in technologies associated with the quantification of these agents. Microbiological plate diffusion assays are now often replaced by more specific immunoassays (radioimmunoassay, enzyme immunoassay, and fluorescence immunoassay) and chromatographic techniques.

Rapid Prediction of Individual Dosage Requirements for Lignocaine

The mean and standard deviation of lignocaine (lidocaine) pharmacokinetic parameters in a patient population were determined on the basis of 327 serum concentration measurements obtained in 42 patients treated for ventricular arrhythmias. The application of a Bayesian forecasting method, which uses the estimates of the population parameters and 1 or 2 serum concentration measurements as feedback information, was tested retrospectively in 17 of the 42 patients (group I, 32 levels), and prospectively in 10 additional patients (group II, 20 levels). With I individual feedback concentration, sampled 2 to 4 hours after the start of lignocaine infusion, serum concentrations at 12 and 24 hours could be accurately predicted. The prediction error (measured minus predicted concentration) ranged between −1.2 and +1.6 (mean −0.03) mg/L in group I, and from −0.7 to +1.5 mg/L (mean +0.13) mg/L in group II; the correlation coefficient of measured and predicted levels were 0.92 and 0.86, respectively.In contrast, a prediction of lignocaine concentrations in these patients using only population parameters without feedback was poor: range of the prediction error = −3.1 to +3.0 mg/L (mean = +0.001 mg/L, r = 0.63, groups I and II, n = 52).The results demonstrate that with the Bayesian forecasting technique, accurate assessment of individual dosage requirements can be obtained within a few hours after starting lignocaine therapy.

Estimates of the population pharmacokinetic parameters and performance of Bayesian feedback: A sensitivity analysis

We investigated the influence of bias in the estimates of the population pharmacokinetic parameters on the performance of Bayesian feedback in achieving a desired drug serum concentration. Three specific cases were considered (i) steady-state case, (ii) lidocaine example, and (iii) mexiletine example. Whereas in the first case both the feedback and the desired concentration represented steady-state values, in the lidocaine and mexiletine examples the feedback concentration was assumed to be sampled shortly after starting therapy. RMSE was used as a measure of predictive performance. For the simple steady-state case the relationship between RMSE and bias in the parameter estimates describing the prior distribution could be derived analytically. Monte Carlo simulations were used to explore the two non-steady-state situations. In general, the performance of Bayesian feedback to predict serum concentrations was relatively insensitive to bad population parameter estimates. However, large changes in RMSE could be observed with small changes in the true variance component parameters in particular in the intraindividual residual variance, σɛ2, indicating that the prediction interval, in contrast to point prediction, is sensitive to bias in the estimates of the population parameters.

Influence of allopurinol on theophylline disposition in adults

Theophylline kinetics after intravenous aminophylline were determined in 5 nonsmoking healthy males before and after allopurinol for 1 wk. There was no significant alteration in theophylline disposition.

Comparison of the pharmacodynamic effects of intravenous and oral propafenone

The effect of propafenone and its major metabolite 5‐hydroxy‐propafenone on ECG intervals was investigated in eight healthy extensive metabolizers after single oral (300 to 450 mg) and intravenous (35 to 50 mg) doses of propafenone in a single‐blind randomized trial. Peak serum concentrations were 278 ± 233 ng/ml (oral) and 295 ±131 ng/ml (intravenous). After oral administration peak 5‐hydroxy‐propafenone levels were 194 ± 65 ng/ml, whereas after intravenous dosing no metabolite was detected, except in one subject. Serum concentrations were related to effects by linear regression including a hypothetical effect‐site compartment in a pharmacokinetic‐pharmacodynamic model. Significant prolongations of ECG intervals were found in both sequences. Comparison of the two concentration‐effect data sets (intravenous, oral) revealed an additive effect of 5‐hydroxy‐propafenone in four of eight subjects for PQ interval and seven of eight subjects for QRS duration. We conclude that 5‐hydroxy‐propafenone exerts pharmacologic activity and could thus contribute to the antiarrhythmic effect of propafenone.