A calculator program for clinical application of the Bayesian method of predicting plasma drug levels.

A pharmacokinetic program that allows individualization of drug dosage regimens through the Bayesian method is described. The program, which is designed for the Hewlett-Packard HP-41 CV calculator, is based upon the one-compartment open model with either instantaneous or zero-order absorption. Individualized estimation of the patient's kinetic parameters (clearance and volume of distribution) is performed by analyzing the plasma levels measured in the patient as well as considering the population data of the drug. After estimating the individual kinetic parameters by the Bayesian method, the program predicts the dosage regimen that will elicit the desired peak and trough plasma levels at steady state. For comparison purposes, the least-squares estimates for clearance and volume of distribution are calculated, and dosage prediction can also be made on the basis of the least-squares estimates. The least-squares estimates can be used to calculate population pharmacokinetic parameters according to the Standard Two-Stage method. Several examples of clinical use of the program are presented. The examples refer to patients with classic hemophilia who were treated with Factor VIII concentrates. In these patients, the Bayesian kinetic parameters of Factor VIII have been estimated through the calculator program. The Bayesian parameter estimates generated by the HP-41 have been compared with those determined by a Bayesian program (ADVISE) designed for microcomputers.

Tamoxifen and oligospermia.

Thirty normogonadotropic oligospermic males were administered Tamoxifen (20 mg/day) for 4 months. A complete evaluation of seminal parameters before and after treatment was performed. An increase of both mean sperm concentration and total sperm count was noted after treatment with Tamoxifen (p less than 0.05), whereas no variation was observed for semen volume, sperm morphologic characteristics, or sperm motility. Hormonal patterns of 5 of these subjects before, during, and after 3 months of treatment with Tamoxifen showed a progressive increase of gonadotropin (especially LH) and 17 beta E2 values; testosterone variations were minimal, and PRL showed a slight decrease.

Kinetic evaluation of four Factor VIII concentrates by model-independent methods.

Single-dose kinetics of 4 Factor VIII concentrates (Kryobulin, Hemofil T, Koate, cryoprecipitate) were studied in 41 patients with haemophilia-A. Model-independent methods were adopted for calculating the kinetic parameters (area under the curve, clearance, area under the moment curve, mean residence time, volume of distribution at steady-state). No substantial difference was observed in the kinetic characteristics of the 4 Factor VIII concentrates. A considerable interindividual variability of the calculated kinetic parameters was demonstrated for all concentrates. Our findings support the need to individualize Factor VIII dosage.

Clinical application of the Mullen and Foster method for individualizing phenytoin dosage.

The Mullen and Foster method was prospectively applied for individualizing phenytoin dosage in 24 epileptic patients. Accuracy and reliability of the method were assessed by comparing predicted and measured values of plasma phenytoin steady-state concentration. The absolute difference between predicted and measured phenytoin levels was less than 15 percent in 22 of 35 cases (63 percent), between 15 and 25 percent in 8 of 35 cases (23 percent) and more than 25 percent in 6 of 35 cases (17 percent).

Individualization of Factor VIII dosage.

The usefulness of a calculator programme that enables individualization of the dosage of Factor VIII, based on the concentration-time data measured after a test-dose, was assessed. The programme was tested in 12 haemophiliacs who required multiple-dose treatment with Factor VIII. Individual kinetic parameters were estimated in each patient from the plasma level data following the test-dose. Then, each patient received the multiple dose treatment with Factor VIII according to the dosage regimen suggested by the calculator programme. The time-curve of Factor VIII plasma levels at steady state was predicted by using the kinetic variables previously estimated. The plasma levels of Factor VIII were measured in all patients at steady state. As a result, good agreement between predicted and measured steady state concentrations was observed (r2 = 0.9797; P less than 0.001). The calculator programme tested in the present study appears to be a useful tool for individualizing the dosage regimen of Factor VIII in haemophiliacs.

A calculator program for least-squares parameter estimation according to the one-compartment kinetic model with zero-order input.

A calculator program that performs a nonlinear least-squares fit to data conforming to the one-compartment model with zero-order input is described. The program, which is designed for the Hewlett-Packard HP-41 CV calculator, is based on the Gauss-Newton iterative algorithm as modified by Hartley. A subroutine for calculation of initial parameter estimates is incorporated into the program. Plasma concentration data relative to a single oral dose of a sustained-release theophylline formulation are used to demonstrate the practical application of the program.

Comparative analysis of the pharmacokinetic techniques available for individualizing phenytoin dosage.

Over the past few years, numerous pharmacokinetic techniques based on Michaelis-Menten principles have been proposed to individualize PHT dosage and predict plasma levels. The choice of one of these techniques for clinical use depends on the number of steady state concentration-versus-dose (Css-D) data pairs that are known in the patient for whom the predictive technique is to be applied. The most frequent clinical situations in which these predictions are made can be divided into three groups for each patient considered--Case A: only one previous Css-D data pair is known; Case B: two previous Css-D data pairs are known; Case C: three previous Css-D data pairs are known. Of the available techniques that can be applied in case A, we compared the population clearance (PC) method and the Bayesian feedback (BF) method. The procedure for comparing the predictive capabilities of these methods was very similar to that adopted in a recent report by Vozeh et al. Our findings showed that the PC method should be preferred for clinical use under this circumstance. Two predictive techniques suitable for use in Case B (BF and Mullen & Foster methods) were compared. In this case, the BF method was shown to be more accurate. As regards Case C, three pharmacokinetic techniques were compared: the Mullen and Foster method, the iterative least-squares (ILS) technique, and the BF method. The ILS technique was found to be the most accurate in this case. Finally, we describe a programmable calculator procedure which uses the PC, BF or ILS methods in Cases A, B and C respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

A new programmable calculator procedure for individualizing phenytoin dosage.

A programmable calculator procedure allowing nonlinear least-squares fit to pharmacokinetic data conforming to the Michaelis-Menten model is described. Model parameter estimation is performed according to the iterative Gauss-Newton technique as modified by Hartley. This procedure thus employs the same theoretical approach used by most pharmacokinetic computer programs. No programming skill is needed to run the program described. The proposed procedure is discussed in detail and applied to some sets of pharmacokinetic data.

Iterative least-squares fitting programs in pharmacokinetics for a programmable handheld calculator.

Programs that perform a nonlinear least-squares fit to data conforming to one-compartment oral or two-compartment intravenous pharmacokinetic models are described. The programs are designed for use on a Hewlett-Packard HP-41 CV programmable calculator equipped with an extended-functions module and one or two extended-memory modules. Initial estimates of variables in the model are calculated by the method of residuals and then iteratively improved by the use of the Gauss-Newton algorithm as modified by Hartley. This modification minimizes convergence problems. The iterative-fitting procedure includes a routine for estimation of lag time for the one-compartment oral model. Clinical applications of the programs are illustrated using previously published data. Programming steps and user instructions are listed. The programs provide an efficient and inexpensive method of estimating pharmacokinetic variables.

Pharmacokinetic predictions based on a variable dosage frequency in chronic treatment.

After repeated intramuscular or oral administration, plasma drug levels are predicted by using a programmable calculator. Predictions are based on a one-compartment, open model with first-order absorption. The actual times of dosing are considered, so that the assumption of a constant dosing interval is not required. A brief analysis of the pharmacokinetic consequences that may result from a variable dosage frequency is presented.