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A pharmacokinetic program that allows individualization of Factor VIII dosage regiments in hemophilia patients undergoing major surgery is described. The program, which is designed for the IBM PC microcomputer and compatible machines, is based upon the one-compartment open model with instantaneous input. In the framework of such a pharmacokinetic model, it is assumed that the elimination of Factor VIII is faster during the early post-operative period and that it decreases progressively over the following days. Since Factor VIII half-life is dependent on the time elapsed since the operation (short half-life values during the early post-operative period, longer half-life values thereafter), the pharmacokinetic model is a nonlinear one. A first-order 'variation' rate constant is used to describe the prolongation of Factor VIII half-life from the initial value immediately after surgery to the final value achieved several days later. Individualized estimation of the patient's kinetic parameters (initial half-life, 'variation' rate constant and volume of distribution) is performed through the Bayesian method. Therefore, for such estimation the program exploits the Factor VIII plasma levels measured in the individual patient as well as the population pharmacokinetic data of Factor VIII. After estimating the individual's Bayesian parameters, the program predicts the dosage regimen that will elicit the desired time-course of Factor VIII plasma levels. If requested, the program is able to calculate the least-squares estimates for the parameters of the pharmacokinetic model and dosage prediction can also be made on the basis of such estimates. The least-squares estimates are useful for calculating population pharmacokinetic parameters according to the Standard Two-Stage method. Some examples of clinical use of the program are presented.

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.