Marzia Matucci

Clinical Pharmacokinetics of Factor VIII in Patients with Classic Haemophilia

SummaryStudies of Factor VIII pharmacokinetics in haemophiliacs can be classified into 2 groups depending on whether single-dose or multiple-dose Factor VIII curves are used. This review analyses information published so far in both these areas, with particular emphasis on the choice of appropriate models for pharmacokinetic analysis.Single-dose studies of Factor VIII kinetics have previously used a wide variety of methods for pharmacokinetic analysis (empirical methods of Factor VIII level prediction, graphical techniques for semilog analysis, 1-compartment and 2-compartment models). However, Factor VIII poses unique problems to the pharmacokineticist because decay curves can be either monophasic (monoexponential) or biphasic (biexponential) for unknown reasons, and because Factor VIII concentrations are generally subject to significant assay error. Problems of compartmental analysis that occurred in previous studies are highlighted, and a model-independent non-compartmental approach for analysing Factor VIII curves is proposed.To date, fewer data have been published on multiple-dose kinetics of Factor VIII. From a clinical point of view, repeated-dose regimens are most commonly required in patients undergoing surgery and in patients with severe bleeding. A fairly well defined ‘therapeutic window’ of optimal Factor VIII plasma concentrations has been identified, particularly in surgical patients. This fact has spurred research aimed at applying to haemophilia patients the pharmacokinetic dosing methods commonly used for therapeutic monitoring of drugs (e.g. Bayesian method for dosage individualisation). A few papers have already been published in this field, and this review summarises problems encountered by previous investigators, and evaluates comparatively the pharmacokinetic methods used.

Pharmacokinetics of a new heat-treated concentrate of factor VIII estimated by model-independent methods

We evaluated the pharmacokinetic properties of Kryobulin TIM3, a new heat-treated Factor VIII concentrate which has recently become available in Europe. Twelve patients with classic hemophilia were studied. In each patient, Factor VIII was given as a single dose (ranging from 11.6 to 30.3 units/kg) after which eight serial blood samples were drawn to characterize the disappearance of Factor VIII from the plasma. Model-independent (noncompartmental) methods were used for pharmacokinetic analysis. The following pharmacokinetic parameters of Factor VIII (mean +/- SD) were estimated: clearance = 3.83 +/- 0.99 ml/h/kg; mean residence time = 15.9 +/- 4.5 h; volume of distribution at steady state = 55.6 +/- 9.3 ml/kg; in-vivo recovery = 129 +/- 29%. The pharmacokinetic parameters of Kryobulin TIM3 obtained in our study are very similar to those previously reported for the untreated concentrate. Thus, our findings suggest that the dosing guidelines previously available for the untreated concentrate need not be revised when using the treated product.

Increased thromboxane A2 generation and altered membrane fatty acid composition in platelets from patients with active angina pectoris.

Lipid composition of platelet membranes and thromboxane A2 (TxA2) generation by platelets were investigated in eighty-seven anginal patients (forty-two with resting angina in active phase and forty-five with effort stable angina or rest angina in inactive phase) and in forty-five clinically healthy subjects of similar age. All subjects were on the same dietary regimen and the adherence to diet was checked by analysis of red blood cell lipids. Platelets from active angina patients produced more TxA2 than platelets from both inactive patients and controls (p less than 0.001). Moreover patients with active angina had higher arachidonic acid (AA, p less than 0.001) and lower eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) levels in phosphatidylcholine (PC, p less than 0.001), than inactive patients and controls. AA and EPA changes in membrane PC significantly correlated with TxA2 production (p less than 0.001) but not with coronary pathoanatomy. Plasma lipids, content of cholesterol, total phospholipids (and their saturated and unsaturated fatty acids) and the different phospholipid fractions in platelet membrane were not different in the three groups. Present results indicate that in platelets from anginal patients phospholipid fatty acid composition is at least in part independent of plasma composition and that in active angina there are modifications leading to increased TxA2 formation and possibly contributing to the occurrence of ischemic attacks.

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 patients 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.

Age related changes in platelet lipid composition.

Platelet lipid composition was investigated in 52 healthy subjects aged 20 to 68 years with similar dietary habits and living in a narrow geographic area in order to search possible changes referrable to aging. No significant variations were observed when platelet cholesterol, total phospholipids and different phospholipid fractions were considered, whereas cholesterol/phospholipid (C/PL) molar ratio significantly increased with aging (p less than 0.01). Moreover, a significant increase in 16:0 + 16:1 fatty acids was found in phosphatidylcholine (PC) and in sphingomyelin (SP) (r = 0.62, p less than 0.001 and r = 0.30, p less than 0.05 respectively) and a decrease in 18:2 n6 in the phospholipid fractions considered (at least p less than 0.05). These results indicate that modifications in platelet lipid composition occur with aging and that they could affect platelet functions so playing a role in the onset of atherosclerosis and in thrombotic phenomena occurring with increasing frequency in the elderly.

Effect of oral treatment with pantethine on platelet and plasma phospholipids in IIa hyperlipoproteinemia.

In a single-blind, crossover, completely randomized study, the effects of oral treatment with pantethine or placebo on fatty acid composition of plasma and platelet phospholipids were investigated in 10 IIa hyperlipoproteinemic patients. A significant decrease of total cholesterol and total phospholipids was observed both in plasma and in platelets after a twenty-eight-day treatment. In plasma, pantethine induced a decrease of the ratio sphingomyelin/phosphatidylcholine. Moreover, a relative increase of n3-polyunsaturated fatty acids both in plasma and in platelet phospholipids and a decrease of arachidonic acid in plasma phospholipids were observed. These results indicate that pantethine can affect plasma and platelet lipid composition with possibly favorable influences on the determinants of cell membrane fluidity.

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.

Decreased number of PGD2 binding sites on platelets from patients with type IIa hyperlipoproteinemia

Platelets from patients with familial hypercholesterolemia (type IIa hyperlipoproteinemia), a condition associated with a high prevalence of atherosclerosis and its ischemic complications, are claimed to be hyperresponsive to aggregating stimuli. We investigated the platelet responsiveness to and the binding of PGD2, a potent endogenous inhibitor of platelet aggregation via stimulation of adenylate cyclase, in a group of 7 patients affected by IIa hyperlipoproteinemia (IIa HLP) and in a control group of 10 healthy subjects. Inhibition by PGD2 of ADP-induced platelet aggregation was significantly lower in IIa HLP patients than in controls. The number of binding sites for PGD2 of platelets from IIa HLP patients was significantly reduced in comparison with that from controls (93 +/- 19 and 232 +/- 23 receptors/platelet, respectively), whereas the affinity for PGD2 was comparable to that of controls (Kd = 68.8 +/- 19.8 nM in patients and 66.1 +/- 15.9 nM in controls). The reduced number of platelet PGD2 binding sites in IIa HLP patients may account for the impaired sensitivity to PGD2 shown in vitro by platelets and may contribute to the increased tendency to thrombotic manifestations observed in IIa HLP.

A Calculator Program for Individualizing Factor VIII Dosage

We developed a calculator program to individualize Factor VIII dosage on the basis of the concentration-time data obtained after a single test-dose. The program is designed for the Hewlett-Packard 41-CV calculator. The calculation procedure is the 1977 version of the Sawchuk and Zaske method. The program performs model parameter estimation through a nonlinear iterative least-squares technique (the modified Gauss-Newton method). We tested our program in three patients with classic hemophilia who required multiple-dose treatment with Factor VIII. In each patient, individual kinetic parameters were estimated from the serial plasma levels measured after the test-dose. The predicted concentration-time curve resulting from all the administered doses was calculated based on the estimated kinetic parameters. Good agreement between predicted and measured levels during the multiple-dose regimen was observed in all patients.

Spontaneous and cold pressor test-induced prostaglandin biosynthesis by human heart

To investigate prostaglandin biosynthesis by the heart, 21 patients undergoing cardiac catheterization and coronary angiography for congenital or acquired heart diseases other than coronary artery disease were investigated. Prostacyclin (as 6-keto-PGF1 alpha), PGE2, PGF2 alpha and TxA2 (as TxB2) were measured by specific radioimmunoassay in blood from coronary sinus, aorta, and a peripheral vein under resting conditions and following cold pressor test (CPT). PGF2 alpha was always found undetectable. In resting conditions, no significant differences in plasma 6-keto-PGF1 alpha, PGE2, or TxB2 concentrations were found among coronary sinus, aorta, and peripheral venous blood and no transcardiac gradient existed (mean: +0.4 +/- 1.2 pg/ml for 6-keto-PGF1 alpha, +0.1 +/- 0.6 pg/ml for PGE2, and -0.4 +/- 9.9 pg/ml for TxB2). CPT was able to induce a significant increase in 6-keto-PGF1 alpha and PGE2 concentration in blood from the different sampling sites and a significant transcardiac gradient was found following CPT (+11.6 +/- 7.4 pg/ml for 6-keto-PGF1 alpha (p less than 0.01) and +5.2 +/- 3.6 pg/ml for PGE2 (p less than 0.001). TxB2 levels significantly increased in peripheral venous blood (from 18.3 +/- 6.2 to 29.2 +/- 20.3 pg/ml, p less than 0.05), but they did not increase either in coronary sinus (from 21.9 +/- 9.7 to 22.9 +/- 9.8 pg/ml) or in aorta (from 22.3 +/- 4.7 to 19.1 +/- 6.5 pg/ml). Present results indicate that a cardiocoronary prostacyclin and PGE2 synthesis is inappreciable under resting conditions but it becomes remarkable following sympathetic stimulation. On the contrary, no TxA2 cardiocoronary biosynthesis seems to occur in patients free from coronary artery disease.