Pharmacokinetic Study of Continuous
Infusion of Intermediate-Purity Factor VIII
in Haemophilia-A Patients Undergoing
Elective Surgery or with Severe Haemorrhage

by Carolyn Rochat

Introduction

Haemophilia A is a sex-linked disorder characterised by a deficiency of factor VIII (FVIII) resulting in bleeding episodes either spontaneously or from trauma. The principal form of therapy has been replacement of the missing factor with concentrates of factor VIII prepared from pooled cryoprecipitate.

Treatment of haemorrhage and prophylaxis against bleeding following surgery is based on the infusion of coagulation factor. Major surgery or life threatening bleeds require normal factor VIII levels to be maintained at all times. Frequent bolus injections or intermittent infusions resulting in high peaks are required to keep the trough factor VIII plasma level above the minimum haemostatic level. A minimum haemostatic level of 0.3 iu/ml is usually necessary to treat relatively mild bleeding episodes, and a level of 0.5 iu/ml is generally considered the minimum for serious bleeding into joints and muscles. This is achieved by frequent monitoring of plasma factor VIII levels. The quantity of factor VIII infused needs to be sufficient to allow for distribution of factor throughout the body and clearance from plasma. An infusion of 1 iu of factor VIII/kg body weight will increase plasma factor VIII level by 0.02 iu per ml.

The short half-life of FVIII in the main obstacle in maintaining such a high blood level of factor VIII x VIII. This limitation is reduced by the administration of intermittent infusions to maintain the desired plasma levels but it would seem more physiological and economical to maintain a steady plasma level of factor VIII activity above that at which there is a risk of bleeding. Therefore continuous infusion therapy has been suggested. Continuous infusion has been shown to be a safe, effective and practical approach to treatment of patients with haemophilia A in a number of studies.

McMillan et al first studied continuous infusion in five boys and concluded that this method provides more precision in replacement therapy than by intermittent infusion alone. Hathaway et al compared continuous and intermittent infusions in 12 severe haemophilia A patients undergoing surgical procedures and found that a higher minimal plasma level (50 iu/dl vs 35 iu/dl) was seen with the same amount of product if infused continuously. They established the following dosage guidelines for surgical procedures: a continuous infusion of 2 iu/kg/h produces a mean FVIII:C level of 0.5 iu/ml. They gave an initial infusion to raise the levels to 100% (1 iu/ml) FVIII:C by application of the following formula: Dosage (iu) = (wt kg)(0.5)(desired plasma level (iu/100ml)). Matucci et al developed a programme for continuous infusion with the dosage adjusted according to the daily calculation of the clearance of FVIII. The dosage was adjusted on a daily basis since they found a progressive decrease in the clearance during the first 3-5 days, which can result in additional cost savings of product as less is required to maintain factor VIII levels. They proposed that the reason for this was the saturation of intracellular storage of FVIII:C during the infusion. They used minipumps to overcome the use of large volumes associated with the additional dilution of product in saline.

Martinowitz et al outlined the following advantages of continuous infusion:

1. It obviates the need for multiple daily bolus injections of factor concentrates.

2. Constant blood levels appear to be more efficacious: subtherapeutic trough levels or excessive peak levels may result from bolus injections.

3. Reduces cost of coagulation factor replacement by 30% when fixed dose infused or as much as 50-90% if adjusted dose infused by using less plasm product.

4. The drawing of blood samples is simpler.

A large variety of procedures employed during the manufacture of factor concentrates are known to cause various degrees of inactivation and/or denaturation of the FVIII molecule. It is important to assess the behaviour of each product when infused in the haemophilic patient. Since a relationship has been established between clinical efficacy and the level of circulating FVIII:C in haemophilic patients, the evaluation of in vivo recovery and the measurement of biological half-life have proven to be valuable efficacy tests. Factor VIII decay curves are normally biphasic (single dose) with an early distribution phase and a late elimination half-life. In practice it can be approximated to a monophasic curve. Traditionally, FVIII pharmacokinetics were evaluated by means of compartmental models which followed the use of graphical techniques. Recently there has been a move to analyse decay curves by means of model-independent analysis, which is of value in problematic kinetic cases such as protein kinetics, such as factor VIII where the assay is not accurate or precise and time-concentration curves do not always fit the model. Model-independent methods also have the advantage that they do not require the assumption of a specific compartmental model. The choice of a compartmental model is problematic because, for unknown reasons, the decay of plasma FVIII activity after a single dose is normally biphasic.

Three basic pharmacokinetic parameters are measured:

1. Total body clearance (CL) -- the overall rate at which plasma is cleared.

2. Volume of distribution at steady state (Vss) -- the ratio of the amount of substance present in body at any time and the corresponding plasma concentration.

3. Mean residence time (MRT) -- is a practical function similar to half-life. The estimation of these from single dose data is based on the calculation of AUC (area under the curve) and AUMC (area under the moment curve). The MRT is the time for 63,2% excretion, therefore in an ideal pharmacokinetic model:

MRT = 1.443 t CL = D/AUC

MRT = AUMC/AUC

MRTiv = MRT - T/2

Vss = CL MRT iv

T (h) duration of continuous infusion (Correction made to account for the duration of infusion)

In vivo recovery (IVR) is a distribution parameter which is calculated as the ratio of the measured peak to declared units (expected peak) per plasma volume. However, there are uncertainties in the calculation of this parameter:

1. The labelled potency (specifications allow for potency plus-minus 20%) may differ from the actual content.

2. There is conflict regarding time to peak value which may be 10, 15, 60 or even 120 minutes after end of infusion. The unpredictable "post-infusion activation" of FVIII makes the calculation of IVR dependent on early blood sampling.

3. Plasma volume is measured empirically resulting in errors (obesity, underweight, low haematocrit, etc.). The actual plasma volume is not usually known accurately and different methods are employed to estimate the volume which yields different values. Also, IVR increases with body weight but this is actually an incorrect deduction as plasma volume as a fraction of total body weight actually decreases with increasing weight.
   

MRT adjusted to iv bolus case.

IVR calculated by using the highest FVIII:C plasma level after infusion as the actual peak of FVIII activity. The theoretical FVIII:C value is calculated as follows:

Plasmavolume(ml) = 80xkgbodyweightx(100-haematocrit) / 100

TheoreticalpeakofFVIII:C = amountofFVIII:Cinjected / Plasmavolume

PercentIVR = ActualFVIII:Cx100 / TheoreticalFVIII:C

Amount of FVIII:C injected = value given by 1 or 2 stage assay x injected volume.

4. ...It assumes FVIII:C distributes only into plasma.

Therefore it is suggested alternative methods to report pharmacokinetics are used e.g. volume of distribution at steady state, as methods for calculation are standardised and the parameter is determined from the entire decay curve and there is no indirect measure of plasma volume involved. When calculating pharmacokinetic parameters in mild haemophiliacs, caution must be exercised, as the baseline FVIII:C level (endogenous synthesis) must be subtracted from the post-dose FVIII:C concentrations to prevent large errors in the half-life.

This study is being undertaken as in South Africa no product is registered for use as a continuous infusion and there is no data of this kind for the intermediate-purity product that is widely used. Research work which can evaluate the local product for this use will be invaluable to the haemophilia community both to provide improved therapy and to reduce costs. Factor VIII therapy is costly. Continuous infusion, in addition to being safe, efficacious and convenient, is highly cost effective. At the same time, the opportunity to more fully elucidate the pharmacokinetic parameters of the Factor VIII product will be taken. To date only in vivo recovery and half-life studies (t 1/2 = 13.1 hours) have been performed.

Objectives

1. To evaluate the pharmacokinetic behaviour of intermediate purity FVIII during continuous infusion to haemophiliacs undergoing elective surgery procedures or with haemorrhage of a severity requiring a minimum of 5 days of infusion with FVIII, and thereby establish an optimum regimen for continuous infusion.
2. To characterise the pharmacokinetic parameters of intermediate purity FVIII, by undertaking a pre-operative pharmacokinetic study, using-model independent methods.
3. To evaluate the cost-benefit of continuous infusion of FVIII versus intermittent bolus infusions.

Study Design

Open, non-randomised trial of continuous infusion therapy in moderate to severe haemophilia A patients undergoing elective surgery (preceded by a pre-operative pharmacokinetic study) or with severe haemorrhage. Due to the small number of patients available, it would be difficult to recruit enough patients in the given time to carry out a randomised, prospective study. Therefore, a retrospective control group of haemophilia A patients who received intermittent bolus infusions after elective surgery will be identified for comparisons with continuous infusion patients. These comparisons will take the form of comparing total FVIII usage, in terms of number of units administered over treatment period.

Site of Study

The study will be conducted at the Johannesburg Hospital under the supervision or Dr. R..Schwyzer, Dr. J. Poole, Sr. Anne Gillham and Sr. A.L. Cruickshank.