Measurement of factor VIII pharmacokinetics in routine clinical practice

S. Björkman* andP. Collins†, for theProject on Factor VIII/factor IX PK of The FVIII/factor IX Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis

*Department of Pharmaceutical Biosciences, UppsalaUniversity, Uppsala, Sweden

†School of Medicine, CardiffUniversity, and University Hospital of Wales, Cardiff, UK

Corresponding author: Sven Björkman, Department of Pharmaceutical Biosciences, Box 591, Uppsala University, Uppsala, S-751 24 Sweden

The members of the Project on Factor VIII/factor IX PK are: Peter Collins (chair), Sven Björkman, Victor Blanchette, Kathelijn Fischer, Massimo Morfini and Edward Tuddenham. All members have reviewed the final version of this manuscript.

Introduction

Prophylaxis for haemophilia A is effective but expensive. Knowledge of a patient’s pharmacokinetic (PK) response to infusion of factor VIII (FVIII) is likely to be useful in clinical management [1].However, the PK of FVIIIcannot be predicted from patient characteristics such as age and body weight (BW), but must be determined empirically [2,3]. Determination of PK in a routine clinical setting may seem daunting.According to guidelines for PK studies on new FVIII concentrates [4], 10-11 blood samples should be takenover 32-48 hours.Useful PK parameters can however be estimated from only a few (well-timed) determinations of drug plasma levels, by means of Bayesian analysis [5]. This hasbeen shown also for FVIII [6-12].During prophylaxis the trough level, or the time/week spent below a certain level, is important [1,8-9,13]. The aim of this communication is to describe PK methodology, suitable topredict individual trough levels, which can be applied in clinical practice.

Blood sampling and Bayesian analysis

An analysis [11]of data from 41 FVIII PK determinations demonstrated that blood sampling at 4, 24 and 48 hours gave practically the same information as a conventional (7-10 sample) study. Sampling at 8 and 30 hours, or at 24 hours alone, gaveuseful, albeit less accurate results. Due to the irregularities of the early part of a FVIII coagulant activity (FVIII:C) versus time curve [3,8,14], blood sampling less thanfour hours after infusion is not meaningful (Figure 1). The sampling should be well spread within the “B” region and the times accurately recorded.

FVIII washout is not needed for estimating PK. TheBayesian analysiscan be performed on data from practically any dosing schedule. Doses and times of preceding infusions must be known for at least five half-lives (after which<3% of a dose remains in the body) before the study infusion. Five FVIII half-lives would correspond to up to five days in prophylaxis patients.

The Bayesian analysis is based on PK information in the relevant population of patients, as described bya population PK model. The central part of the population modelis the structural (compartmental) model, which is defined by the shape of the FVIII:C versus time curve. Concomitantly, a covariate model describes relationships between PK parameters and patient characteristics, and a statistical model the variance between individuals as well as residual (random) variance.For example (from [2]):

-Structural model: two-compartment.

-Covariate model for clearance (CL; relationships with BW and age):

-Coefficient of variation (%CV) of CL between individuals: 28%.

Several similar population PK models for FVIII have been published [2,11,15-17].

Then, according to the Bayesian principle the first assumption about an individual’s PK, before any FVIII:Cdata have been obtained, is that it corresponds to the values calculated from the covariate models. The most likely CL isthus calculated from BW and age. Acquisition of data shifts the estimate towards the individual’s actual value. Since biological measurements are never exact, a balance is maintained;with few measurements the estimate of PK is a compromise between the model-prediction and the best fit to the data, while with more measurements reliance on the data increases. This balance is regulated by the %CV of PK parameters between individuals in comparison to the residual variance.It should be noted that any variance in PK between types of FVIII concentrates (except new, long-acting ones) is included into, or obscured by, the general inter-individual variance. User-friendly software for Bayesian analysis is available.TCIWorks ( which is freely available for download,has been evaluated for FVIII PK [12].

Application in clinical practice

If adjusting prophylaxis to an appropriate trough level based on individual PK, in addition to monitoringbleed pattern, is useful then the introduction of limited blood sampling PK has major benefits. Different trough levels may be targeted dependent on circumstances; higher levels may be desired to manage target joints, highly active patients or those more prone to bleed, alternatively lower levels may be allowedin a patient who hasnot bled for a long time. Because PK changes with growth in young children [2,3,17], and breakthrough bleeds are potentially more damaging,PK information is likely to be more useful at this age.

Due to the inevitable random variance in PKover time, as well as assay uncertainty, itis probably better to perform limited sampling studies on several occasions (and continuously update the Bayesian estimates of PK) than to perform one multi-samplestudy at a single occasion. No comparative clinical trial of these approaches has however been performed.

Conclusion

Proof of concept has been presented for the use of sparse blood sampling and Bayesian analysis formeasuring PK and using this information to dose tailor in prophylaxis.Validation of these methods for patients with inhibitors, or during surgery or bleeding, is lacking.The procedure could allow routine determination of individual PK in the clinic,potentiallymaking prophylaxis more cost-effective.

References

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  2. BjörkmanS, Folkesson A, Jönsson S. Pharmacokinetics and dose requirements of factor VIII over the age range of 3-74 years: A population analysis based on 50 patients with long-term prophylactic treatment for haemophilia A. Eur J Clin Pharmacol 2009; 65: 989-998
  3. BjörkmanS, Blanchette VS, Fischer K, Oh M, Spotts G, Schroth P, Fritsch S, Patrone L, Ewenstein BW, Collins PW: Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring. J Thrombos Haemostas 2010; 8:730-736
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  14. Björkman S, Carlsson M, Berntorp E, Stenberg P: Pharmacokinetics of factor VIII in humans. Obtaining clinically relevant data from comparative studies. Clin Pharmacokinet 1992; 22: 385-395
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Figure and legend:

Figure 1. Representative curve of factor VIII coagulant activity (FVIII:C; data from one patient in [14]) versus time. Levels at 48hours (C) may be close to the assay limit and/or the endogenous baseline, thus a measurement here may be inaccurate. Region B defines theterminal half-life of FVIII:C, andlevels can be measured accurately. In region A, FVIII:C levels often lie above the terminal half-life regression line, due to “post-infusion activation” and/or “two-compartment” pharmacokinetic behavior of FVIII:C. Thus, the best sampling for estimating trough levels are within region B.

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