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Haemophilia (2006), 12, (Suppl. 3), 17

The pharmacokinetics of coagulation factors

M. LEE,* M. MORFINI, C. NEGRIER, and V. CHAMOUARD
*UCLA School of Public Health, Los Angeles, CA, USA; Azienda Ospedale, Careggi, Florence, Italy; and Hopital
Edovard Herriot, Lyon, France

Summary. In this article, we provide a summary of

the generally accepted approaches to the design and
analysis of studies examining the pharmacokinetic
(PK) profile of an infused coagulation factor in
patients with a deficiency of one or more of these
factors. Furthermore, we briefly review the known
PK results for various commercially available coagu-

Introduction
As with any biologic or drug, a good understanding
of the pharmacokinetics (PKs) of these preparations
is essential to the development of proper dosing
regimens, especially with regards to the frequency of
administration. In this paper, we will review the
current status of the design of studies to evaluate PKs
of coagulation factors, the specific results with
regards to Factors VIII (FVIII) and IX (FIX), particularly with regards to recombinant DNA-derived
preparations, and the specific considerations necessary for continuous infusion of these factors.

lation factor preparations under single and continuous infusion.

Keywords: coagulation factor preparations, continuous infusion, pharmacokinetic studies, statistical
design

points out that the central focus of these guidelines is

on the PKs of coagulation factors after a single bolus
infusion, although later in this discussion focus will
be given to continuous infusion studies.
Control preparation
A control preparation that is of the same type as the
test product (if such a preparation exists) is usually
needed. For example, a recombinant Factor VIII
(rFVIII) product would be compared with another
rFVIII. Clearly, however, this will not always be
possible (e.g., with the first recombinant product of
its kind, e.g., rFVIIa).

Design and analysis of pharmacokinetic studies

In 1991, a set of guidelines for the determination of
half-life and recovery in studies of FVIII and FIX was
published [1]. These recommendations were an
attempt to provide a comparable way of conducting
PK studies, and most of the trials over the subsequent
years followed those recommended principles. However, changes in the regulatory requirements for the
conduct of these studies and the increased level of
complexity that resulted, necessitated a complete
revision of the original guidelines. The approaches
recommended here were primarily intended for
clinical trials of factor concentrates that are being
compared with other similar preparations. This also

Correspondence: Martin Lee, UCLA School of Public Health,

3944 Eureka Drive, Los Angeles, CA 91604, USA.
Tel.: +1 818 985 8920; Fax: +1 818 769 2880;
e-mail: martin.l.lee@att.net

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Sample size
Most PK studies have as their goal the establishment
of statistical bioequivalence between the test and the
control preparations. Therefore, the sample size
should be based on statistical considerations. Of
course, this requires a definition of bioequivalence.
One such criterion that has been frequently used in
the literature is the notion that the test material result
should be within 80125% of that for the control
preparation [2].
To implement this criterion, it is necessary to focus
on one particular aspect of the possible PK outcomes.
Regardless of that choice, the sample size can be
determined from the following standard formula [2]:
n > ta=2; 2n
2 tb; 2n
22 cv=202
where t [x,y] is the upper xth percentile of the
Students t-distribution with y degrees of freedom,

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a the chosen significance level (size of the Type 1

error), b the chosen size of the Type 2 error and cv the
coefficient of variation (namely its SD divided by its
mean) of the chosen primary PK parameter. Note that
the formula would have to be evaluated iteratively as
n appears on both sizes of the inequality. Thus, the
sample size to be used would be the smallest one that
satisfies the inequality. To illustrate, suppose that
CV 30%, a 0.05 and b 0.20, then approximately 40 subjects would be required in the study. [All
receiving both preparations (see below)]. Some may
find this number out of the question. Therefore, we
point out that if the study is intended for descriptive
rather than strict comparative purposes, then a
minimum of 12 subjects might still be sufficient.
Outcome variables
Historically, the terminal (b-phase) half-life and
in vivo recovery have been the focus of PK studies.
However, in traditional PKs, the key parameter is
the area-under-the-time-versus-concentration curve
(AUC) determined using the trapezoidal rule [3]. The
specific AUC referred to is the area from time 0
(baseline) to the last time point of measurement.
There are many other possible outcomes that can and
should be considered and these include:
1. Half-life;
2. Incremental recovery (determined as the peak
level in the factor in the first hour after the
infusion and reported as [U dL)1]/[U kg)1]);
3. Clearance (Cl) [4,5] (mL h)1 kg)1), the amount
of plasma made free of the drug per unit of time;
4. Volume of distribution steady state [4,5]
(mL kg)1);
5. Cmax (U mL)1), the maximum concentration of
factor achieved; and
6. Tmax (h), the time at which the maximum factor
concentration was achieved.
Clinical status of the patient
The patient should have moderate to severe haemophilia, i.e. a factor level of less than 0.05 U ml)1 at
baseline. They should be in a non-bleeding state. For
FVIII and FIX patients, there should not be a
detectable inhibitor (<0.6 BU) at the initiation of
the study infusions. There are no restrictions on HIV
status, but HIV-positive subjects must be asymptomatic and not on anti-retroviral treatment. There are
no restrictions on liver disease with the exception
that haemophilia B patients would be excluded if
their prothrombin time is less than 70% of the lower

Haemophilia (2006), 12, (Suppl. 3), 17

limit of normal or their international normalized

ratio is greater than 1.3. Finally, all individuals
should be at least 12 years of age. (Due to the
amount of sampling involved, children less than
12 years of age should be excluded.)
Dosage
The goal in dosing the subject is to achieve a plasma
concentration of the factor under study of about
1 U mL)1 (with the exception of FVIIa). Under these
circumstances, the dosages recommended are FVIII,
2550 U kg)1 and FIX, 5075 U kg)1. For rFVIIa,
90 lg kg)1 is recommended based on clinical experience. For other factors, the dose will need to be
titrated to achieve the concentration requirement.
The dose given in any instance should be based on
the labelled potency of the product. As the infusion
time may have an effect on the outcome (M. Morfini,
unpublished data), it is recommended that the
infusion be completed within 15 min of initiation.
Potency assessment
For FVIII, either the one-stage or the chromogenic
assay should be utilized on the plasma samples and
the same approach must be employed for both sets of
results. For FIX, the one-stage assay should be used,
while for FVII, a one-stage assay using a calibrated
thromboplastin reagent is appropriate. For other
factors, the assay of choice would be made on the
basis of the available scheme for that factor.
Time points for patient sampling
In order to adequately assess the PKs for both the
presumed phases of uptake and utilization, careful
selection of the time points for blood sampling is
required. For all factors, sampling is needed at the
following times: baseline (preinfusion), 1015 min
(times refer to the interval after the completion of the
infusion), 30 min and 1 h. Beyond that, the recommended times depend on the factor being infused:
1. FVIII: additional points to include are 3, 6, 9,
24, 28 and 32 h postinfusion; a 48 h sample is
optional, provided the patient was given at least
50 U kg)1.
2. FIX: additional points to include are 3, 6, 9, 24,
48 and 50 h postinfusion; a 72 h sample is optional, provided the patient was given at least
75 U kg)1.
3. FVII: additional points to include are 2, 4, and
8 h postinfusion.

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4. Other factors: five additional points out to 22.5

half-lives of the factor.
For evaluation of prophylaxis, as it is typically
performed in children under 5 years of age, a rough
idea of the PKs prior to initiation of prophylaxis (as
it pertains to FVIII or FIX) can be obtained from the
following limited time points: baseline, 1 h, 10 h,
24 h and 48 h.
Determination of area-under-the-curve
This is calculated using the trapezoidal rule [3] and
leads directly to the determination of related parameters such as mean residence time (MRT), Cl and
volume of distribution based on the model independent (non-compartmental) method [4,5].
Determination of half-life
Calculation of half-life requires the specification of a
particular statistical model relating time after infusion to the factor concentration, such as the biexponential (derived from a two compartmental
physiological model) [6] or approximate approaches
based on piecewise linear models [7,8].
Determination of in vivo recovery
Recovery should be determined from the peak factor
level that occurs in the first hour postinfusion. This
figure should be reported as an incremental value, i.e.
after subtracting the baseline (preinfusion) level, and
then reported on a per dosage basis as (U mL)1)/
(U kg)1). Estimates of this quantity as well as other
statistical calculations should include an indication
of precision of the estimate, possibly by the use of a
confidence interval or similar statistical quantity.

Pharmacokinetics of various factor VII/VIII/IX

preparations (recombinant vs. plasma derived)
Short remarks on methodology
A controversy between the supporters of compartmental analysis and non-compartmental analysis
(model-independent or free methods) started some
years ago. The first group pointed out that drug
development can be achieved only by a mathematical
model and regard the model-independent analysis as
limited. The second group considered the compartmental methods as cumbersome, affected by artefacts
of the best-fitting procedure, especially when the
assays are not accurate, sensitive or in limited

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number. However, the major argument against the

compartmental approach is that we do not know
exactly what is the correct biological model for each
clotting factor. This is the primary reason why the
model-independent methods have became so popular, particularly among the regulatory agencies, who
are more concerned about bioequivalence issues than
biological knowledge. It must be remembered that as
far as clotting factor concentrates are concerned,
there are only a very few data: the administered dose
and plasma factor concentrations. In addition, the
plasma volume is difficult to evaluate by an indirect
method (haematocrit). Until a few years ago, nothing
was known about the cellular uptake of clotting
factors or the relationship between them.
Model-independent analysis is easy to perform: the
mathematical procedure can be run on a spreadsheet
and the time-concentration points do not need to be
fitted but only need to be connected by straight lines,
according to the trapezoidal rule. The AUC, the
moment of AUC (product of AUC by time) and the
dosage are the data from which all other parameters
are developed. Cl, MRT and volume of area distribution (VdArea) are the most important parameters.
Taken together, these parameters can describe
exactly the behaviour of clotting factor decay.
Compartmental analysis also should take into
account the statistical error in the data, i.e. the
deviation of observed data from the expected results
based on the statistical model. The residual is the error
that the model cannot explain because the model does
not completely explain the biology of the situation.
Factor VII pharmacokinetic studies
Plasma-derived FVII concentrate was an offshoot of
the manufacture of the original prothrombin complex
concentrates containing FII, FVII, FIX and FX. Very
few PK studies have been carried out in FVII-deficient
patients [9,10], and these have demonstrated a short
half-life of 56 h. Even shorter half-life has been
displayed by rFVIIa when administered in volunteers
on oral anticoagulant therapy (OAT) [11], in patients
with cirrhosis [12], in adult haemophilia A or B
patients [12] and even in healthy subjects [13]. In all
these patients, the Cl was very high, ranging from
34.5 7.0 to 34.9 16.5 mL h)1 kg)1. The highest Cl has been observed in children (58
78 mL h)1 kg)1) [14] and in FVII-deficient patients
(70.879.1 mL h)1 kg)1) [15]. In patients with inherited FVII deficiency, probably the lack of competition
between FVII and rFVIIa for transcription factor (TF)
binding is the reason for a faster formation of

Haemophilia (2006), 12, (Suppl. 3), 17

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TFrFVIIa complex (followed by inactivation by

tissue factor pathway inhibitor). This may also
account for the lower dosage of rFVIIa in the
treatment of these patients (2040 mcg kg)1) when
compared with haemophiliacs (90120 mcg kg)1).
Factor VIII pharmacokinetic studies
As far as plasma-derived FVIII concentrates are
concerned, a number of single-dose kinetic studies
have been carried out in the past [16]. From a large
(n 87) population study performed under steady
conditions (blood sample timing, FVIII assay and
model independent analysis) after infusion of intermediate purity concentrates [17], the following
reference values have been found: Cl, 3.85 1.94
mL h)1 kg)1; MRT, 15.9 7.1 h; VdArea, 58.2
21.3 mL kg)1 and terminal half-life: 11.0 4.9 h.
Sixty-seven percent (86/128) of these decay curves
were monophasic. On the contrary, 83% (123/147)
of curves from high purity or monoclonal plasmaderived and recombinant concentrates showed a
biphasic decay [18,19]). A very high Cmax, followed
by steeper a and flat b half-life have been reported.
That behaviour can explain the higher than the
theoretical 2.0 U dL)1 U)1 kg)1 incremental recovery, 2.40 0.97 for Recombinate [20], 2.9 0.7 for
Kogenate [21,22] together with a larger VdArea and
increased Cl observed in some crossover [23] or
bioequivalence studies. The crossover studies, usually conducted for regulatory purposes, confirmed
the correspondence of modern high purity plasmaderived FVIII concentrates and rDNA-derived ones
[2022]. No studies comparing old intermediate
purity FVIII/von Willebrand factor (VWF) concentrates with rDNA concentrates are available because
of the general feeling that purer is better. Although
comparison with non-crossover studies may be
misleading, there is no doubt that Haemate-P
showed a smaller Cl and VdArea as well as a longer
MRT [24].
For the majority of haemophiliacs, the switch to
rDNA products occurred many years ago when these
products became available. Today, the fear of
inhibitor development has not allowed the patients
still on plasma-derived FVIII concentrates to be
enrolled in a crossover study with recombinant
products. In any event, the role of VWF in the final
formulation of FVIII concentrates and the baseline
level in recipients should be more accurately investigated, particularly for B-domain-deleted (BDD)rFVIII . [25,26].
The well-known large inter- and intra-patient
variability in results from PK studies is particularly

Haemophilia (2006), 12, (Suppl. 3), 17

evident when different designs or methods have been

used. A crucial role of the FVIII assay has been
pointed out by several studies. Discrepancies have
been observed among methods (one-stage, two-stage
clotting and chromogenic substrate), reference standards (plasma working, international standards or
product-specific standard), partial thromboplastins,
labelled potency assay (predilution with buffer or
haemophiliac plasma) and equipment and procedures (coagulometer, dilutions, etc.). The discrepancy between one-stage and chromogenic substrate
assay has been particularly noteworthy for BDDrFVIII concentrate [27]. The differences among
assays of postinfusion FVIII concentrations can affect
the PK parameters, as has been shown in two studies
[28,29].
The prolongation of the half-life of FVIII may be
possible after the discovery of low-density lipoprotein receptor-related protein (LRP-R) involvement
in the FVIII distribution phase [3034]. A receptor
antagonist protein (RAP) was able to modify, in
animal models, the a distribution phase, without
affecting the b elimination half-life. As far as BDDFVIII is concerned, it has been shown that the
binding to asiologlycoprotein receptor (ASGPR) is
responsible for the half-life, as a RAP-independent
mechanism. Competitive binding of antagonist of
ASGPR can improve the b decay [35]. Unfortunately, the very interesting results from both
studies do not seem to hold true in clinical usage.
In addition, non-covalent binding to PEGylated
liposomes seems to significantly enhance the rFVIII
half-life [36].
Factor IX pharmacokinetic
The low in vivo recovery (IVR) (5459%) and large
VdArea (127190 mL kg)1) of FIX has been repeatedly seen in studies of the original prothrombin
complex concentrates [3740] as well as in modern
monoclonal ones [41,42]. The MRT is always quite
long (2432 h) in comparison with FVIII. However,
even lower IVR has been demonstrated in the
crossover MononineBeneFIX study: 4270% and
2453%, respectively [43,44]. No differences were
seen in terminal half-life (17.6 and 18.1 h, respectively). The clearance of BeneFIX was faster than that
of Mononine (8.4 and 3.84.3 mL h)1 kg)1, respectively). Because the IVR and Cl are the leading
parameters for loading dosage and infusion rate
during continuous infusion, it is easy to understand
how the amount needed to achieve the same haemostatic level are by far higher for BeneFIX than for
plasma-derived FIX concentrates.

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Pharmacokinetics and continuous infusion of

coagulation preparations
Individualized dosing adjustments for replacing the
missing clotting factor in haemophiliacs should be
carried out according to specific criteria. This decision usually includes the clinical circumstances (minor
bleed or major surgery), the severity of the coagulation factor deficiency and the environmental conditions (home or hospital). It has long been recognized
that substantial inter-patient variability does exist
with respect to in vivo recovery and half-life of both
FVIII and FIX clotting factor concentrates. In addition, intra-individual variability, particularly in
terms of clearance of the clotting factor, has been
described in some situations such as surgeries. More
subtle differences have also been described, depending on the type and the origin of the concentrate or
the age of the patients. All these variables indicate
that at least for some clinical situations (e.g. new
FVIII/FIX clotting factor concentrates, optimization
of prophylaxis dosing, inhibitor occurrence, continuous infusion), a PK evaluation may prove to be
useful. Continuous infusion was reported to represent a mode of delivery of clotting factor materials
some decades ago, and more recently it was described as a cost-effective delivery system with the use
of portable minipumps, as approximately 30% of the
total consumption of the concentrate can be saved,
when compared with intermittent bolus dosing.
Needless to say that in a cost-saving environment
of health care that argument is of primary interest.
When a continuous infusion approach is to be used,
the appropriate dosing of the coagulation factor
needs a PK adaptation. Some centres recommend the
performance of a PK evaluation prior to the surgery,
as the results will help to adjust the preoperative dose
in order to achieve the target plasma level. In
addition, it gives useful information at steady state
to rule out the possibility of an unexpected inhibitor
effect that would not be detected with the Bethesda
assay. During a prototypic case, such as total knee
replacement, the clearance of the coagulation factor
commonly increases during the surgical and early
postoperative phases as a result of the important
physiologic modifications induced by the surgery
itself, the anaesthesia, the various drugs infused
including the fluid replacement and the blood loss
itself. The important variations during the first
postoperative day require precise adjustments to be
performed according to the individual PK parameters, in order to avoid excessive concentrations of
plasma clotting factors. These variations are mainly

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due to fluctuations of clearance, the importance of

blood loss and the nature and volume of expansion
fluids infused. Although clearance can be calculated,
there is still no formal algorithm taking into account
the two other main parameters. The maintenance of
desired therapeutic plasma levels during the postoperative days is usually calculated according to the
following principle: rate of infusion clearance desired FVIII/FIX plasma level. Maintenance
of a steady state via continuous infusion theoretically
requires the replacement of the coagulation factor at
a rate corresponding to its elimination. Although the
demonstration was never clearly performed, one
could anticipate that the incidence of postoperative
bleeding complications might decrease, as the issue
of potential subtherapeutic trough levels does not
exist. Therefore, PK evaluation is increasingly recognized as a useful tool to optimize and individualize
treatment strategies in a cost-effective manner. Some
ongoing debates like potential immunogenicity associated with continuous infusion will need further
clarification using prospective data collection. The
development of user-friendly adaptation tools would
be welcomed to facilitate and expand the scope of
continuous delivery of clotting factor concentrates in
order to ensure the adequate consumption of healthcare resources.

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