(Clinical Chemistry. 1998;44:1474-1480.)
© 1998 American Association for Clinical Chemistry, Inc.
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Drug Monitoring and Toxicology |
Cross-reactivity of fosphenytoin in two human plasma phenytoin immunoassays
Alan R. Kugler1,a,
Thomas M. Annesley2,
Gerald D. Nordblom3,
Jeffrey R. Koup3,
and Stephen C. Olson3
1
Department of CNS Clinical Research and Development, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105.
2
Department of Pathology, University of Michigan, Ann
Arbor, MI 48109.
3
Department of Pharmacokinetics, Dynamics, and
Metabolism, Parke-Davis Pharmaceutical Research, Division of
Warner-Lambert Company, Ann Arbor, MI 48105.
a Address correspondence to this author at: 2800 Plymouth Road, Ann Arbor, MI 48105. Fax 734-622-7428; e-mail Alan.Kugler{at}wl.com.
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Abstract
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The cross-reactivity of fosphenytoin, a phosphate ester prodrug of
phenytoin, was investigated in the Abbott phenytoin
TDx®/TDxFLxTM fluorescence polarization
immunoassay (TDx) and the Behring Diagnostics phenytoin
Emit® 2000 enzyme-multiplied immunoassay (Emit). The first
part of our study investigating cross-reactivity utilized in vitro
correlation of the two immunoassays with a validated and specific
phenytoin HPLC method used to assay plasma samples prepared in several
phenytoin and fosphenytoin concentration combinations. Fosphenytoin
cross-reacted with both immunoassays, but to a greater extent with TDx.
In the second part of the study, empirically-derived models that best
explained the in vitro data were used to predict
"immunoassay-derived" phenytoin concentrations in plasma samples
collected from actual patients after intravenous (IV) or intramuscular
(IM) fosphenytoin dosing. The greatest degree of phenytoin
concentration overestimation occurred at times when fosphenytoin
concentrations were highest: within 1 to 2 h after IV infusion or
during the first 2 to 4 h after IM injection. It is recommended that
phenytoin concentrations not be monitored using these or other
potentially nonspecific immunoanalytical methods for at least 2 h
after IV fosphenytoin infusion or 4 h after IM fosphenytoin
injection.
 |
Introduction
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Parenteral phenytoin is a therapy of choice for treating patients
with status epilepticus, for general loading dose administration in
patients with seizures, and for loading and maintenance dose
administration in patients unable to take oral anticonvulsants.
However, phenytoin is poorly soluble in aqueous solution, requiring an
alkaline pH and organic solvent vehicle; it precipitates in commonly
used intravenous (IV) fluids (1) and may crystallize at the
injection site after intramuscular (IM) administration (2).
Fosphenytoin (Cerebyx®, Parke-Davis) is a recently
approved, freely water-soluble phosphate ester prodrug of phenytoin
that delivers phenytoin into the systemic circulation with ~100%
bioavailability, after IM or IV administration. After administration to
humans, fosphenytoin is rapidly converted to phenytoin, with a
plasma fosphenytoin half-life typically <15 min. Because of improved
solubility, administration of fosphenytoin results in better tolerance
at the infusion or injection site with fewer of the complications
frequently associated with parenteral phenytoin (2)(3)(4)(5)(6)(7)(8)(9)(10),
while still providing the same therapeutic benefits as phenytoin.
Determination of plasma fosphenytoin concentration may be of research
interest but has little clinical value because fosphenytoin is
short-lived and is not pharmacologically active. In contrast, plasma
phenytoin concentration is strongly correlated with seizure control and
with toxicity. The therapeutic range of phenytoin is narrow and its
elimination kinetics are saturable, necessitating plasma phenytoin
concentration monitoring as a guide to dose individualization.
Phenytoin dosage is typically titrated to attain trough therapeutic
total phenytoin concentrations of 1020 mg/L. (11) Numerous
methods are commercially available for rapid determination of phenytoin
concentrations in plasma. Two of the most widely used methods
(12) are enzyme-multiplied immunoassay (Behring Diagnostics
Emit® 2000 and others) (13) and fluorescence
polarization immunoassay (Abbott TDx®/TDxFLxTM
and others) (14). Phenytoin and fosphenytoin have a high
degree of chemical similarity. The potential exists that high
fosphenytoin concentrations in plasma after IV and IM administration
(rarely exceeding 200 and 40 mg/L, respectively) might lead to
aberrantly high phenytoin concentration determinations when
immunoassays are used. Such an overestimation of actual plasma
phenytoin concentrations might lead to an inappropriately conservative
dosing regimen and failure to achieve therapeutic phenytoin
concentrations. Here, we describe the extent of fosphenytoin
cross-reactivity with TDx and Emit assay systems. In addition,
empirical models derived from this in vitro data are applied to
fosphenytoin and phenytoin concentrations determined via HPLC only from
actual patients. The modeling approach illustrates the potential impact
of this cross-reactivity in a clinical setting. This methodology for
assessing the degree of fosphenytoin cross-reactivity is expected to be
generally applicable to other nonspecific analytical methods.
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Materials and Methods
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apparatus
The TDx/TDxFLx analyzer was manufactured by Abbott Laboratories.
Emit 2000 phenytoin determinations (Behring Diagnostics) were
performed using a MIRA analyzer (Hoffmann-La Roche Laboratories). HPLC
determination of fosphenytoin and phenytoin concentrations were
performed by Pharmaco-LSR on a Waters WISP 712 apparatus (Waters
Corporation) utilizing a Waters µBondapak C18, 10
µm, 3.9 x 150 mm column for fosphenytoin and a Whatman RAC-2,
Partisil 5ODS-3, 4.6 x 100 mm column (Whatman) plus an Applied
Biosystems Spheri-5, 5 µm, RP-18, 4.6 x 100 mm column in series
for phenytoin.
materials
All reagents used were reagent grade and of the highest quality
and purity available. Omnisolv® HPLC grade water (EM
Science) was used for HPLC and for preparation and dilution of all
solutions. Fosphenytoin (75 g/L, 5-mL ampoule) was manufactured by
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert
Company. Phenytoin was from Aldrich. Hydrochloric acid (1 mol/L) was
from Mallinckrodt and sodium hydroxide (500 g/L solution) was from EM
Science. Fresh (unfrozen; shipped refrigerated), EDTA-treated human
plasma was purchased from the Interstate Blood Bank. Phenytoin TDx
reagents and calibrators were from Abbott, and phenytoin Emit reagents
and calibrators were from Behring Diagnostics.
stock solutions and plasma samples
Seven aqueous fosphenytoin stock calibrator solutions, ranging
from 0 to 8 g/L, were prepared by dilution of a 75 g/L fosphenytoin
ampoule with distilled water. Six phenytoin stock calibrator solutions,
ranging from 0 to 4 g/L, were prepared by dilution of a stock solution
of phenytoin (8 g/L in 0.1 mol/L NaOH) with 0.1 mol/L NaOH.
Fresh EDTA-treated human plasma lots were pooled and had a measured pH
of 7.45. The pH was adjusted to 7.30 with 0.1 mol/L HCl to ensure that
the addition of basic phenytoin stock calibrator solutions would bring
the final pH to 7.40. Plasma specimens containing phenytoin and
fosphenytoin were prepared in the concentration combinations shown in
Table 1
by adding 0.1 mL of phenytoin and 0.2 mL of fosphenytoin
stock calibrator solution to a 10-mL volumetric flask partially filled
with plasma and bringing the total volume to 10 mL with plasma. After
preparation, plasma samples were divided into two plastic tubes and
frozen at -20 °C pending analysis. The sample collection and
storage conditions used have been previously shown to maintain
stability of fosphenytoin and phenytoin (15)(16)(17).
assay procedures
TDx phenytoin reagents and calibrators were used to measure
phenytoin in each plasma sample with a fluorescence polarization
immunoassay analyzer, according to the manufacturer's instructions.
The immunoassay performed on the Abbott TDx utilizes a polyclonal
antisera. Similarly, Emit phenytoin reagents and calibrators were used
to measure phenytoin in each plasma sample with a MIRA analyzer,
according to the manufacturer's instructions. The Emit assay uses a
monoclonal antibody reagent. In both immunoassays, samples containing
combinations of drug that assayed at concentrations above the reporting
range of the assay (40 mg/L) were diluted with EDTA-anticoagulated
plasma and reanalyzed to obtain a quantitative result. For the
specimens with added fosphenytoin and phenytoin listed in Table 1
, the
immunoassay analyses were performed in triplicate. The duplicate set of
plasma samples described above was also analyzed by a validated HPLC
assay to determine baseline phenytoin and fosphenytoin concentrations
for subsequent calculation of fosphenytoin cross-reactivity in the TDx
and Emit assays. The HPLC assay was based on the method of Gerber et
al. (18). Briefly, 1 mL of plasma was deproteinized with 2
mL of acetonitrile. The supernatant was then partitioned between
methylene chloride (4 mL) and an ammonium phosphate buffer (0.5 mL,
0.067 mol/L (NH4)2HPO4, pH 6.5).
The resulting aqueous phase was analyzed for fosphenytoin, and the
resulting organic phase was analyzed for phenytoin after evaporation.
Fosphenytoin was quantitated by UV spectroscopy (
= 214 nm) after
separation on a Waters µBondapak C18 column at 35 °C
in a mobile phase containing 700 mL/L 0.05 mol/L
(NH4)2HPO4, pH 6.5, and 300 mL/L
methanol. Phenytoin was quantitated by UV spectroscopy (
= 220 nm)
after separation on a Whatman RAC-2, Partisil 5ODS-3 column and a PE
Applied Biosystems Spheri-5 RP-18 column in series in a mobile phase
containing 530 mL/L methanol and 470 mL/L
(NH4)2HPO4, pH 7.0. Mean measured
concentrations of quality-control samples analyzed with study samples
deviated -3.32% to 14.0% and -4.10% to 2.89% from nominal
concentrations for fosphenytoin and phenytoin, respectively. Precision
of quality-control samples, determined as coefficients of variation,
ranged from 4.11% to 4.63% and 2.68% to 9.65% for fosphenytoin and
phenytoin, respectively.
data analysis
Plasma fosphenytoin and phenytoin concentration data were
converted to molar concentrations before cross-reactivity calculations.
In the calculations, molecular weights of 252.3 and 362.3 were used for
phenytoin and fosphenytoin, respectively. Cross-reactivity of
fosphenytoin with the phenytoin immunoassays was defined as the
"phenytoin" concentration determined from the immunoassay procedure
([PHT]Immunoassay) minus the phenytoin concentration
determined by the validated phenytoin HPLC assay procedure
([PHT]HPLC) divided by the fosphenytoin concentration
determined from the fosphenytoin HPLC assay procedure
([FOS]HPLC), expressed as a percentage (multiplied by
100%; Eq. 1
).
 | (1) |
To assess the impact of any cross-reactivity from Eq. 1
in an
actual clinical setting, models were fit to the TDx or Emit in vitro
data obtained for the plasma specimens listed in Table 1
. All models
were derived empirically using SAS (SAS Release 6.12, SAS Institute
Inc. Each model used the mean TDx or Emit immunoassay-determined
phenytoin concentrations as the dependent variable and the
HPLC-measured phenytoin and fosphenytoin concentrations as the
independent variables. Using data obtained from both prepared plasma
samples and actual patient specimens, the adequacy of each derived
model was explored further by plotting model-predicted concentrations
vs measured immunoassay phenytoin concentrations.
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Results and Discussion
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All nominal and experimentally determined phenytoin and
fosphenytoin concentrations are listed in Table 1
. Fosphenytoin
cross-reacted with both assays, but the extent of cross-reaction was
much greater with TDx. The degree of fosphenytoin cross-reactivity in
the TDx immunoassay decreased with increasing fosphenytoin
concentration. For example, in the absence of phenytoin, 4 mg/L
fosphenytoin produced 120% cross-reactivity, whereas 75 mg/L
fosphenytoin produced only 22% cross-reactivity. In the presence of
phenytoin, the more clinically relevant situation, the same
relationship held true. However, the magnitude of fosphenytoin
cross-reactivity increased with increasing phenytoin concentration. In
the absence of phenytoin, 4 mg/L fosphenytoin produced 120%
cross-reactivity. The same concentration of fosphenytoin produced 193%
cross-reactivity in the presence of 5 mg/L phenytoin and 315%
cross-reactivity in the presence of 20 mg/L phenytoin. Thus, phenytoin
appears to facilitate the cross-reactivity of fosphenytoin in the TDx
assay.
Although fosphenytoin also exhibited cross-reactivity in the Emit
assay, the degree of cross-reactivity was far less than that observed
in the TDx assay. Furthermore, the fosphenytoin cross-reactivity
profiles presented in Table 1
do not exhibit the nonlinearities
(saturability and facilitation) observed for the TDx assay. In general,
the cross-reactivity of fosphenytoin in the Emit assay was <10%
except in some samples with low fosphenytoin concentrations, in which
cross-reactivity estimates are more variable, probably because of
analytical error.
The phenomena of difference in effect of added phenytoin to
cross-reactivity of the two immunoassays has been described elsewhere
for both digoxin and phenytoin. Matheke and Valdes (19) and
Miller and Valdes (20) showed that when cross-reactivity of
digoxin-like immunoreactive factor was tested in immunoassays for
digoxin, the effect of added digoxin was variable among assays. In one
assay, added digoxin increased the cross-reactivity of digoxin-like
immunoreactive factor, whereas in another there was a decreased effect.
The authors speculated that the effect was due to differential affinity
of the analyte and cross-reactant for each antibody and would "be
observed even with monoclonal antibodies". Rainey et al.
(21) observed, using the TDx phenytoin assay, that there was
an increased cross-reactivity with the major phenytoin metabolite
in the presence of phenytoin.
The substantial cross-reactivity of fosphenytoin in both phenytoin
immunoassays and the potential for cross-reactivity in all immunoassays
suggest that this interaction should be assessed before use of a
phenytoin immunoassay in a clinical setting where fosphenytoin is being
administered. To evaluate the potential impact of the observed
cross-reactivity in the clinical setting, empirical models were derived
that best explained the TDx and Emit in vitro data, using the
immunoassay-determined phenytoin concentrations ([PHT]TDx
and [PHT]Emit, respectively) as the dependent variables
and HPLC-measured phenytoin and fosphenytoin concentrations
([PHT]HPLC and [FOS]HPLC, respectively) as
independent variables. The TDx and Emit in vitro data were best
explained by Eqs. 2
, and 3
, respectively.
 | (2) |
 | (3) |
The adequacy of each model was tested by construction of 95%
confidence intervals for the four numerical coefficients in Eq. 2
(identified as TDx coefficients A-D in Table 2
) and the three numerical coefficients in Eq. 3
(identified as
Emit 2000 coefficients A-C in Table 2
). The predicted vs observed
phenytoin concentrations from the in vitro experiments were then
plotted (Fig. 1
). The models fit the in vitro data extremely well. The
empirical models were then evaluated further by plotting predicted vs
assayed phenytoin concentrations for a set of plasma specimens from
individuals receiving fosphenytoin. The data in Fig. 2
illustrate that the observed immunoassay results for actual
patient specimens agree quite well with values predicted by the
formulas, especially so for the TDx assay.

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Figure 2. Model-predicted phenytoin concentration vs observed
immunoassay phenytoin concentrations for actual patient specimens.
(Top) TDx/TDxFLx; (Bottom) Emit 2000. Data points
are means of duplicate measurements. Solid lines are the
lines of regression (TDx: y = 0.970x +
0.885, Sy x = 3.64; Emit: y =
0.881x + 0.960, Sy x = 1.70).
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Lastly, the empirical models were used to predict
"immunoassay-derived" phenytoin concentrations in 1185 plasma
specimens from 144 subjects and patients participating in fosphenytoin
clinical trials. The plasma specimens had been assayed previously for
phenytoin and fosphenytoin by HPLC. The difference between the
phenytoin concentration predicted using Eqs. 2
, and 3
and the observed
(HPLC) concentration was calculated and plotted against time to examine
the over-prediction of phenytoin concentrations in the presence of
fosphenytoin, using the immunoassay procedures (Fig. 3
). Fig. 3
illustrates that the greatest degree of phenytoin
concentration overestimation occurs at times immediately after IV
infusion or shortly after IM injection. Although conversion to
phenytoin begins immediately with IV fosphenytoin administration,
initial plasma fosphenytoin concentrations may approach 200 mg/L before
declining with a half-life of <15 min. In general, plasma fosphenytoin
concentration-time profiles after IM administration are lower and more
sustained than those after IV administration.

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Figure 3. Phenytoin concentration difference (model-predicted
concentration - HPLC-derived concentration) vs time, using
TDx/TDxFLx (Top) and Emit 2000 (Bottom)
immunoassay-derived data.
Time referenced from the end of IV infusion (+) or time of IM injection
( ).
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For treatment of status epilepticus, or for loading dose administration
in patients with seizures, the goal of IV or IM fosphenytoin is to
obtain a rapid therapeutic concentration of phenytoin in blood. After
IV administration, maximum fosphenytoin concentrations have been
observed to occur near the end of the infusion (18). In the
same study, the concentration of phenytoin reached 90% of its maximum
12 min after the end of IV fosphenytoin infusion, whereas
dose-dependent peak phenytoin concentrations occurred at a median times
of 3045 min (18). Because of the longer half-life of
phenytoin, concentrations slowly decrease from peak values. Other
reports also support the fact that substantial concentrations of free
or total phenytoin are attained rapidly after IV infusion or IM
injection (16)(22)(23). Because of
this, plasma phenytoin concentrations could conceivably be monitored
soon after administration of fosphenytoin to verify that therapeutic
concentrations were achieved. However, after IV or IM administration,
our data derived from 144 patients indicated that fosphenytoin
cross-reactivity is clinically significant for up to 4 h in TDx
determinations and for 1 h in Emit determinations. These findings
reemphasize the importance of evaluating fosphenytoin cross-reactivity
before use of an immunoassay to titrate phenytoin concentrations during
fosphenytoin administration. It should be noted that, in a recent HPLC
method development study (16), discrepant phenytoin results
between TDx and HPLC were reported for an IV fosphenytoin-treated
patient, which are explained by the data in Table 1
and Fig. 3
.
It could be argued that the cross-reactivity for diluted samples in
Table 1
may not be the same at the higher concentrations and that
multiplication of results to correct for dilution could lead to errors
in the coefficients derived for the empirical model defined in Eqs. 2
, and 3
. Although experiments like those in Table 1
could be designed
such that the combined cross-reactivity of the analytes would not
exceed the analytic range, there were several reasons why we chose to
drive empirical equations for all data points in the table. First, for
TDx data a substantial number of the test samples required dilutions to
bring results within assay range. Second, specimens from Table 1
that
required dilution were known to contain concentrations of phenytoin or
fosphenytoin that have been reported in clinical studies
(16)(18). Third, in actual practice, clinical
laboratories will generally dilute any results exceeding the assay
limit and report a value that is corrected for the dilution factor,
regardless of immunoreactivity that may be concentration dependent.
Thus, the apparent plasma phenytoin concentrations in Table 1
represent
the concentrations that would realistically be observed by a
laboratory. Because of these considerations, we attempted to derive
mathematical equations that reflected real life circumstances.
However, to validate further that these two mathematical equations
could be used to accurately predict immunoassay phenytoin values, we
also derived a second set of formulas based solely on apparent
phenytoin concentrations from undiluted specimens in Table 1
. Although
some subtle changes in the coefficient values were observed when these
alternative equations were applied to actual undiluted patient
specimens from the data set shown in Fig. 2
, the slope and intercept
for the regression data were nearly the same (TDx slope, 0.942;
intercept, -0.179; Emit slope, 0.873; intercept 0.342) as the values
obtained for the original models illustrated in Fig. 2
.
Chromatographic assay methods (e.g., HPLC) accurately quantitate
phenytoin concentrations in biological fluids in the presence of
fosphenytoin. However, even with specific assay methods, phenytoin
concentrations measured before conversion of fosphenytoin is complete
will not reflect the phenytoin concentrations ultimately achieved. It
is, therefore, advised that blood samples to assess phenytoin
concentration should not be obtained for at least 2 h after IV
fosphenytoin infusion or 4 h after IM fosphenytoin injection.
(22).
In conclusion, considerable fosphenytoin cross-reactivity occurs in
the TDx and Emit phenytoin immunoassays. The potential for this
interaction exists with any phenytoin immunoassay and has its most
profound impact immediately after IV fosphenytoin infusion or within a
few hours of IM fosphenytoin injection, while fosphenytoin
concentrations are substantial. The methodology presented should prove
to be universally applicable in assessing the extent of
cross-reactivity of other assays.
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