Beruflich Dokumente
Kultur Dokumente
REVIEW
otherwise, the word absorption in this review should also be variability in drug exposure because of the different factors
understood to be synonymous with bioavailability. influencing the bioavailability. In contrast, when the mean
bioavailability is low (e.g. 10%), a large inter-individual
variability will be expected, with some subjects having a very
ABSOLUTE VS. RELATIVE BIOAVAILABILITY low (e.g. 5%), and with others having a higher bioavailability
(e.g. 20%), thus leading to exposures varying from 1 to 4, i.e. by
Absolute bioavailability is the actual percentage of the 400% (and consequently, a lack of reproducibility of this
administered dose (from 0 to 100%), which reaches the general formulation in terms of clinical efficacy).
circulation. Estimation involves comparing drug exposure fol- Fig. 1 shows the relationship between absolute bioavailability
lowing extravascular (e.v.) administration of the tested dosage and inter-individual variability for a set of drugs in man
form with that of an intravenous administration (i.v.), assumed (Hellriegel et al., 1996). In veterinary medicine, similar obser-
to be 100% available. vations can be made, e.g. in the horse, the bioavailability of
Relative bioavailability involves comparison of two formula- rifampicin when the drug is administered 1 h before feeding is
tions (or two routes of administration of the same formulation) 68 ± 26% (coefficient of variation ¼ 38%), whereas when the
without reference to an i.v. administration. It should be same drug is administered 1 h after feeding, the bioavailability is
emphasized that interpretation of a relative bioavailability trial 26 ± 17%, i.e. with a coefficient of variation of 67% (Baggot,
can be of limited value if the absolute bioavailability of the 2001). In pigs, the mean absolute bioavailability of chlortetra-
reference formulation is not known. Indeed, improving by 100% cycline administered by the oral route in fasted animals is low
the bioavailability of a given reference formulation (e.g. either by (19%) and variable, ranging from 9 to 30% (Kilroy et al., 1990),
manipulating the food regimen in the case of oral administration which is not satisfactory in terms of the prudent use of
or modifying the formulation) has different meanings if the antibiotics. Indeed, the emergence of resistance is often because
reference formulation is 5 or 50% bioavailable. In the former of an underexposure of small animal population subgroups
case, the improvement lacks interest, whereas in the latter it is despite an appropriate average dose.
very significant! Whenever bioavailability is low, drug companies may attempt
to increase the dose to achieve an appropriate drug exposure.
However, it may not be recognized that the dose is generally
BIOAVAILABILITY VS. BIOEQUIVALENCE increased more than proportionally to the mean bioavailability
factor in order to ensure drug efficacy in animals having the
Although bioavailability is used as an endpoint in bioequivalence lowest bioavailability. For instance, for a hypothetical drug
trials, bioavailability and bioequivalence trials are conceptually having a mean bioavailability of 33% (with some subjects
different. A bioequivalence trial aims to establish the therapeutic having 20% bioavailability, and others 50%) and for which an
equivalence of two formulations (or two routes of administra-
tion). It is not concerned with documenting the physiological
factors capable of influencing systemic exposure of the drug. In a 125
bioequivalence trial, animals are only biological test-tubes,
required for an in vivo quality control for different formulations
(Toutain & Koritz, 1997). In contrast, in a bioavailability trial, it
100
is the animal physiology and possibly pathology (age, sex, food
intake, disease state and severity, etc.) which are of primary
interest.
75
CV (%)
Overexposure of some
AUC animals (side effects) Undesired concentrations
Undesired
exposure
B
a poorly hydrosoluble drug. In order to administer it by the i.v. Dose ¼ Body clearance AUC: ð2Þ
route, a hydrosoluble ester has been synthesized (methylpredni-
solone sodium succinate or Solumedrol). This is a pro-drug of Equation 1 is the reduced form of the following equation:
methylprednisolone, and the ester must be hydrolysed to release AUCe:v: Cle:v: Dosei:v:
its active moiety (i.e. methylprednisolone). In the dog, it was F% ¼ ð3Þ
AUCi:v: Cli:v: Dosee:v:
shown that the i.v. bioavailability of methylprednisolone from its
succinic ester was only 40% (Toutain et al., 1986) (Fig. 4). Other and Eqn 3 reduces to Eqn 1 if Cli.v. ¼ Cle.v., i.e. if the body
examples of pro-drugs are inactive esters of macrolides, antibi- clearance is a dose and time invariable parameter (linear phar-
otics such as pivampicillin and chloramphenicol succinate and macokinetics).
antiviral pro-drugs. Generally, bioavailability is measured experimentally using a
crossover study design and it is necessary to check for a possible
carry-over effect, i.e. a differential residual effect of the first period
THE MEASUREMENT OF ABSOLUTE BIOAVAILABILITY over the second one. For example, hepatic enzymatic inhibition
(or induction) after the first administration can modify the
There are many methods used to evaluate the extent of systemic clearance during the second period. Therefore, the washout
availability, the most classical one consisting of comparing period should be long enough, not only to guarantee the absence
plasma exposure (AUC) after an i.v. and an e.v. administration. of residual drug plasma concentration but also the lack of residual
Classically, the bioavailability factor is obtained by the following drug effect on clearance (induction/inhibition). This nonlinearity
equation: due to time dependency is also called nonstationarity.
The presence of a significant (differential) carry-over effect can
AUCe:v: Dosei:v:
F% ¼ 100: ð1Þ be detected by properly analysing the design (by testing the
AUCi:v: Dosee:v:
sequence effect), but if an unbalanced design has been carried
out (i.e. by performing i.v. route of administration for all animals
In Eqn 1, AUC is the area under the plasma (total or free) drug
in the first period, and e.v. in the second period), an equal carry-
concentration or total blood concentration–time curve and
over will be obtained, which can be totally confounded with a
Dosei.v. and Dosee.v. are the doses actually administered to
period effect leading to a possibly large overestimation (or
evaluate F%.
underestimation) of bioavailability. With this type of design, a
There is a compelling assumption underlying Eqn 1: the i.v.
bioavailability higher than 100% can be computed.
and the e.v. clearances must be equal. Indeed, according to the
For random inter-occasion clearance variability, it has been
mass balance consideration, what is actually measured when
suggested to correct the computed bioavailability factor by the
using Eqn 1, is the ratio of the bioavailable doses after an e.v. and
terminal half-life (Wagner, 1967) using the following equation:
an i.v. administration; the bioavailable dose actually corresponds
to the dose eliminated from plasma, as given by the general AUCe:v: t1=2; i:v:
F% ¼ 100: ð4Þ
relationship: AUCi:v: t1=2; e:v:
10 5 equation:
10 4 0:693 Vd
t1=2 ¼ : ð5Þ
Clearance
10 3 MP after IV administration of MP
Assuming that Vd is invariable, t1/2 can be incorporated as a
surrogate of clearance in Eqn 3.
10 2 MP after administration of MPS This correction should be used cautiously and accepted only
MPS if it results in a substantial decrease in the variability of the
10
results, or in order to avoid a mean bioavailability higher than
0 60 120 240 360 480 min 100%. Indeed, the estimation of terminal half-life (contrary to
body clearance) is not very robust. In addition, if the terminal
Fig. 4. Absolute bioavailability of methylprednisolone in the dog.
half-life does not represent the drug elimination but rather
Methylprednisolone (MP) is a nonhydrosoluble steroid which can be
administered by the i.v. route using a hydrosoluble salt of a succinate drug absorption (flip-flop), the correction becomes totally illicit
ester (methylprednisolone sodium succinate, MPS). After i.v. adminis- and its unjustified use may lead to markedly underestimated
tration of MPS, its concentration decreases rapidly providing the active F%. For the same objective, an equation correction can be
moiety, i.e. MP. Using this MP plasma concentration profile to estimate made using renal clearance, which could be independently
the MP bioavailability of another formulation would lead to gross evaluated during a bioavailability trial. According to Karlsson
overestimation of the true MP bioavailability, because only 44% of the and Sheiner (1994), the best way to handle random inter-
administered MPS was transformed into MP. The true bioavailability of
occasion clearance variability is to analyse all the subjects
an MP formulation should be obtained by administering MP itself via the
i.v. route (Toutain et al., 1986). simultaneously with a nonlinear mixed effect model.
In some instances, the measurement of plasma concentration of For some drugs having a long terminal half-life (e.g. avermec-
the administered drug is impossible, either because an appropriate tins, moxidectin, salicylanilides, etc.) the absolute bioavailability
analytical technique is not available, or more often because the is seldom measured, because trials involving two (long) periods
drug is rapidly transformed into an active metabolite (e.g. 4- separated by a washout period of 10 times the terminal half-life
methylaminoantipyrine or 4-MMA from dipyrone). In these are considered as prohibitive. In addition, nothing guarantees
conditions, the drug absolute bioavailability can be evaluated by the invariance of the plasma clearance over such a prolonged
measuring the AUC of its metabolite using the following equation: period of time, especially in growing animals, thus making
metabolite invalid the use of Eqn 1.
AUCe:v:; parent drug
F% ¼ metabolite
100: ð6Þ A possible solution to this problem is to consider the
AUCi:v:; parent drug estimation of bioavailability by a semi-simultaneous drug
administration such as that described by Karlsson and
The condition for using Eqn 6 is that the metabolite must not Bredberg (1990). The principle of this method comprises
be formed at the administration site or by a first-pass effect. In administering one of the two doses (i.v. then e.v., or e.v. then
the same circumstance (no first-pass effect) a nonspecific assay i.v.) at an optimal interval and fitting simultaneously the
(e.g. radioactivity), measuring both the drug and its metabo- entire curve obtained with an appropriate model, including
lite(s), can be used to determine bioavailability. However, a and estimating the rate constant of absorption, lag, and the
nonspecific assay cannot be used for nonlinear systems. bioavailability factor.
If a drug is metabolized solely by the liver and subjected to a It was shown that the precision of the method was influenced
significant hepatic first-pass effect, then Eqn 1 will be appropriate by the dose rate, the order of administration, the e.v. vs. i.v. dose
to measure the absolute bioavailability of an oral formulation, ratio, the duration of the sampling, and the interval between the
whereas Eqn 6 will give the fraction of the dose actually absorbed doses. This approach deserves to be encouraged in veterinary
after the oral administration (for more information see Weiss, medicine as a screening method, when intra-animal variability is
1990). expected (e.g. time-dependent variation of clearance during
growth), or to reduce the total number of blood samplings. The
most appropriate design can be determined by Monte Carlo
MEASUREMENT OF BIOAVAILABILITY USING URINARY simulations. The relative bioavailability of two e.v. formulations
CONCENTRATIONS can also be documented using this approach.
equation of a straight line (y ¼ mx + c) which can be WHY MAY A BIOAVAILABILITY HIGHER THAN 100%
visualized by plotting Dose/AUCe.v. against ClR; the slope is 1/ BE COMPUTED?
F and the intercept ClnR/F. These two parameters of the line
are obtained by curve fitting (Fig. 5). The conditions for this Bioavailabilities higher than 100% are regularly reported, which
approach are twofold: the drug must be cleared mainly by the is conceptually impossible. The reasons for this are numerous,
renal route (or any other measurable route), and patients including experimental errors and nonfulfilment of the assump-
under investigation should display a large inter-individual tion for computation of absolute bioavailability (Martinez,
variability in their renal clearance (see Hinderling, 2003 for 1998). Table 1 gives the main reasons for obtaining a bioavail-
application of the method). ability higher than 100%.
If it is known that a drug is exclusively (or almost
exclusively) eliminated by an experimentally accessible route
of elimination (urine, faeces), as is the case for eprinomectin, RELATIVE BIOAVAILABILITY BETWEEN TWO
which is almost totally eliminated unchanged by faeces in FORMULATIONS OR TWO E.V. ROUTES OF
cattle, absolute bioavailability can be obtained without i.v. ADMINISTRATION
administration by collecting all the effluents (mass balance
principle). However, for a long acting drug (e.g. avermectins), Relative bioavailability can be measured by comparing the AUC
collecting all the faeces can be cumbersome. An alternative of the two tested formulations at the same dose levels using the
and less demanding method would involve measuring, for following equation:
some limited periods of time (e.g. 24 h), the faecal clearance AUCtest
(Clfaeces) using the following equation: F% ¼ 100: ð13Þ
AUCreference
Amount exerted in faeces over a given period of time
Clfaeces ¼ :
Plasma AUC over the same period of time Relative bioavailability can also be evaluated under steady-
ð11Þ state conditions (Fig. 6), because the total AUC over a dosing
interval at steady-state (i.e. AUCs) is equal to the total AUC0–¥
Simultaneously, the total plasma AUC0–¥ should be evaluated after a single dose administration.
(this is easier to determine than to collect all the faeces over Therefore, under steady-state conditions (obtained for exam-
several weeks), and the absolute bioavailability can then be ple with formulation A), AUCs,A is measured; then formulation
computed using the following equation: B is immediately administered (i.e. without any washout
AUC01 Clfaeces period), and when a new steady-state is obtained with
F% ¼ : ð12Þ formulation B (i.e. after a delay of 4–5 times the terminal
Administered dose
half-life), AUCs,B is then measured. This method is useful for
Here Clfaeces is assumed to be equal to the total body drugs having a long terminal half-life, and for which a
clearance, and consequently the quantity eliminated via faeces conventional cross-over design cannot be extended over several
(Clfaeces · AUC0–¥) is equal to the bioavailable dose. months because of the requirement for a washout period of
approximately 10 times the terminal half-life. Another advant-
age of this method is that fewer data points are required to
characterize the AUC over the dosing interval as the time
course of drug concentration at equilibrium is more stable than
Dose after a single dose administration. The condition required to use
1 this method is that all the bioavailable amounts of the two
AUCe.v. = slope
F tested formulations have been absorbed during the dosing
interval, i.e. that absorption does not continue after the end of
the dosage interval. Urinary excretion data can be used in the
1 same way. Urinary excretion data can be used at steady-state
Intercept = Cl nr using the following equation:
F
Cl R
SS
Xu; test
F% ¼ SS
100; ð14Þ
Fig. 5. Evaluation of absolute bioavailability when intravenous (i.v.) Xu; reference
administration is not possible. When i.v. administration is not possible
but urine sample collection is possible (or any other matrix as faeces, where XuSS denotes the amount of drug excreted in the urine over
etc.), then absolute bioavailability can be measured. The absolute a dosing interval at steady-state. Equation 14 is used for the
clearance of the excretory pathway should be evaluated and the inter- same dosage regimen for both formulations. The advantage of
individual variability of this absolute clearance should be large enough to
this approach is the duration of the collecting period (corres-
use a regression approach in order to compute bioavailability. Bioavail-
ability is estimated by the slope of the straight line between the measured ponding to the dosage interval), which can be much shorter than
absolute (renal) clearance and the apparent extra-vascular (Dose/AUC) after a single dose administration. The condition to apply Eqn 14
clearance (see text for further explanation). is to have reached an initial steady-state with the reference
Formulation A Formulation B SS
(after equilibrium) (after new equilibrium) formulation and to have measured Xu; reference . Then, without
washout, to have administered the test formulation and to have
SS
measured Xu; test over a dosing interval when the new steady-
state is obtained.
Plasma
(AUCA) 0
Time Many methods for the computation of AUC have been proposed
(Yeh & Kwan, 1978; Purves, 1992). Attention should be paid to
F % = (AUCA,ss/ AUCB,ss) × 100
the sampling design in order to avoid either an underestimation
of AUC (not enough sampling times in the ascending phase of the
Fig. 6. Measurement of bioavailability under steady-state conditions.
Relative bioavailability can be measured in steady-state conditions and kinetics) or an overestimation of AUC (not enough sampling
without any washout period between two formulation administrations times in the descending part of the curve) (Fig. 7). A too sparse
(as for a cross-over design). In this type of trial, the formulation A is sampling strategy may lead to doubling of the bioavailability.
administered until reaching steady-state conditions. Under these condi- When a sparse sampling is used (e.g. for the assessment of drug
s
tions AUCA;SS 0 is equal to the ðAUCA Þ1 0 following a single dose exposure in toxicological studies), the evaluation of AUC using
administration. Then, the second formulation is immediately adminis-
s nonlinear mixed effect modelling may provide more accurate
tered until the new steady-state condition is reached, and AUCB;SS 0
information, not only for the mean value of AUC but also for the
which equals to ðAUCB Þ1 0 is measured. The ratio AUCA ⁄ AUCB in steady-
state conditions gives the relative bioavailability. The condition for this estimate of inter-animal variability (Burtin et al., 1996). Fur-
approach is that the whole of the administered drug is absorbed over the thermore, when the concavity of the curve is pronounced, a log-
dosing interval s. linear trapezoidal rule is more accurate (see Fig. 7).
A
AUC = S1+S2+…+Sn+S extrapol
Clast (observed or calculated)
Sextrapol = terminal slope
Sextrapol
12 3 4 5 6 7 8 Sn
7.2 µg/mL
B 5.3 µg/mL
Fig. 7. Evaluation of area under the curve
S8 (AUC) by the trapezoidal rule. The arithmetic
4 7 Time (h) trapezoidal rule consists of evaluating the AUC
Linear trapezoidal rule of the entire curve by using the sum of
(arithmetic mean) individual trapezoids (S1, S2…); an arithmetic
S8 = [(7.2+5.3)/2] × (7–4) mean of the plasma concentrations being used
S8 = 18.75 µg.h.mL–1 to evaluate the trapezoid. If the sampling
C design is too sparse (curve C), the arithmetic
Log linear rule trapezoidal rule will overestimate the true
(geometric/logarithmic mean) area (by the black shaded position of the
S8 = ² 7.2 × 5.3 × (7–4) curve). Under this condition, a log-linear
S8 =18.53 µg.h.mL–1 trapezoidal rule is preferred. In contrast, if not
enough samples are obtained during the
initial phase (curve B), the AUC can be under-
estimated (by the shaded portion of the curve).
The question of extrapolation to infinity also needs to be curve reflects only the elimination phase, which is a drug
carefully addressed especially for long-acting formulations. property and not that of the formulation (Lovering et al., 1975;
Beyond the last measured point (Clast), the area is estimated Martinez & Jackson, 1991). This approach is appropriate for
using the following equation: drugs having a long terminal half-life and which are rapidly
AUCClast1 ¼ Clast =kz ; ð15Þ absorbed. However, the use of this approach cannot be
encouraged if the effective end of the absorption phase is
where kz is the slope of the terminal phase. Any bias in the unknown (Gibaldi & Perrier, 1982).
estimation of kz can lead to estimation of bioavailability higher
than 100%. In practice, the extrapolation portion of the AUC
should remain as limited as possible and represent no more than C M A X AND T M A X ARE NOT APPROPRIATE MEASURES OF
20% of the total AUC. THE RATE OF ABSORPTION
Finally, it is preferable to use the truncated AUC when the
level of quantification of the analytical technique is relatively It is frequently stated that ‘absorption’ is rapid because visual
low. Indeed, the use of partial area in comparative bioavailability inspection of the curve shows that the time (Tmax) of the
studies is theoretically possible because the terminal part of the maximum plasma concentration (Cmax) is observed rapidly after
the drug administration.
This ‘visual evaluation’ can be very misleading. Cmax and Tmax
Concentrations
K10 of A or Ka of B are single point determined, and their precision depends on the
sampling schedule. More importantly, an early Tmax can also be
associated with a formulation having a very low rate of drug
Ka of A or K 10 of B absorption. Indeed, Tmax and Cmax are hybrid variables influ-
enced by both the rate of drug elimination and absorption. In
Time
ln Ka – ln K10 addition, Cmax is influenced by the extent of absorption. For a
T max = = 2.558 h
Ka – K10 mono-compartmental model (no distribution), Tmax is given by
the relationship:
Drug A : K a = 1.0 K10 = 0.1 t1/2 (abs) = 0.693 h
ln Ka ln K10
Drug B : K a = 0.1 K10 = 1.0 t1/2 (abs) = 6.93 h Tmax ¼ ; ð16Þ
Ka K10
Fig. 8. Tmax and flip-flop situation for a drug obeying a mono- where Ka and K10 are the first-order rate constants of absorption
compartmental model. This figure exemplifies the fact that exactly the
and elimination, respectively. Inspection of Eqn 16 shows that Ka
same Tmax can be obtained with two different drugs (A and B) having
very different rate constants of absorption (Ka). This is due to the fact that and K10 play a symmetric role, and exactly the same Tmax can be
Tmax is a hybrid parameter reflecting both the rate constant of absorption observed for two drugs having the same Ka and K10, but in a flip-
and the rate constant of elimination (K10). flopped circumstance (Fig. 8).
100 100
Concentrations
the process of drug absorption. This figure
Ka1+Ka2
Amount
1 Ka1 1 Ka1+Ka2
corresponds to a drug obeying a mono-
0.1
absorption
compartmental model with a phase of 0.1
absorption. The reported half-life of absorption 0.01
0.01
(t1/2Ka) does not reflect unequivocally the
0.001
0.001
process of drug absorption (here presented by 0 2 4 6
0 6 12 18 24
Ka1, the first-order rate constant of drug Time (h) Time (h)
transfer from the injection site to the central
compartment) but the sum of Ka1 and Ka2, Ka2
being the rate constant reflecting the irre-
versible loss of drug at the administration site.
t1/2Ka reflects unequivocally drug absorption Ka2 K10
only if Ka2 ¼ 0, i.e. if the bioavailability is Irreversible loss of drug Elimination from the
total. Here Ka1 + Ka2K10. from the injection site central compartment
given by:
Ka1
F% ¼ 100: ð17Þ
Ka1 þ Ka2 Tmax, B A
MEASUREMENT OF THE RATE OF ABSORPTION USING observed curve that could correspond to very different
CURVE FITTING situations with respect to the absorption process.
where MATp.o. is the mean time of drug absorption, MRTp.o. is BIOAVAILABILITY WHEN DRUG DISPOSITION IS
the value of MRT after the oral drug administration, and MRTi.v., NONLINEAR
the MRT after the i.v. drug administration.
This approach can be extended to other steps which separate The evaluation of bioavailability by Eqn 1 requires the assump-
drug administration from the resulting plasma concentration tion of drug linear elimination (i.e. clearance must be a
profile (Riegelman & Collier, 1980). For example, the drug can parameter, not a dose or a time-dependent variable). However,
be administered as a tablet (or a slow release bolus into the bioavailability can still be measured using Eqn 1 if the
rumen). The resulting plasma concentration profile reflects the distribution or the absorption process itself is nonlinear. If the
process of dissolution (or release), the process of absorption and drug elimination process behaves in a nonlinear way (clear-
the process of drug elimination. If the mean dissolution time ance), the situation becomes more complex and several options
(MDT) corresponds to the mean time a drug stays in a solid form are possible including use of the mass balance approach. When
in the tablet, the overall measured MRT after a tablet admin- clearance nonlinearity is due to a nonlinear binding to plasma
istration (MRTtablet) is: proteins, another option consists of modelling total drug
disposition, and in computing the free concentration which
MRTtablet ¼ MRTi:v: þ MAT þ MDT; ð19Þ can follow a linear disposition; as shown for inhibitors of
angiotensin-converting enzyme (ACEI) (Toutain et al., 2000), i.e.
where MRTi.v. and MAT are as defined above. By difference: to use a model-dependent approach that recognizes the nonlin-
earity. For ACEI it was shown that incorrect use of the measured
MDT ¼ MRTtablet ðMRTi:v: þ MATÞ: ð20Þ plasma concentration in order to estimate the absolute bioavail-
ability may actually double the true absolute bioavailability as
Equation 20 indicates that with a 3-period trial, MRTi.v., MAT
measured using the free plasma ACEI concentration.
and MDT can be evaluated and provide information on the input
process in a compact and useful unit (namely time).
For example, a short MAT suggests a rapid absorption and an
CONCLUSION
MAT longer than MRTi.v. suggests a flip-flop situation. The
attractiveness of the MRT concept is the additivity of time. If the
Absolute bioavailability is a key pharmacokinetic parameter
MDTs (or mean release time) of different dosage forms are
which must be systematically estimated for a new drug
independently known (e.g. from dissolution tests), then the
formulation or a new modality of administration. Many possible
overall in vivo MRT can be readily predicted, if MRTi.v. and MAT
approaches exist to evaluate both rate and extent of bioavaila-
(which are drug properties, not formulation properties) are
bility, including situations for which intravenous drug admin-
known from in vivo studies.
istration is not possible. Veterinary pharmacologists should pay
In the framework of compartmental model, it can be shown
special attention to possible misinterpretations when Cmax, Tmax,
that MAT is related to Ka using the following equation:
MAT or t1/2Ka are used to estimate the rate of drug absorption.
MAT ¼ 1=Ka : ð21Þ
REFERENCES
Equation 21 indicates that MAT is also subjected to the
same limits as Ka, to put it in physiological terms. As Ka
Anonymous (2001) Note for guidance on the investigation of bioavail-
actually represents the rate of drug disappearance from ability and bioequivalence. In Evaluation of Medicines for Human Use
its administration site, MAT is the stochastic view of this Committee for Proprietary Medicinal Products. pp. 1–18. The European
process and a shorter MAT can be because of a poor Agency for the Evaluation of Medicinal Products, London.
bioavailability (a high Ka2, see Fig. 10), and not to a Baggot, J.D. (2001) The Physiological Basis of Veterinary Clinical Pharma-
rapid transfer of the drug from the administration site to cology. Blackwell Science, Oxford.
Bai, S.A., Walle, U.K. & Walle, T. (1985) Influence of food on the
the central compartment (see Veng-Pedersen, 1989a,b).
intravenous and oral dose kinetics of propranolol in the dog. Journal of
A limitation of the statistical moment approach relates to
Pharmacokinetics and Biopharmaceutics, 13, 229–241.
the possible lack of precision in the estimation of the different Bailey, D.G., Dresser, G.K., Kreeft, J.H., Munoz, C., Freeman, D.J. & Bend,
MRT. As for AUC, bias in the estimation can be because of an J.R. (2000) Grapefruit-felodipine interaction: effect of unprocessed fruit
inappropriate sampling time and to the difficulty of extrapo- and probable active ingredients. Clinical Pharmacology and Therapeutics,
lation, but error is more severe with MRT because the terms 68, 468–477.
in time raised to square are now estimated and negative Bonnin, P., Huynh, L., L’Haridon, R., Chene, N. & Martal, J. (1999)
Transport of uterine PGF2 alpha to the ovaries by systemic circulation
MAT values can be spuriously computed.
and local lymphovenous-arterial diffusion during luteolysis in sheep.
In addition, MAT estimated by Eqn 18 is obtained with low
Journal of Reproduction and Fertility, 116, 199–210.
precision when its value is much shorter than the MRTi.v., and, Brouwer, K.R. & McNamara, P.J. (1986) Use of simultaneous computer
in this circumstance, negative MAT can be estimated due to fitting to estimate the apparent absorption rate constant. Journal of
either a slight over-evaluation of MRTi.v. or to a slight under- Pharmaceutical Sciences, 75, 452–455.
evaluation of MRTp.o..
Burtin, P., Mentre, F., van Bree, J. & Steimer, J.L. (1996) Sparse sampling Martinez, M.N. (1998) Article V: clinically important errors in data
for assessment of drug exposure in toxicological studies. European interpretation. Journal of American Veterinary Medical Association, 213,
Journal of Drug Metabolism and Pharmacokinetics, 21, 105–111. 1564–1569.
Chiou, W.L. (2001) The rate and extent of oral bioavailability versus Martinez, M.N. & Jackson, A.J. (1991) Suitability of various noninfinity
the rate and extent of oral absorption: clarification and recom- area under the plasma concentration-time curve (AUC) estimates for
mendation of terminology. Journal of Pharmacokinetics and Biophar- use in bioequivalence determinations: relationship to AUC from zero to
maceutics, 28, 3–6. time infinity (AUC0-INF). Pharmacological Research, 8, 512–517.
Cutler, D. (1981) Assessment of rate and extent of drug absorption. Murata, K. & Kohno, K. (1989) Estimation problem due to multiple
Pharmacology and Therapeutics, 14, 123–160. solutions in pharmacokinetic curve fitting to two-compartment
Doki, K., Hayakawa, T., Lin, W., Yanaguimoto, H., Ding, G. & Inotsume, model and its avoidance. Biopharmaceutics and Drug Disposition, 10,
N. (2003) Effects of absorption rate on the pre-systemic chiral inver- 15–24.
sion of ibuprofen in rabbits. Journal of Pharmacy and Pharmacology, 55, Purves, R.D. (1992) Optimum numerical integration methods for esti-
1091–1097. mation of area-under-the-curve (AUC) and area-under-the-moment-
Dupuy, J., Larrieu, G., Sutra, J.F., Lespine, A. & Alvinerie, M. (2003) curve (AUMC). Journal of Pharmacokinetics and Biopharmaceutics, 20,
Enhancement of moxidectin bioavailability in lamb by a natural fla- 211–226.
vonoid: quercetin. Veterinary Parasitology, 112, 337–347. Riegelman, S. & Collier, P. (1980) The application of statistical moment
Garrett, E.R. (1994) The Bateman function revisited: a critical reevalu- theory to the evaluation of in vivo dissolution time and absorption time.
ation of the quantitative expressions to characterize concentrations in Journal of Pharmacokinetics and Biopharmaceutics, 8, 509–534.
the one compartment body model as a function of time with first-order Rowland, M. & Tozer, T.N. (1995) Clinical Pharmacokinetics. Concepts and
invasion and first-order elimination. Journal of Pharmacokinetics and Applications, 3rd edn. Williams and Wilkins, London.
Biopharmaceutics, 22, 103–128. Toutain, P.L. & Koritz, G.D. (1997) Veterinary drug bioequivalence
Gibaldi, M. & Perrier, D. (1982) Pharmacokinetics, 2nd edn. Marcel Dek- determination. Journal of Veterinary Pharmacology and Therapeutics, 20,
ker, New York. 79–90.
Gibson, D.M., Taylor, M.E. & Colburn, W.A. (1987) Curve fitting and Toutain, P.L., Koritz, G.D., Fayolle, P.M. & Alvinerie, M. (1986) Phar-
unique parameter identification. Journal of Pharmaceutical Sciences, 76, macokinetics of methylprednisolone, methylprednisolone sodium suc-
658–659. cinate, and methylprednisolone acetate in dogs. Journal of
Hellriegel, E.T., Bjornsson, T.D. & Hauck, W.W. (1996) Interpatient Pharmaceutical Sciences, 75, 251–255.
variability in bioavailability is related to the extent of absorption: Toutain, P.L., Lefebvre, H.P. & King, J.N. (2000) Benazeprilat disposition
implications for bioavailability and bioequivalence studies. Clinical and effect in dogs revisited with a pharmacokinetic/pharmacodynamic
Pharmacology and Therapeutics, 60, 601–607. modeling approach. Journal of Pharmacology and Experimental Ther-
Hinderling, P.H. (2003) Evaluation of a novel method to estimate apeutics, 292, 1087–1093.
absolute bioavailability of drugs from oral data. Biopharmaceutics and Toutain, P.L. & Bousquet-Mélou, A. (2004) Plasma clearance. Journal of
Drug Disposition, 24, 1–16. Veternary Pharmacology and Therapeutics, 27, 415–425.
Hinderling, P.H. & Shi, J. (1995) Absolute bioavailability estimated from Veng-Pedersen P. (1989a) Mean time parameters in pharmacokinetics.
oral data. Journal of Pharmaceutical Sciences, 84, 385–386. Definition, computation and clinical implications (Part I). Clinical
Karlsson, M.O. & Bredberg, U. (1990) Bioavailability estimation Pharmacokinetics, 17, 345–366.
by semisimultaneous drug administration: a Monte Carlo simula- Veng-Pedersen, P. (1989b) Mean time parameters in pharmacokinetics.
tion study. Journal of Pharmacokinetics and Biopharmaceutics, 18, 103– Definition, computation and clinical implications (Part II). Clinical
120. Pharmacokinetics, 17, 424–440.
Karlsson, M.O. & Sheiner, L.B. (1994) Estimating bioavailability when Wagner, J.G. (1967) Method of estimating relative absorption of a drug
clearance varies with time. Clinical Pharmacology and Therapeutics, 55, in a series of clinical studies in which blood levels are measured after
623–637. single and/or multiple doses. Journal of Pharmaceutical Sciences, 56,
Kilroy, C.R., Hall, W.F., Bane, D.P., Bevill, R.F. & Koritz, G.D. (1990) 652–653.
Chlortetracycline in swine – bioavailability and pharmacokinetics in Wagner, J.G. (1983) Pharmacokinetic absorption plots from oral data
fasted and fed pigs. Journal of Veterinary Pharmacology and Therapeutics, alone or oral/intravenous data and an exact Loo-Riegelman equation.
13, 49–58. Journal of Pharmaceutical Sciences, 72, 838–842.
Liang, E. & Derendorf, H. (1998) Pitfalls in pharmacokinetic multi- Weiss, M. (1990) Use of metabolite AUC data in bioavailability studies to
compartment analysis. Journal of Pharmacokinetics and Biopharmaceu- discriminate between absorption and first-pass extraction. Clinical
tics, 26, 247–260. Pharmacokinetics, 18, 419–422.
Lovering, E.G., McGilveray, I.J., McMillan, I. & Tostowaryk, W. (1975) Yamaoka, K., Nakagawa, T. & Uno, T. (1978) Statistical moments in
Comparative bioavailabilities from truncated blood level curves. Journal pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics, 6,
of Pharmaceutical Sciences, 64, 1521–1524. 547–558.
Madden, F.N., Godfrey, K.R., Chappell, M.J., Hovorka, R. & Bates, R.A. Yeh, K.C. & Kwan, K.C. (1978) A comparison of numerical integrating
(1996) A comparison of six deconvolution techniques. Journal of algorithms by trapezoidal, Lagrange, and spline approximation. Journal
Pharmacokinetics and Biopharmaceutics, 24, 283–299. of Pharmacokinetics and Biopharmaceutics, 6, 79–98.