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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5329_Библиотеки_им_академика_М_И_Перельмана
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systemic circulation. Typically, the hepatic-portal vein of the animal has to be
cannulated in order to conduct this type of dosing.
PK studies with HPVadministration may provide valuable information about firstpass metabolism of the compound and may be used as a diagnostic tool to determine
if low oral bioavailability is driven by low permeability or fast metabolism.
The choice of formulation and maximum dose volume is similar between HPV
and IV administration.
INTRADUODENAL ADMINISTRATION A direct intraduodenal administration of compound
may help estimate first-pass metabolism across the gastrointestinal mucosa [98].
Continuous Administration The most commonly used continuous administration
of a compound is IV infusion.
SINGLE-DOSE IV INFUSION Single-dose IV infusion of a compound is typically done via
an infusion pump attached to a cannula inserted into a jugular vein. This type of dosing
allows for achieving a steady-state concentration of compound in both the systemic
circulation and the organs into which the compound distributes. IV infusion can
provide a more accurate estimation of clearance of compounds with low solubility.
Analysis of compound in the organs and tissues collected shortly after the termination
of the IV infusion provides the steady-state distribution of the compound in those
organs. This information may be valuable for better understanding of PK/PD and
exposure–toxicity relationships.
Escalated Single-Dose Administrations PK studies with escalating dose are typically conducted in preparation for animal efficacy or safety studies .
The purpose of pre-efficacy escalating dose studies is usually to identify a dose
range that provides exposures that are sufficient for achieving target in vivo concentrations that are close to or above an expected efficacious compound concentration. Ideally the d ose escalation study should be performed in the same animal strain
with the same health status as will be used in the efficacy study. Certain diseases
may impact the physiology of the animals and, as a result, the PK properties of the
compound.
The purpose of pretoxicology dose escalation studies is to determine the maximum dose for subsequent toxicology studies and thus referred to as dose-range
finding (DRF) studies. The maximum dose in DRF studies may be based upon either
toxicology observations at higher doses or the leveling of the exposures at higher
administered doses. Most frequently, the DRF studies are conducted in roden ts
(usually rats) and nonrodent species (usually dogs and less frequently monkeys)
to match the species that are expected to be used in the subsequent toxicology
studies.
Multiple Administrations via Different Routes (Crossover) The crossover studies
are conducted by the PO administration of a compound followed by an IV administration after a washout period (typically 24 h but may be longer for the compounds
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with a long terminal half-life). In order to ensure that the compound is cleared from the
body between the first and the second adm inistration, the PO dose is usually initially
administered. This is because the PO dose typically generates lower exposures due to
less than 100% oral bioavailability compared to the IV administration.
The purpose of the crossover study design is to decrease the impact of animalto-animal variability on PK data by using each animal as its own control between the
two routes of administration. An additional benefit of the crossover design is that it
reduces the number of animals especially larger animals that are typically nonterminal (dogs, monkeys, etc.).
Multiple Administrations via the Same Route PK studies with multipl e doses
administered sequentially with frequencies such as daily (QD or SID), twice daily
(BID), three times a day (TID), four times a day (QID), or with some other dosing
regimen, aim to achieve a steady-state concentration to mimic exposure to compound
in chronic efficacy or toxicology studies. The frequency and duration of the
administration required to achieve steady state is described in Section 5.4.4.
Cassette Versus Singleton Dosing If an animal PK model is used in compound
screening, throughput may become a bottleneck in the discovery project. A potential
solution to this problem is to combine several compounds in a cassette and dose
them together. The biggest challenge of the cassette PK studies is data interpretation
due to a potential drug–drug interaction. To mitigate the risk of DDI, the dose levels of
individual compounds in the cassette are reduced to compare typical singleton
studies. The number of individual compounds in a cassette does not usually exceed
10 with 4 or 5 being more reasonable from a practical and a scientific standpoint.
This may present analytica l challenges for compounds with poor mass spectrometer
source ionization properties. Additionally, compounds with the same exact mass
(isobaric) should not be used in the cassette studies because their quantitation in
biological samples may be challenging unless these compounds can be separated by
using chromatography or some capabilities of triple-quadrupole mass spectroscopy
(Section 5.6.2.7).
5.6.2.5 Sampling Collecting biological samples from the animal after administration of a compound is a critical step in evaluation of PK parameters of the
compound. Figure 5.28 shows some typical routes of sample collection.
The most important parameters of the sample collection step of a PK study are the
type of collected biological matrix, collection frequency, sample handling, and
storage.
Biological Matrices Collected for PK Purposes Typical biological samples collected in a PK experiment are blood (or derived plasma or serum), urine, bile, feces,
and tissues. Each of these matrices has its unique properties and has to be understood
and considered during sample collection and storage.
There are some additional biological matrices (cerebrospinal fluid and synovial
fluid) that can be collected for more specialized purposes.
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BLOOD Blood can be collected from multiple points representing a systemic circu-
lation or in certain cases from the hepatic-portal vein representing presystemic
circulation. The blood samples collected from the systemic circulation represent a
central PK compartment. This route of sampling is by far the most frequently used for
the majority of PK studies. Blood sampling from the portal vein is typically used to
evaluate the level of first-pass metabolism and the fraction absorbed after PO
administration.
COLLECTING BLOOD FROM RATS Rats can be bled manually from jugular, saphenous,
submandibular, and tail veins. These sampling procedures may or may not require
using anesthesia depending upon the comfort and competence of the ADME scientist.
Blood samples can be collected via retro-orbital (RO) bleeding but requires anesthesia.
Blood can be collected from rats either manually or via a cannula (catheter)
implanted into a certain vessel usually jugular or carotid. Cannulation of rats
facilitates blood sample collection and provides less stress on the animals. Cannulation requires a surgical modification of the animal, which may not be successful
in 100% of the cases. The cannula may not be patent (stay intact) over a prolonged
period of time and rats should be used for PK studies within 2 weeks of cannulation.
Manual bleeding of rats is typically used in toxicology studies especially in longer
term studies for which the cannulas most likely will not remain patent. Another reason
for using manual blood collection in toxicology studies is a desire to minimally impact
the physiology of the animals due to surgical intervention.
The total blood volume that can be collected from rats within 2 weeks is limited to
approximately 1% of the total body weight. Approximately 3 mL of blood can be
collected from a 300 g rat. Different animal use protocols (AUP) may permit slightly
different maximum allowed blood volumes. The terminal blood volume is usually
collected via cardiac puncture and provides a larger sample (2 mL) suitable for
additional analyses (e.g., safety measures such as hematology and clinical pathology
as well as biomarker or metabolite ID work).
COLLECTING BLOOD FROM MICE Most frequently each individual mouse provides a
single blood sample collected by cardiac puncture or from the posterior vena cava
upon termination of an animal. Approximately 0.25–1 mL of blood is collected,
depending on the body weight of the animal.
There are some procedures for collecting more than one sample from an individual
mouse. Blood samples can be collected via tail or saphenous veins, or by submandibular or retro- orbital bleeding. Multiple sample collection (serial bleeding) from
mice may provide serial PK data instead of “population” (composite) PK and PD
profiles similar to larger animals. Serial bleeding from mice can be done manually or
via a cannula inserted in the jugular vein or carotid artery similar to cannulated rats.
Cannulation of mice is much less common than cannulation of larger animals such as
rats. This technique requires more specialized surgical skills and improper placement
of the catheter may lead to frequent failure of the surgery and less catheter patency.
Manual mouse bleeding via jugular vein or carotid artery does not require the use
of anesthesia as opposed to retro-orbital bleeding.
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The maximum blood volume that is allowed for the collection from each mouse is
typically limited to 1% of the total body weight for a 2 week period but may be as
large as 1.8% for certain AUPs. Approximately 0.3 mL of blood can be collected
from a 30 g mouse.
If multiple (serial) blood samples are collected from each mouse, the size of each
sample is much smaller than the size of samples collected from, for example, rats. The
quantitation of drug in mouse samples may require using more sensitive bioanalytical
methods.
COLLECTING BLOOD FROM DOGS Dogs are usually bled manually from the cephalic or
jugular vein. For frequent initial blood collections, a catheter can be placed in the
cephalic vein of each dog prior to dosing.
Due to the larger size of dogs (10–15 kg for an adult male dog), the maximum
total blood volume that can be collected from each animal does not usually represent
a hurdle for a PK study.
COLLECTING BLOOD FROM MONKEYS Monkeys are usually bled manually from femoral,
cephalic, or saphenous veins [97]. This procedure does not require using anesthesia.
Similar to the dog, the larger size of monkeys (2 kg for young adults and up to
10 kg for mature adults) allows a greater maximum total blood volume collected
from each animal and does not usually represent a hurdle for a PK study.
PLASMA/SERUM Once the whole blood is collected from an animal, it can be
centrifuged to deliver plasma (typically with 40–50% yield). The blood samples
have to be collected in tubes containing an anticoagulant to prevent the blood from
rapid clotting. Alternatively, the blood can be collected without using an anticoagulant so the blood coagulates with time (usually within 30 min) to produce the
serum. The primary difference between the composition of the plasma and the serum
is that the serum lacks the blood-clotting proteins.
The maximum volume of plasma that can be collected from the laboratory animal
is determined by the volume of the blood allowed for the collection.
URINE Urine is collected for the evaluation of renal clearance by quantitation of the
parent compounds and their metabolites. The urine is usually collected in time
intervals using cages equipped with devices for separation of the urine from the feces.
The urine samples are usually collected in time intervals unlike the blood samples
collected at certain time points. The urine volume collected at different time intervals
may significantly vary in volume because the animals urinate voluntarily. It is critical
then to measure and record the urine volume collected per time interval. It is also
important to record the actual weight of each individual animal in order to calculate
urinary recovery and renal clearance. The accuracy of the urine collection is typically
lower than the accuracy of the blood collection so the calculated urine cle arance may
be subject to higher variability.
BILE Bile can be collected for measuring biliary clearance of compound as well for
evaluation of Phase II metabolism, especially glucuronide formation and excretion.
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PK experiments in bile-duct cannulated rats are usually conducted with quadruple
cannulated animals: the jugular vein and carotid artery for IV dose administration
and sample collection as well as the bile duct and duodenum for bile collection and
bile salt infusion. Typically a solution of bile salts or the natural bile from additional
animals should be returned back to the study rats to minimize the potential impact of
bile removal on rat physiology.
As with urine collection, bile is collected in time intervals. The bile volumes
collected in each interval have to be measured and recorded as does the weight of each
animal used for the BDC PK experiment.
FECES Feces may provide some information about the amount of compound not
absorbed after PO administration. Some compounds excreted in the bile may be
measured in the feces. A potential degradation of compound in the feces due to
digestion by intestinal microflora needs to be taken into consideration when planning
and interpreting data from the PK experiment.
The collection of the feces is not used very frequently in discovery PK experiments.
ORGANS AND TISSUES The collection of organs and tissues may provide valuable
information about compound distribution and organ-specific metabolism. Measuring
the actual concentration of the compound in a target organ may be critical for
establishing translatable PK/PD relationships.
The collection of organs and tissues is typically done upon termination of the
experimental animals at a predetermined time point. Nont erminal sample collection
procedures can be used in larger animals (dogs, monkeys, or chimpanzees). In this
case, a needle biopsy from the liver can be performed on anesthetized animals
although the number of nonterminal sampling is usually limited to 1–2 samples.
The collection of highly perfused organs may require removal of the blood in those
organs prior to or immediately after the termination of the animals to differentiate
compound located in the organ or blood. If the organs are not perfused upon
collection, it is necessary to correct the concentrations of the test compound in the
organ ho mogenate for the amount of the blood in the organ. The values for the blood
content in different rat organs are summarized in Appendix 5.A.4. This data should
be used with caution since the results were obtained using different techniques from
various labs and are not always consistent.
Organs that are typically collected from experimental animals are liver, kidneys,
brain, heart, lungs, adrenal glands, testes, and muscles.
Duration and Frequency of PK Sampling The duration and frequency of sample
collection may have a significant impact on the quality of the PK data and in certain
cases may lead to erroneous or misleading PK data. The frequency of sampling
typically represents a compromise between a desire to obtain a more complete PK
profile with denser sampling and some practical and regulatory considerations. The
latter may be the speed that in vivo scientists can collect the first blood sample after IV
administration, the availability of animal technicians to collect samples after work
hours, the total blood volume that can be collected, etc.
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Awell-executed PK study will continue to collect samples until 4–5 half-lives of a
drugs disposition is complete. This is based on the premise that by 4–5 half-lives,
more than 95% of the drug has been eliminated from the body (Table 5.5) and the
disposition of the drug is almost complete. The use of the word “almost” is deliberate
because all drugs eventually follow an exponential decline and, as such, concentrations approach zero but never attain it. Drug elimination from the body does not
refer to all drug-based entities (metabolites, impurities, etc.) in the body, but to the
existence of the drug as a distinct chemical entity only.
It is relatively easy to design a PK study if the disposition of the drug is known, but
how does one design a PK study for a new chemical entity that has never been dosed
before? In a discovery setting, particularly at a lead development stage, costs and
adherence to aggressive timelines and schedules should be adapted to experimental
study designs.
FREQUENCY OF PK SAMPLING
IV Bolus Administration The frequency of blood sampling after IV administration has to be sufficient to capture the initial phase of the PK profile especially for
compounds with very rapid distribution. In this case, an insufficient frequent sampling
may lead to an underestimation of the AUC and initial systemic concentration and
cause an overestimated clearance and volume of distribution, respectively.
An insufficient frequent sampling at the terminal elimination phase of the
PK profile may provide fairly inaccurate terminal half-life (t
1/2
) of the compound.
Extravascular Bolus Administration The most characteristic PK parameters of
a compound after an extra-vascular administration (e.g., PO, IP, SC, or IM) are the
C
max/Tmax
and the terminal t
1/2
. Insufficient blood sampling around the maximum
concentration on the PK curve may lead to inaccurate values for C
max
and T
max
.
Similarly to IV administration, inadequate frequent sampling at the terminal phase of
the PK profile may provide inaccurate values of terminal half-life.
IV Infusion The duration of an IV infusion administration is driven by the time
necessary to achieve a steady state of the compound concentration in the blood. For
practical purposes, the duration of IV infusion can be estimated as approximately
seven terminal half-lives of the compound after IV bolus administration. It is common
to collect at least several blood samples during the infusion especially close to the end
of the infusion to ensure that at least the last two blood concentrations are close in
value. After the termination of the infusion, blood samples can be collected for the
period of time and with the frequency similar to the IV bolus administration with the
first sample collection being as close as practically possible to the infusion termination time.
Sample Handling and Storage Samples collected from a PK study must be handled
appropriately so that the analytes of interest do not degrade during the storage process.
Approaches to sample handling and storage may vary depending on the purpose of the
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PK study, the type of the collected biological matrix, and the properties of the
compound of interest (analyte) that need to be quantified.
BLOOD When collecting blood, hemolysis of the red blood cells should be prevented.
Blood collected in tubes should be maintained on wet ice but not frozen until used
for further processing.
Blood can be collected and stored in a liquid or dry form. If the total concentration
of compound in the blood is a desired PK measure, the compound has to be released
from the red blood cells to ensure complete recovery of the analyte. Mixing the blood
samples with water is a common method for disrupting the RBC. It may be practical
to sonicate the processed blood samples to reduce potential capturing of the analyte
by the blood components.
As an alternative to using liquid blood, the blood sample can be placed on a filter
paper to form a so-called dried blood spot (DBS) that can be used for subsequent drug
bioanalysis [99] similar to clinical DBS analysis [100]. The extent and the rate of the
partitioning of the drug to the cellular components of the blood, primarily red blood
cells is critical [14].
PLASMA Once separated from red blood cells, the plasma can be frozen and stored
at 20 to 80
C until processed for analysis. It is important to ensure that there is
adequate anticoagulant in the blood collection tubes such that the plasma does not
coagulate on storage.
URINE Urine should be collected on ice/dry ice and can be treated and stored similar
to plasma.
BILE The handling of the bile samples is similar to urine samples.
FECES After the wet weight of the sample is recorded, a weighed amount of solvent
(invariably water or methanol) should be added and the sample homogenized and
stored at –20 or –80
C until further analysis.
ORGANS AND TISSUES Collecting different organs and tissues is usually conducted by
experienced in vivo scientists and may require some additional skills and knowledge.
The most common way of preserving tissues and organs is freezing in dry ice or liquid
nitrogen.
5.6.2.6 Animal Handling Ethical and scientifically reasonable handling of experimental animals used for preclinical testing is more likely to lead to better quality
animal data due to reduced animal stress. This should allow better prediction of
human PK, which will reduce the risk of incorrect prediction of human exposures in
initial human studies and harm to healthy volunteers in first-in-human studies. In
effect, better care of laboratory animals is more likely to lead to better care of human
beings.
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IACUC It is mandatory in the United States, European Union, and some other
countries and federations that animal study protocols (or animal use protocols) be
reviewed and approved by the local animal use committee. The group consists of
scientists and representatives of the community to ensure ethical treatment of animals
used for PK and other animal studies. In the United States, the IACUC (Institutional
Animal Care and Use Committee) is a self-regulating entity that, according to US
federal law, must be established by institutions that use laboratory animals for
research or instructional purposes to oversee and evaluate all aspects of the institutions animal care and use program. Some additional information about IACUC
functions and procedures can be found at the American Association for Animal
Laboratory Science (AALAS) at their website (www.aalas.org).
It is important for medicinal chemists and other scientists to realize that any new
animal study design or changes to an existing study design have to be reviewed and
approved by the IACUC before the new study protocol is allowed for execution.
In general, there are well-accepted principles known as the “3Rs” that should be
applied to all studies in laboratory animals [101]:
.
Refinement of the use of research animals to use less painful or the least invasive
procedures whenever possible.
.
Reduction of the numbers of animals used in each study to the absolute minimum
necessary to obtain valid results.
.
Replacement of animal experiments with nonanimal experiments such as
mathematical models, computer simulations, and in vitro biological systems
wherever appropriate.
Fed Versus Fasted Rats are fasted overnight prior to PO dosing and access to food
provided at 4 h post dose. Access to water is usually ad lib. Animals should be fasted
no longer than 24 h without justification.
The animals used for an IV study are usually not fasted before dosing. Animals are
typically not fasted during any PK studies with multiday administration of compound.
The quality and quantity of animal feeding and the feeding time may impact the
PK profile of certain compounds, especially compounds that are poorly soluble or
are substrates of transporters or efflux pumps located in the intestinal mucosa. Food
effects are well documented in the literature [102–109].
Dosing Volume The allowed and most commonly used dosing volumes for different
routes of administration are described in Section 5.6.2.4.
Total Blood Volume The volume of the blood allowed for collection in different
animal species is described in Section 5.6.2.5.
Anesthesia Some sample collection techniques may require using anesthesia
because they may be distressful or painful to the animals. Avoiding animal pain is
based not only on the ethical consideration for the study but also should be based on
a scientific consideration due to a potential impact of the animal pain and stress on the
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PK parameters of the study. Retro-orbital bleeding, penile vein dosing, and surgical
implanting of catheters and osmotic pump require anesthesia.
The choice of an anesthetic for the study should be carefully evaluated based on the
prior knowledge and experience with a particular anesthetic or based on some general
principles of animal physiology [110, 111].
Certain types of anesthesia may not be compatible with frequent sample collection.
ACO
2/O2
anesthesia may cause animal dysfunction or even death if applied too
frequently.
Animal Stres s Animal dosing and sampling may be stressful for animals especially
if some invasive procedures are used in the PK study (e.g., manual bleeding). Since
stress may modulate the animals physiology and subsequently PK parameters of a
studied compound, it is ethical as well as scientifically rational to minimize animal
stress. Methods to reduce stress include using anesthesia when possible, reducing
sample frequency, reducing sample size via microsampling (Microsampling section),
using cannulated animals (Cannulated Versus Noncannulated Animals section), and
using automated instead of manual blood collection (Automated and Manual
Bleeding section).
Cannulated Versus Noncannulated Animals The use of cannulated animals may
ease the sample collection process, reduce the chances of human error (e.g., missing
the vein for dosing or bleeding), and reduce the stress on the animals used for a
PK study.
Many animal species and strains are commercially available in a single or a
multiple cannulated form. There are different sites that can be used for cannulation
such as jugular, carotid, and portal vein. The catheters can be installed to access the
stomach or the duodenal section of the small intestine.
The disadvantage of the cannulated animals is commercial availability and when
available are more expensive than noncannulated animals. The patency of the cannula
may be limited to a fairly short period of time (e.g., couple of weeks in rats).
Automated and Manual Bleeding Automated collection of blood samples from
cannulated rats and mice has become possible due to the relatively recent development of new automated blood sampling (ABS [112]) instrumentation such as Culex
by BASi (www.basinc.com/products/culex) [113] and AccuSampler by DiLab (www.
dilab.com). Each system has its own advantages and disadvantages so the selection of
the most appropriate ABS may depend on the specific needs of the studies, familiarity,
and prior experience with a particular system, etc.
The use of ABS can greatly reduce the stress involved with serial sampling. Stress
can possibly alter the PK resulting in inconsistent and even faulty PK and PK/PD data.
ABS greatly reduces the human workload allowing for fewer employees to generate
a high-quality and high-throughput PK data. By automating the blood-drawing time
course, technicians are not required to be in the vivarium at extreme hours of the night.
Microsampling Collecting less than conventional size blood samples from mice
may present the benefit of generating serial PK profiles in each individual
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animal. There are some examples of serial bleeding from mice described in the
literature [114–120].
5.6.2.7 Bioanalysis Some basic concepts of bioanalysis of PK samples using
liquid chromatography and mass spectrometry are described. LC/MS is undoubtedly
the most frequently used method of quantitation of drugs, their metabolites, and
biomarkers in the animal PK samples. A more detailed description of bioanalytical
techniques and instrumentation can be found in the literature [121–135].
Basic Concepts of LC–MS/MS Quantitation LC–MS/MS refers to a quantitation
method combining liquid chromatography with tandem mass spectroscopy (MS/MS).
A typical triple–quadrupoleinstrument allows for the selection of an ion (“parent” ion)
on the first quadrupole followed by fragmentation in a collision cell (second quadrupole), after which the most abundant fragments (“daughter” ions) can be selected using
the third quadrupole. Such a double selection of the parent and daughter ions is called
single reaction monitoring (SRM) or multiple reaction monitoring (MRM). This
monitoring provides LC–MS/MS quantitation as very specific and sensitive and
allows for measuring nanomolar and picomolar concentrations of the analytes in very
complex biological matrices. Several SRM modes can be combined for simultaneous
quantitationof multipleanalytesin a multiplereactionmonitoringmethod.LC–MS/MS
methodology does not provide high-accuracy or high-precision quantitation.
Calibration Curves, Sensitivity, and Dynamic Range Since the ionization of
different compounds may depend on their structure, calibration standards are
typically prepared and analyzed in the same or similar biological matrix that is used
for PK sample collection. Calibration standards typically cover a broad range of
concentrations expected in the PK study samples. A separate calibration curve for
each analyte is typically developed based on the best fit of the nominal standard
concentrations and the actual MRM signal measured for each standard. Acceptance or
rejection of individual calibration standards for each calibration curve is based on the
comparison of the fitted (expected) signal intensity and the actual (observed) signal.
This comparison characterizes the accuracy of the calibration standards. If multiple
calibration standards are prepared and analyzed at the same nominal concentration,
the dispersion of their values represents the precision of the method.
Although some LC–MS/MS methods may occasionally have relatively high
accuracy and precision, the most frequently used acceptance criteria even for a
well-established validated method may be within 15% for all the standards and 20%
for the lowest concentration sample representing the lowest level of quantitation
(LLOQ) [136]. The highest calibration standard that meets the acceptance criteria is
called the upper limit of quantitation (ULOQ).
The ratio of the ULOQ to LLOQ represents the range of concentrations that can be
quantified using the calibration curve.
The concentration of the analyte in the study sample is calculated based on
comparison of the experimentally measured intensity of the signal in those samples
with the calibration curve. If the calculated concentration is lower than the LLOQ, it is
considered undetermined and labeled as below the quantitation limit (BQL or BLQ).
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