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A Resource and Data Quality Comparison : Absolute Bioavailability Data from an Oral / IV Crossover and an IV Isotopic Tracer Clinical Design
G Lappin1, M Seymour1, J Hague1, D Higton2 and P Dickinson2
Xceleron Ltd, York, UK (www.xceleron.com; [email protected]; T: +44 1904 561 561)
1:
INTRODUCTION
Park, UK
Fig 2 : Concomitant IV Isotopic Tracer Design
Fig 1 : Oral / IV Cross-over Design
The majority of drugs are given extravascularly, with oral administration predominating
as this is the most convenient and least invasive route. Pharmacokinetic data obtained
using the clinically relevant route of administration are a routine and essential part of
drug development. However, pharmacokinetic data obtained using an intravenous (IV)
route are equally valuable as they provide the fundamental parameters of clearance,
volume of distribution and, in conjunction with extravascular data, absolute bioavailability
(Fabs) [1]. In addition, such data can give insight into absorption kinetics, flip-flop effects
and biliary excretion [2] and obtaining IV and oral pharmacokinetics for solid and liquid
dose forms allows determination, by appropriate modelling and de-convolution, of the in
vivo absorption and dissolution rates, thereby establishing the pharmacokinetic platform
of the in vitro / in vivo correlation [3].
2: AstraZeneca, Alderley
mg oral dose ‘cold’
mg IV dose
mg oral dose
X
Time Comparison
Figure 3 illustrates the significant amount of time which may be required to formulate an IV
dose at therapeutically relevant dose levels. This clearly depends on the properties of the
drug in question. However, with the prevalence of contemporary compounds with low
solubility, this can be a highly resource intensive activity. Usually IV toxicology will also be
required to support the therapeutically relevant IV dose, which can also take some months to
perform.
LC-MS/MS
LC+AMS
This poster describes a novel study design whereby an IV isotopic tracer is
administered concomitantly with a pharmacologic oral dose and Accelerator Mass
Spectrometry (AMS) is used to quantify plasma concentrations of drug arising from the
tracer dose. This approach is contrasted with a traditional oral / IV crossover design in
terms of cost (money and time) and the quality of the data produced.
Oral
IV
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Plasma concentration
Plasma concentration
Plasma concentration
For oral therapeutics, a human absolute bioavailability study is often not performed due
to the high demands on resources for these types of studies. However, the human Fabs
study provides insight into fundamental pharmacokinetics and can elucidate the reasons
for low exposure observed following oral dosing, thus assisting in formulation
development and providing a key dataset for regulatory filing packages. Whilst human
Fabs is not regarded as a requirement by most regulatory authorities (Australia’s TGA
does expect to see human Fabs for all new chemical entities), it has been observed that
such data are being requested by regulators with greater frequency.
Plasma concentration
LC-MS/MS
OBJECTIVES
Oral
Assuming that the IV tracer dose can be administered as part of an existing clinical study
(e.g. AstraZeneca has used this approach in Food Effect Studies [5]) then no time costs are
incurred clinically. As stated above, formulation requirements are minimal so little time and
energy is required in this regard. Overall, significant time savings accrue from the IV tracer
approach.
IV
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Time (h)
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Time (h)
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Time (h)
METHODS
Traditional oral / IV cross-over study design (Fig 1)
A therapeutically relevant dose is formulated for IV dosing. The aim is to produce a
similar level of exposure as is likely to be experienced from the oral dose. However, as
the human Fabs is unknown, this may not be achieved. Blood samples are taken over a
designated time period, analysed for example by LC-MS/MS and the parent compound
AUC associated with the IV dose calculated. In the same cohort of volunteers, after a
sufficient washout period, a therapeutically relevant oral dose is administered, blood
samples taken and analysed using LC-MS/MS and the parent compound AUC
associated with the oral dose calculated. Absolute bioavailability for the oral dose is
then calculated:
350
Scientific Comparison
The concomitant IV isotopic tracer design virtually eliminates issues of non-equivalent
clearance and pharmacokinetically is the most appropriate design, given the ability to
measure concentrations arising from the oral and IV doses in the same sample, taken from
the same subject at the same time. The technique can also be applied when the oral dose is
administered to steady state, thereby accounting for changes to bioavailability that might only
occur upon repeat dosing.
CONCLUSIONS
Fig 3. Cross-over Resource
$2M
Fig 4. Concomitant IV Resource
Analysis
*:
14C
#:
clinical costs minimal if 14C tracer
added to an existing clinical study
FDA
Label may already be available
IV Tox
$0.5m
Analysis
1. Lappin, G, Rowland, M and Garner, RC. The use of isotopes in the determination of
absolute bioavailability of drugs in humans. Expert Opin Drug Metab Toxicol 2(3), 419427 (2006).
2. Lappin, G, Shishikura, Y, Jochemsen, R, et al. Pharmacokinetics of fexofenadine:
Evaluation of a microdose and assessment of absolute oral bioavailability. . Eur J Pharm
Sci 40, 125–131 (2010).
3. Lappin, G. and Stevens, L., 2008. Biomedical accelerator mass spectrometry: recent
applications in metabolism and pharmacokinetics. Expert Opin Drug Metab Toxicol 4(8):
1021-1033.
4. ICH Topic M3. Note for guidance on nonclinical safety studies for the conduct of human
clinical trials and marketing authorization for pharmaceuticals (2009). CPMP/ICH/286/95
Clinical#
Formulation
& Manufacture
0
Using IV tracers in a concomitant administration design, coupled with the use of LC+AMS,
provides fundamental pharmacokinetic data in humans faster and more cost effectively than
using a traditional oral / IV cross over design. Moreover, the approach is scientifically
superior, producing more reliable, higher quality data.
REFERENCES
Clinical
Trial
 AUCoral  Doseiv 


Fabs = 
 AUCiv  Dose oral 
Concomitant IV isotopic tracer study design (Fig 2)
A therapeutically relevant oral dose (non-labelled) is administered concomitantly with a
low level IV dose (typically 10 µg) containing an isotopic tracer (14C; typically ≤ 10 kBq).
The IV dose is ideally infused over a short period of time, with the end of infusion
coinciding with Tmax of the oral dose. Blood samples are taken over a designated time
period and samples analysed by both LC-MS/MS (to determine the parent drug
concentration arising from the oral dose) and LC+AMS (to determine parent drug
concentrations arising from the IV dose). AUC’s from both routes of administration are
calculated and absolute bioavailability is computed using the equation above.
Cost Comparison
As shown in Figure 3, the Oral / IV Cross Over design can require significant IV dose
formulation development effort given the relatively high dose levels used. This can be
especially true for BCS Class II compounds and may take many months, at a cost of in the
order of $1m. The IV dose will also need to be supported by IV toxicology, which takes many
months and costs in the order of $750k. The clinical study is usually stand-alone and will cost
of the order of $200k. LC-MS/MS analysis costs of the order of $50k including validation.
As illustrated in Figure 4, the Concomitant IV Tracer design requires little in the way of IV
formulation development, given the low µg dose, and there is no need for IV toxicology since
the safety studies performed to support the oral dose will cover the IV dose [3]. A stand-alone
clinical study would cost of the order of $150k. However, the IV tracer can be ‘bolted on’ to an
existing clinical protocol, such as a food effect study, in which case little extra clinical cost is
added apart from manufacture of the IV dose (ca $50k). Analysis by LC-MS/MS and
LC+AMS costs around $150k, including validation. Many drug developers have 14C tracer
available at this stage however, if not, Figure 4 suggests a cost of ca $150k.
µg IV isotopic tracer dose
However, obtaining intravenous pharmacokinetic data in humans is not straightforward
because a package of safety toxicology data using the IV route is required and
considerable effort may be needed to obtain a formulation suitable for IV use, particularly
with compounds exhibiting limited solubility. Furthermore, errors can occur in the
determination of absolute bioavailability if the value for clearance differs between the
treatments when using a classical cross-over study design [1]. In particular, the plasma
concentrations of a compound arising from the extravascular and IV doses can be very
different and, if clearance is concentration dependent, then the cross-over design may
give erroneous results.
RESULTS
F&M
5. Dr Andy Gray (AZ) @ Exploratory Clinical Development Conference, London, 2010
14C Label*
6 months
12 months
0
3 months
6 months
T2365