Download Using Positron Emission Tomography (PET) microdosing

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Using Positron Emission
Tomography (PET) microdosing
to improve CNS drug development
Authors
Lars Farde1, Stuart Heminway2, Chi-Ming Lee2, Dennis McCarthy2, Ingrid Nordgren1
and Svante Nyberg1
AstraZeneca R&D, Sodertalje SE-15185, Sodertalje, Sweden and 2AstraZeneca
Pharmaceuticals, 1800 Concord Pike,Wilmington, DE 19850, USA
1
Corresponding author: Chi-Ming Lee ([email protected])
Key words
Positron Emission Tomography microdosing,
PET, biodistribution, radiolabelling,
pharmacodynamic response, improving drug
development
Abstract
The pharmaceutical industry is committed
to continuous investment in technologies
to improve the drug R&D process in spite
of relatively flat product approvals over the
past two decades. Human Positron Emission
Tomography (PET) microdosing is technology
that allows the safe and early evaluation
of biodistribution of radiolabelled drugs in
plasma and target organs. Using appropriate
radiotracers, PET can in addition be used to
study interactions with specific drug targets,
assess pharmacodynamic response, visualise
disease pathology and monitor effect of
treatment. In this article, we reviewed the
relevant EU and US regulatory guidelines
governing PET microdosing studies. It is
envisaged that these recently introduced
guidelines will stimulate the use of PET
microdosing in efforts to improve the drug
development process.
Increasing Pharma R&D cost,
decreasing productivity and need
for early human testing
In a recent interview with the Next
Generation
Pharmaceutical
Magazine
(December 2006), Jean-Pierre Garnier (CEO
of GlaxoSmithKline) indicated that “In 1980,
the industry spent $2 billion in R&D and the
US Food and Drug Administration (FDA)
approved about 30 new products. Twenty
years later the industry spent $26 billion and
again the FDA approved 30 products. On
top of this, clinical trials used to cost around
$2000 per patient in early 1980s, compared
with $20,000 nowadays”. Currently, the
average cost for bringing a drug to market
is close to one billion US dollars and the
process typically takes 10-15 years.
A key problem facing the pharma industry
is that a majority of drug candidates
entering clinical studies fail, resulting in
only an 8% chance of reaching the market,
falling from the historic 14%. Most drugs
fail in clinical testing because they do not
behave as predicted in pre-clinical models.
For instance, up to 40% of drug candidates
fail already in Phase I clinical studies due
to inappropriate pharmacokinetics or
inadequate safety (Dimasi, 2001). Efficacy
and most toxic effects of drugs are related
to the dose administered. A drug can thus
fail unnecessarily if inappropriate doses are
selected for the clinical studies. Traditionally,
the initial clinical doses in human have been
selected based on dose-response data from
pre-clinical models. To predict exposure in
human, the metabolic and pharmacokinetic
properties of a drug are characterized by in
vitro (hepatocytes and enzyme preparations)
and in vivo studies using different animal
species from rodents and dogs to non-human
primates. Results from these studies are then
used to model and predict the absorption,
distribution, metabolism and excretion
of the drug candidate in human subjects.
Unfortunately, such allometric scaling has not
been predictive in approximately one out of
three occasions (Garner and Lappain, 2006).
The hurdle for central nervous system
(CNS) drugs is even higher since they have
to pass the blood-brain-barrier (BBB) to
provide sufficient brain exposure. It has been
estimated that 98% of small molecule drugs
do not cross the BBB effectively, while many
are transported back to plasma by various
transport proteins at the BBB, resulting in
inadequate brain exposure for the intended
targets in the brain (Pardridge, 2007).
Indeed, the lack of sufficient brain exposure
has contributed to a significant number of
failures in the development of CNS drugs
(Taylor, 2002).
In spite of efforts to develop better and
more predictive animal models, it is clear
that there will always be some uncertainty
in extrapolating pre-clinical animal data to
human. Based on the argument that the best
e xperimental model for human subjects are
humans themselves, Phase zero microdosing
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has been recommended as a safe, efficient
and ethical approach to obtain useful drug
metabolism and pharmacokinetics (PK)
data in human at an early stage of clinical
development (Garner and Lappin, 2006).
Human PET microdosing to
obtain biodistribution and
pharmacokinetics data
drug may not predict the behaviour at clinical
doses. This concern was addressed by the
recent CREAM (Consortium for Resourcing
and Evaluating AMS Microdosing) trial. It was
concluded that the pharmacokinetic (PK)
results obtained from microdosing were
largely predictive (70%) of those obtained
at pharmacological doses (Wilding and Bell,
2005; Lappin and Garner, 2006).
Microdosing refers to the administration
Although both AMS and PET can provide
of a drug candidate in human subjects at
comparable sensitivity in assessing PK of drug
subpharmacological doses to obtain in vivo
candidates in plasma, PET also allows a nonPK data. Microdosing studies are dependent
invasive method to assess the concentrations
on ultrasensitive analytical techniques such
as positron emission tomography (PET; in target and non-target organs, including the
brain (Brooks, 2005; Lee and Farde, 2006).
Lee and Farde, 2006) or accelerator mass
spectrometry (AMS; Lappin and Garner, The utility of PET imaging for PK assessments
may be limited by the relatively short half-life
2003). Both techniques rely on the analysis
of radionuclides incorporated into the test
of common radionuclides (20 min for 11C
14
11
18
compound (eg, C for AMS and C or F for
and 110 min for 18F) as compared to AMS
PET) and both allow the detection of radio­
(5740 years for 14C). The acquisition of PET
-12
tracers in the range of about 10 mol/l. This
derived PK data has thus to be completed
means that sufficient signal can be obtained
within the first few hours following dose
even when the amount of radiolabelled
administration. However, AMS provides
drug administered to a subject is very low
plasma concentration values only whereas
(typically in the low microgram range). A
PET provides drug concentration in organs.
general
concern is that a microdose of a
If it can be demonstrated
the drug
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not distributed at expected level within the
target organ, then the development of the
drug can be stopped without going through
the time and expense of a conventional
clinical trial.
Measuring exposure-response by
PET to assist dose selection
Dose prediction in humans has been
particularly difficult for CNS drugs resulting
in a risk for testing either too low (thus
ineffective) or too high (thus producing
unwanted side effects) doses in initial trials.
In addition, there are examples of inverted
U-shape dose response where the efficacy
of a drug can be lost if the dose is too high.
A powerful approach to assist dose
selection for CNS drugs is to use PET
radioligands suitable for quantitative
study of drug binding to target receptors
in the brain. Here, the drug itself is not
radiolabelled. Instead, the degree at which
a candidate drug inhibits radioligand binding
is determined at pharmacological doses. The
degree of inhibition is commonly referred to
as receptor occupancy. Correlations among
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plasma exposure, receptor occupancy, and
functional changes in pharmacodynamic (PD)
animal models, can then be used to estimate
the likely pharmacological dose in humans
for a candidate drug. In addition, data from
such studies can be used to estimate cost of
goods, optimize formulation and determine
dosing regimen (Brooks, 2005; Lee and
Farde, 2006).
An example is PET imaging of dopamine
D2 receptor occupancy which has been
successfully used to select doses of
antipsychotics that are effective in treating
psychosis without inducing extrapyramidal
side effects. The resulting defined dose range
can then be used in a translational fashion
to measure pharamcodynamic changes (eg,
transmitter release) in animal and human
in vivo (Farde, 1996; Lee and Farde, 2006).
More recently, PET imaging has been used to
invalidate the neurokinin 1 (NK1) receptor
for the treatment of depression. Despite
promising pre-clinical and early clinical
findings, NK1 receptor antagonist aprepitant
was found not to be effective in depressive
patients in Phase III clinical trials in which doses
and dosing intervals were confirmed by PET
imaging to block effectively over 95% of the
CNS NK1 receptors (Bergstrom et al, 2004).
Aprepitant was subsequently terminated
for development as a monotherapy for
depression.
Using PET microdosing to study
pharmacodynamic responses in vivo
PET microdosing can also be used to measure
a drug’s effect on important pharmcodynamic
responses in the brain. For example, the
binding of [11C]MNPA or [11C]Raclopride to
the dopamine D2 receptor has been shown
to be sensitive to the release of endogenous
dopamine in the brains of monkeys or humans
after dosing with amphetamine or nicotine
(Marenco et al., 2004; Seneca et al., 2006).
These PET imaging tools can thus provide
proof of mechanism by the assessment of a
PD response in the primate brain.
Using PET microdosing to study
pathophysiology in neurol ogical
diseases
In recent years, there has been an increasing
interest in the development of PET
radiotracers as biomarkers for disease
pathology in various neurological diseases.
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Particular progress has been made in the
development of amyloid plaque binding PET
tracers for Alzheimer’s disease (Lockhart,
2006). Such approaches offer a plethora
of opportunities for further understanding
of the pathophysiology, early diagnosis of
Alzheimer’s disease as well as stratification
of patients (Small et al, 2006). Importantly,
the technology is non-invasive and allows
for longitudinal studies to follow disease
progression and monitor treatment
responses in patients.
US and European regulatory
initiatives to improve pharma R&D
In the beginning of the 21st century, both
the FDA and the European Agency for the
Evaluation of Medicinal Products (EMEA)
introduced initiatives to facilitate the drug
R&D process. Major initiatives are the
FDA’s Critical Path (2004) and the EMEA’s
medicines legislation and the Road Map to
2010. The main focus of these initiatives is
to support early clinical evaluation of drug
candidates in a safe and efficacious manner
including the use of biomarkers and imaging
tools (Milne, 2006).
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In the European Union (EU) clinical studies
using PET imaging require a Clinical Trial
Application (CTA) and are covered by
a Position Paper on microdosing studies
(Position Paper on non-clinical safety
studies to support clinical trials with a single
microdose, CPMP/SWP/2599/02/Rev 1, June
23, 2004). In the United States (US) PET
studies are covered by the Investigational
New Drug Application (IND) regulations
(21 CFR 312), the exploratory IND (eIND)
guidance (Guidance for Industry, Investigators,
and Reviewers - Exploratory IND Studies,
January 2006), or by the Radioactive Drug
Research Committee (RDRC) regulations
(21 CFR 361.1). No specific guidelines for
microdosing studies have been issued in
Japan. In this article we focus our discussion
on the relevant EU and US guidelines related
to research applications of PET imaging and
provide suggestions on how to further
streamline the process.
Regulatory requirements for PET
imaging
Both the EMEA and the FDA have defined
a “microdose” as less than 1/100th of a
pharmacologically active dose (or predicted
therapeutic dose) as derived from preclinical models and not more than 100
micro-grams (EMEA, 2004; FDA 2006).
Due to the very low doses being studied,
there is reduced regulatory requirement
of pre-clinical safety studies and bulk drug
synthesis (CMC requirements). The studies
and documentation required for conducting
a clinical PET study in EU and in US are
summarized in Tables 1 and 2, respectively
(see pages 7 and 8).
The regulatory requirements to evaluate
a radiolabelled drug at micro-dose con­
centrations are the same for biodistribution
studies and receptor occupancy studies.
However, in the latter case, the use of
unlabelled drugs at pharmacologic doses
requires conduct under applicable IND / CTA
regulations unless otherwise exempted.
The pre-clinical safety studies required
by both regulatory agencies for a Phase
zero microdosing study include: a singledose tox study in one mammalian species
with a two-week observation period. The
choice of tox species has to be justified by
comparative in vitro biological activity (eg,
binding affinity) and metabolism data. In the
tox studies, the drug has to be administered
via the intended clinical route (and include
intravenous administration to satisfy the EU
regulatory guidelines). If the intended route
of clinical administration is intravenous then
this single route of exposure is sufficient for
the toxicology study.
The EU Position Paper allows clinical studies
with a) a single compound or b) a cocktail of
closely related compounds. In either case the
total amount of compounds administered
may not exceed 100 micrograms. The EU
Position Paper does not apply to biologicals
and such products will be considered on a
case-by-case basis.
In US clinical PET-studies, the radiotracers are
viewed either as new drugs requiring an IND
for investigational use (21 CFR 312) OR as
generally recognized as safe and effective when
the radiotracers are administered under the
conditions specified in the Radioactive Drug
Research Committee (RDRC) regulations
(21 CFR 361.1). Potential alternatives to
traditional IND studies are those conducted
to support clinical investigation under an
exploratory IND (eIND). The FDA guidance
(Guidance for Industry, Investigators, and
Reviewers - Exploratory IND Studies, 2006)
describes some approaches consistent with
regulatory requirements, enabling sponsors
to move ahead more efficiently with the
develop­ment of promising candidate products
while maintaining needed human subject
protections (Table 2). Additionally, with regard
to biologicals, the maximum dose for protein
products is defined as ≤30 nanomoles.
In Europe, genotoxicity study is required for
microdosing, although abbreviated versions
are acceptable for compounds belonging
to a chemical class not known to cause
concern in this respect. The exact pre-clinical
toxicity programme should be based on the
known chemical and biological properties.
For compounds within a well-known
pharmacological class of similar chemical
structure, an abridged toxicology package
may be considered. The mutagenicity
package include full or abridged bacterial
reverse mutation test (Ames et al, 1975) to
detect point mutations. It also includes an in
vitro cytogenetic evaluation of chromosomal
damage in mammalian cells (human
peripheral lymphocytes or Chinese hamster
ovary cells) OR a full or abridged in vitro
gene mutation and clastogenic test (mouse
lymphoma assay).
PET micro-dosing studies are typically
done with the administration of 1-2 µg
of the PET radiotracer. A risk assessment
for administration of a potential genotoxic
compound using the Threshold of
Toxicological Concern (TTC) approach
indicates that a TTC value of ~1.5µg/day
over a lifetime could be considered to be
associated with an acceptable cancer risk of 1
in 100,000 to 1 in a million. As a comparison,
the current lifetime risk of developing cancer
is 1 in 4. For short-term exposure, such as
a PET investigation, higher dose limits for
administration may be justified (Guideline
on the limits of genotoxic impurities, EMEA/
CHMP/QWP/251344/2006, June 28, 2006).
For instance, applying the same level of risk as
for lifetime administration, an intake of ~120
µg/day for ≤1 month would be acceptable
(Muller et al, 2006), which is much higher
than the low µg level administered in a PET
microdose study. In the US, no genotoxicity
study is required for PET microdosing.The EU
general requirement for genotoxicity studies
for PET microdosing is currently under
discussion and an EMEA Concept Paper in
2006 suggests potential simplification of the
tox package required for PET microdosing
studies (Concept Paper on the development
of a CHMP guideline on the non-clinical
requirements to support early Phase I clinical
trials with pharmaceutical compounds,
EMEA/CHMP/SWP/91850/2006).
In the US, the Radioactive Drug Research
Committee (RDRC) can permit basic
research using radioactive drugs in human
subjects without an IND when the drug is
administered for basic science research (eg,
metabolism and excretion “mass balance”
and “non-invasive” functional or molecular
imaging) and is done for the purpose of
advancing scientific knowledge as a research
tool (eg, not for therapeutic or diagnostic
purposes and not intended to determine
the safety and effectiveness of a radioactive
drug in humans). For RDRC approval the
pharmacologic dose of the radioactive drug
must be below levels known to cause any
clinically detectable pharmacologic effect in
humans and the radiation exposure justified
Regulatory Rapporteur – June Issue 2007
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by the quality of the study. Examples of
RDRC imaging studies that could meet the
conditions of 361.1 include:
Conclusion
Under the current RDRC rules, there
should be:
Based on the considerably simplified preclinical requirements described in the
Exploratory IND draft guidance and the
EMEA position paper on microdosing, a
microdosing study in human can be done
on the basis of gram quantities, within 4-6
months and with a budget of $0.2-0.4 million
for pre-clinical toxicology and safety testing.
This is in contrast to kilogram quantities,
more than 12 months, and $1-2 million for a
traditional IND / CTA. In addition to the cost
saving, PET microdosing adds value to the
safe and early evaluation of drug candidates
in human subjects and enables rational risk
management and decision-making in the
drug development process.
•No First-in-Human (FIH) administration
References
• Biodistribution
• Pathophysiology (eg, tumour uptake)
• Receptor binding or occupancy
• Transport processes
• Enzyme activity
•Multi-step processes (eg, DNA
synthesis, cellular proliferation,
apoptosis).
of the radiotracer
•
No individual patient decision-making.
A further applicable US guidance is the
“PET Drug Products – Current Good
Manufacturing Practice (CGMP)” which
is available as a draft and relates to the
manufacture and control of PET Drug
Products. Concurrent with the issuance of
this draft guidance the FDA is proposing
CGMP requirements under 21 CFR Part 212.
The proposed regulations and draft guidance
apply to all PET drugs, but draw a distinction
for PET drugs that are produced under
an IND OR with the approval of a RDRC
and used in basic research. The proposed
regulation requires that for investigational
and research PET drugs, CGMP would be
met by producing PET drugs in accordance
with Chapter <823> of the 2004 version
of the United States Pharmacopeia,
"Radiopharmaceuticals for Positron Emission
Tomography–Compounding." Under the
new Phase I CGMP guidance, the FDA has
relaxed the requirements for clinical supplies
for microdosing studies. US researchers (in
academic and industrial labs) will now be
allowed to make smaller amount of drug
candidates and test them in humans. They
can be made according to Good Laboratory
Practices and do not need to be processvalidated.
Ames, B. et al. Methods for detecting
carcinogens and mutagens with the
Salmonella/mammalian-microsome
mutagenicity test. Mutation Research 1975,
31: 347-364.
Bergstrom, M. et al. Human positron emission
tomography studies of brain neurokinin
1 receptor occupancy by aprepitant. Biol.
Psychiatry 2004, 55: 1007-1012.
Brooks, D.J. Positron Emission Tomography
and single-photon emission computed
tomography in central nervous system drug
development. J. Am. Soc. Exp. NeuroTher. 2005;
2: 226-236.
Dimasi, J.A. Risks in new drug development:
approval success rates for investigational
drugs. Clin. Pharmacol. Ther. 2001; 69: 297-307.
EMEA Position Paper from June 23, 2004
(Position Paper on non-clinical safety
studies to support clinical trials with a single
microdose; CPMP/SWP/2599/02/Rev1).
Farde, L. The advantage of using positron
emission tomography in drug research.
Trends in Neuroscience 1996; 19:211-214.
FDA (2004) Innovation or stagnation: challenge
and opportunity on the critical path to new
medical products. http://www.fda.gov/oc/
initiatives/criticalpath/whitepaper.html
Garner, R. C. and Lappin, G. The Phase 0
microdosing concept. Br. J. Clin. Pharmacol.
2006; 61: 367-370.
Lappin, G. and Garner, R.C. Big physics, small
doses: the use of AMS and PET in human
microdosing of development drugs. Nature
Rev Drug Discovery 2003; 2: 151-154.
Lappin, G. and Garner, R.C. A review of
human Phase 0 (microdosing) clinical
trials following the US Food and Drug
Administration exploratory investigational
new drug studies guidance.. Int. J. Pharm. Med
2006; 20: 159-165.
Lee, C.-M. and Farde, L. Using positron
emission tomography to facilitate CNS drug
development. Trends in Pharmacol. Sci. 2006;
27: 310-316.
Lockhart, A. Imaging Alzheimer’s disease
pathology: one target, many ligands. Drug
Discov. Today 2006; 11: 1093-1099.
Marenco, S. et al. Nicotine-induced dopamine
release in primates measured with [11C]
Raclopride PET. Neuropsychopharmcology
2004; 29: 259-268.
Milne, C.-P. US and European regulatory
initiatives to improve R&D performance.
Expert Opin. Drug Discov. 2006; 1: 11-14.
Muller et al. A rationale for determining,
testing and controlling specific impurities
in pharmaceuticals that possess potential
for genotoxicity. Regulatory Toxicology and
Pharmacology 2006; 44: 198-211.
Pardridge, W.M. Blood-brain barrier delivery.
Drug Discovery Today 2007; 12: 54-61.
Seneca, N. et al. Effect of amphetamine on
dopamine D2 receptor binding in nonhuman
primate brain: a comparison of the agonist
radioligand [11C]MNPA and antagonist
[11C]Raclopride. Synapse 2006; 59:260-269.
Small, G.W. et al. Seeing is believing: neuro­
imaging adds to our understanding of cerebral
pathology. Curr. Opin. Psychiatry 2006; 19:
564-569.
Taylor, E.M. The impact of efflux transporters
in the brain on the development of drugs
for CNS disorders. Clin. Pharmacokinet. 2002;
41: 81-92.
Wilding, I.R. and Bell, J.A. Improved early
clinical development through human
microdosing studies. Drug Discov. Today 2005;
10: 890-894.
TOPRA – The Organisation for Professionals in Regulatory Affairs
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Table 1: The EU documentation requirements for conducting a clinical PET study
•An extended single dose toxicology study in one mammalian species.
•The choice of species has to be justified based upon in vitro metabolism and primary pharmacology data.
•Two routes of administration, iv as well as intended clinical route, should be studied. If iv is the intended clinical route, this route
should be sufficient in the toxicology study.
•Preferably both genders should be included in the study.
•The study period should be 14 days with an interim sacrifice on day 2.
•The aim of the study is to establish the dose inducing a minimal toxic effect.
•For compounds of low toxicity a safety factor of 1000 should be used to set the limit dose.
•The study should be designed to obtain information on haematology and clinical chemistry on days 2 and 14 and on
histopathology.
•Information on other organ systems where the compound localises, eg, organs intended to be studied by PET, should be provided.
•If available other information on the compound or closely related compounds should be provided, eg, HERG activity, receptor
binding profile.
•
Local tolerance
•Could be assessed in the extended single dose study. No separate study required.
• In vitro genotoxicity studies should be performed according to ICH guidelines.
• In the extended single dose study and the genotoxicity studies the corresponding stable isotope should be used.
•Non-clinical studies should be performed according to GLP principles.
Regulatory Rapporteur – June Issue 2007
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Table 2: The documentation required for conducting a eIND PET study in US
•
An extended single dose study in one mammalian species.
•The choice of a single mammalian species (both sexes) can be used if justified by in vitro metabolism data and by comparative
data on in vitro pharmacodynamic effects.
•The route of exposure in animals should be by the intended clinical route.
•The study period should be 14 days with an interim sacrifice typically on day 2.
•Endpoints evaluated should include body weights, clinical signs, clinical chemistries, haematology, and histopathology (high dose
and control only if no pathology is seen at the high dose).
•The study should be designed to establish a dose inducing a minimal toxic effect, or alternatively, establishing a margin of safety.
•To establish a margin of safety, the sponsor should demonstrate that a large multiple (eg, 100X) of the proposed human dose
does not induce adverse effects in the experimental animals.
•Scaling from animals to humans based on body surface area can be used to select the dose for use in the clinical trial. Scaling
based on pharmacokinetic/pharmacodynamic modelling would also be appropriate if such data are available.
•Pharmacokinetic/pharmacodynamic modelling would also be appropriate if such data are available.
•
•
No specific requirement for local tolerance.
In vitro genotoxicity and safety pharmacology studies.
•Routine genetic toxicology testing is not required, microdose studies involve only single exposures to microgram quantities of test
materials and because such exposures are comparable to routine environmental exposures.
•For similar reasons, safety pharmacology studies are also not recommended.
•
Non-clinical studies should be performed according to Good Laboratory Practices (GLP) principles. It is expected that all pre-clinical safety
studies supporting the safety of an exploratory IND application will be performed in a manner consistent with GLP (21 CFR Part 58).
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