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Studies 
Microdosing
Dr. Ashutosh Tiwari 
PG Resident (IInd Year) 
Pharmacology 
SAIMS 
04/09/2014
PRESENTATION LAYOUT 
• Introduction 
• Concept of microdosing 
• Basic features & Goals 
• Regulatory guidelines 
• Procedure & Analytical methods 
• Uses of Microdosing 
• Advantages & Limitations 
• Indian scenario 
• Challenges 
• Conclusion
INTRODUCTION 
• Drug development is a long, complex and expensive activity. 
• requires 10-15 years of sustained efforts, and a cost of US $ 500 million 
to $1 billion for a single marketed drug 
• Surveys over the past 10 years have shown that whereas R & D 
expenditure is increasing almost exponentially year on year, the number 
of new molecular entities being registered for marketing is either static or 
declining 
• The situation has become so serious that the FDA published the 
document ‘critical path’, highlighting the problems in drug development 
and encouraging novel approaches to be incorporated into the current 
drug development paradigm 
• The European Medicines Agency (EMEA), published a position paper on 
the non-clinical safety studies needed to support human clinical trials 
with a single dose of a pharmacologically active compound using the 
microdose technique
INTRODUCTION
INTRODUCTION 
• Nearly one-third of the investigational new drugs (INDs) fail in the phase- 
1 trials, many due to PK / PD, safety or efficacy issues 
• Too low concentrations of drug at the target organ for lesser time can 
lead to efficacy failures, 
• Wrong concentrations reaching wrong targets for longer time may lead to 
toxicity. 
• Toxicity failures in animals may be through metabolic routes or pathways 
that do not occur in humans. 
• Horrobin questioned the value of animals in drug development, stating 
that too much focus was being placed on animal models that may not 
mirror what happens in humans 
• Horrobin DF. Modern biomedical research: an internally self- consistent universe with little 
contact with medical reality? Nature Rev Drug Discovery 2003; 2: 151–4.
INTRODUCTION 
• The latest estimate from the Tufts Center for the Study of 
Drug Development is that it costs up to $15 million and 
takes 18 months to get a molecule through Phase I. 
• If the development programme were to be terminated at this 
stage, then the human volunteers would have been un-necessarily 
exposed to a failed drug and large numbers of 
animals would have been used 
• Thus, a new experimental approach has been developed, 
known as Phase 0 or microdosing studies, to address 
issues pertaining to drug metabolism and 
pharmacokinetics. 
• It offers a way of developing drugs in a faster, more cost-effective 
and ethical way than ever before
THE CONCEPT 
• The principle of human microdosing is that of safely 
administering sub-pharmacological amounts (microdoses) 
of NCEs and NMEs to humans to gain valuable 
information on human pharmacokinetics, 
pharmacodynamics & metabolism at a much earlier stage 
• Central to this approach is the concept that – 
“the best model for man is man”
THE CONCEPT 
• Since such low doses are unlikely to have any 
pharmacodynamic effects and would be too small to cause any 
major side effects after a single dose, it should be possible to 
undertake such studies in humans without having to complete 
the whole range of classical toxicology studies at therapeutically 
effective doses that are mandated prior to regular Phase 1 trials. 
• By using only a very tiny amount of active substance, one can 
establish the likely pharmacological dose and thereby determine 
the first dose for the subsequent Phase I study.
What is a Phase 0 trial?
PHASE 0 / MICRODOSING STUDTY 
• Because human microdosing studies are performed prior to 
Phase I, they have come to known as Phase 0 studies 
• (although the regulatory authorities never adopted the 
terminology and prefer to call them exploratory clinical trials) 
• Whilst other methods of pharmacokinetic prediction rely on 
extrapolation of data from in vitro, in silico or animal models, 
micro- dosing obtains data directly from the target species - that 
is human.
PHASE 0 / MICRODOSING STUDTY 
• In a human microdose study a sub-pharmacologically active 
dose of drug is administered and samples (typically plasma) are 
collected and analysed for parent drug or metabolites. 
• Since the very small doses administered are of low toxicological 
risk, regulatory agencies allow a microdose to be administered 
to human subjects based upon a reduced safety package 
compared to that required for a full Phase I clinical trial 
• (that is with no genotoxicology investigations and a single- dose 
rodent toxicology study).
BASIC FEATURES OF PHASE 0 TRIALS 
• First-in-human trial conducted prior to traditional 
Phase 1 study 
• Small number of subjects (≈10-15) 
• Limited drug exposure 
• Low, non-toxic doses 
• Short duration (≈ ≤7 days) 
• One course only 
• No therapeutic intent (clinical benefit) 
• Phase 0 trials are not definitive studies (further 
studies are required)
VARIOUS GOALS OF PHASE 0 TRIAL 
14 
• Provide human PK-PD relationship data prior to 
definitive Phase 1 testing 
• Evaluate human PK (e.g., bioavailability) to select 
most promising candidate for further development 
• Eliminating “bad” agents early in clinical development 
because of poor PD or PK properties 
• e.g., lack of target effect, poor bioavail., very rapid clearance 
“Fail fast, fail early”
Conventional vs Microdosing study 
Extrapolation from animal or in vitro to human via 
often complex mathematical models 
Traditional models 
human to human directly reflecting PK 
Microdose
CONVENTIONAL VS MICRODOSING STUDY 
Variable Phase 1 Trial Phase 0 Trial 
Preclinical 
toxicology study 
Full IND-directed 
Less required; 
sufficient to support 
ExpIND 
Regulatory 
requirements 
established firmly very few & limited 
Primary objective & 
dose-escalation 
scheme 
Establish dose-limiting 
toxicities and MTD 
(maximal tolerable dose) 
Establish a dose-range 
that modulates 
target, for use in 
subsequent Phase 1 
trials
MICRODOSING VS CONVENTIONAL STUDY 
Variable Phase 1 Trial Phase 0 Trial 
Duration of dosing 
Repetitive; multiple 
cycles until disease 
progression or 
unacceptable toxicity 
Limited dosing (e.g., 
1-7 days); one cycle 
only 
Evaluation for 
therapeutic benefit 
Yes No 
PK/PD analysis 
Samples usually 
batched and analyzed at 
a later time point, 
generally after 
completion of the trial 
Performed in “real-time”
MICRODOSING VS CONVENTIONAL STUDY 
Variable Phase 1 Trial Phase 0 Trial 
Special 
requirements 
None 
Radiolabelled 
compound 
Amount of drug 
required 
about 100 gm less than 100 μg 
Time from 
preclinical to first in 
human studies 
12-18 months 6-8 months 
Cost of early phase 
drug development 
US$ 1.5-5 million US $ 0.3-0.5 million
THE ETHICAL DIMENSION 
• Central to the whole debate about human microdosing is the 
question of ethics 
• Is it right to expose healthy volunteers to an NCE at the 
Phase I stage with only animal and in vitro data to support 
the dose administered? 
• If we have the ability to reduce the failure rate of drug 
candidates at Phase I for PK / PD reasons, shouldn’t we be 
doing it? 
• Conversely, how many perfectly good ‘druggable’ candidates 
have been thrown out due to inappropriate animal results 
which may have been ‘saved’ by human microdosing?
HISTORY 
• The concept of microdosing first appeared in the late 1990s as a 
method of assessing human pharmacokinetics prior to full 
Phase I clinical trials and the first data appeared in the literature 
in 2003 
• Garner RC. Accelerator mass spectrometry in 
pharmaceutical research and development-a new 
ultrasensitive analytical method for isotope measurement. 
Curr Drug Metab 2000;1(2):205-13 
• Lappin G, Garner RC. Big physics, small doses: the use of 
AMS and PET in human microdosing of development drugs. 
Nat Rev Drug Discov 2003;2(3):233-40
MICRODOSING & REGULATORY GUIDELINES 
• Position paper from the European Medicines Agency in 2004 
• EMEA Position Paper on Non-clinical Safety Studies to Support 
Clinical Trials with a Single Microdose. CPMP/SWP/ 23. 2599; 
2004 
• Guidelines from the FDA in 2006 
• Food and Drug Administration US Department of Health and 
Human Services Guidance for Industry Investigators and 
Reviewers. Exploratory 24. IND Studies (January 2006) 
• Guidelines from The Ministry of Health, Labor and Welfare, Japan in 
2008 
• ICH international guideline in 2009 
• ICH Topic M3 Note for Guidance on non-clinical safety 
pharmacology studies for human pharmaceuticals CPMP/ICH/ 
286/95; 2009
MICRODOSING & REGULATORY GUIDELINES 
• There are similarities and differences in the regulations governing 
microdosing currently in place in the European Union and in the United 
States. 
• While both guidances define a microdose in a similar manner, the US 
FDA guidance, published later, permits repeated doses for up to 7 days. 
• Both require one toxicology study in a single mammalian species at 
multiple dose levels, with the highest dose inducing minimal toxic effects. 
• But the EMEA guidance requires the use of the IV route in addition to the 
intended route of administration, a separate genotoxicity study, and a 
1000x safety margin if no toxic effects are elicited with the highest doses, 
while the FDA guidance requires only one route of administration and a 
100x safety margin. 
• Overall, the US regulation is more flexible, allowing more innovative use 
of the microdosing tool.
MICRODOSING & REGULATORY GUIDELINES 
Microdosing Definition – 
• A microdose is defined in all of these regulatory documents as being a dose 
of drug that is 1% (1/100th )of the pharmacologically active dose determined 
from animal models and in vitro systems, up to a maximum of 100 μg. 
• The microdose of drug defined by the USFDA is analogous to that defined by 
EMEA. In addition, it states an upper dose limit of 30 nanomol for protein 
products. 
• The latest ICH M3 guideline, now universally accepted, allows a microdose 
to be administered to human subjects based on a single-dose toxicity study 
(usually in the rat), followed by 14 days observation, using the intended route 
of administration (or via the intravenous route), plus some in vitro target 
receptor data.
MICRODOSING PROCEDURE 
• a minimal toxicology package is 
required prior to a microdose study 
and hence only laboratory-scale 
quantities of drug substance are 
required 
• A microdose is typically administered 
to four to six healthy male subjects 
(although female subjects have been 
used) 
• followed by the collection of plasma 
and sometimes excreta or biopsy 
samples over time 
• The samples are analysed for target 
analytes such as parent drug or 
metabolites to ascertain the 
pharmacokinetic profile.
ANALYTICAL METHODS 
• The low dose administered in a human microdose study will lead to 
low plasma-drug concentrations 
• therefore sensitive analytical technologies are necessary in order to 
make the requisite measurements over an appropriate time. 
• Microdosing is dependent on the availability of ultrasensitive analytical 
methods able to measure drug and metabolite concentrations in the 
low picogram to femotgram range. 
• These include accelerator mass spectrometry (AMS) and positron 
emission tomography (PET) 
• Both these techniques rely on the assessment and analysis of the 
radio isotopes incorporated into the drug under study.
ANALYTICAL METHODS 
• In the case of AMS, [14C] is the most useful isotope for drug 
metabolism studies whereas for PET [11C] is proving to be the 
most useful. 
• AMS is used for determining PK data by taking body samples 
over time, processing the samples in the laboratory and then 
analysing their drug content. 
• PET provides primarily PD data through real-time imaging and 
some limited PK data.
FLOW DIAGRAM OF MICRODOSE PROCEDURES
EXPLORATORY PHARMACOKINETIC DATA 
• There are 44 drugs where the data are in the peered reviewed 
literature comparing microdose PK to therapeutic dose PK data: 
• Oral (34) and IV (11) routes of administration 
• Of the oral drugs, 82% were scalable 
• Of the IV drugs, 100% were scalable 
• Reasons for non-linearity with oral dose 
• Target mediated disposition 
• Saturability of enzyme and transporter systems 
• In order for pharmacokinetic prediction to improve, it is important to 
understand the underlying mechanisms responsible for non-linearity 
with oral dose
EXPLORATORY PHARMACOKINETIC DATA 
• Target mediated disposition 
• plasma concentrations decrease rapidly as the drug attaches to its 
binding site 
• At higher doses, as the binding site becomes saturated, then the 
plasma concentrations are proportionally higher and the rapid 
decrease in concentration at the early time points is no longer 
observed 
• seen with warfarin, monoclonal antibodies 
• Saturability of enzyme and transporter systems 
• seen in case of Propafenone, where bioavailability increases 
disproportionally to dose, as CYP2D6 become saturated as the 
dose increases, thereby reducing the effect of first -pass 
metabolism
PRINCIPAL PUBLISHED HUMAN MICRODOSE TRIALS 
• CREAM (Consortium for Resourcing and Evaluating AMS Microdosing) 
• Lappin et al (2006) Clin Pharmacol Ther 80, 203-215 
• EUMAPP (European Union Microdose AMS Partnership Programme) 
• Lappin, et al (2010) Eur J Pharm Sci 40, 125–131 
• Lappin et al (2011) Eur J Pharm Sci 43, 141-150 
• NEDO (New Energy and Industrial Technology Development Organization) 
Microdosing project, Japan 
• Yamane et al 2009 Drug Metab Pharmacokinet 2009; 24(4): 389- 
403. 
• Tozuka et al 2010, Clin Pharmacol Ther 2010; 88(6): 824-30. 
• Yamazaki et al (2010), J Clin Pharm Ther 2010; 35(2): 169-75.
EMERGING USES OF MICRODOSING 
• Although the emphasis has been on pharmacokinetic prediction, 
there are other applications of microdosing that are emerging 
• Microdosing has also been applied to the study of 
• drug-drug interactions 
• measuring drug concentrations at the site of action 
• metabolic profiling 
• study in vulnerable populations
EMERGING USES OF MICRODOSING 
• Drug-drug interactions: 
• The pharmacokinetics of a development drug administered as 
a microdose before and after administration of 
pharmacological active doses of a suitable inducer or inhibitor 
of a chosen enzyme or transporter is compared. 
• Measuring drug concentrations at the site of action 
• A drug that exhibits an appropriate concentration at its site of 
action for a required period of time, but is also present off - 
target (e.g., in the plasma) to only a limited extent, will stand 
the best chance of having the necessary balance between 
high efficacy and low toxicity
EMERGING USES OF MICRODOSING 
• Metabolic profiling 
• To obtain preliminary data on the metabolism of a candidate, drug 
samples from microdose studies have been metabolically profiled. 
• Study in Vulnerable populations 
• The inherent toxicological low risk of a microdose allows 
pharmacokinetic studies to be performed in vulnerable populations 
(children, pregnant women, elderly, hepatically and renally 
impaired), who are routinely excluded from clinical trials due to 
safety concerns.
MICRODOSING STUDIES: ADVANTAGES 
• help in the early selection of promising compounds for further 
development before the traditional phase-1 trials 
• help in overall acceleration in the process of drug development by 
focusing only on the promising compounds 
• avoid unnecessary exposure of the participants in the trial to the 
not so promising compounds 
• the not so promising molecules can be eliminated earlier, thereby 
saving costs
MICRODOSING STUDIES: ADVANTAGES 
• pose less risk of human toxicity owing to the low dose of the test substance, 
less duration of administration/ exposure to the drug and very limited number of 
subjects involved 
• such trials mostly involve a single dose administration as compared to a dose 
escalation study in the traditional phase-1 trials, thereby further minimizing the 
risk 
• lesser pre- clinical safety package is required as compared to the traditional 
phase-1 studies 
• less number of animals is used 
• small quantity of the test drug is required; the test drug may be prepared as per 
the principles of the Good Laboratory Practices (GLP) unlike Good 
Manufacturing Practices (GMP) compliance as required for the traditional 
phase-1 studies
MICRODOSING STUDIES: ADVANTAGES 
• the drug can be tested in the sensitive population like patients with 
renal impairment, women in their reproductive age, cancer 
patients, etc, 
• helpful in establishing the likely pharmacological dose and thereby 
determining the first dose for the subsequent phase-1 study 
• the PK data for initial dose selection can be obtained in nearly six 
months as compared to nearly 18 months in case of conventional 
phase-1 studies 
• the overall cost of conducting a microdose study (US$ 0.3 – 0.5 
million) is far less as compared to that of a conventional phase-I 
study (US$ 1.5 -3 million)
MICRODOSING STUDIES: LIMITATIONS 
• We still do not have enough studies to clearly exemplify whether the body's 
reaction to a particular compound is similar, when used as microdose and in its 
pharmacological dose; 
• it could lead to false negatives (compound being rejected) or 
• false positives (compound acceptable based on microdose data but rejected 
subsequently when used in pharmacological doses). 
• caution needs to be exercised while applying this methodology to 
the drugs showing complex/non-linear kinetics 
• since certain drugs dissolve readily at low doses but exhibit limited 
solubility at higher doses, it may be difficult to predict the 
absorption characteristics at the microdose levels
MICRODOSING STUDIES: LIMITATIONS 
• there is lack of any therapeutic and/or diagnostic intent 
• as there is no therapeutic intent, it may be difficult to motivate 
the volunteers to become a part of the trial 
• there is requirement of ultra sensitive and high tech equipments 
like AMS and PET which are scarcely available 
• For both PET and AMS, drugs must be labelled at metabolically 
stable sites. 
• The database for microdosing studies is very small
STATUS IN INDIA: CURRENT STATUS 
• In 200708 the Indian Society for Clinical Research (ISCR) 
proposed a change in regulation that would allow the regulators to 
recognize and permit microdosing studies in India. 
• The Drugs Technical Advisory Board unanimously approved the 
proposal together with other farreaching amendments in 
regulation. 
• The proposals were, nevertheless, disregarded by the government 
due to nontechnical sensitivities that surround clinical research and 
drug development in India. 
• Since then, regulatory reform in drug development science has 
stagnated.
STATUS IN INDIA: FUTURE 
• Regulatory change enabling Phase 1 and microdosing studies 
would open the door to the science of early clinical development, 
setting the stage for rapid growth and scientific advancement in 
pharmaceutical development in the country 
• this could bring India into the mainstream of pharmaceutical 
research and laying the foundation for a possible central role for 
the country in global drug development
MICRODOSING STUDIES: CHALLENGES 
• there seems to be scientific inertia & length of time required to get 
new approaches adopted 
• failure to recognize the potential benefits of microdose studies 
• human microdosing is a promising strategy and despite several 
obstacles in terms of infrastructure, existing regulations and ethical 
challenges, the issue is worth considering. 
• There is a need for scientifically validating microdosing studies in 
the field of drug development with an aim of benefiting the 
patients, the animals, the pharmaceutical industry and the mankind 
as a whole.
CONCLUSION 
• Human microdosing holds significant promise as an analytical tool. 
• Microdosing may help both patients and the pharmaceutical industry with 
earlier availability of new test medication and reduced attrition of 
compounds at later stages of drug development. 
• Microdosing allows not only selection of drug candidates more likely to 
be developed successfully, but also helps in determination of the first 
dose for the subsequent Phase I clinical studies. 
• In the coming years, as research methods and technology involved in 
Phase 0 trials become more sophisticated microdosing is likely to 
become an accepted approach in drug development so that eventually all 
first in human studies will commence with a Phase 0 study.
“the difficulty lies not in the new ideas, 
but escaping from the old ones” 
- John Meynard Keynes

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Microdosing (Phase 0) studies

  • 2. Dr. Ashutosh Tiwari PG Resident (IInd Year) Pharmacology SAIMS 04/09/2014
  • 3. PRESENTATION LAYOUT • Introduction • Concept of microdosing • Basic features & Goals • Regulatory guidelines • Procedure & Analytical methods • Uses of Microdosing • Advantages & Limitations • Indian scenario • Challenges • Conclusion
  • 4. INTRODUCTION • Drug development is a long, complex and expensive activity. • requires 10-15 years of sustained efforts, and a cost of US $ 500 million to $1 billion for a single marketed drug • Surveys over the past 10 years have shown that whereas R & D expenditure is increasing almost exponentially year on year, the number of new molecular entities being registered for marketing is either static or declining • The situation has become so serious that the FDA published the document ‘critical path’, highlighting the problems in drug development and encouraging novel approaches to be incorporated into the current drug development paradigm • The European Medicines Agency (EMEA), published a position paper on the non-clinical safety studies needed to support human clinical trials with a single dose of a pharmacologically active compound using the microdose technique
  • 6. INTRODUCTION • Nearly one-third of the investigational new drugs (INDs) fail in the phase- 1 trials, many due to PK / PD, safety or efficacy issues • Too low concentrations of drug at the target organ for lesser time can lead to efficacy failures, • Wrong concentrations reaching wrong targets for longer time may lead to toxicity. • Toxicity failures in animals may be through metabolic routes or pathways that do not occur in humans. • Horrobin questioned the value of animals in drug development, stating that too much focus was being placed on animal models that may not mirror what happens in humans • Horrobin DF. Modern biomedical research: an internally self- consistent universe with little contact with medical reality? Nature Rev Drug Discovery 2003; 2: 151–4.
  • 7. INTRODUCTION • The latest estimate from the Tufts Center for the Study of Drug Development is that it costs up to $15 million and takes 18 months to get a molecule through Phase I. • If the development programme were to be terminated at this stage, then the human volunteers would have been un-necessarily exposed to a failed drug and large numbers of animals would have been used • Thus, a new experimental approach has been developed, known as Phase 0 or microdosing studies, to address issues pertaining to drug metabolism and pharmacokinetics. • It offers a way of developing drugs in a faster, more cost-effective and ethical way than ever before
  • 8. THE CONCEPT • The principle of human microdosing is that of safely administering sub-pharmacological amounts (microdoses) of NCEs and NMEs to humans to gain valuable information on human pharmacokinetics, pharmacodynamics & metabolism at a much earlier stage • Central to this approach is the concept that – “the best model for man is man”
  • 9. THE CONCEPT • Since such low doses are unlikely to have any pharmacodynamic effects and would be too small to cause any major side effects after a single dose, it should be possible to undertake such studies in humans without having to complete the whole range of classical toxicology studies at therapeutically effective doses that are mandated prior to regular Phase 1 trials. • By using only a very tiny amount of active substance, one can establish the likely pharmacological dose and thereby determine the first dose for the subsequent Phase I study.
  • 10. What is a Phase 0 trial?
  • 11. PHASE 0 / MICRODOSING STUDTY • Because human microdosing studies are performed prior to Phase I, they have come to known as Phase 0 studies • (although the regulatory authorities never adopted the terminology and prefer to call them exploratory clinical trials) • Whilst other methods of pharmacokinetic prediction rely on extrapolation of data from in vitro, in silico or animal models, micro- dosing obtains data directly from the target species - that is human.
  • 12. PHASE 0 / MICRODOSING STUDTY • In a human microdose study a sub-pharmacologically active dose of drug is administered and samples (typically plasma) are collected and analysed for parent drug or metabolites. • Since the very small doses administered are of low toxicological risk, regulatory agencies allow a microdose to be administered to human subjects based upon a reduced safety package compared to that required for a full Phase I clinical trial • (that is with no genotoxicology investigations and a single- dose rodent toxicology study).
  • 13. BASIC FEATURES OF PHASE 0 TRIALS • First-in-human trial conducted prior to traditional Phase 1 study • Small number of subjects (≈10-15) • Limited drug exposure • Low, non-toxic doses • Short duration (≈ ≤7 days) • One course only • No therapeutic intent (clinical benefit) • Phase 0 trials are not definitive studies (further studies are required)
  • 14. VARIOUS GOALS OF PHASE 0 TRIAL 14 • Provide human PK-PD relationship data prior to definitive Phase 1 testing • Evaluate human PK (e.g., bioavailability) to select most promising candidate for further development • Eliminating “bad” agents early in clinical development because of poor PD or PK properties • e.g., lack of target effect, poor bioavail., very rapid clearance “Fail fast, fail early”
  • 15. Conventional vs Microdosing study Extrapolation from animal or in vitro to human via often complex mathematical models Traditional models human to human directly reflecting PK Microdose
  • 16. CONVENTIONAL VS MICRODOSING STUDY Variable Phase 1 Trial Phase 0 Trial Preclinical toxicology study Full IND-directed Less required; sufficient to support ExpIND Regulatory requirements established firmly very few & limited Primary objective & dose-escalation scheme Establish dose-limiting toxicities and MTD (maximal tolerable dose) Establish a dose-range that modulates target, for use in subsequent Phase 1 trials
  • 17. MICRODOSING VS CONVENTIONAL STUDY Variable Phase 1 Trial Phase 0 Trial Duration of dosing Repetitive; multiple cycles until disease progression or unacceptable toxicity Limited dosing (e.g., 1-7 days); one cycle only Evaluation for therapeutic benefit Yes No PK/PD analysis Samples usually batched and analyzed at a later time point, generally after completion of the trial Performed in “real-time”
  • 18. MICRODOSING VS CONVENTIONAL STUDY Variable Phase 1 Trial Phase 0 Trial Special requirements None Radiolabelled compound Amount of drug required about 100 gm less than 100 μg Time from preclinical to first in human studies 12-18 months 6-8 months Cost of early phase drug development US$ 1.5-5 million US $ 0.3-0.5 million
  • 19. THE ETHICAL DIMENSION • Central to the whole debate about human microdosing is the question of ethics • Is it right to expose healthy volunteers to an NCE at the Phase I stage with only animal and in vitro data to support the dose administered? • If we have the ability to reduce the failure rate of drug candidates at Phase I for PK / PD reasons, shouldn’t we be doing it? • Conversely, how many perfectly good ‘druggable’ candidates have been thrown out due to inappropriate animal results which may have been ‘saved’ by human microdosing?
  • 20. HISTORY • The concept of microdosing first appeared in the late 1990s as a method of assessing human pharmacokinetics prior to full Phase I clinical trials and the first data appeared in the literature in 2003 • Garner RC. Accelerator mass spectrometry in pharmaceutical research and development-a new ultrasensitive analytical method for isotope measurement. Curr Drug Metab 2000;1(2):205-13 • Lappin G, Garner RC. Big physics, small doses: the use of AMS and PET in human microdosing of development drugs. Nat Rev Drug Discov 2003;2(3):233-40
  • 21. MICRODOSING & REGULATORY GUIDELINES • Position paper from the European Medicines Agency in 2004 • EMEA Position Paper on Non-clinical Safety Studies to Support Clinical Trials with a Single Microdose. CPMP/SWP/ 23. 2599; 2004 • Guidelines from the FDA in 2006 • Food and Drug Administration US Department of Health and Human Services Guidance for Industry Investigators and Reviewers. Exploratory 24. IND Studies (January 2006) • Guidelines from The Ministry of Health, Labor and Welfare, Japan in 2008 • ICH international guideline in 2009 • ICH Topic M3 Note for Guidance on non-clinical safety pharmacology studies for human pharmaceuticals CPMP/ICH/ 286/95; 2009
  • 22. MICRODOSING & REGULATORY GUIDELINES • There are similarities and differences in the regulations governing microdosing currently in place in the European Union and in the United States. • While both guidances define a microdose in a similar manner, the US FDA guidance, published later, permits repeated doses for up to 7 days. • Both require one toxicology study in a single mammalian species at multiple dose levels, with the highest dose inducing minimal toxic effects. • But the EMEA guidance requires the use of the IV route in addition to the intended route of administration, a separate genotoxicity study, and a 1000x safety margin if no toxic effects are elicited with the highest doses, while the FDA guidance requires only one route of administration and a 100x safety margin. • Overall, the US regulation is more flexible, allowing more innovative use of the microdosing tool.
  • 23. MICRODOSING & REGULATORY GUIDELINES Microdosing Definition – • A microdose is defined in all of these regulatory documents as being a dose of drug that is 1% (1/100th )of the pharmacologically active dose determined from animal models and in vitro systems, up to a maximum of 100 μg. • The microdose of drug defined by the USFDA is analogous to that defined by EMEA. In addition, it states an upper dose limit of 30 nanomol for protein products. • The latest ICH M3 guideline, now universally accepted, allows a microdose to be administered to human subjects based on a single-dose toxicity study (usually in the rat), followed by 14 days observation, using the intended route of administration (or via the intravenous route), plus some in vitro target receptor data.
  • 24. MICRODOSING PROCEDURE • a minimal toxicology package is required prior to a microdose study and hence only laboratory-scale quantities of drug substance are required • A microdose is typically administered to four to six healthy male subjects (although female subjects have been used) • followed by the collection of plasma and sometimes excreta or biopsy samples over time • The samples are analysed for target analytes such as parent drug or metabolites to ascertain the pharmacokinetic profile.
  • 25. ANALYTICAL METHODS • The low dose administered in a human microdose study will lead to low plasma-drug concentrations • therefore sensitive analytical technologies are necessary in order to make the requisite measurements over an appropriate time. • Microdosing is dependent on the availability of ultrasensitive analytical methods able to measure drug and metabolite concentrations in the low picogram to femotgram range. • These include accelerator mass spectrometry (AMS) and positron emission tomography (PET) • Both these techniques rely on the assessment and analysis of the radio isotopes incorporated into the drug under study.
  • 26. ANALYTICAL METHODS • In the case of AMS, [14C] is the most useful isotope for drug metabolism studies whereas for PET [11C] is proving to be the most useful. • AMS is used for determining PK data by taking body samples over time, processing the samples in the laboratory and then analysing their drug content. • PET provides primarily PD data through real-time imaging and some limited PK data.
  • 27. FLOW DIAGRAM OF MICRODOSE PROCEDURES
  • 28. EXPLORATORY PHARMACOKINETIC DATA • There are 44 drugs where the data are in the peered reviewed literature comparing microdose PK to therapeutic dose PK data: • Oral (34) and IV (11) routes of administration • Of the oral drugs, 82% were scalable • Of the IV drugs, 100% were scalable • Reasons for non-linearity with oral dose • Target mediated disposition • Saturability of enzyme and transporter systems • In order for pharmacokinetic prediction to improve, it is important to understand the underlying mechanisms responsible for non-linearity with oral dose
  • 29. EXPLORATORY PHARMACOKINETIC DATA • Target mediated disposition • plasma concentrations decrease rapidly as the drug attaches to its binding site • At higher doses, as the binding site becomes saturated, then the plasma concentrations are proportionally higher and the rapid decrease in concentration at the early time points is no longer observed • seen with warfarin, monoclonal antibodies • Saturability of enzyme and transporter systems • seen in case of Propafenone, where bioavailability increases disproportionally to dose, as CYP2D6 become saturated as the dose increases, thereby reducing the effect of first -pass metabolism
  • 30. PRINCIPAL PUBLISHED HUMAN MICRODOSE TRIALS • CREAM (Consortium for Resourcing and Evaluating AMS Microdosing) • Lappin et al (2006) Clin Pharmacol Ther 80, 203-215 • EUMAPP (European Union Microdose AMS Partnership Programme) • Lappin, et al (2010) Eur J Pharm Sci 40, 125–131 • Lappin et al (2011) Eur J Pharm Sci 43, 141-150 • NEDO (New Energy and Industrial Technology Development Organization) Microdosing project, Japan • Yamane et al 2009 Drug Metab Pharmacokinet 2009; 24(4): 389- 403. • Tozuka et al 2010, Clin Pharmacol Ther 2010; 88(6): 824-30. • Yamazaki et al (2010), J Clin Pharm Ther 2010; 35(2): 169-75.
  • 31. EMERGING USES OF MICRODOSING • Although the emphasis has been on pharmacokinetic prediction, there are other applications of microdosing that are emerging • Microdosing has also been applied to the study of • drug-drug interactions • measuring drug concentrations at the site of action • metabolic profiling • study in vulnerable populations
  • 32. EMERGING USES OF MICRODOSING • Drug-drug interactions: • The pharmacokinetics of a development drug administered as a microdose before and after administration of pharmacological active doses of a suitable inducer or inhibitor of a chosen enzyme or transporter is compared. • Measuring drug concentrations at the site of action • A drug that exhibits an appropriate concentration at its site of action for a required period of time, but is also present off - target (e.g., in the plasma) to only a limited extent, will stand the best chance of having the necessary balance between high efficacy and low toxicity
  • 33. EMERGING USES OF MICRODOSING • Metabolic profiling • To obtain preliminary data on the metabolism of a candidate, drug samples from microdose studies have been metabolically profiled. • Study in Vulnerable populations • The inherent toxicological low risk of a microdose allows pharmacokinetic studies to be performed in vulnerable populations (children, pregnant women, elderly, hepatically and renally impaired), who are routinely excluded from clinical trials due to safety concerns.
  • 34. MICRODOSING STUDIES: ADVANTAGES • help in the early selection of promising compounds for further development before the traditional phase-1 trials • help in overall acceleration in the process of drug development by focusing only on the promising compounds • avoid unnecessary exposure of the participants in the trial to the not so promising compounds • the not so promising molecules can be eliminated earlier, thereby saving costs
  • 35. MICRODOSING STUDIES: ADVANTAGES • pose less risk of human toxicity owing to the low dose of the test substance, less duration of administration/ exposure to the drug and very limited number of subjects involved • such trials mostly involve a single dose administration as compared to a dose escalation study in the traditional phase-1 trials, thereby further minimizing the risk • lesser pre- clinical safety package is required as compared to the traditional phase-1 studies • less number of animals is used • small quantity of the test drug is required; the test drug may be prepared as per the principles of the Good Laboratory Practices (GLP) unlike Good Manufacturing Practices (GMP) compliance as required for the traditional phase-1 studies
  • 36. MICRODOSING STUDIES: ADVANTAGES • the drug can be tested in the sensitive population like patients with renal impairment, women in their reproductive age, cancer patients, etc, • helpful in establishing the likely pharmacological dose and thereby determining the first dose for the subsequent phase-1 study • the PK data for initial dose selection can be obtained in nearly six months as compared to nearly 18 months in case of conventional phase-1 studies • the overall cost of conducting a microdose study (US$ 0.3 – 0.5 million) is far less as compared to that of a conventional phase-I study (US$ 1.5 -3 million)
  • 37. MICRODOSING STUDIES: LIMITATIONS • We still do not have enough studies to clearly exemplify whether the body's reaction to a particular compound is similar, when used as microdose and in its pharmacological dose; • it could lead to false negatives (compound being rejected) or • false positives (compound acceptable based on microdose data but rejected subsequently when used in pharmacological doses). • caution needs to be exercised while applying this methodology to the drugs showing complex/non-linear kinetics • since certain drugs dissolve readily at low doses but exhibit limited solubility at higher doses, it may be difficult to predict the absorption characteristics at the microdose levels
  • 38. MICRODOSING STUDIES: LIMITATIONS • there is lack of any therapeutic and/or diagnostic intent • as there is no therapeutic intent, it may be difficult to motivate the volunteers to become a part of the trial • there is requirement of ultra sensitive and high tech equipments like AMS and PET which are scarcely available • For both PET and AMS, drugs must be labelled at metabolically stable sites. • The database for microdosing studies is very small
  • 39. STATUS IN INDIA: CURRENT STATUS • In 200708 the Indian Society for Clinical Research (ISCR) proposed a change in regulation that would allow the regulators to recognize and permit microdosing studies in India. • The Drugs Technical Advisory Board unanimously approved the proposal together with other farreaching amendments in regulation. • The proposals were, nevertheless, disregarded by the government due to nontechnical sensitivities that surround clinical research and drug development in India. • Since then, regulatory reform in drug development science has stagnated.
  • 40. STATUS IN INDIA: FUTURE • Regulatory change enabling Phase 1 and microdosing studies would open the door to the science of early clinical development, setting the stage for rapid growth and scientific advancement in pharmaceutical development in the country • this could bring India into the mainstream of pharmaceutical research and laying the foundation for a possible central role for the country in global drug development
  • 41. MICRODOSING STUDIES: CHALLENGES • there seems to be scientific inertia & length of time required to get new approaches adopted • failure to recognize the potential benefits of microdose studies • human microdosing is a promising strategy and despite several obstacles in terms of infrastructure, existing regulations and ethical challenges, the issue is worth considering. • There is a need for scientifically validating microdosing studies in the field of drug development with an aim of benefiting the patients, the animals, the pharmaceutical industry and the mankind as a whole.
  • 42. CONCLUSION • Human microdosing holds significant promise as an analytical tool. • Microdosing may help both patients and the pharmaceutical industry with earlier availability of new test medication and reduced attrition of compounds at later stages of drug development. • Microdosing allows not only selection of drug candidates more likely to be developed successfully, but also helps in determination of the first dose for the subsequent Phase I clinical studies. • In the coming years, as research methods and technology involved in Phase 0 trials become more sophisticated microdosing is likely to become an accepted approach in drug development so that eventually all first in human studies will commence with a Phase 0 study.
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  • 44. “the difficulty lies not in the new ideas, but escaping from the old ones” - John Meynard Keynes