Starting at phase zero

Michael Butler looks at the value a microdose study adds to a drug development programme.

What is a microdose study?
Michael Butler. A microdose study is a human clinical study that is typically conducted very early in the development of a new drug and which is defined by the dose administered. Microdose studies are ideally conducted just before or in parallel with preclinical and CMC development. A well-designed microdose study will yield PK and ADME data on a promising drug lead or candidate series. Because of their role in very early clinical development, microdose studies are also known as phase 0 clinical studies.

What is the regulatory environment for microdose studies?
MB. As part of the FDA’s Critical Path Initiative to streamline drug development and improve the understanding of drugs early in the clinical process, the Agency has produced guidance on ‘Exploratory Investigational New Drug Studies’. Microdose studies are included as one approach that could allow pharmaceutical researchers to study sub-therapeutic doses of a drug in humans.

The EMEA in Europe and FDA in the US both define a microdose as 100th of the predicted pharmacologic dose or 100 µg whichever is smaller. These small doses are considered inherently safer than pharmacologically active doses. Therefore, the regulatory authorities are comfortable with a much reduced safety toxicology package. This allows the drug candidate to be administered to human volunteers earlier, faster and with less expenditure compared to a phase I clinical study.

In order for a microdose approach to be useful, the results from such studies must be representative of the situation under pharmacologically active doses. Can you comment?
MB. Microdose studies must yield results that can be relied upon to represent a similar investigation conducted at a pharmacologically active dose. This issue has been the subject of considerable debate over the past 10 years.

Pharmaceutical companies have collaborated twice to investigate the representativeness of a microdose to a pharmacologic dose. These are the so-called CREAM and EUMAPP studies (www.eumappp.com).  At Xceleron, we also benefit from our experience from proprietary client investigations.

Of the results in the public domain, the microdose intravenous pharmacokinetics is almost 100 percent representative of that seen at a therapeutic dose.  For orally administered drugs, the PK of about 79 percent of the drugs given as a microdose are within a factor of ±2 of the therapeutic dose (a widely accepted criterion used in allometric scaling).

Why is microdose data for a minority of compounds not representative of the pharmacologically active dose?
MB. One reason we see is that certain enzyme systems might be saturated at higher doses, thus leading to differences between a microdose and a pharmacologically active dose.

How are the low levels of drug in microdose studies measured?
MB. The bioanalytical technologies most often used to measure such low doses of drug are accelerator mass spectrometry (AMS) and LC-MS/MS. The choice of instrumentation is determined by the need for sensitivity to ensure that the drug is measured over a suitably long period of time in all of the tissues and compartments of interest.

Xceleron provides its customers with the more sensitive AMS option. Under the right circumstances, we can quantify in the femto to attogram range (10-15 to 10-18 g) or typically three to four orders of magnitude more sensitive than LC-MS/MS. It’s important to use a fit-for-purpose approach. If a microdose study is deemed appropriate, then the next question to be asked is which bioanalytical approach is better.

How does a microdose study add value to a drug development programme?
MB. There are situations in which such studies make perfect sense and situations in which they add no value. We have observed changes over time in the way that pharmaceutical companies use microdose studies and differences between large and small companies.

We have conducted microdosing studies for drug candidate selection, on drugs which have conflicting animal ADME/PK data, on drugs with a novel mechanism of action for which there may be no human precedent, to investigate drug/drug interactions and to enrich PET imaging studies.

Smaller companies often use microdosing to investigate individual compounds for better decision making and to add value for potential financing opportunities. Larger companies tend to study multiple compounds concurrently. When the ADME/PK of multiple compounds is studied it is often for two reasons; as a screen of multiple pre-clinical candidates; and to expedite the development of back-up compounds where the lead has performed poorly in phase I.

We can also gather much more than simple PK/ADME data from a microdose study. In one Xceleron study, a respiratory anti-infective was administered orally and intravenously. Blood and excreta were collected, lung biopsies were taken and a bronchoalveolar lavage (BAL) was performed. We demonstrated that the IV pharmacokinetics were very favorable. Conversely, the oral kinetics showed that the drug was poorly absorbed and underwent extensive first pass metabolism. We also demonstrated that the drug accumulated in the lung tissue plus the alveolar macrophages. Therefore, once in circulation, this drug candidate was likely to provide very effective exposure. Since an oral formulation was less likely to be effective, the inhalation route was prioritised. The microdose data provided invaluable insight to enable informed choices to be made early. Irrespective of the use, these early human investigations provided invaluable insight to enable informed choices to be made early. You may hear others refer to this as de-risking downstream drug development.

What do you see in the future of microdosing?
MB. In addition to the applications I’ve already mentioned, I’d expect to see more studies in sensitive populations such as pediatrics, more studies looking beyond the systemic circulation as we did with BAL and more imaging.

You mentioned that you use a 14C microtracer to measure drug levels from microdose studies. What are other uses?
MB. There is still confusion around the terms microtracer and microdose. Microtracer in our world is a small amount of 14C labeled drug and it’s used it in all of the studies in which AMS is the bioanalytical method of choice. A microdose study is just one of many that can use a 14C microtracer.

Just as we’ve seen the utility of microdose studies grow with time, we’ve witnessed growth in the use of 14C microtracer generally. We have used 14C microtracer in microdosing, IV/PK absolute bioavailability, MIST solution, drug/drug interactions, regulatory ADME, straight bioanalytical and investigations of proteins. Our microtracer regulatory ADME studies have been submitted in the filings of six marketed drugs. That aside, phase I is probably the area of greatest interest for us because of the opportunity to gain vital information within existing safety studies at small incremental expense. This is especially the case for absolute bioavailability and MIST elucidation. In the case of the former, complexity warrants addition internal standard approaches to ensure that the quantitative bioanalytical data is representative

I’d like to finish on a point that is important to me and others at Xceleron. We recognize that 14C AMS studies and microdose studies in particular may not always be the answer. We must take a fit-for-purpose approach in offering our clients a drug development solution. However, under the right circumstances, a microdose study can provide quite unique clinical insight at an early stage. The cost-effectiveness of this approach should not be under-estimated.
 
Michael Butler is CEO of Xceleron. He has 20 years of experience in science-driven businesses in Europe, US and Asia. Butler has been President, Scientific Operations and Chief Scientific Officer with Aptuit, Group Vice President at MDS-PS and Group Director, Business Development for Huntingdon Life Sciences.