A new road map to successful drug formulation
Estimates vary, but it is thought that approximately 20% to 30% of all new chemical entities (NCEs) currently in development show suboptimal pharmacokinetic profiles. 1-2 Why is this important? Tolerability of a drug and an easy-to-take regimen can lift a product above its competition. Because simplified dosing leads to improved patient compliance, a once-a-day tablet is an increasingly desirable objective in pharmaceutical development.
Achieving this goal often requires a modified release (MR) oral formulation, however, which poses significant challenges for development and formulation scientists. With a drug that shows less than ideal pharmacokinetics, realizing the once-a-day tablet is even more challenging.
But there are new approaches to understanding the complex drivers of bioavailability in humans, offering valuable early insight into a drug's potential for once-a-day delivery. In contrast to current practice, establishing this potential early in the drug delivery process can save considerable time and resources and reduce late-stage attrition.
Developing MR dosage forms is difficult because variations in gastrointestinal (GI) tract transit, absorption and retention, and physical and pharmacological properties of the drug all play a role. Often, development of formulations is based on in silico predictions and in vitro profiles that must then be correlated with in vivo performance. This sets up a test-modify-test cycle. Many prototypes developed in this way fail to perform in vivo.
Bioavailability, the rate at which maximum plasma concentration of a drug is reached and the length of time it is sustained, clearly predicts the drug's degree of pharmacological-or toxicological-effect. Figure 1 (see p. 27, top) shows an "ideal" pharmacokinetic (PK) curve, while Figure 2 (see p. 27, bottom) illustrates a range of suboptimal profiles.
Teasing out the reasons behind poor bioavailability is crucial to completing a successful formulation development program. For example, PK variability, nonlinearity, or low bioavailability could be a result of solubility, metabolism, or permeability issues, none of which is fully characterized by data obtained from in vitro assays, preclinical experiments, or even clinical studies in humans, in which just simple PK measurements are taken.
With so many missing links, even the most knowledgeable scientist, someone with detailed understanding of the complexities involved, may be reduced to speculative assessment of why a formulation is failing.
A NEW ROAD MAP
An alternative approach, pioneered by Pharmaceutical Profiles (Nottingham, England), is built on the principle that hard data on bioavailability provides the foundation for the development and validation of formulations in human volunteers-and proof of concept in patients. In order to understand a drug's performance in the body and develop an effective formulation, scientists need to understand both "input" and "output" components.
By combining the techniques of gamma scintigraphic imaging with intravenous pharmacokinetic (IV/PK) studies and Enterion regional absorption studies, Pharmaceutical Profiles has developed in vivo study protocols that tackle both the input and output profiles of the bioavailability equation in humans. 3
The Enterion is a remote-controlled drug delivery device that provides a noninvasive means to evaluate human regional drug absorption of most major oral formulation types. A gamma-emitting radionuclide sealed inside the tracer port of the capsule enables tracking by a gamma camera in real time as it passes through the gut (see Figure 3, p. 28).
When the capsule reaches a specific target location, the volunteer simply stands inside an activation unit, and an external electronic signal causes the capsule to expel its contents. Enterion studies, usually compared to an oral immediate release or intravenous reference formulation, can provide detailed information not only on regional absorption but also on active transport and gut wall metabolism parameters.
DRUG IN, DRUG OUT
In the fasted state, a drug may only stay in the stomach and small intestines for approximately five hours. In contrast, residence time in the colonic region is approximately 20 hours (see Table 1, p. 28). Therefore, a drug needs to show adequate absorption from the colon if it is to have potential as an MR formulation. If this is not achieved, MR development will be difficult-maybe impossible.
Having undertaken more than 150 clinical studies delivering drugs to specific sites in the GI tract, Pharmaceutical Profiles uses the Enterion capsule to assess the regional absorption of drugs and has developed a rule of thumb for determining the feasibility of MR development. If relative colonic bioavailability is less than 30% of that for the immediate release product, MR development is likely to be very difficult, probably impossible. Relative bioavailability of 30 to 60% suggests challenging but achievable MR development, and if relative bioavailability is over 60%, MR development should be relatively straightforward.
While dissolution testing and animal bioavailability studies may help predict the performance of different prototype formulations on plasma drug concentrations, a complete understanding of the drug's PK characteristics is needed to account for the complex and often confounding physiological influences within the human body. It is not until PK performance is tested in humans that a developer can truly gain a comprehensive picture of a formulation's performance. In addition, knowing how a drug is eliminated from the body once it has been absorbed adds valuable insight about what is driving the shape of the PK profile.
A combination of oral and intravenous microtracer studies, using extremely sensitive accelerator mass spectrometry (AMS) detection, can provide valuable information early in the drug development process. The technique allows for the assessment of absolute bioavailability, apparent dose-related changes, routes and rates of elimination, metabolite profiles, and potential for drug-drug interactions, along with the associated inter-subject variability. 5-7
In addition, AMS analysis of trace-radio labeled active pharmaceutical ingredient now fulfills the regulatory requirements of NCEs for new drug applications and marketing authorization application approval. It evaluates absolute bioavailability, identifies and quantifies metabolites, and confirms in vitro and in vivo correlation of metabolite profiles. 8
OUTPUT PROFILING TECHNOLOGY
Another helpful tool is the IVmicrotracer methodology, which allows human intravenous PK data to be generated for a fraction of the cost and time needed for more traditional approaches because the regulatory requirements are greatly reduced. 9 In human IVmicrotracer studies, a sub-pharmacological, intravenous dose of the novel drug candidate(s) is administered at the time of maximum concentration for the oral therapeutic dose.
The data provide clear understanding of metabolism and elimination processes and avoid the issue of nonlinear pharmacokinetics because the oral therapeutic dose serves to saturate rate-limiting processes such as active transport. Blood and urine samples are collected just prior to and then regularly throughout a period of time-from 24 to 60 hours-post-dose. This collection period must extend across at least three, and preferably five, plasma half-lives for most drug candidates.
The proportion of parent drug in either plasma or urine is quantified by extraction followed by chromatographic separation and AMS analysis of the parent drug fraction. A single chromatography run provides information on both the amount of parent drug and the extent of metabolism, although further sub-fractionation is possible if necessary. Standard metabolites obtained from in vitro incubations or from whole-animal studies can be used as references in co-chromatography of radioactive peaks to provide a strong indication of metabolite structure. 10
These methods are readily accepted by regulatory authorities. Experience at Pharmaceutical Profiles shows that the average Medicines and Healthcare products Regulatory Agency (MHRA) response time for clinical trial applications of this type is just 15 days-and can be even shorter. IVmicrotracer studies can provide early, critical human PK data for decision making in early drug development and can be added onto any other pharmacokinetic protocol at incremental cost. 7
A POSITIVE PAYBACK
The new early development road map described here offers enormous opportunities to an industry under pressure from multiple sources. The methods used are cost effective to perform, particularly when they are run in a good laboratory practices/good manufacturing practices/good clinical practices integrated facility that supports rapid development and manufacture of dosage forms for efficient integration into clinical studies.
Generating this information early in the development of an oral dosage form allows a developer to concentrate on those formulations most likely to succeed, helping to avoid wasted expense on those that may disappoint in later-stage clinical trials.
Each day that a drug's launch is delayed-whether because of extended clinical trials or regulatory non-approval leading to additional development-can cost up to $23 million in lost sales in the United States alone and can add approximately $37,000 in development costs, according to Datamonitor News. Up-front investment in strategies that will guarantee the generation of viable drug formulations will inevitably save millions and will allow companies to back the winners early. ¦
Dr. Jones is vice president of marketing; Dr. Bacon is director of marketing; Dr. Stevens is senior research fellow; and Dr. Rankin is chief scientific officer at Pharmaceutical Profiles, Ltd. For more information, contact them at firstname.lastname@example.org or +44 (0) 115 974 9000.
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2. Matheson S. Microdosing as a tool in early development. Paper presented at: Fourth Drug Discovery and Development Summit; October 2005; San Diego.
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4. Connor A, King G, Jones K. Evaluation of human regional bioavailability to assess whether modified release development is feasible. Paper presented at: AAPS Annual Meeting and Exposition; November 2007; San Diego.
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