1.2.1 Evolving Role of DMPK: Paradigm Shift
It has long been well recognized that the drug discovery and development process is very expensive, largely due to a high development attrition rate and prolonged development time to meet the requirement for more extensive and complex clinical trials [1, 6â8]. In 1990s, poor human PK and bioavailability were the most significant cause of attrition for SM drugs, accounting for approximately 40% of all attrition in development. This number was dramatically reduced to approximately 8% by 2000 [7]. Such a drastic difference has been attributable primarily to a Paradigm shift in the roles of DMPK from little involvement decades before 1990 to active participation in SM drug early discovery starting in late 1980s [5]. Previously, compounds were selected mainly based on in vitro potency and in vivo efficacy in animal studies, with little attention being paid to the exposure or PK as an important measure connecting pharmacodynamics (PD)/efficacy/safety profiles, or consideration to commonly observed differences in these profiles between animals and humans. The integration of DMPK support as a key component of the overall drug discovery process helped to better understand ADME properties and filled these gaps, thus enabling proper data interpretations and rationale-based predictions of DMPK-related properties in humans [9â13]. As a result, potential liabilities of new chemical entities in humans were dialed out as early as possible, leading to increased likelihood for preclinical candidates to be developed successfully as therapeutic agents.
1.2.2 Key Enablers to Successful DMPK Support
The aforementioned successful DMPK support would not have been possible without numerous advances over the past few decades in drug metabolism sciences and technologies, which have provided powerful tools to enable DMPK scientists to shape SM drug metabolism research. Of special note are two key enablers, signifying game changers within the time period of interest (late-1980s to late-1990s): (i) rapid advancement of cytochrome P450 (CYP) science and (ii) availability of liquid chromatographyâmass spectrometry (LCâMS). As will be described in later sections, these elements and associated wealth of information generated over the last few decades can be leveraged and applied to support LM drug development.
The CYP enzymes play central roles in the metabolism of SMs; it is estimated that more than 70% of marketed SM drugs were eliminated primarily by CYPs [13]. CYP enzymes were discovered in 1958, and research on their structure, function, regulation, and tissue expression levels, as well as their role in drug metabolism, was rapidly expanded in the 1980â1990s [14â16]. Such rapid advancement provided fundamental concepts and important tools that helped leverage preclinical/in vitro results as a bridge to clinical outcomes, consequently enabling one to predict, understand, and manage clinical findings, particularly with respect to human clearance and PK variability due to factors such as CYP-mediated drugâdrug interaction (DDI) or CYP polymorphism [13, 16â18]. Specifically, for compounds with CYPs as the major or sole contributor to their metabolism, human metabolic clearance can be reasonably predicted based simply on in vitro metabolism studies with recombinant CYP isoforms, corrected for relative expression levels of each isoform in tissues [19]. In addition, the knowledge of CYP substrate specificity, multiplicity, and responses to factors, such as inducers and inhibitors, has provided a means to quantitatively predict, based on in vitro studies with specific CYP marker substrates or inhibitors/inducers, the magnitude of DDI, thus enabling a selection of candidates at discovery stage that do not bear considerable liability to serious clinical DDIs, either as perpetrators or victims [16â18, 20]. The DDI prediction results have also been used (and accepted by regulatory agencies) to inform inclusion and exclusion criteria for clinical programs, decide whether a clinical DDI study is needed, and inform product labeling with respect to dosage adjustment and warning/contraindication when used with other medications [21, 22]. Collectively, advances in understanding CYPs, the primary determinant for clearance mechanism of majority of SM drugs, has helped reduce drug development failure rate due to undesirable human PK properties.
In the area of tools and technologies, the successful coupling of high performance liquid chromatography with mass spectrometry (MS) has provided unprecedented sensitivity, selectivity, and high throughput that has facilitated the rapid assessment of ADME properties and the multiplicity of their governing factors for SM candidates in animals and humans [23â26]. Capitalizing on chromatographic separation and mass selectivity, the LCâMS technology enables the quantitation of coeluting or overlapping analytes, which otherwise would be constrained by chromatographic resolution. A dramatic outcome of this feature is the various in vivo and in vitro cassette studies in which more than one compounds were administered or incubated for the screening of DMPK properties, including metabolic stability, DDI liability, and plasma protein binding [23â25]. Along with the accelerated method development similarly attributed to the extraordinary selectivity and sensitivity of LCâMS, this practice has tremendously facilitated the speed and throughput of analyses of samples of low concentrations or of small volumes. Likewise, LCâMS technology has reshaped the business of metabolite characterization, allowing rapid detection and identification of major metabolites of drug candidates so that the result can be fed back into the cycle in time to influence the synthetic chemistry effort. Together, this powerful technology has enabled informed decisions to be made rapidly on a large number of candidates, each available in a small quantity, during the discovery stage. It has also enabled other in-depth mechanistic investigations into the governing factors of ADME processes, as well as detailed and accurate characterization of ADME properties of development candidates required for risk mitigation and regulatory submission [5, 10, 26]. With the recent advent of new chromatographic techniques, such as ultraperformance liquid chromatography, and more sophisticated MS, such as high resolution MS [27], this technology will continue to be the most powerful tool for drug discovery and development for SMs, and potentially for LMs alike.
1.2.3 Regulatory Considerations
Successful development of a drug candidate requires the right set of high quality data to help inform decisions not only internally, but also decisions by regulatory authorities. In-depth industry analysis by PhRMA has attributed much of the increasing R&D costs to the extending development times in clinical phases (10â15 years), greatly influenced by the increased regulatory demands in todayâs low risk, low tolerance environment, and stemmed primarily from the withdrawal of several prominent prescription drugs from the market over the past decades for safety reasons. Of special note was the withdrawal of the drugs from the U.S. market in 1990s, half of which due to serious and unmanageable safety issues as a result of PK and/or PD DDIs. These occurrences prompted the FDA to publish guidance documents for industry to encourage the characterization of DDI potential for a new molecular entity early in the drug development process [21]. The first two guidance documents: one on in vitro DDI, published in 1997, and the other on in vivo DDI, published in 1999, focused on metabolic DDI due to CYPs, and was based primarily on considerable advances in our understanding of roles of the CYP family at the time. In the latest draft DDI guidance recently issued [22], there are recommendations to conduct many additional drug transporters, and drug interaction studies for LMs have been included for the first time. Given the current status and understanding of drug transporter sciences relative to the CYPs [28], the inclusion of drug transporters in the latest guidance suggested that the FDA has become more proactive in embracing evolving sciences in their decision making. Likewise, much less is known about LM drugs in their DMPK properties and underlying DDI mechanisms in comparison with SM drugs. Consistent with this, the time span between the first approved LM drug in 1986 and the anticipated DDI guidance is much shorter than the corresponding time span of many decades for SM drugs. This apparently speedy process for LMs may be attributable to the decision of the 2003 FDA...
