October 27, 2022 /

Drug metabolism and pharmacokinetics (DMPK) are essential to understanding important characteristics of drug candidates, including absorption, distribution, metabolism, excretion, toxicity (ADMET), and pharmacokinetic (PK) properties. DMPK studies are conducted at the preclinical and clinical stages as well as post-approval. Preclinical DMPK studies involve both in vitro studies to evaluate drug candidate characteristics such as protein binding affinities and interactions with transporters and enzymes as well as in vivo analyses to assess toxicity and pharmacokinetics such as half-life, bioavailability, excretion, absorption, and distribution in preclinical animal models. Drug characteristics are further evaluated during clinical trials, including assessment of safety, dosage, side effects, efficacy, and drug-drug interactions (DDIs) in human participants. Post-approval studies involve preparing labeling restrictions for the market as well as collecting safety and effectiveness data in larger populations once available. 

Nearly 90% of drug candidates fail after entering clinical trials.  This high failure rate at late stages in the drug development pipelines results in wasted time and resources that could have been utilized for more promising candidates. In a 2016 estimation from the Tufts Center for the Study of Drug Development, each approved drug has an estimated price tag of $2.87 Billion ($3.65 Billion in 2022 dollars). The main driving factor for this high cost is the failure rate for other products. Analyses have revealed that the top reasons for drug candidate failures between 2010 and 2017 from the largest pharmaceutical companies were:

1. Lack of clinical efficacy (40-50%)
2. Unmanageable toxicity (30%)
3. Poor drug properties (10-15%)
4. Lack of market/commercial strategy (10%)

Proper preclinical DMPK studies can address the second and third most frequent causes of attrition: unmanageable toxicity and poor drug properties. Combined, these account for 40-45% of all drug failures. Identifying these characteristics earlier in the drug development pipeline could cut costs for pharmaceutical companies and shorten the time to effective therapeutics for patients. The risk is even higher for smaller companies. Smaller biotech companies tend to pursue riskier drug candidates, which are critical for innovative therapies, but when combined with limited resources and experience for conducting proper DMPK studies, contribute to a high rate of attrition.

A variety of DMPK techniques can be used to assess the preclinical toxicology of drug candidates. Toxicity is temporal, with the potential for both acute and chronic effects. Proper in vivo preclinical toxicology studies can evaluate the acute effects of multiple dosing strategies as well as long-term effects such as carcinogenicity or impacts on reproductivity. Toxicology studies may evaluate any metabolites that might form or transcriptional changes that result from administration and may indicate toxicity based on previously characterized compounds. By using multiple species for toxicity studies, investigators can choose species that have similar metabolic profiles to humans, allowing for more relevant comparisons.  

Poor drug properties such as absorption, distribution, metabolism, excretion (ADME), or pharmacokinetics account for 10-15% of drug attrition. Fifty years ago, these poor drug properties accounted for nearly 40% of candidate attrition. The progress of DMPK scientists in assessing these characteristics has come a long way in that time. These measurements can be obtained via in vitro assays with human-derived cells or tissues as well as in vivo animal studies. Two of the approaches currently used to predict human PK include allometric scaling and in vitro-in vivo extrapolation. Allometric scaling is used to predict human PK by relating in vivo-derived parameters collected in animal models. In vitro-in vivo extrapolation is an estimate of metabolic clearance by measuring the clearance in human cells or tissue in vitro and then scaling up.  

Twenty years ago, the focus of many DMPK studies for pharmaceuticals was primarily to characterize the kinetic properties of drug candidates for clinical trial design and regulatory registration. Since then, the field has shifted dramatically with new analyses including pharmacogenetics, pharmacogenomics, drug-drug interaction (DDI) predictions, and measurements of asymmetric organ or tissue exposure based on the organ-specific expression of drug transporters and metabolizing enzymes. 

In 2020, the FDA released updated guidance regarding DDI evaluation for drug candidates. These guidelines outlined in vitro experimental conditions as well as details for model-based DDI prediction strategies. Preclinical DDI studies are used for the design of trials to inform participant recruitment as well as for generating label restrictions and guidance post-approval. 

Pharmacogenomics is an emerging field of DMPK that evaluates the accumulative effect of genetic variants on drug responses and efficacy.  Genetic polymorphisms in genes that encode metabolizing enzymes or transports can vastly affect the pharmacokinetic properties of a given drug as well as how patients respond to therapy.  These biomarkers can affect dosing, and risks associated with the therapy, both important for labeling guidance and restrictions. They can also impact trial design and endpoints.  The FDA pharmacogenetic biomarkers in drug labeling list contains FDA-approved drugs with known pharmacogenomic biomarkers that affect the therapeutic response.  

Proper design and execution of DMPK studies can reduce drug candidate attrition, cut costs, and conserve resources for the most promising drug candidates. Smaller biotech companies often lack the resources to conduct robust DMPK studies, making it even more important to outsource these studies to a CRO with extensive experience and validated models. Because no individual model is a perfect comparison to humans, in vivo DMPK studies can be conducted in multiple models or species to compare ADMET properties across species. PharmaLegacy has an extensive set of preclinical animal models (> 600 validated models) to conduct DMPK studies from multiple species, including non-human primate models, with the capacity to run more than 200 concurrent animal studies. Scientists at PharmaLegacy also have years of experience performing DMPK/ADMET studies to help speeding up your drug discovery effort, minimizing toxicity liabilities, and ultimately reducing attrition rate in the clinic. PharmaLegacy can meet your company’s DMPK needs while remaining compliant with all applicable regulatory agencies.  

See the difference proper DMPK studies from PharmaLegacy can offer your company.

References

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