DMPK Studies are a Big Part of ADME Testing

DMPK Studies
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Wednesday, June 30, 2010

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Check out our DMPK Services section for more information or to find companies that provide these services.

DMPK: Definition, Tests, and Purpose

DMPK, or Drug Metabolism and Pharmacokinetics, is part of a larger battery of studies often referred to as ADME (absorption, distribution, metabolism, and elimination). Determining the DMPK properties of a drug allows the drug developer to understand the safety and efficacy data required for regulatory approval. Some of the properties determined in DMPK studies are bioavailability, pharmacokinetics, drug exposure analysis, and metabolic fate. Bioavailability is a term used to describe the fraction of an administered drug that remains unchanged after entering systemic circulation. A second measure is pharmacokinetics (PK), which refers to changes in blood drug concentrations over time. Other DMPK measurements include tissue distribution of drug, the potential for changes in drug exposure upon repeated dosing, and the metabolic fate of a drug. “All of these measurements are essential to interpreting safety and efficacy data by allowing dosage levels and dosing regimens to be related to actual exposure within the body,” says Daniel W. Sved, PhD, director, metabolism and analytical chemistry, WIL Research Laboratories, LLC, Ashland, Ohio.

“In the drug discovery process, early in vitro ADME screening and in vivo PK profiling provide a basis for choosing chemical structures and lead compounds that have desirable drug metabolism, pharmacokinetic or safety profiles, necessary for drug candidate selection and late stage pre-clinical development,” says Hong Wan, PhD, senior director, DMPK and bioanalysis, Crown Bioscience Inc., Jiangsu Province, China. “CrownBio is building a complete DMPK and Bioanalysis platform with full capabilities for pre-clinical service to support integrated drug discovery programs from early physicochemical property screening and in vitro ADME to late stage in vivo PK profiling for [New Drug Application (NDA)/Investigational New Drug (IND) application].”

Tools, Technologies for DMPK Studies

DMPK studies are performed using many of the major tools and technologies available to the pharmaceutical industry. Two examples of such tools are the liver microsome fraction and the whole hepatocyte, which are used in in vitro ADME models. Both of these tools contain major metabolism enzymes such as CYP450 for phase I metabolism and UGT (UDP-glucuronosyltransferase) for phase II metabolism. Other cell-based assays are performed on transfected cell line models such as Caco-2; there are also MDCK cell-based intestinal permeability assays. AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care)-accredited animals, such as mice, rat, and dog, are used to yield in vivo pharmacokinetic data like drug clearance, bioavailability, half life, and distribution volume.

High throughput screening for both quantitative and qualitative analyses relies on the highly sensitive and selective analytical tool and bioanalytical technique, liquid chromatography coupled with mass spectrometry (LC-MS). “The major technologies used in DMPK studies are focused on the qualitative and quantitative analysis of drugs and their metabolites,” says Sved. “Liquid chromatography is routinely used for separating drugs and metabolites in various samples. For quantitative measurements of small-molecule drugs and their metabolites, LC coupled with a triple quadrupole mass spectrometer is one of the most sensitive and selective technologies available. For qualitative analysis (i.e., metabolite identification), LC coupled with ion trap mass spectrometers or mass spectrometers designed to provide exact mass measurements, such as orbitrap or time-of-flight mass spectrometers, can provide the mass spectral data necessary to elucidate the structure of the compounds. Nuclear magnetic resonance (NMR) can be useful in resolving slight differences in the position of functional groups in the drug itself.”

Also, according to Sved, the use of radioisotopes—and various technologies for measuring radioactivity, such as liquid scintillation counting—is essential for ensuring that all of the administered drug can be accounted for as the drug itself or as metabolites (i.e., mass balance). Whole-body autoradiography using phosphor-imaging techniques is useful for examining tissue distribution.

FDA’s DMPK requirements

The following DMPK studies are required by FDA:

  • In vitro and in vivo PK profiles of parent drug such as metabolic stability, absorption and clearance, etc.
  • Drug metabolism profile for the parent drug and its major metabolites, reactive metabolite info, and info on metabolism and excretion pathways for the drug.
  • Drug distribution data such as plasma protein binding, distribution in plasma and tissues, and mass balance data.   
  • Drug-drug interaction studies such as CYP metabolism-based inhibition and induction, as well as transporter-based DDI like analysis of P-glycoprotein (P-gp).
  • Drug safety margin studies such as DDI risk-benefit assessment, drug exposure studies, and therapeutic window.
  • Predicted dose in man.
  • PK/PD studies, such as dose response.
  • Toxicokinetics data such as maximum tolerated dose.
  • GLP and non-GLP Tox package such as multiple dose and repeated dose toxicology/safety pharmacology studies in rat and dog.

“The FDA requires various DMPK data to be submitted at either the IND or NDA stage of the approval process depending on the route of administration and intended application,” says Sved.  “Typically, prior to submitting an IND application, in vitro studies must be performed to determine if a drug induces or inhibits various drug metabolizing enzymes (particularly various isoforms of cytochrome P450) or serves as a substrate for major drug transporters.” These studies are especially important for understanding the potential for drug-drug interactions.

In summary, DMPK studies are part of ADME testing and a crucial part of the drug approval process. The many tools and technologies utilized in DMPK studies will continue to evolve as the needs of drug developers and service providers change.

Check out our DMPK Services section for more information or to find companies that provide these services.