Here’s The Last Word on PK Issues: FAIL!

//Here’s The Last Word on PK Issues: FAIL!

Here’s The Last Word on PK Issues: FAIL!

The Importance of failing in DM & PK

Attrition rates as high as 40% due to pharmacokinetics issues are blowing holes in drug development pipelines. That’s tragic for patients and for drug developers.

Fortunately, there’s good news: Companies with top quality Drug Metabolism & Pharmacokinetics (DM & PK) programs are cutting clinical failures to as little as 10%.

[1]

But what if your organization doesn’t have a solid DM & PK program? You could be staring with one of the worst four-letter words in drug development: FAIL.

MPI Research offers the expertise in IND-enabling studies needed for successful IND submissions and clinical PK success. Our expert knowledge in DM & PK covers four distinct data types for your drug:

  • Physiochemical Properties
  • Qualitative Metabolic Profiles
  • Quantitative-Kinetic Profiles
  • Genotype/Phenotype/Enzymology

Drug Metabolism and Pharmacokinetics Necessary for IND-enablement
Following is a brief explanation of how the four data types mentioned above should be considered for IND purposes. MPI Research offers expertise in all these areas, and stands ready to help Sponsors turn compounds with PK issues into FAILs and approved INDs into WINs.

Physiochemical Properties

  • Solubility in PBS, methanol, acetonitrile, etc.
  • Stability in plasma & solvents
  • Ambient, -20 ºC, -80 ºC[2]

Qualitative DM & PK: Drug Metabolite Profiles [3]

  • In vitro metabolic profiles in microsomes and plated hepatocytes
  • In vivo qualitative metabolic profiles (4 species; IV/PO). Collect samples from the PK or toxicokinetics (TK) studies.
  • Plasma is most important for safety margin estimation, (i.e., exposure), and is considered in nonrodent toxicology species and additional studies using drug metabolites.
  • Urine and feces are important for clearance mechanism determination; special tissues/fluids and bile excretion studies should be considered.

Quantitative DM & PK: Rates of Metabolism and Disposition

  • GLP Bioanalytical Method Development; consider stable-isotope dilution mass spectrometry as the best way to proceed.
  • Definitive protein binding:
    • Equilibrium dialysis or ultrafiltration
    • Four Species
    • Blood/plasma partitioning
  • Pharmacokinetics(F%, T1/2, Cmax, CL, Vdss):
    • Assessed using WinNonLin
    • Can be conducted as part of dose-ranging TK to reduce cost
    • Disappearance rate in microsomes and hepatocytes (4 species minimum)
    • Definitive PK in rodents, dogs, nonhuman primates, or other nonclinical species

Genotype, Phenotype, Enzymology

  • Drug uptake and efflux transporters
  • Human liver induction assay
  • Metabolism phenotype and CYP inhibition (7-11 CYPs)
  • UTGTs if warranted (OK to move to NDA), Other enzymes

Contact us at info@MPIResearch.com to receive cost-effective and comprehensive DM & PK expertise!

1Kola, I., and Landis, J. (2004). Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug Discovery 3, 711-716.
2 Assumes that physical characteristics such as Log P have been collected.
3 Role of Phase I, Phase II metabolism, the kidney, and the liver in clearance mechanisms of interest. Assumes that radiolabeled drug is not available. Note: Quantitative disposition cannot be done unless a radiolabeled drug is available, however, useful estimates of the relative amounts can be made using MS.

By | 2017-07-04T10:29:21+00:00 May 16th, 2012|News|Comments Off on Here’s The Last Word on PK Issues: FAIL!

About the Author:

MPI Research, with global headquarters in Mattawan, Mich., provides safety evaluation, discovery, bioanalytical and analytical services to the biopharmaceutical, medical device, animal health, and chemical industries. The company offers comprehensive imaging solutions including preclinical imaging, radiochemistry, and data analysis. Scientific knowledge and experience, responsiveness, integrity, trust, teamwork, and dedication to strong and enduring Sponsor relationships are the defining attributes that characterize MPI Research as a high-performance, high-quality organization that is committed to bringing safer and more effective products to the world.