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Pre-clinical in vivo PK/PD/efficacy relationship studies: identify the most appropriate in vivo pharmacology solution to accelerate your drug discovery program

As pharmacokinetics (PK) focuses on determining concentration profiles and the fate of drug molecules in the body, pharmacodynamics (PD) examines the effect of the drug on the body.  To prove efficacious, a drug delivered into the patient must reach the necessary concentration in plasma and in relevant tissues (as measured by PK studies). This is necessary to effectively modulate the activity of the target protein (as measured by PD studies) in the body.  PD biomarkers are used to identify whether biological processes and/or pathways regulated by the targeted protein are modulated by the drug. The ideal PD biomarker should be quantifiable, should be modulated in a dose-dependent manner, and should correlate with efficacy.

The rationales for in vivo PK-PD-efficacy relationship studies in preclinical models are to:

  1. provide a quantitative analysis of dose–response relationships;
  2. describe and predict the time-course effects resulting from one or multiple drug doses;
  3. understand for how long and how much the target must be modulated to observe statistically significant efficacy;
  4. ultimately identify efficacious dosing regimens with an acceptable therapeutic index.

Inclusion in vivo PK-PD-efficacy studies at early stages during the lead identification and optimization stages of a drug development program can significantly accelerate the selection of the most promising compounds. This is done by informing on the precise mechanisms of action and by rapidly identifying unexpected toxicity and/or off-target activities in vivo.

Properly planned and executed PK-PD-efficacy studies requires a team of experts in:

  1. the establishment of the most relevant and appropriate animal model(s);
  2. animal dosing and handling;
  3. the measurement of efficacy in different models;
  4. the identification of the most appropriate PD readout for the drug and for the model being tested;
  5. the design, optimization and execution of quantitative PD assays and/or measurements;
  6. the measurement of drug concentrations in different tissue matrices;
  7. the evaluation and analysis of PK data;
  8. the analysis of relationships between PK, PD and efficacy.

Here at IRBM, all this expertise is localized in the same building and the team works in close contact with our in vitro biologists, ensuring that each project is followed from the beginning to the end by scientists who have a deep knowledge of your project, have the bandwidth to troubleshoot possible issues, pro-actively propose simple and effective solutions.

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