Candidate Selection

Candidate Selection Studies

 

To optimize the ADME properties of a small number of drug candidates, a series of studies may be conducted during the candidate selection process to identify the NCE with the best chance of success. A typical data package to support nomination of a NCE from discovery to development status may include the following studies:

 

  • Single IV and oral dose in rodent and non-rodent species to determine the pharmacokinetics and oral bioavailability of the drug candidate

    • Administer a pharmacologically active dose to establish the systemic exposure required for biological activity

    • Determine Cmax, Tmax, AUC, t½, and oral bioavailability

    • Select the candidate with the best pharmacokinetic properties

  • Plasma protein binding in rodent, non-rodent and human

    • Use ultrafiltration or equilibrium dialysis

    • Determine the extent of binding to plasma proteins

    • Select the candidate with the highest free fraction

  • In vitro inhibition of CYP in human liver microsomes

    • Use CYP specific substrates to determine the potential of lead candidates to inhibit the activity of human liver CYPs

    • Rank order of lead compounds based on potential to inhibit the CYPs

    • Select the candidate with the lowest potential to cause metabolism-based clinical drug-drug interactions

  • Preliminary in vitro metabolism studies to assess potential active metabolites

    • Use human and animal preparations (microsomes, hepatocytes, etc.) to determine major in vitro metabolites

    • Identity structure of major metabolites and determine their biological activity

  • Temporal relationship between biological activity and plasma concentration

    • Administer lead compounds to animal efficacy models to establish that biological activity is correlated to plasma levels

    • Minimize the selection of lead compounds with active metabolites

    • Eliminate the nomination of pro-drugs

  • Optimization of oral formulation

    • Select the candidate with the best combination of biological activity, pharmacokinetic properties and ease of formulation for solid dosage form

  • Toxicokinetics

    • Determine the systemic exposure of lead compounds as part of single-dose and dose-ranging toxicology studies

    • Determine therapeutic index of the lead compound by calculating the ratio of the concentration at the “no observed adverse effect level” dose and the concentration after an active pharmacological dose


Completion of the candidate selection studies will provide the data to support the nomination to development status of the best compound within a list of potential candidates. Depending on the rigor of study designs and appropriateness of the data, most, if not all, of the data package can be included as part of an IND submission.