Assessing your Drug-Drug Interaction Testing Risk

During development of new chemical entities (NCEs), an investigation into the likelihood of drug-drug interactions (DDI) is vital to the progression of these drug candidates. Possible drug-drug interactions can alter the pharmacokinetics of concomitantly administered medications, altering efficacy or toxicity. Drug-drug interaction testing provides a definitive assessment of these risks and should be performed early after selection of a lead candidate. As part of IQVIA Laboratories suite of ADME services, our scientists routinely evaluate these risks through validated, in vitro assays to determine the cytochrome P450 enzymes responsible for metabolism of NCEs and to assess the potential for NCEs to inhibit and/or induce these enzymes. These data will be included in the filing of the Investigational New Drug (IND) application to provide guideposts for clinical DDI assessments during the further development of drug candidates.

In Vitro IND-Enabling DDI Assays

Time-dependent Inhibition of CYP Enzymes

• Assess the potential of test article to induce CYP1A2, CYP2B6, and CYP3A4 through mRNA analysis and/or enzymatic activity
• Pretests to inform top concentration of test article include assessment of solubility in incubation media and cytotoxicity in a single lot of hepatocytes
• Test article is incubated with plated cryopreserved human hepatocytes pre-characterized to be responsive to CYP1A2, CYP2B6, and CYP3A4 induction before analysis of mRNA levels and/or addition of probe substrate(s) to assess enzymatic activity
• Optional determination of the induction of CYP2C8, CYP2C9, and CYP2C19 is available
• Fold-induction over vehicle control is calculated. EC₅₀ and E_max values to be calculated if induction is concentration-dependent and >2-fold at max
• Full QC reviewed, regulatory style report

CYP Reaction Phenotyping

• Determine the CYP enzymes involved in the metabolism of a test article using two complementary assay designs
• Evaluating the percent contribution of each of 7 CYP enzymes in the metabolism of the test article by sequentially inhibiting CYP activity
• Test article is incubated with HLM and NADPH in the absence and presence of selective CYP-specific inhibitors
• Fraction metabolized by each CYP enzyme will be calculated (f_m,CYP)
• Evaluating the percent contribution of CYP enzymes in the metabolism of the test article using recombinantly expressed CYP enzymes
• Individual CYP relative activity factors (RAF) will be used to estimate fraction metabolized by each CYP enzyme
• Full QC reviewed, regulatory style report