Drug-Drug Interaction Studies

• When appropriate, we can accelerate start-up times. We have started a trial in as little as four weeks. Typical study start-up times range from eight to 12 weeks.

DDI studies typically evaluate PK and PD endpoints, and can include but are not limited to:

• Metabolic enzyme inhibition and induction — confirming if a drug can act as a precipitant, i.e., inhibit or induce the activity of enzymes (like CYP enzymes) that metabolize other drugs (the object), potentially affecting plasma concentration.
• Drug transporter interactions — evaluating if a drug inhibits or induces the activity of transporters involved in absorption, distribution, and excretion, which affects the drug's availability at its target site.
• Plasma protein binding displacement — examining if a drug displaces another from binding sites on plasma proteins, which leads to increased free drug concentration and potential toxicity.
• Synergistic or antagonistic effects — studying whether the combined effect of two drugs is greater (synergistic) or less (antagonistic) than their individual effects.
• Target site competition — assessing if two drugs compete for the same receptor or target molecule, potentially modifying each other's pharmacological activity.

Not only can a sponsor’s drug inhibit or induce the activity of enzymes/transporters, but the drug can also be the object of metabolic enzymes and/or transporters. This will affect the efficacy of that drug or its safety profile.

• The gold standard for clinical DDI studies is a prospective crossover (one-sequence or randomized) design conducted in healthy normal volunteers. This approach minimizes interindividual variability, as participants serve as their own controls. Variability is further reduced in healthy individuals who have normal kidney and liver function, do not take additional medications, and lack other interfering factors such as smoking. Confinement under a controlled environment during the entire study may also help to reduce variability and risk of dropouts.
• In two-way pharmacokinetic crossover DDI studies, sample sizes around 10 to 20 participants are often sufficient to detect significant interactions, though larger groups (two to three times the size) may be needed to confirm the absence of interactions. Additionally, the washout period between study phases must be long enough to ensure complete clearance of drugs, metabolites, and their effects, even when elimination is delayed by strong inhibitors.
• Parallel designs may be considered as an alternative study design when a crossover is not suitable (e.g., for drugs with a long half-life).

• Feasibility/risk assessment – from receipt of first requirements until study completion
• Daily investigator assessment of participants
• 24/7 Advanced Cardiac Life Support (ACLS) provider coverage on-site
• Basic Cardiac Life Support certification for all clinical staff
• Crash carts on-site
• Scenario-based response training
• Telemetry with pulse oximetry
• Strategically placed panic buttons

• Yes, our experts in study design and conduct can adapt to the needs of your program with custom drug-interaction study design, taking into account the drugs involved, the DDI study design itself, dosing regimen, cocktail approach, recruitment specifics, and PK/PD parameters, to deliver safe, robust data in a timely way.

• We maintain a large selection of common interacting substrates known as strong index substrates, validated for various drug interactions, including Theophylline, caffeine – CYP1A2, Efavirenz, bupropion/hydroxybupropion – CYP2B6, Repaglinide – CYP2C8, S-warfarin – CYP2C9, Omeprazole – CYP2C19, Desipramine and dextromethorphan – CYP2D6, Midazolam – CYP3A4/5,
• We have additional validated assays for strong index inhibitors: Fluvoxamine – CYP1A2, Fluconazole – CYP2C19, Paroxetine – CYP2D6, Clarithromycin and Itraconazole – CYP3, Ramipril
• Strong index inducers: Rifampin – CYP2C19 and 3A; Carbamazepine – CYP2B6 and 3A, Phenytoin – CYP3A
• Transporter substrates: Dabigatran and digoxin – P-gp; Rosuvastatin – BCRP and OATP1B1/1B3, Furosemide – OAT1/3, Metformin – MATE1/2K and OCT2
• Transporter inhibitors: Itraconazole – P-gp, Dolutegravir – MATE1/2K, OCT2
• Transporter inducers: Cyclosporine – P-gp, BCRP, OATP (also an inhibitor of BCRP, OATP1B1/1B3)