Table 1.
List of recommended considerations and requirements of interventional DDI studies and examples of potential pitfalls in DDI studies and their interpretation
| Typical requirements of a DDI study | Potential pitfalls of DDI studies |
|---|---|
| General design issues | |
| Healthy volunteers if no safety concerns | Risky drugs given to healthy subjects |
| Patients if safety concerns or clinical focus | Bias and confounding in observational patient studies |
| Crossover design | Parallel group design may produce bias |
| Sufficient washout to eliminate carry‐over effects | Insufficient washout (e.g., a slowly eliminated metabolite still present) |
| Placebo control and blinding (e.g., in case of pharmacodynamic end points) | |
| Dietary control/restrictions as necessary | |
| Appropriate sample collection, storage and analytical method to cover > 80–90% of the AUC of the victim drug and metabolites | Inaccurate or insensitive analytical method, degradation of analytes during storage or analysis |
| Monitoring of perpetrator pharmacokinetics (compliance, quantification of exposure, presence after washout) | Perpetrator exposure not documented |
| Pharmacodynamic assessment | Pharmacodynamic assessments neglected |
| DNA samples | |
| Biomarker samples in selected cases | |
| Necessary prior knowledge considered in design | Deficiencies in preclinical and early clinical data (e.g., in mass‐balance studies) |
| Safety issues | |
| Strict exclusion criteria (e.g., contraindications, pregnancy) | Careless exclusion criteria leading to risk of adverse effects |
| History, clinical examination, laboratory tests, and genotyping as necessary | |
| Safety monitoring and sufficient follow‐up | Insufficient follow‐up (residual drug effects) |
| Precautions and interventions to avoid adverse effects, even in the worst‐case DDI scenario | Rescue interventions not prearranged |
| Blood sampling should generally not exceed the volume of blood donation | |
| Perpetrator (inhibitor/inducer) | |
| Selectivity and strength of index inhibitor (> 5‐fold increase in AUC possible) |
Suboptimal strength Nonselective inhibitor |
| Clinically relevant (high) dose depending on tolerability | Too low dose, leading to weak inhibition |
| Dosing to reach and maintain steady‐state, including time‐dependent inhibition and induction |
Clinically atypical dosing Duration of dosing too short/long to document maximal DDI |
| Victim substrate | |
| Sensitivity of index substrate | Lack of sensitivity (particularly if not considered in interpretation) |
| Documented selectivity of index substrate | Lack of selectivity (particularly if not considered in interpretation) |
| High first‐pass and short half‐life preferable | Long half‐life victim with a short‐acting or “presystemic” inhibitor |
| Monitoring a specific metabolic ratio can be useful | |
| Dose, expecting the worst‐case scenario | Too high dose |
| Staggered dosing | Victim drug administered too soon (or too long) after perpetrator to document maximal DDI |
AUC, area under plasma concentration‐time curve; DDI, drug–drug interaction.