Assessment of TPs as potential DDI perpetrators or victims
| Assessment | Questions and Considerations |
|---|---|
| TP as DDI perpetrator | |
| 1. TP is a cytokine, anti-cytokine, or cytokine modulator or causes release of cytokines in vivo or in a CRA. | Which cytokines are affected? Have effects of those cytokines on P450 and transporters been previously reported? If yes, no in vitro testing is required. If no, additional in vitro testing may be required to determine which P450s are likely to be affected. Is it known what cytokine levels are typical in the intended patient population? |
| 2. TP candidate is intended to be used in combination with SM and/or other TP drugs. | What is the therapeutic index of those SM or TP drugs? What are the clearance mechanisms of the concomitant NTI TP? If the NTI compound is cleared via any of the P450s listed in 1, TP DDI clinical investigation involving intensive PK profiling of the NTI will probably be needed. If it is cleared via other pathways, PK data may be collected but not necessarily via intensive sampling. If any of the NTI clearance mechanisms (other than P450) are expected to be affected by the TP drug candidate, develop a risk-based strategy for addressing DDIs. |
| 3. TP candidate is an immunomodulator. | Potential DDIs if concomitant medication is a mAb and Fcγ receptors are involved in its clearance |
| TP as DDI victim | |
| 1. Therapeutic index of TP drug candidate | If NTI, develop a risk-based strategy for addressing DDIs. |
| 2. Target and target type | What are the biological consequences of inhibiting this target? Soluble/cell surface target and can it be shed? Will blocking this target affect clearance of endogenous proteins, etc.? |
| 3. Clearance mechanisms of TP drug candidate (target-mediated clearance, peptidates, binding proteins, Fcγ receptors, etc.) | If contribution of target-mediated clearance is significant at the clinical dose and concomitant drug may affect target expression potential for DDI. |
| 4. TP candidate (through its mechanism of action) modulates expression of downstream receptors involved in elimination of concomitant TP or its own elimination. | Potential for DDIs |
| 5. TP drug candidate interacts with endogenous proteins (other than target). | Potential for DDIs if concomitant medications alter levels of endogenous proteins that are involved in clearance of the TP |
CRA, cytokine release assay; NTI, narrow therapeutic index.