TABLE 1

Unique challenges of NPDI Research that will be addressed using the Recommended Approaches (Table 2) and decision trees (Figs. 13)

Challenge Unique to NPDI ResearchRecommended ApproachDecision Tree
1. NP characterization should account for structural isomers and metabolites of phytoconstituents.2, 6I
2. Human-derived in vitro systems should be used for screening the DME or transporter inhibition and induction by NP.1, 3, 6I
3. In vitro screening of isolated individual phytoconstituents and their admixture should be considered; identification of marker constituents predictive of the complex NP mixture would streamline pharmacokinetic modeling and simulations.1, 2, 3, 5, 6I
4. Positive controls should be included during both in vitro screening and the design of clinical NPDI studies to serve as benchmarks for judging NPDI magnitude.3, 5I, III
5. Clinical pharmacokinetic profiling (e.g., bioavailability, metabolites) of key phytoconstituents should inform the screening strategy; interactions in the gut should be considered for phytoconstituents not available systemically.3, 4, 5II
6. The clinical NPDI study should consider chronic dosing of NP to assess induction and/or accumulation of precipitating constituents with long elimination half-lives.3, 4, 5II
7. Systemic exposure to NP constituent metabolites (particularly conjugated metabolites) should be assessed in the clinical NPDI study.1, 4, 5II, III
8. The clinical NPDI study should assess clinical relevance by considering the NP formulation and bioactive dose and identifying vulnerable subpopulations with covariates (genotypes, organ dysfunction, disease states, etc.).1, 2, 5, 6III
9. Additional clinical NPDI studies involving specific drugs (e.g., drugs with narrow therapeutic indices) should be considered if the clinical NPDI study involving phenotypic probe(s) as the object drug(s) indicates a significant DME-mediated and/or transporter-mediated interaction.1, 4, 5, 6III