Drug Development and Drug Interactions: Possible Models for Decision-Making

• CYP-Based Drug-Drug Interaction Studies
• P-gp-Based Drug-Drug Interaction Studies
• P-gp Inhibitor and Digoxin Interaction Studies

 Possible Model for Decision Making: CYP-Based Drug-Drug Interaction Studies

 Figure 1. CYP-Based Drug-Drug Interaction Studies

• Refer to Journal of Clinical Pharmacology, 39:1006-1014, 1999

• See page 21 of the MaPP "Clinical Pharmacology and Biopharmaceutics NDA Review Template" (PDF - 333KB)

   

NME: New molecular entity

* Additional population pharmacokinetic analysis may assist the overall evaluation.

+ negative results from an in vivo cocktail study would preclude further evaluation to determine whether an NME is an inhibitor or an inducer of a particular CYP enzyme

 Possible Models for Decision-Making: P-gp-Based Drug-Drug Interaction Studies

Figure 2. Possible model for decision-making: whether an investigational drug is a substrate for P-gp and whether an in vivo drug interaction study with a P-gp inhibitor is needed.

Reference: Lei Zhang, John M. Strong, Wei Qiu, Lawrence J. Lesko, and Shiew-Mei Huang. Modified from Scientific Perspectives on Drug Transporters and Their Role in Drug Interactions  Mol Pharm. 2006; 3(1), 62-69, Epub Jan 4 2006. [PDF] [external link]

*For Caco-2 cells, net flux ratio is calculated as (Permeability app, B-A/Permeability app, A-B); For MDR1-overexpressed cell lines, net flux ratio is calculated as ratio of (Permeability app, B-A/Permeability app, A-B) MDR1 to (Permeability app, B-A/Permeability app, A-B,) wild-type.
(a) An acceptable system produces next flux ratios of probe substrates similar to the literature values. A net flux ratio >2 for the investigational drug is a positive signal for further evaluation. Note: there is a concern that this value is too liberal and will lead to too may positive results. An alternative is to use a % value (net flux of investigation drug relative to a probe substrate, such as digoxin).
(b) reduction of the flux ratio significantly (> 50%) or to unity

 Possible Model for Decision Making: P-gp Inhibitor and Digoxin Interaction Studies

Figure 3. Possible model for decision-making: whether an investigational drug is an inhibitor for p-gp and whether in vivo drug interaction studies with a P-gp probe substrate, such as digoxin, is needed

Reference: Lei Zhang, John M. Strong, Wei Qiu, Lawrence J. Lesko, and Shiew-Mei Huang. Modified from Scientific Perspectives on Drug Transporters and Their Role in Drug Interactions Scientific Perspectives on Drug Transporters and Their Role in Drug Interactions (PDF - external link) Mol Pharm. 2006; 3(1), 62-69, Epub Jan 4 2006.

* For Caco-2 cells, net flux ratio is calculated as (Permeability app, B-A/Permeability app, A-B); For MDR1-overexpressed cell lines, net flux ratio is calculated as ratio of (Permeability app, B-A/Permeability app, A-B) MDR1 to (Permeability app, B-A/Permeability app, A-B,) wild-type.

Note that [I] represents the mean steady state C_max value for total drug (bound and unbound) following administration of the highest proposed clinical dose.