Response from the International Transporter Consortium

Abstract

We are grateful for the comments on our article (Membrane transporters in drug development. Nature Rev. Drug Discov. 9, 215-236 (2010)) 1 from Shi, Zhang and Yeleswaram (The relevance of assessment of intestinal P-gp inhibition using digoxin as an in vivo probe substrate. 31 Dec 2010 (doi:10.1038/nrd3028-c1)) 2 regarding their assessment of the utility of digoxin as an in vivo probe for P-glycoprotein (P-gp). Overall, the International Transporter Consortium (ITC) is in agreement with their comments and supports future research to identify better in vivo probes for P-gp. Below are further thoughts from the ITC on some of the salient points highlighted by Shi and colleagues.Utility of digoxin as an in vivo probe. The ITC Review did highlight (in the "Decision trees for P-glycoprotein or BCRP inhibitor interactions" (Box 3)) a number of the same limitations of digoxin as a clinical probe as those pointed out by Shi and colleagues. For instance, digoxin was noted as a "unique drug" and may not be the best reference for decisions regarding interaction studies with other P-gp substrate drugs. However, owing to its narrow therapeutic index, interactions that alter the area under the curve (AUC) for digoxin ≥ 1.25-fold, whether driven by P-gp, other transporters or solubility enhancement, are clinically important for digoxin, as dose adjustment may be warranted. The ITC advised readers to be cautious and not to over-extrapolate the significance of P-gp drug-drug interactions based on the importance of these findings for digoxin.Further guidance was also given that, if the new molecular entity (NME) is a pure P-gp inhibitor, no drug-drug interaction (DDI) studies may be required other than for clarifying a digoxin dose adjustment requirement, depending on the therapeutic area of the NME and its drug-labelling considerations. It is of crucial importance that the decision to conduct a clinical P-gp DDI study is based on an integration of all the nonclinical and clinical data for the NME. In summary, because digoxin has a narrow therapeutic index and it is a substrate for intestinal P-gp (discussed below), the ITC thinks that clinical DDI studies with drugs that are inhibitors of P-gp should be considered as described in the decision tree.Importance of solubility and formulation on digoxin absorption. The ITC did mention the importance of considering the digoxin formulation to use in the clinical DDI study, as the different formulations of digoxin have different bioavailability values. As pointed out by the ITC and Shi and colleagues, the standard digoxin tablet has an absolute bioavailability of ~70%, whereas bioavailability for the liquid-filled formulation (that is, the Lanoxicaps capsule) is ~90%. It is of note that the Lanoxicaps capsule product has not been commercially available in the US market since March 2008 (REF. 3); the formal withdrawal due to commercial reasons was requested in July 2010.Shi and colleagues present an interesting position that a clinical interaction study with digoxin should be mandatory fo...