ITC Commentary on the Prediction of Digoxin Clinical Drug–Drug Interactions from In Vitro Transporter Assays

Abstract

The "P-glycoprotein" IC50 working group reported an 18- to 796-fold interlaboratory range in digoxin transport IC50 (inhibitor concentration achieving 50% of maximal inhibition), raising concerns about the predictability of clinical transporter-based drug-drug interactions (DDIs) from in vitro data. This Commentary describes complexities of digoxin transport, which involve both uptake and efflux processes. We caution against attributing digoxin transport IC50 specifically to P-glycoprotein (P-gp) or extending this composite uptake/efflux IC50 variability to individual transporters. Clinical digoxin interaction studies should be interpreted as evaluation of digoxin safety, not P-gp DDIs.

Variability in In Vitro OATP1B1/1B3 Inhibition Data: Impact of Incubation Conditions on Variability and Subsequent Drug Interaction Predictions

“…Interlaboratory variability involving inhibition of transporters, specifically P‐gp, has been discussed and addressed in previous years, however, a similar analysis has not yet been performed for OATPs . With the importance of OATP1B1/1B3 in drug disposition becoming increasingly apparent, addressing this variability, and the subsequent effect on in vivo predictions, is prudent.…”

Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations

“…In the current study the mechanistic kidney model was developed, accounting for the contribution of OATP4C1 and P-gp to digoxin renal secretion (Mikkaichi et al, 2004; Lee et al, 2014). Despite a large amount of available clinical plasma and urine concentration data for digoxin, the P-gp transporter kinetic parameter was practically nonidentifiable because of the lack of measured intracellular digoxin concentrations or sufficiently high temporal resolution of the urinary excretion rate data.…”

“…Digoxin secretion in kidney is considered to be mediated predominantly by the OATP4C1 and P-gp transporters, expressed on the basolateral and apical proximal tubule membranes, respectively (Tanigawara et al, 1992; Mikkaichi et al, 2004; He et al, 2014; Lee et al, 2014). A wide range of in vitro K m and V max values were available for P-gp in the literature, with two studies reporting in vitro data for OATP4C1 (Supplemental Table S3).…”

Drug–Drug Interactions Related to Altered Absorption and Plasma Protein Binding: Theoretical and Regulatory Considerations, and an Industry Perspective

“…However, recently an unidentified sodium‐dependent transport process was found for digoxin complicating interpretation of drug interaction results. The international transporter consortium recommended “clinical digoxin interaction studies should be interpreted as evaluation of digoxin safety, not Pgp DDIs.” The authors further proposed replacing digoxin with dabigatran etixilate as an alternative Pgp benchmark. However, poor absorption and extensive fecal elimination of de‐esterified dabigatran suggest that interpretation of dabigatran etixilate results may also be confounded by other processes.…”