Impact of ignoring extraction ratio when predicting drug-drug interactions, fraction metabolized, and intestinal first-pass contribution

Abstract

Many mathematical models for in vitro to in vivo prediction of drug-drug interactions (DDIs) of orally administered victim drugs have been developed. However, to date, none of these models have been applicable to all intravenously administered victim drugs. We derived and conducted a sensitivity/error analysis of a modification to the existing multiple mode interaction prediction model such that it is applicable to all intravenously administered victim drugs. Using this model we showed that ignoring the hepatic extraction ratio (EH) (as low as 0.3) of intravenously administered victim drugs can result in 1) substantial underestimation of f(m, CYPi) (the fraction of hepatic clearance of the victim drug via a given enzymatic pathway) and 2) error in dissecting the contribution of intestinal and hepatic components of DDIs for orally administered drugs. Using this model we describe DDI boundaries (degree of inhibition or induction) at which ignoring the EH of commonly used victim drugs results in ≥30% error in the predicted area under the concentration-time curve (AUC) ratio or contribution of intestinal interaction to a DDI (CYP3A probes only). For the most widely used victim drug midazolam, these boundaries for AUC ratio are net inhibition (I/K(i) or λ/k(deg)) ≥1.3 or fold induction ≥2.1; for intestinal contribution the boundaries are 0.37 and 1.5, respectively. To accurately predict the intravenous AUC ratio, intestinal contribution, or f(m, CYPi) 1) for all induction DDIs irrespective of EH of the victim drug and 2) for modest to potent inhibition DDIs even when the EH is moderate (≥0.3), we propose that our model be used.

Fig. 1.

Impact of EH on estimating intestinal contribution to DDIs. The effect of ignoring the EH of an intravenously administered victim drug in estimation of the effect of a DDI on intestinal enzymes shows the following. A, the percent error in estimated fraction of intestinal intrinsic clearance remaining (f_Clint^GI) rapidly increases as fold induction (f_Clint^Hep and f_Clint^GI increase above 1) and EH increase. Net inhibition (f_Clint^Hep and f_Clint^GI <1) is greatly underpredicted as EH and degree of inhibition increase. B, the percent error in the predicted F_G′/F_G ratio (or fold change in intestinal bioavailability) shows that for net inhibition (f_Clint^Hep and f_Clint^GI <1), F_G′/F_G is overpredicted when EH is moderate to high (≥0.35) and underpredicted for net induction (f_Clint^Hep and f_Clint^GI >1) even when EH is low (≤0.3). C, the estimated F_G′ is shown to increase beyond the maximum theoretical value of 1.0 by greater than 30% (F_G′ ≥1.3) when the EH is ≥0.35 and net inhibition is ≥90% (f_Clint^Hep and f_Clint^GI ≤ 0.1). Note: the fraction of hepatic (f_Clint^Hep) and intestinal (f_Clint^GI) clearance remaining was set equal and varied between 25 and 0.0001; hepatic extraction ratio was varied between 0.1 and 0.9. The fraction of hepatic (f_Clint^Hep) and intestinal (f_Clint^GI) intrinsic clearance remaining axes are on a logarithmic scale.

Fig. 2.

Impact of F_G on estimating intestinal contribution to DDIs. The effect of ignoring the EH of 0.25 across varying F_G values for an intravenously administered victim drug when the effect of a DDI on intestinal enzymes is estimated shows the following. A, the percent error in the estimated fraction of intestinal intrinsic clearance remaining (f_Clint^GI) increases to greater than 200% as fold induction increases above 2- to 3-fold irrespective of F_G and is greatly underpredicted by as much as −100% for 90% inhibition (f_Clint^Hep and f_Clint^GI = 0.1) for F_G >0.3. B, the percent error in the predicted F_G′/F_G ratio is independent of F_G. Note: the fraction of hepatic (f_Clint^Hep) and intestinal (f_Clint^GI) intrinsic clearance remaining was set equal and varied between 25 and 0.0001; intestinal bioavailability was varied between 0.1 and 0.9. The fraction of hepatic (f_Clint^Hep) and intestinal (f_Clint^GI) clearance remaining axes are on a logarithmic scale.

Fig. 3.

Impact of EH on estimating f_{m, CYPi}. A, when the f_{m, CYPi} of a victim drug is determined by intravenous administration of the drug in the presence and absence of potent inhibition, ignoring the EH of the victim drug affects the estimated f_{m, CYPi}, and the error in this parameter is a function of both EH and f_{m, CYPi}. B, the impact of this error is most apparent in the percent error in the maximum oral AUC ratio. This error is linear with respect to EH with a slope equal to −f_{m, CYPi} · 100 and therefore can be directly calculated as percent error = −f_{m, CYPi} · EH · 100.