UCSF

Introduction

It has been recognized that significant transporter interactions result in volume of distribution changes in addition to potential changes in clearance. For drugs that are not clinically significant transporter substrates, it is expected that drug-drug interactions would not result in any changes in volume of distribution.

Methods

An evaluation of this hypothesis proceeded via an extensive analysis of published intravenous metabolic drug-drug interactions, based on clinically recommended index substrates and inhibitors of major cytochrome P450 (CYP) isoforms.

Results

Seventy-two metabolic drug interaction studies were identified where volume of distribution at steady-state (V_ss) values were available for the CYP index substrates caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), theophylline (CYP1A2), and tolbutamide (CYP2C9). Changes in exposure (area under the curve) up to 5.1-fold were observed; however, ratios of V_ss changes have a range of 0.70-1.26, with one outlier displaying a V_ss ratio of 0.57.

Discussion

These results support the widely held founding tenant of pharmacokinetics that clearance and V_ss are independent parameters. Knowledge that V_ss is unchanged in metabolic drug-drug interactions can be helpful in discriminating changes in clearance from changes in bioavailability (F) when only oral dosing data are available, as we have recently demonstrated. As V_ss remains unchanged for intravenous metabolic drug-drug interactions, following oral dosing changes in V_ss/F will reflect changes in F alone. This estimation of F change can subsequently be utilized to assess changes in clearance alone from calculations of apparent clearance. Utilization of this simple methodology for orally dosed drugs will have a significant impact on how drug-drug interactions are interpreted from drug development and regulatory perspectives.