Volume of Distribution is Unaffected by Metabolic Drug–Drug Interactions

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.