Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations. Sheila Annie Peters

2 A REVIEW OF DRUG–DRUG INTERACTIONS

      CONTENTS

2.1 INTRODUCTION

Concomitant administration of drugs can lead to drug–drug interactions (DDI), if one of them (perpetrator of DDI) has the potential to inhibit or induce an enzyme or drug transporter that is critical to the metabolism, distribution, and elimination of another drug (victim of DDI). DDIs can be caused either by a reversible competitive, noncompetitive, or uncompetitive inhibition or time‐dependent inhibition (TDI) (Venkatakrishnan and Obach, 2007), induction, or downregulation of enzymes and/or transporters. A time‐dependent inhibitor causes an inactivation of the drug‐metabolizing enzyme (DME), permanently removing the DME from the pool of enzymes, until restored by the natural turnover of the enzyme. The inactivation is generally through a mechanism‐based inhibition (MBI), in which an inhibitor gets activated by an enzyme and reversibly alters it. Alternatively, the inactivation can be through the formation of a metabolic intermediate complex (MIC), in which a metabolic product or intermediate of a drug coordinate tightly to the prosthetic heme (Silverman and Hiebert, 1988) or covalently binds to the apoprotein. An example of a MIC is nitroso group formed from primary amines. Functional groups with likelihood for MIC formation have been reviewed (Kalgutkar et al., 2007; Riley et al., 2007; Hollenberg et al., 2008). Enzymes or transporter induction can be brought about either by increasing the rate of synthesis of an enzyme isoform or by a stabilization of the protein. Cytochrome P450 enzyme enzymes (CYPs) are primarily induced by the former mechanism. Regulation of CYP transcription is controlled by nuclear receptors such as aryl hydrocarbon receptor (AHR), the pregame X receptor (PXR), and the constitutively active receptor (CAR). An inducer binds to one of these nuclear receptors, thereby increasing the rate of transcription of the enzyme. A corresponding increase in the rate of translation of the induced enzyme follows. Interactions related to plasma protein binding, in which transient changes in unbound concentrations can occur due to disease state or due to concomitant drugs are not generally clinically significant, unless the victim drug is highly bound, have a high extraction ratio, and a short equilibration time for efficacious or toxic effects, compared to the time taken to regain equilibrium or if the victim drug has a narrow therapeutic index, making it sensitive to such an interaction. Different mechanisms leading to DDI are summarized in Figure 2.1.

Drug–drug interactions (DDIs) can impact clinical pharmacokinetics in patients undergoing polytherapy, exposing them to an increased risk for toxicity if victim drug concentrations exceed maximum tolerated concentration or to reduced efficacy, if the victim drug concentrations fall below therapeutic concentration. The efficacy of a prodrug is also affected, if the metabolic route responsible for its conversion to active drug is inhibited. DDIs have been responsible for the early termination of development, refusal of regulatory approval, and market withdrawals. For example, in 1997, FDA recalled the first nonsedating antihistamine (Seldane) based on its potential to reach lethal blood levels when coadministered with an antibiotic such as erythromycin. Both drugs are primarily metabolized by CYP3A4. The clinical result was an increase in the blood levels of Seldane to toxic levels resulting in lethal arrhythmias. Other examples of market withdrawals primarily due to DDI include victim drugs such as terfenadine (CYP3A4), cerivastatin (CYP2C8), and perpetrator drugs such as mibefradil (CYP3A4). The CYP3A and CYP2C subfamilies are the ones commonly implicated in DDI. In order to mitigate the risk of a costly developmental failure, DDI risk assessments have been integrated into decision‐making processes even in the discovery stage. Regulatory guidelines (USFDA 2020a, USFDA 2020b, EMA 2013, MHLW 2018) for DDI evaluation recommend in vivo interaction studies, if in vitro studies indicate a high risk for DDI.