Pharmacokinetics bases of adverse drug-drug interactions

Abstract

A drug reactions (ADRs) are a leading cause of morbidity and mortality. A major contributing factor to ADRs is Drug-Drug Interactions (DDIs), which often results from pharmacodynamic (PD) and pharmacokinetics (PK) changes due to co-administration of one or more therapeutic agents. Clearly, the chances of such interactions are higher in therapeutic areas requiring administration of a cocktail therapy such as that in cancer, HIV, epilepsy and CNS disorders.The PD interactions typically occur at the receptor site and may be additive, synergistic or antagonistic in nature. The PK bases for DDIs often entail changes in the activity and expression of drug metabolizing enzymes and/or transporters leading to altered ADME (absorption, distribution, metabolism and excretion) characteristics. Changes in PK parameters such as bioavailability, systemic clearance (resulting from altered hepatic, renal or biliary clearance) manifest in altered systemic exposure (peak drug levels or Cmax and the overall area under the plasma concentration-time curve or AUC). While a few DDIs are utilized for therapeutic benefit (best example is the use of ritonavir for enhancing systemic exposure of co-administered anti-retroviral drugs), most DDIs are deleterious, which require careful changes in dosing regimen and/or therapeutic monitoring, especially for narrow therapeutic index drugs. This seminar will discuss the mechanistic bases for DDIs mediated by PK alterations (induction and inhibition of enzymes and transporters), and the current status of in vitro and in vivo/clinical approaches for assessment of such interactions. Clinically relevant examples leading to adverse toxicities and measures to circumvent such toxicities will be underscored.