Ritonavir (DB00503): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Ritonavir is a small-molecule drug with a multifaceted and storied history in modern medicine. Initially developed and approved in 1996 as a primary antiretroviral agent for treating Human Immunodeficiency Virus (HIV) infection, its clinical role has undergone a remarkable evolution. Ritonavir functions through two distinct mechanisms: as a direct inhibitor of the HIV-1 protease enzyme and, more significantly, as one of the most potent clinical inhibitors of the cytochrome P450 3A4 (CYP3A4) enzyme system. This secondary characteristic, initially a source of complex drug interactions, was ingeniously repurposed, establishing ritonavir as the prototypical pharmacokinetic (PK) enhancer, or "booster." In this capacity, low doses of ritonavir are used to increase the plasma concentrations and prolong the half-lives of other co-administered protease inhibitors, a strategy that revolutionized HIV therapy by improving efficacy, simplifying dosing regimens, and enhancing patient adherence.

The drug's development was marked by a near-catastrophic post-marketing event in 1998, when the emergence of a new, less-soluble crystalline polymorph rendered the original formulation ineffective, forcing its temporary withdrawal from the market. This "Ritonavir crisis" became a landmark case study in pharmaceutical science, fundamentally altering industry standards and regulatory requirements for solid-state characterization of new drug substances.

Beyond HIV, ritonavir's role as a PK enhancer has proven to be a reusable pharmacological platform, enabling the development of effective oral therapies for other major viral diseases. It is a critical component in combination treatments for chronic Hepatitis C virus (HCV) and, most notably, serves as the indispensable booster for nirmatrelvir in the oral COVID-19 treatment, Paxlovid.