Monograph of Efavirenz

Introduction

Efavirenz is a non‑nucleoside reverse transcriptase inhibitor (NNRTI) that has played a pivotal role in combination antiretroviral therapy (ART) for patients infected with human immunodeficiency virus type 1 (HIV‑1). Its emergence in the early 1990s introduced a novel class of agents that bind directly to the reverse transcriptase enzyme, inducing a conformational change that prevents nucleic acid synthesis. The drug’s pharmacokinetic profile, characterized by a long half‑life (t_1/2 ≈ 40–55 h) and extensive hepatic metabolism via cytochrome P450 2B6 and 3A4, has made it both a cornerstone and a source of therapeutic complexity in ART regimens.

Current therapeutic guidelines continue to recommend efavirenz as a preferred backbone component in first‑line regimens, particularly when availability of newer agents is limited. Its established efficacy, once‑daily dosing convenience, and well‑defined resistance patterns render it an essential topic for pharmacy and medical curricula. Moreover, the drug’s neuropsychiatric side‑effect profile and interactions with concomitant medications require a nuanced understanding of pharmacodynamics and drug‑drug interaction principles.

Learning objectives for this chapter include:

• Describe the chemical classification of efavirenz.
• Explain the mechanisms of action and resistance development.
• Elucidate the key pharmacokinetic parameters and factors influencing drug disposition.
• Identify common clinical indications, contraindications, and monitoring strategies.
• Apply knowledge to case scenarios involving therapeutic choices and management of adverse events.

Fundamental Principles

Classification and Chemical Structure

Efavirenz belongs to the family of non‑nucleoside reverse transcriptase inhibitors. Chemically, it is a tricyclic benzofuranyl derivative with a chlorinated phenyl ring, contributing to its lipophilicity and blood–brain barrier penetration. The structural features that confer its high affinity for the allosteric binding pocket of reverse transcriptase are detailed in the literature, although the exact molecular interactions are beyond the scope of this monograph.

Mechanism of Action

Reverse transcriptase (RT) catalyzes the conversion of viral RNA into DNA, a critical step in the HIV replication cycle. Efavirenz binds to a hydrophobic pocket adjacent to the active site of RT, inducing a conformational shift that impairs nucleic acid chain elongation. By obstructing the proper alignment of the substrate, the drug effectively halts viral replication. This indirect inhibition distinguishes NNRTIs from nucleoside analogues, which act as chain terminators.

Pharmacokinetic Foundations

After oral administration, efavirenz is absorbed with peak plasma concentrations (C_max) achieved within 2–4 h. Bioavailability is high, but inter‑individual variability is substantial, largely due to genetic polymorphisms in CYP2B6 (*6 allele) and CYP3A4. The drug is extensively metabolized in the liver, with primary metabolites being 8‑hydroxyefavirenz and 7‑hydroxyefavirenz. Elimination follows a first‑order kinetic pattern, expressed by the equation C(t) = C₀ × e^-kt, where k is the elimination rate constant. The long t_1/2 permits once‑daily dosing, yet the accumulation potential necessitates careful dose adjustment in hepatic impairment.

Key Terminology

• Non‑nucleoside reverse transcriptase inhibitor (NNRTI): A class of antiretroviral drugs that bind non‑competitively to RT.
• Pharmacogenetics: Study of genetic factors influencing drug response.
• Cytochrome450 (CYP): Enzyme family responsible for drug metabolism.
• Genotypic resistance: Mutations in viral genes that confer reduced drug susceptibility.
• Therapeutic drug monitoring (TDM): Measurement of drug concentrations to optimize therapy.

Detailed Explanation

Pharmacokinetics in Depth

Efavirenz demonstrates a volume of distribution (V_d) of approximately 200 L, reflecting extensive tissue penetration. The drug’s lipophilicity facilitates accumulation in adipose tissue and the central nervous system, contributing to both efficacy and neuropsychiatric adverse events. Clearance (Cl) is primarily hepatic, with an average value of 4–6 mL min^-1 kg^-1. Clearance can be approximated from the relationship AUC = Dose ÷ Clearance, where AUC is the area under the plasma concentration–time curve.

Genetic polymorphisms in CYP2B6 significantly alter efavirenz metabolism. Individuals carrying the *6 allele may exhibit a 3–5 fold increase in plasma exposure, increasing the risk of adverse events. Consequently, therapeutic drug monitoring is recommended when steady‑state concentrations exceed 4 µg/mL, as higher levels correlate with elevated neuropsychiatric symptoms.

Pharmacodynamics and Resistance

Efavirenz’s antiviral activity is concentration‑dependent, with an inhibitory concentration 50 (IC₅₀) of approximately 0.1 µM against wild‑type HIV‑1. Resistance emerges through mutations in the RT gene, notably K103N, Y181C, and G190A. These alterations diminish drug binding, necessitating regimen modification. Genotypic assays can detect these mutations, guiding clinicians to switch to alternative NNRTIs or to include protease inhibitors (PIs) in the regimen.

Drug–Drug Interactions

Efavirenz is a potent inducer of CYP3A4, leading to reduced plasma concentrations of co‑administered substrates such as statins, oral contraceptives, and certain antiepileptics. Conversely, strong inhibitors of CYP2B6 (e.g., fluconazole) may raise efavirenz levels, heightening toxicity. The interplay between efavirenz and antidiabetic agents, particularly sulfonylureas, can precipitate hypoglycemia due to altered hepatic metabolism. Clinicians should evaluate the interaction profile before initiating therapy, employing dose adjustments or alternative agents where necessary.

Adverse Event Profile

Neuropsychiatric manifestations, including vivid dreams, dizziness, and mood disturbances, are the most frequently reported adverse events. These events typically manifest within the first four weeks of therapy and may resolve with dose adjustment or therapy discontinuation. Hepatotoxicity, although less common, can occur, especially in patients with pre‑existing liver disease. Skin reactions such as rash and Stevens–Johnson syndrome have been reported, warranting prompt recognition and management. The incidence of these events is dose‑dependent, reinforcing the importance of maintaining therapeutic concentrations within the recommended range.

Mathematical Modeling of Drug Concentration

For clinical pharmacokinetic modeling, the one‑compartment model with first‑order absorption and elimination is often employed. The concentration at time t after a dose D can be expressed as:

C(t) = (F × D ÷ V_d) × e^-k×t

where F is the bioavailability, typically assumed to be 1 for efavirenz. Using patient‑specific parameters, this equation facilitates prediction of peak and trough concentrations, aiding dose optimization.

Clinical Significance

Role in Antiretroviral Therapy

Efavirenz remains a foundational component of first‑line ART, particularly in resource‑constrained settings. Its once‑daily oral dosing improves adherence, a critical factor in viral suppression. The drug’s ability to penetrate the central nervous system also provides prophylaxis against HIV‑associated neurocognitive disorders. Nonetheless, the propensity for resistance development underscores the necessity of baseline resistance testing and routine viral load monitoring.

Monitoring and Follow‑Up

Routine assessment of liver function tests (ALT, AST) and complete blood counts is advised during the initial months of therapy. Neuropsychiatric symptoms should be evaluated using standardized scales, such as the Brief Psychiatric Rating Scale, to guide therapeutic decisions. Therapeutic drug monitoring may be implemented when patients exhibit signs of toxicity or when pharmacogenetic testing indicates high metabolic variability.

Special Populations

In pregnancy, efavirenz exposure is associated with neural tube defects when administered during the first trimester; thus, alternative agents are preferred. Pediatric dosing requires weight‑based calculations and consideration of developmental pharmacokinetics. In patients with renal impairment, dose adjustments are typically unnecessary due to predominant hepatic clearance, yet caution is warranted if concomitant nephrotoxic agents are used.

Clinical Applications/Examples

Case Scenario 1: First‑Line Therapy in a Treatment‑Naïve Adult

A 32‑year‑old man presents with a CD4 count of 150 cells/mm³ and a plasma HIV‑1 RNA level of 200,000 copies/mL. Baseline genotypic testing reveals no resistance mutations. The recommended regimen includes efavirenz 600 mg once daily combined with tenofovir disoproxil fumarate and emtricitabine. Over 24 weeks, viral load declines below the detection limit, and CD4 count rises to 400 cells/mm³. The patient reports mild insomnia that resolves after the first month. This scenario exemplifies typical efficacy and tolerability in a first‑line setting.

Case Scenario 2: Managing Neuropsychiatric Adverse Events

A 45‑year‑old woman on efavirenz therapy experiences vivid dreams and anxiety. Her plasma efavirenz concentration is 4.5 µg/mL, exceeding the upper therapeutic threshold. Dose reduction to 400 mg daily is implemented, resulting in symptomatic improvement and a trough concentration of 3.2 µg/mL. This illustrates the utility of dose adjustment guided by pharmacokinetic principles to mitigate adverse events.

Case Scenario 3: Drug–Drug Interaction with Oral Contraceptives

A 28‑year‑old patient on efavirenz concurrently uses oral contraceptive pills (OCPs). Serum estradiol levels are subtherapeutic, indicating reduced OCP efficacy due to efavirenz‑induced CYP3A4 induction. Switching to a non‑hormonal contraceptive method is advised. This case highlights the necessity for clinicians to anticipate and manage pharmacokinetic interactions.

Case Scenario 4: Resistance Development and Regimen Modification

A 50‑year‑old patient with a history of poor adherence presents with persistent viremia. Genotypic testing identifies the K103N mutation. Efavirenz is discontinued and replaced with a boosted protease inhibitor regimen, leading to viral suppression within 12 weeks. This demonstrates the importance of resistance testing and timely regimen alteration.

Summary / Key Points

• Efavirenz is a non‑nucleoside reverse transcriptase inhibitor with a long half‑life, enabling once‑daily dosing.
• Its pharmacokinetics are influenced by CYP2B6 and CYP3A4 polymorphisms, necessitating consideration of genetic testing and therapeutic drug monitoring.
• Mechanism of action involves binding to an allosteric pocket of reverse transcriptase, inducing conformational changes that halt viral DNA synthesis.
• Common adverse events include neuropsychiatric symptoms and hepatotoxicity; dose adjustments can alleviate toxicity.
• Drug–drug interactions, particularly with CYP3A4 substrates and inhibitors, must be carefully managed.
• Resistance mutations such as K103N reduce efficacy, requiring regimen modification based on genotypic assays.
• Clinical scenarios illustrate typical therapeutic outcomes, adverse event management, and interaction considerations.
• Regular monitoring of viral load, liver function, and neuropsychiatric status is essential for optimal patient care.

By integrating pharmacological principles with clinical practice, this monograph aims to equip medical and pharmacy students with a comprehensive understanding of efavirenz, facilitating informed therapeutic decisions and improved patient outcomes.

References

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