Monograph of Efavirenz

Introduction

Efavirenz is a non‑nucleoside reverse transcriptase inhibitor (NNRTI) that has played a pivotal role in the management of human immunodeficiency virus (HIV) infection. The drug was first introduced in the mid‑1990s and rapidly became a cornerstone of combination antiretroviral therapy (cART) due to its once‑daily dosing regimen and high barrier to resistance. While efavirenz has largely been supplanted in certain settings by newer NNRTIs and integrase inhibitors, its continued use in resource‑limited regions and as part of salvage regimens underscores the enduring importance of understanding its pharmacologic profile.

Efavirenz’s unique mechanism of action, extensive metabolic pathways, and distinctive adverse effect spectrum provide a rich platform for exploring the interplay between pharmacodynamics, pharmacokinetics, and clinical outcomes. Consequently, a thorough monograph is essential for pharmacy and medical students to appreciate the drug’s therapeutic potential and limitations.

Learning Objectives

• Describe the pharmacologic classification and mechanism of action of efavirenz.
• Explain the pharmacokinetic parameters, including absorption, distribution, metabolism, and elimination.
• Identify key drug–drug interactions and genetic polymorphisms influencing efavirenz response.
• Discuss the clinical indications, dosing strategies, and monitoring requirements.
• Analyze case scenarios to apply pharmacologic principles in therapeutic decision‑making.

Fundamental Principles

Classification and Core Concepts

Efavirenz belongs to the non‑nucleoside reverse transcriptase inhibitor (NNRTI) class, which directly binds to an allosteric site adjacent to the active site of reverse transcriptase. This binding induces a conformational change that impairs polymerase activity. Unlike nucleoside reverse transcriptase inhibitors (NRTIs), efavirenz does not require phosphorylation for activity and therefore exhibits a distinct safety and pharmacokinetic profile.

Theoretical Foundations

The therapeutic efficacy of efavirenz is predicated upon maintaining plasma concentrations above the effective concentration (EC₅₀) for a sufficient duration to suppress viral replication. Pharmacodynamic modeling suggests that steady‑state trough concentrations (C_min) should exceed the *in vitro* EC₅₀ by a safety margin to mitigate resistance emergence. The drug’s long half‑life (≈ 40–55 h) facilitates once‑daily dosing but also necessitates careful consideration of accumulation and drug–drug interactions.

Key Terminology

• EC₅₀: Concentration required to achieve 50% of maximal antiviral effect.
• Half‑life (t_1/2): Time required for plasma concentration to decrease by 50%.
• Clearance (CL): Volume of plasma from which the drug is completely removed per unit time.
• Area Under the Curve (AUC): Integral of plasma concentration over time, representing overall drug exposure.
• Volume of Distribution (V_d): Hypothetical volume in which the total amount of drug would need to be uniformly distributed to produce the observed concentration.
• Cytochrome P450 (CYP): Enzyme family responsible for hepatic metabolism.

Detailed Explanation

Pharmacodynamics and Mechanism of Action

Efavirenz binds to the NNRTI pocket of HIV‑1 reverse transcriptase with high affinity, forming a non‑covalent complex. The binding induces a subtle shift in the β‑hairpin region, thereby reducing the enzyme’s ability to catalyze the incorporation of nucleotides into viral DNA. The drug’s inhibition is non‑competitive with nucleic acids and exhibits a slow dissociation rate, which contributes to its high potency.

Mathematical representation of the inhibitory effect can be described by the following equation:

V_max / (1 + (C / IC₅₀))

where V_max is the maximum rate of reverse transcription, C is efavirenz concentration, and IC₅₀ denotes the concentration that reduces enzyme activity by 50%.

Pharmacokinetics

Absorption

Efavirenz is administered orally and exhibits high bioavailability (≈ 80–90%). Absorption is concentration‑dependent and occurs primarily in the small intestine. Food intake enhances absorption, increasing C_max by up to 30%; however, the drug’s pharmacokinetic variability is largely attributed to inter‑individual differences in metabolism rather than absorption.

Distribution

The drug binds extensively to plasma proteins, particularly albumin (≈ 90%) and alpha‑1 acid glycoprotein. The volume of distribution is large (≈ 1,500 L), reflecting significant penetration into tissues, including the central nervous system (CNS). The high lipophilicity facilitates crossing the blood–brain barrier, which is clinically relevant given the CNS adverse effect profile.

Metabolism

Efavirenz is predominantly metabolized by hepatic cytochrome P450 enzymes, notably CYP2B6, with contributions from CYP3A4 and CYP2A6. The primary metabolic pathway involves 8‑hydroxylation, yielding an inactive metabolite (8‑OH‑efavirenz). Genetic polymorphisms in CYP2B6, particularly the 516G→T variant, can reduce enzymatic activity, resulting in higher plasma levels and increased risk of toxicity.

Elimination

Metabolites are excreted primarily via the biliary route; renal excretion accounts for a minor fraction (< 5%). The elimination half‑life is prolonged (≈ 40–55 h), and the drug demonstrates a linear pharmacokinetic profile across the therapeutic dose range of 200–600 mg daily. Clearance (CL) can be estimated using the relationship:

CL = Dose ÷ AUC

where Dose is administered daily and AUC reflects total exposure over a dosing interval.

Mathematical Relationships and Models

The concentration–time profile of efavirenz following a single oral dose can be approximated by a one‑compartment model with first‑order absorption and elimination:

C(t) = (F × Dose × k_a ÷ V_d × (e⁻k_elt – e⁻k_at)) ÷ (k_el – k_a)

where F denotes bioavailability, k_a is the absorption rate constant, k_el is the elimination rate constant (k_el = ln(2) ÷ t_1/2), and V_d is the volume of distribution.

Factors Affecting Pharmacokinetics

• Genetic Polymorphisms: CYP2B6 516G→T variant leads to decreased metabolism and elevated drug exposure.
• Drug‑Drug Interactions: Concomitant use of strong CYP3A4 inducers (e.g., rifampicin) reduces efavirenz levels, while inhibitors (e.g., ketoconazole) increase exposure.
• Age and Gender: No clinically significant differences reported; however, elderly patients may exhibit reduced hepatic clearance.
• Hepatic Function: Severe hepatic impairment necessitates dose adjustment or avoidance.
• Pregnancy: Physiologic changes may alter metabolism; efavirenz is contraindicated in the first trimester due to teratogenic risk.

Clinical Significance

Therapeutic Indications

Efavirenz is approved for use as part of first‑line or salvage antiretroviral regimens in HIV‑1 infection. Common combinations include efavirenz with tenofovir disoproxil fumarate and emtricitabine or lamivudine. The drug is also employed in treatment‑naïve patients or those with resistance to other NNRTIs, provided cross‑resistance patterns are absent.

Clinical Applications and Dosing

The standard dosing regimen is 600 mg once daily, taken approximately 1 hour before bedtime with or without food. A reduced dose of 400 mg may be considered in patients with mild hepatic impairment or those experiencing CNS toxicity. In patients with significant hepatic dysfunction, discontinuation is recommended due to impaired metabolism and increased toxicity risk.

Monitoring Parameters

• Viral Load: Suppression below 50 copies/mL is the primary therapeutic endpoint.
• CD4 Count: Monitoring immune recovery over time.
• Liver Function Tests: ALT and AST should be checked periodically to detect hepatotoxicity.
• Blood Glucose: Hyperglycemia can occur; monitoring is advised in diabetic patients.
• Plasma Efavirenz Concentrations: Therapeutic drug monitoring may be employed in patients with suspected resistance or adverse reactions, aiming for trough concentrations between 1–4 µg/mL.

Adverse Effects and Contraindications

CNS adverse effects, such as dizziness, vivid dreams, and visual disturbances, are dose‑related and may resolve with time or dose reduction. Rash, hepatotoxicity, and reversible visual hallucinations have been reported. Contraindications include pregnancy (first trimester) and severe hepatic impairment. The drug should be used cautiously in patients with pre‑existing ocular or neurologic conditions.

Clinical Applications/Examples

Case Scenario 1: Treatment‑Naïve Patient

A 35‑year‑old male presents with newly diagnosed HIV‑1 infection, CD4 count of 350 cells/mm³, and plasma viral load of 200,000 copies/mL. Baseline liver function tests are within normal limits. The patient is prescribed a standard regimen comprising efavirenz 600 mg daily, tenofovir disoproxil fumarate 300 mg daily, and emtricitabine 200 mg daily. Over 12 weeks, viral load falls below 50 copies/mL and CD4 count rises to 600 cells/mm³. Two weeks into therapy, the patient reports vivid dreams and mild dizziness. Dose reduction to 400 mg is considered, and symptoms diminish; viral suppression is maintained.

Case Scenario 2: Drug Interaction with Rifampicin

A 28‑year‑old female with HIV‑1 infection and tuberculous meningitis is started on rifampicin 600 mg daily. Efavirenz 600 mg daily is also initiated. Over 4 weeks, viral load remains unsuppressed, and plasma efavirenz trough concentrations are measured at 0.5 µg/mL, below therapeutic thresholds. Rifampicin’s potent CYP3A4 induction reduces efavirenz clearance. Switching to a regimen with a CYP3A4 non‑inducing antituberculous agent or increasing efavirenz dose is contemplated, balanced against potential CNS toxicity.

Case Scenario 3: Genetic Polymorphism Impact

A 52‑year‑old male with HIV‑1 infection is prescribed efavirenz 600 mg daily. He experiences severe CNS side effects: disorientation and visual disturbances. Pharmacogenomic testing reveals the CYP2B6 516G→T variant. Dosage adjustment to 400 mg daily results in tolerable side effects while maintaining viral suppression. This case illustrates the clinical utility of pharmacogenomics in optimizing efavirenz therapy.

Problem‑Solving Approach

1. Identify the clinical issue (e.g., subtherapeutic drug levels, adverse effects, drug interaction).
2. Assess patient factors (hepatic function, genetics, concomitant medications).
3. Consider pharmacokinetic adjustments (dose reduction, alternative agents, therapeutic drug monitoring).
4. Monitor efficacy and safety post‑adjustment (viral load, CD4 count, toxicities).
5. Adjust further as needed, ensuring adherence to evidence‑based guidelines.

Summary / Key Points

• Efavirenz is a NNRTI that inhibits reverse transcriptase by binding to an allosteric site, inducing a conformational change.
• Its long half‑life (≈ 40–55 h) permits once‑daily dosing but necessitates vigilance for accumulation and drug‑drug interactions.
• CYP2B6 polymorphisms significantly influence plasma concentrations; the 516G→T variant is associated with higher exposure and CNS toxicity.
• Standard dosing is 600 mg daily; dose reduction to 400 mg may mitigate adverse effects or accommodate hepatic impairment.
• Therapeutic monitoring with plasma trough concentrations (1–4 µg/mL) may be useful in resistant or intolerant patients.
• Efavirenz is contraindicated in pregnancy (first trimester) and severe hepatic dysfunction; caution is advised in patients with ocular or neurological disorders.
• Clinical decision‑making should integrate pharmacokinetic principles, patient genetics, and co‑administered drugs to achieve optimal therapeutic outcomes.

References

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