Molecular and Clinical Pharmacokinetics of NNRTI

RegimensKatie Buckingham

School of Life Sciences

Human Immunodeficiency Virus

• HIV-1, HIV-2

• Acquired immunodeficiency syndrome (AIDS)

• Affect >30million people worldwide

• 1.5million deaths in 2013 (WHO, 2013)

Structure of HIV-1

Image source: http://www.quia.com/jg/1272861list.html

The HIV life cycle

Image source: http://hivconsult.in/hiv-treatment/how-hiv-treatment-works

NNRTI’s• Allosteric, non-competitive binding to the NNRTI-binding pocket

Figure2: The NNRTi Efavirenz bound to HIV-1 reverse transcriptase (Wright, DW, et al. 2012)

NNRTI’s• First line regimen for HIV-1 infection• Combination therapy• Not recommended for second-line treatments

ADVANTAGES DISADVANTAGES

Lower side effects High resistance profile

Better patient compliance Cross resistance common

Long plasma half life Require strict patient adherence

Current Approved NNRTI’s

Image source: Johnson BC, et al. 2012

Nevirapine• Viramune© - 200mg• Bioavailability >90%• Linear kinetics at therapeutic dosing

Adverse effects• Hypersensitivity• Hepatotoxicity

Image source: avimedi.net

Delavirdine• Rescriptor© - 400mg 3x daily• Bioavailabilty – 85%• T1/2 = 2.4h

Adverse effects• Anxiety, insomnia• GI and respiratory effects• Steven-Johnson’s syndrome

Efavirenz• Sustiva© - 600mg• Bioavailability 40-45%• T1/2 = 52-76hrs

Adverse effects• CNS side effects – 55%• CNS toxicity – Cmin >4ng/mL• Mild rash

Etravirine• Intelence© - 200mg 2x daily• Treatment experienced patients• Highly lipid soluble

Adverse effects• Rash• GI effects

Rilpivirine• Edurant© - 25mg• High bioavailavility• Fasting decreases AUC and Cmax

Adverse effects• Rash• Nausea• Abnormal dreams/nightmares

Drug Interactions• Unpredictable• Hepatic clearance• Metabolised by CYP450 isoenzymes• Other inhibitors/inducers of P450 enzymes

Nevirapine CYP3A4, CYP2B6 Auto-inducer

Delavirdine CYP3A4 Auto-inhibitor

Efavirenz CYP3A4, CYP2B6 Auto-inducer

Etravirine CYP3A* CYP2C9, CYP2C19 -

Rilpivirine CYP3A* -

Special Populations

Future Developments• Injectable formulations

-Rilpivirine-pre/post-prophylaxis-ease of use

• Novel drugs-Doravirine-Efficacy and safety-Resistance profiles

• Pharmacogenomics

Any questions?