An overview of the molecular and clinical pharmacokinetics of the 5 current FDA approved non-nucleoside reverse transcriptase inhibitors for the treatment of HIV-type 1 virus.

1. Molecular and Clinical Pharmacokinetics
of NNRTI Regimens
Katie Buckingham
School of Life Sciences

2. Human Immunodeficiency Virus
• HIV-1, HIV-2
• Acquired immunodeficiency syndrome (AIDS)
• Affect >30million people worldwide
• 1.5million deaths in 2013 (WHO, 2013)

3. Structure of HIV-1
Image source: http://www.quia.com/jg/1272861list.html

4. The HIV life cycle
Image source: http://hivconsult.in/hiv-treatment/how-hiv-treatment-works

5. 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)

6. 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

7. Current Approved NNRTI’s
Image source: Johnson BC, et al. 2012

8. Nevirapine
• Viramune© - 200mg
• Bioavailability >90%
• Linear kinetics at therapeutic dosing
Adverse effects
• Hypersensitivity
• Hepatotoxicity
Image source: avimedi.net

9. Delavirdine
• Rescriptor© - 400mg 3x daily
• Bioavailabilty – 85%
• T1/2 = 2.4h
Adverse effects
• Anxiety, insomnia
• GI and respiratory effects
• Steven-Johnson’s syndrome

10. Efavirenz
• Sustiva© - 600mg
• Bioavailability 40-45%
• T1/2 = 52-76hrs
Adverse effects
• CNS side effects – 55%
• CNS toxicity – Cmin >4ng/mL
• Mild rash

11. Etravirine
• Intelence© - 200mg 2x daily
• Treatment experienced patients
• Highly lipid soluble
Adverse effects
• Rash
• GI effects

12. Rilpivirine
• Edurant© - 25mg
• High bioavailavility
• Fasting decreases AUC and Cmax
Adverse effects
• Rash
• Nausea
• Abnormal dreams/nightmares

13. 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* -

14. Special Populations

15. Future Developments
• Injectable formulations
-Rilpivirine
-pre/post-prophylaxis
-ease of use
• Novel drugs
-Doravirine
-Efficacy and safety
-Resistance profiles
• Pharmacogenomics

16. Any questions?