CHAPTER 1 INTRODUCTION AND OBJECTIVES

1.10 Drug Profile

Figure 1.5 Structure of Nevirapine

1.10.1Nevira
pine

1) Chemical name: 11- Cyclopropyl-4-methyl-5, 11-dihydro-6H-dipyride [3,2-

b:2’,3’-e] [1,4] diazepin-6-one.

2) Molecular formula: C15H14N4O

3) Molecular weight: 266.88 g/mol

4) Category: Non –Nucleoside Reverse transcriptase Inhibitor

(NNRTI) belongs to anti-retroviral class

5) Dosage forms: Tablet (Viramune, Boehringer Ingelheim)

6) Appearance: White, amorphous powder.

7) Melting point: 243.06 0C

8) pKa value : 5.06

9) Solubility: Slightly soluble in water, propanol & freely soluble

in methanol and Acetonitrile.

Sinhagad Institute of Pharmacy Narhe Pune - 41 25

CHAPTER 1 INTRODUCTION AND OBJECTIVES

11) Pharmacodynamic profile

Nevirapine selectively inhibit HIV-1 (but not HIV – 2) reverse transcriptase (RT) in a
non-competitive manner.

At 84 nmol/L nevirapine inhibits 50% of HIV-1 RT activity in vitro.

Nevirapine binds preferentially to the p66 subunit of RT at a hydrophobic peptide region

between tyrosine 181 (Tyr-181) and Tyrosine 188 (tyr-188). The binding site is distinctly
separate from the catalytic site of RT. Therefore, substrate binding is unaffected.

Nevirapine inhibits RT by slowing the rate of a magnesium ion dependent chemical

reaction catalyzed by the enzyme . Specifically, Nevirapine binding is thought to alter
the position of the aspartate Carboxyl ligands, which results in the slowing of the
catalytic reaction rate, but it has no effect on nucleotide binding or nucleotide – induced
conformational change.

Nevirapine produces a direct stimulatory effect on HIV RT ribonuclease (RNase H)

activity and alter the cleavage specificity of RNase H. The alternation in RNase H
specificity facilitate multiple cleavage instead of the usual primary cleavage at 18 th
nucleotide from the DNA 3’Terminus.

Nevirapine inhibits HIV-1 RT RNA and DNA dependent DNA polymerase activities in a
template dependent manner, incorporation of deoxyguanosine monophosphate is
preferentially inhibited in the RNA-dependent process versus deoxy thymidine
monophosphate in the DNA- dependent process.

12) Pharmacokinetic properties:

a) Absorption and distribution: NVP is small lipophillic molecule that is rapidly

and almost completely absorbed after oral administration in human .
Maximum plasma concentration achieved at about 4 h after drug administration
and the absolute bioavailability is 93% for the tablet formulation. Ingestion of
nevirapine with food delays the absorption but doesnot affect the bioavailability.
NVP can thus be taken with or without food. It is extensively distributed in the
body with cerebralspinal fluid (CSF) and semen, having concentration of about
30% and 60% respectively.

Sinhagad Institute of Pharmacy Narhe Pune - 41 26

CHAPTER 1 INTRODUCTION AND OBJECTIVES

b) Metabolism and excretion:

The drugs 17 beta-chloromethyl ester function is hydrolyzed to an inactive
carboxylic acid moiety.

13) Mechanism of action:

NNRTI binds allosterically at a distinct site away from the active site termed the
NNRTI pocket.As all NNRTI bind with in the same pocket, viral strain which are
resistant to nevirapine are usually also resistant to other NNRTI’s efavirenz and
delavirdine however second generation NNRTI’s like relpivirdine and etravirine are
effective in treatment for HIV Strain resistant to nevirapine and other first generation
drug in that same class.

14)Adverse effects35:

The most common adverse effect of Nevirapine is the development of mild or

moderate rash (13%) and severe orlife threatening skin reaction have been observed
like Stefenjohnson syndrome, toxic epidermal necrolysis and hypersensitivity (1.5%)

15) Drug interaction:

 NVP interact with anti tuberculosis drug like rifampicin, that results in
decrease of its level in blood. Interaction with antiretroviral drug like
Efavirenz, Indinavir, Lopinavir, Nelfinavir, Saquinavir and antifungal drugs
like Clarithromycin , Ketoconazole, NVP reduces the level of these drugs
during co-administration.

 NVP decreases anticoagulant effect of Acenocoumaraol, Dicumarol and

Anisindione. As NVP is strong CYP3A4 inducer, it decreases the effect of
Atazanavir, Ketoconazole, Estradiol, Atorvastatin,Roflumilast, Simvastatin,
Lovastatin by increasing their metabolism.It also increases the risk of toxicity
when taken in combination with Quinupristine

Sinhagad Institute of Pharmacy Narhe Pune - 41 27

 CHAPTER 1 INTRODUCTION AND OBJECTIVES

1.11 Literature survey

Table 1.9: Literature Survey chart
Sr. YEAR AUTHORS TITLE DETAILS
No
1. 2014 Sichilongo.K, Comparative Chromatography Comparison of GC-MS ,LC-UV in
Chingyana.C, MS Studies on Nevirapine determination of NVP in human
Massele.A. . plasma
2. 2013 Valuru.R, Phani. LC-MS/MS for simultaneous C18 column equipped with a 2.1 ×
B, Reddy.B, determination of Ziduvidine, 10 mm guard column.0.1% Formic
Bagul.R. Lamivudine, Nevirapine in Human acid in Water:Methanol (15:85 v/v)
plasma isocratic. pH 6.3
3. 2013 Zoubir.D, Validation of fast method for C-18 kromasil column ,
Cathenne.F, quantitative analysis of 16 drug Phosphate:Acetonitrile (60:40 v/v)
Claire.T et.al including Nevirapine by UPLC-MS/MS pH 4.6
4. 2013 Valluro.R , LC-MS/MS for simultaneous C-18 AQ Column , 1mM
Kilaru.N. determination of tenofovir, Ammonium Acetate :Acetonitrile
lamivudine,Nevirapine in human plasma (50:50 v/v)
pH 6.5
5. 2012 Umbelina.C, Evidence for Nevirapine bioactivation in First step in mechanism of
Alexandra M. man Nevirapine toxicity.

6. 2012 Murali.K, Simultaneous quantitation of C-18 column

Nageswara.M, lamivudine,ziduvidine, nevirapine in Acetonitrile:Formic acid
Jaswanth.K. human plasma by LC-MS and (76:24 v/v), pH 5.8
application to pharmacokinetic Flow rate 0.8ml/min

7. 2009 Prasada C, Development and validation of RP- C-18 column, Methanol: Acetate
Channabvaraj.C, HPLC method for estimation of buffer (60:40 v/v), pH = 3, flow
Aswini.G. nevirapine in bulk drug and tablet rate 1ml/min ,Wavelength =280nm

8. 2009 Nageswaranrao.R, 2D LC-MS/MS determination of C-18 column for separation by LC

Dhananjay.K, antiretroviral drug in rat serum and urine
Shinde,D.

9. 2009 Fengue.Q, Identification of a process impurity Impurities investigated by series of

Pennino.S, formed during synthesis of Nevirapine photo and oxidative studies
Bussaco.A. Analogue HIV NNRT Inhibitor using 0.1% formic acid and acetonitrile
LC/MS

10. 2007 Thomas.R. Quantitation of five nevirapine oxidative C-18 column 0.8 % Formic acid in
Gregor.T, metabolite in human plasma using LC- Water : Methanol (45:55 v/v)
Campbell.S, et.al MS

11. 2007 Tarinas.A, Bioequivalence study of two nevirapine Dose 200mg

Tapanes.R, tablet in HIV-Infected patient AUC 0.86-1.17
Gorizalez.D. Tmax -2.64
(duration of 12hr)

Sinhagad Institute of Pharmacy Narhe Pune - 41 28

 CHAPTER 1 INTRODUCTION AND OBJECTIVES

12. 2007 Mistri.N, High throughput LC-MS Simultaneous C-18 column

Jangid.A, estimation of Lamivudine , 0.5% glacial Acetic acid in water:
Pudage.A et.al Stavudine,Nevirapine in Human plasma Acetonitrile
(20:80 v/v)

13. 2006 Sarkar.M, Development and validation of RP- C-18 column

Khaisdavilli.R HPLC and UV method of analysis for Wavelength =313nm .
Parichagnala.R, quantitative estimation of antiretroviral 0.1% Formic acid in water:
et.al drug in pharmaceutical dosage forms Methanol (50:50 v/v)

14. 2003 Kaul.N, HPTLC Method for determination of Mobile phase

Agarwal.H, Nevirapine in Pharmaceutical dosage TouleneCarbon :
Paradkar.A. form Tetrachloride:Methanol:acetone:am
monia (3.5:3.5:2:1:0.05 % v/v)
Wavelength =289nm

15. 2003 Jingduanchi A, LC-MS/MS method for determination of Mobile phase

Judith.A, Nevirapine in human plasma Buffer:Acetonitrile (80:20% v/v)
Francesca.T. pH = 4.1
m/z of Nevirapine 267/226 628/421
for internal std
16. 2002 Marchei.E, RP-LC determination of Ziduvidine and C-18 column
Valvo.L, Pacifi.R. Nevirapine in Human Plasma Mobile phase
Pot. Dihydrogen phosphate and
acetonitrile (83:17v/v) pH 6.5
wavelength =265 nm

Sinhagad Institute of Pharmacy Narhe Pune - 41 29