Pharmacokinetic Profile of Truvada

(Emtricitabine and Tenofovir Disoproxil

Fumarate)

Assignment Topic: Truvada

Course: Clinical Pharmacokinetics
Course Code: PHR426, Section: 01
—
Course Instructor:
Dr. G.M. Sayedur Rahman
Associate Professor, Department of
Pharmaceutical Sciences,
North South University.
—
Prepared By -
Name: Indrajit Barua Muthsuddy
ID: 1620793049
 Pharmacokinetic Profile of Truvada
(Emtricitabine and Tenofovir
Disoproxil Fumarate)

Truvada is a prescription medicine that is a combination of emtricitabine and tenofovir

disoproxil fumarate. Emtricitabine and tenofovir both are nucleoside reverse-transcriptase
inhibitors used to treat HIV infection. Emtricitabine is a synthetic nucleoside analog of
cytidine. Tenofovir is an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-
monophosphate.

Figure: Marketedly available capsule shape blue coloured tablet TRUVADA®, manufactured by
Gilead Sciences.

Truvada is mainly used as pre-exposure prophylaxis that can help reduce the risk of getting
HIV-1 through sex, when taken every day and used together with safer sex practices.
However, it is also used to treat HIV-1 infection with other agents of highly active
antiretroviral therapy (HAART).

 Chemistry
Pharmacokinetic Profile of Truvada PAGE 1
Truvada is a film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir
disoproxil fumarate, (which is equivalent to 245 mg of tenofovir disoproxil), as active
ingredients.

 Emtricitabine (1)
Emtricitabine is a white to off-white crystalline powder. It is the (-) enantiomer of a
thio analog of cytidine, which differs from other cytidine analogs in that it has a
fluorine in the 5-position (1).

Chemical name: 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)- 1,3-oxathiolan-5-

yl]cytosine.

Molecular formula: C8H10FN3O3S

Molecular weight: 247.24

Structural formula:

 Tenofovir disoproxil fumarate (1)

Tenofovir disoproxil fumarate is a fumaric acid salt of the bis-
isopropoxycarbonyloxymethyl ester derivative of tenofovir. It is a white to off-white
crystalline powder.

Chemical Name: 9-[(R)-2 [[bis[[(isopropoxycarbonyl)oxy]

methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1).

Molecular formula: C19H30N5O10P•C4H4O4

molecular weight: 635.52

Structural formula:

Pharmacokinetic Profile of Truvada PAGE 2

Ingredients used in Truvada (1)

As active pharmaceutical ingredients, 200 mg of emtricitabine and 300 mg of tenofovir

disoproxil fumarate are used in each film-coated tablet. Tenofovir disoproxil fumarate 300
mg is equivalent to 245 mg of tenofovir disoproxil. To formulate truvada tablets following
excipients are used: croscarmellose sodium, lactose monohydrate, magnesium stearate,
microcrystalline cellulose, and pregelatinized starch (gluten-free).

 Routes of administration & dosage forms

Truvada (emtricitabine and tenofovir disoproxil fumarate) is only found as a film-coated
tablet (200mg/300mg), which is for oral administration (2).

 Liberation

Liberation is the procedure where a pharmaceutical substance is discharged from the

formulation is conveyed in. This must happen before the medication can be absorbed into
the body.

Truvada has a disintegration time of 9.58±0.03 min, in vitro drug release for 45min in
0.01N HCl is found to be 99% and 99.8% for Emtricitabine and Tenofovir disoproxil
fumarate respectively (3). Truvada follows a drug release kinetics that is first-order release
model with fickian diffusion mechanism (3).

Truvada shows in-vitro drug discharge in 0.01N HCl over a time of 45 min uncovered that
sodium starch glycolate is seen as the better disintegrant when contrasted with lycatab-C (3).

Table: Pharmacokinetic parameters of truvada ( emtricitabine 200mg / tenofovir disoproxil

fumarate 300mg) (4)

Parameters Emtricitabine Tenofovir

Pharmacokinetic Profile of Truvada PAGE 3

 Fasted Oral Bioavailability (%) 92 (83.1–106.4) 25 (NC–45.0)
Plasma Terminal Elimination 10 (7.4–18.0) 17 (12.0–25.7)
Half-Life (hr)
Cmax (µg/mL) 1.8 ± 0.72 0.30 ± 0.09
AUC (µg·hr/mL) 10.0 ± 3.12 2.29 ± 0.69
CL/F (mL/min) 302 ± 94 1043 ± 115
CLrenal (mL/min) 213 ± 89 243 ± 33

 Absorption

pKa(2)

 The pKa for emtricitabine is 2.65

 The pKa for tenofovir is 3.75

Factor

 Food does not have a marked effect on the oral absorption of FTC or TDF, and
FTC/TDF may be administered with or without food (2).
Other Details

Though it is said that the administration of truvada with or without food does not make a
significant difference. A delayed Cmax time of tenofovir by approximately 0.75 hours is
shown when truvada is taken after high fat-containing food (2). The mean rise in AUC and
Cmax of tenofovir are approximately 35% and 15%, respectively (2).

Truvada is not available for IV administration. As tenofovir shows a little absorption rate, the
salt form tenofovir disoproxil fumarate is used to get better absorption. Emtricitabine and
tenofovir are both found as white to off-white crystal. But any the effect of the polymorphism
is not found.

 Distribution

Distribution is the procedure where a pharmaceutical substance is reversibly delivered

through the blood to the different organs in the body.

Pharmacokinetic Profile of Truvada PAGE 4

Volume of Distribution

 Emtricitabine shows an apparent central volume of distribution is 42.3L, and a

peripheral volume of distribution is 55.4L (5).
 Tenofofir shows a volume of distribution for both central and peripheral is 100 L (6).
Log p

 The partition coefficient (log p) of tenofovir disoproxil is 1.25, and for emtricitabine is
-0.43 (7).

Solubility

 Tenofovir shows a solubility of 13.4 mg/mL in water at 25 °C. Where, emtricitabine

shows a solubility of approximately 112 mg/mL in water at 25 oC (7).

Plasma Half Life

 FTC and tenofovir have plasma long half-life of 10 and 17 hrs, respectively (7).

AUC (µg·hr/mL)

 Emtricitabine shows a AUC (µg·hr/mL) rate of 10.0 ± 3.12 .

 Tenofovir shows a AUC (µg·hr/mL) rate is 2.29 ± 0.69.

Protein Binding (percentage and concentration)

 In vitro, The plasma proteins binding of emtricitabine is <4% and independent of

concentration over the range is 0.02−200 µg/mL (7). The shows a AUC
(µg·hr/mL) rate of 10.0 ± 3.12.
 In vitro, The plasma protein binding of tenofovir is <0.7% and the independent of
concentration over the range is 0.01– 25 µg/mL (7). It shows a AUC (µg·hr/mL)
rate is 2.29 ± 0.69.

Though truvada is not available for IV administration, marketed preparation of

emtricitabine and tenofovir can be found. The volume of distribution of emtricitabine

Pharmacokinetic Profile of Truvada PAGE 5

 and tenofovir on IV administration are approximately 1.4 L/kg and 800 mL/kg,
respectively.

Until now, Tissue binding and tissue extraction rates are not available for truvada.

 Metabolism

The process of phosphorylation mainly metabolizes Truvada. It does not affect CYP 450. So,
induction or inhibition of CYP 450 does not affect the biotransformation of emtricitabine
and tenofovir disoproxil fumarate (8).

There is limited metabolism of emtricitabine. The biotransformation of emtricitabine

includes oxidation of the thiol moiety to form the 3'-sulphoxide diastereomers
(approximately 9% of the dose) and conjugation with glucuronic acid to form 2'-O-
glucuronide (approximately 4% of the dose).  Also, emtricitabine did not inhibit uridine-5'-
diphosphoglucuronyl transferase, the enzyme responsible for glucuronidation (2).

Other factors that may influence the biotransformation are lipids composition, HIV
infection, host response to HIV, and other drugs in the ARVD regimen.

 Elimination
The drug Emtricitabine undergoes with limited metabolism, and primarily it excrete through
the kidney. As the primary elimination root of emtricitabine is kidney, it is completely
recovered (≈86% in the urine and ≈14% in the feces) (9). The systemic clearance of
emtricitabine is average 307 mL/min. Following oral administration, the elimination half-
life of emtricitabine is approximately 10 hours.

The kidney primarily excretes tenofovir by both filtration and an active tubular transport
system, with approximately 70-80% of the dose excreted unchanged in urine following
intravenous administration (9). The apparent clearance of tenofovir averaged approximately
307 mL/min. Renal clearance is approximately 210 mL/min, which is in excess of the
glomerular filtration rate. Following oral administration, the elimination half-life of
tenofovir is approximately 12 to 18 hours.

Factors affecting: Truvada is mainly eliminated by the process of glomerular filtration

and active tubular secretion. So patients who have kidney diseases or any kind of renal
impartments, the elimination process of tuvada will not work properly. They immediately

Pharmacokinetic Profile of Truvada PAGE 6

stop taking truvada. Coadministration of truvada with other drugs that are eliminated by
active tubular secretion may hamper elimination and increase the half-life.

 Pharmacology & M/A

Both FTC and TDF can be classified as nucleoside reverse transcriptase inhibitors (NRTIs)

Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated

by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate
inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural
substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA
which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of
mammalian DNA polymerase α, β, ε and mitochondrial DNA polymerase γ (4).

Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate is an acyclic nucleoside

phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate
requires initial diester hydrolysis for conversion to tenofovir and subsequent
phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate
inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-
triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir
diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial
DNA polymerase γ (4).

 Pregnancy class

The pregnancy category of truvada is B. FDA advised not to give this drug to pregnant
women unless it is needed clearly.

 Toxicity
 Kidney problems: Truvada can exhibit severe kidney problems including kidney
failure. Before prescribing truvada, physicians should check the condition of a patient
(10).
 Lactic acidosis: Truvada can cause serious lactic acidosis that can lead to a medical
emergency. One should contact the doctor if the following symptoms arise: weakness
or tiredness, unusual muscle pain, short or fast breathing, fast or abnormal
heartbeat, stomach pain with nausea and vomiting, cold or blue hands and feet (10).

Pharmacokinetic Profile of Truvada PAGE 7

  Severe liver problems: Truvada may produce toxic effects on the liver that may
lead to several liver problems. One should contact the health care provider if the
following symptoms arise: yellowish skin, the white part of eyes become yellowish,
dark "tea-coloured" urine, light-coloured stools, more prolonged loss of appetite and
stomach-area pain (10).
 Bone problems: Truvada exhibit severe toxic effect on the bone which includes
bone pain, softening or thinning, bone fractures (10).

 Side effects

Common side effects include headache, stomach pain, diarrhea, headache, dizziness,
depression, joint pain, back pain, colour change in the skin, decreased weight, etc (10).

 Adverse effect: (10)

 Immune system disorders: Allergic reaction
 Metabolism and nutrition disorders: Hypophosphatemia, Lactic acidosis
Respiratory, thoracic, and mediastinal disorders: Dyspnea
 Gastrointestinal disorders: Abdominal pain, Increased amylase, Pancreatitis
 Hepatobiliary disorders: Increased liver enzymes, Hepatitis
 Renal and urinary disorders: Renal insufficiency, Renal failure, Acute renal
failure, Fanconi syndrome, Proximal tubulopathy, Proteinuria, Increased creatinine,
Acute tubular necrosis, Nephrogenic diabetes insipidus, Polyuria, Nephritis.

 Indications
 As Pre-exposure prophylaxis (PrEP) of HIV-1 Infection: to reduce risk of
sexually acquired HIV-1 in at-risk uninfected adults and adolescents in combination
with safer sex practices (11).

 As Treatment of HIV-1 Infection: in combination with other antiretroviral

agents like nonnucleoside reverse transcriptase inhibitors or protease inhibitors,
truvada is used to treat HIV-1 infection (12).

 Contraindication
 When truvada is used for the treatment of HIV-1 infection:

• It should not be administred as a component of a triple nucleoside regimen.

Pharmacokinetic Profile of Truvada PAGE 8

 • It should not be coadministered with emtriva, viread or lamivudine containing
drugs.

 When truvada is used as Pre-exposure prophylaxis (PrEP):

 HBV infection: Patients with HBV should not take truvada. It will worsen the
HBV.
 Already infected by HIV-1: Truvada should not be used for pre-exposure
prophylaxis of HIV-1 infection to those who have infected already (11).
 Kedney disease: Truvada should not be used to patients with creatine
clearance rate less than 30 mL/min, acute kidney failure, requiring hemodialysis,
and other severe kidney disease. Since it is eliminated through renal tubular.
 Bone disease: Patients with decreased calcification or density of bone, broken
bone due to disease or illness and several other bone diseases should not take
truvada. It increases the severity of bone disease.

 Dosage
 The treatment of HIV-1 infection, the dosage of truvada and administration procedure
are given here (12):
 Adults:

200 mg/day emtricitabine and 300 mg/day tenofovir DF PO.

 Geriatric:

200 mg/day emtricitabine and 300 mg/day tenofovir DF PO.

 Adolescents:

weight 35 kg or more: 200 mg/day emtricitabine and 300 mg/day tenofovir DF PO.

weight 28 to 34 kg: 167 mg/day emtricitabine and 250 mg/day tenofovir DF PO.

 Children:

weight 35 kg or more: 200 mg/day emtricitabine and 300 mg/day tenofovir DF PO.

weight 28 to 34 kg: 167 mg/day emtricitabine and 250 mg/day tenofovir DF PO.

weight 22 to 27 kg: 133 mg/day emtricitabine and 200 mg/day tenofovir DF PO.

weight 17 to 21 kg: 100 mg/day emtricitabine and 150 mg/day tenofovir DF PO.

weight less than 17 kg: Safety and efficacy have not been established.

Pharmacokinetic Profile of Truvada PAGE 9

 For pre-exposure prophylaxis, the dose of truvada is one tablet (containing 200 mg of
emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily (13).

There is no sustain release dosage form available for truvada.

 Administration

The tablet should take orally with or without food. Patient should swallow the whole tablet;
not chew, crush, break, or dissolve (13).

 Re-purposing

To treat SARS-CoV-2 viral infection: Currently, a Gilead Sciences funded study is going
on for trying to repurposing the combination drug Truvada (emtricitabine/ tenofovir) in the
treatment of SARS-CoV-2 viral infection (14).

To treat Bladder Cancer: There is also a study going on the repurpose issue that is trying
to use truvada to treat bladder cancer (15).

Reference:

1. Drug Approval Package: Truvada (Emtricitabine and Tenofovir Disoproxil

Fumarate) NDA #021752 [Internet]. [cited 2020 Jun 13]. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021752s000_Tr
uvadaTOC.cfm

2. Dando TM, Wagstaff AJ. Emtricitabine/tenofovir disoproxil fumarate. Vol. 64,

Drugs. Springer; 2004. p. 2075–82.

3. Srilatha U, Rama Krishna M, Vasavi Reddy D, Devireddy SR. Formulation and

evaluation of emtricitabine and tinofovir disoproxil fumarate film coated
tablets. Int J Res Pharm Chem. 2015;5:116–25.

4. Plosker GL. Emtricitabine/tenofovir disoproxil fumarate: A review of its use in

HIV-1 pre-exposure prophylaxis. Vol. 73, Drugs. Springer; 2013. p. 279–91.

Pharmacokinetic Profile of Truvada PAGE 10

5. Valade E, Tréluyer JM, Bouazza N, Ghosn J, Foissac F, Benaboud S, et al.
Population pharmacokinetics of emtricitabine in HIV-1-infected adult patients.
Antimicrob Agents Chemother. 2014;58(4):2256–61.

6. Barditch-Crovo P, Deeks SG, Collier A, Safrin S, Coakley DF, Miller M, et al.

Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of
tenofovir disoproxil fumarate in human immunodeficiency virus-infected
adults. Antimicrob Agents Chemother. 2001;45(10):2733–9.

7. Muñoz de Benito RM, Arribas López JR. Tenofovir disoproxil fumarate-

emtricitabine coformulation for once-daily dual NRTI backbone. Expert Rev
Anti Infect Ther. 2006;4(4):523–35.

8. Metabolic Effects of Preexposure Prophylaxis With Coformulated Tenofovir

Disoproxil Fumarate and Emtricitabine [Internet]. [cited 2020 Jun 12].
Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051460/

9. Blum MR, Chittick GE, Begley JA, Zong J. Steady-State Pharmacokinetics of

Emtricitabine and Tenofovir Disoproxil Fumarate Administered Alone and in
Combination in Healthy Volunteers. J Clin Pharmacol [Internet]. 2007 Jun 1
[cited 2020 Jun 13];47(6):751–9. Available from:
http://doi.wiley.com/10.1177/0091270007300951

10. Palacios R, Hidalgo C, Ríos MJ, Rivero A, Muñoz L, Lozano F, et al.

Effectiveness and safety of simplification from tenofovir-lamivudine (TDF-
3TC) to tenofovir-emtricitabine (TDF-FTC) co-formulation (Truvada®) in
virologically suppressed HIV-infected patients on HAART. Eur J Clin
Microbiol Infect Dis. 2009 Apr 8;28(4):399–402.

11. South HTB. FDA approve Truvada to reduce the risk of sexual transmission.

12. Smith C. HIV treatment. Vol. 410, Economist (United Kingdom). Economist
Newspaper Ltd; 2014. p. 271–93.

13. Gazzard BG. Use of tenofovir disoproxil fumarate and emtricitabine

combination in HIV-infected patients. Expert Opin Pharmacother. 2006
Apr;7(6):793–802.

14. A Running List Of Covid-19 Treatments And Vaccines In Development |

Pharmacokinetic Profile of Truvada PAGE 11

 BiopharmaTrend [Internet]. [cited 2020 Jun 10]. Available from:
https://www.biopharmatrend.com/covid-19-treatments-and-vaccines/

15. Nguyen TM, Muhammad SA, Ibrahim S, Ma L, Guo J, Bai B, et al. DeCoST: A
new approach in Drug Repurposing from Control System Theory. Front
Pharmacol. 2018 Jun 5;9(JUN).

Pharmacokinetic Profile of Truvada PAGE 12