PHARMACEUTICAL

BIOTECHNOLOGY
ASSIGNMENT
ON
ENFUVIRTIDE
(PK AND PD PARAMETERS)
BY

MEDHA BANERJEE
IMTH-8A
1660091
ENFUVIRTIDE
Enfuvirtide (INN) is an HIV fusion inhibitor, the first of a class of
antiretroviral drugs used in combination therapy for the treatment of
HIV-1 infection. It is marketed under the trade name Fuzeon (Roche).

Mechanism of action

Enfuvirtide works by disrupting the HIV-1 molecular machinery at the

final stage of fusion with the target cell, preventing uninfected cells
from becoming infected. A biomimetic peptide, enfuvirtide was
designed to mimic components of the HIV-1 fusion machinery and
displace them, preventing normal fusion. Drugs that disrupt fusion of
virus and target cell are termed entry inhibitors or fusion inhibitors.HIV
binds to the host CD4+ cell receptor via the viral protein gp120; gp41, a
viral transmembrane protein, then undergoes a conformational change
that assists in the fusion of the viral membrane to the host cell
membrane. Enfuvirtide binds to gp41 preventing the creation of an
entry pore for the capsid of the virus, keeping it out of the cell.
Enfuvirtide is also an activator of the chemotactic factor receptor,
formyl peptide receptor 1, and thereby activates phagocytes and
presumably other cells bearing this receptor. The physiological
significance of this activation is unknown.

Dosage forms

By virtue of its peptide nature, enfuvirtide is marketed in injectable

form. The lyophilised enfuvirtide powder must be reconstituted by the
patient and administered twice daily by subcutaneous injection. Due to
the chronic nature of this kind of therapy, this dosage form may be a
major problem for the patient's adherence to this drug regimen.
Following a 90-mg single subcutaneous injection of FUZEON into the
abdomen: HIV-1 infected subjects:

Cmax: 4.59±1.5μg/mL

AUC: 55.8±12.1μg•h/mL

Tmax: 8 hours

Bioavailability: (using a 90-mg intravenous dose as a reference) was

84.3%±15.5%.

Following 90-mg bid dosing of FUZEON subcutaneously in combination

with other antiretroviral agents in 11 HIV-1 infected subjects:

Cmax: 5.0±1.7μg/mL

AUC: 48.7±19.1μg•h/mL

Tmax: 4 hours

Steady-state volume of distribution after intravenous administration of

a 90-mg dose of FUZEON (N=12) was 5.5±1.1 L

Elimination half-life of enfuvirtide is 3.8±0.6 h

Apparent clearance was 24.8±4.1mL/h/kg

A method for measuring a human immunodeficiency virus (HIV) cell

membrane fusion inhibitor (T-20/Ro 29-9800) and its metabolite (M-
20/Ro 50-6343) in human plasma by liquid chromatography tandem
mass spectrometry (LC-MS/MS) was developed. The relatively large
peptide analytes and their corresponding deuterated (d(10)) peptides
used as internal standard were isolated from plasma by protein
precipitation with two volumes of acetonitrile to plasma. A large pore
size reversed-phase C(18) column was employed to elute the peptides.
A triple quadrupole mass spectrometer with electrospray interface
operating in positive ion and multiple reaction monitoring modes with
transitions m/z 1124-->1343 for both T-20 and M-20 was utilized for
peak detection. The advantages of the method were a simple sample
preparation, specific and sensitive MS/MS detection, and a wide
dynamic range of 10-2000 ng/ml for T-20. The method was validated
and used for analyzing samples from clinical studies to provide
pharmacokinetic profiles of the HIV fusion inhibitor peptide drug and its
metabolite.

Pediatric vs Adult pharmacodynamics

Enfuvirtide is approved for HIV treatment in adults and dosage

recommendations exist for children aged six years or older. The safety
and efficacy study of 2.0 mg/kg subcutaneous enfuvirtide twice daily
for 48 weeks was conducted in 52 treatment-experienced, HIV-1-
infected pediatric patients (ages 3–16 years). There was no
significant difference observed in the enfuvirtide mean ± SD
pharmacokinetic parameters in children (n = 12, ages 5–11 years)
and adolescents (n = 13, ages 12–16 years): steady-state Cmax 6.43 ±
2.15 vs. 5.88 ± 2.81 µg/mL; Ctrough 2.87 ± 1.49 vs. 2.98 ± 1.66 µg/mL;
AUC0-12h 56.1 ± 19.4 vs. 52.7 ± 27.4 h·µg/mL. There was no
meaningful difference in the pharmacokinetic values between
children and adolescents. Pharmaceutics 2010,2407 treatment-
experienced HIV-1-infected children (3–12 years), 60 mg/m2
subcutaneous enfuvirtide twice daily reported mean single dose
AUC0-12h of 56.4 h·µg/mL, which is comparable to AUC0-12h of
55.8 h·µg/mL in adults and also similar to AUC0-12h of 48.7 h·µg/mL in
adults after s.c. BID 90 mg enfuvirtid. The pediatric study showed that
the body weight adjusted dosing in children was independent of age,
body weight, body surface area, and sexual maturity. In a
population pharmacokinetic analysis study by Zhang et al., 43 patients
(20 adolescents and 23 children) were included, with a mean age of
11 years, and a mean body weight of 35.7 kg [113]. Body weight was a
covariate for CL/F but not V/F. The population parameters CL/F, V/F,
and Ka for a 33 kg patient were 1.31 L/h, 2.31 L, and 0.105 h-1,
respectively. Age did not seem to affect the enfuvirtide exposure. This
analysis approves the body weight based enfuvirtide dosing in
pediatrics. In HIV-1-infected adults, enfuvirtide reported a small volume
of distribution (5.48 L), low clearance (1.4 L/h), and high plasma protein
binding (92%). Body weight based dosing (2 mg/kg BID) provides similar
pharmacokinetic profiles to those observed with 90 mg BID [114].
Pharmacokinetic parameter CL/F (1.31 L/h for a 33 kg patient) from
the pediatric study is comparable to the reported value from a previous
study in HIV-1-infected pediatric patients (CL = 1.42 L/h and F = 0.90
for a 21.3 kg patient) [20], and also comparable to the adult
population analysis with CL/F of 1.82 L/h for a 70 kg male patient
and 1.45 L/h for a 70-kg female patient [115]. The mentioned
pediatric enfuvirtide study by Soy et al involved 26 children (mean age
8.2 years and range 4.0–12.1 years) [20]. Patient weight was found to
have an effect on CL and V, but the effect was not statistically
significant. However, their predicted “adult” PK parameters were not
comparable with those observed in adults by Zhang et al [113].
Additionally, in the plot of CL (L/h) vs. weight, even though the data
covers a large weight range, it does not seem to capture all differences
between children and adults.