Enfuvirtide clinical pharmacology

# Clinical Pharmacology

## Pharmacokinetics
The pharmacokinetic properties of enfuvirtide were evaluated in HIV-1 infected adult and pediatric subjects.

### Absorption
Following a 90-mg single subcutaneous injection of FUZEON into the abdomen in 12 HIV-1 infected subjects, the mean (SD) Cmax was 4.59  1.5 g/mL, AUC was 55.8  12.1 gh/mL and the median Tmax was 8 hours (ranged from 3 to 12 h). The absolute bioavailability (using a 90-mg intravenous dose as a reference) was 84.3%  15.5%. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean (SD) steady-state Cmax was 5.0  1.7 g/mL, Ctrough was 3.3  1.6 g/mL, AUC0-12h was 48.7  19.1 gh/mL, and the median Tmax was 4 hours (ranged from 4 to 8 h).
Absorption of the 90-mg dose was comparable when injected into the subcutaneous tissue of the abdomen, thigh or arm.

### Distribution
The mean (SD) steady-state volume of distribution after intravenous administration of a 90-mg dose of FUZEON (N=12) was 5.5  1.1 L.
Enfuvirtide is approximately 92% bound to plasma proteins in HIV-infected plasma over a concentration range of 2 to 10 g/mL. It is bound predominantly to albumin and to a lower extent to -1 acid glycoprotein.
The CSF levels of enfuvirtide (measured from 2 hours to 18 hours after administration of enfuvirtide) in 4 HIV-infected subjects were below the limit of quantification (0.025 g/mL).

### Metabolism/Elimination
As a peptide, enfuvirtide is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool.
Mass balance studies to determine elimination pathway(s) of enfuvirtide have not been performed in humans.
In vitro studies with human microsomes and hepatocytes indicate that enfuvirtide undergoes hydrolysis to form a deamidated metabolite at the C-terminal phenylalanine residue, M3. The hydrolysis reaction is not NADPH dependent. The M3 metabolite is detected in human plasma following administration of enfuvirtide, with an AUC ranging from 2.4% to 15% of the enfuvirtide AUC.
Following a 90-mg single subcutaneous dose of enfuvirtide (N=12) the mean SD elimination half-life of enfuvirtide is 3.8  0.6 h and the mean SD apparent clearance was 24.8  4.1 mL/h/kg. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean SD apparent clearance was 30.6  10.6 mL/h/kg.

### Special Populations
Formal pharmacokinetic studies of enfuvirtide have not been conducted in subjects with hepatic impairment.
Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is not affected in patients with creatinine clearance greater than 35 mL/min. The results of a renal impairment study indicate clearance of enfuvirtide was reduced by 38% in subjects with severe renal impairment (CL = 11  35 mL/min; n = 4) and by 14 - 28% in subjects with end-stage renal disease maintained on dialysis (n = 8) compared to subjects with normal renal function (CL >80 mL/min; n = 8). Hemodialysis did not significantly alter enfuvirtide clearance.
No dose adjustment is recommended for patients with impaired renal function.
Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is 20% lower in females than males after adjusting for body weight.
Enfuvirtide clearance decreases with decreased body weight irrespective of gender. Relative to the clearance of a 70-kg male, a 40-kg male will have 20% lower clearance and a 110-kg male will have a 26% higher clearance. Relative to a 70-kg male, a 40-kg female will have a 36% lower clearance and a 110-kg female will have the same clearance.
No dose adjustment is recommended for weight or gender.
Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide was not different in Blacks compared to Caucasians. Other pharmacokinetic studies suggest no difference between Asians and Caucasians after adjusting for body weight.
The pharmacokinetics of enfuvirtide have been studied in 23 pediatric subjects aged 6 through 16 years at a dose of 2 mg/kg. Enfuvirtide pharmacokinetics were determined in the presence of concomitant medications including antiretroviral agents. A dose of 2 mg/kg twice daily (maximum 90 mg twice daily) provided enfuvirtide plasma concentrations similar to those obtained in adult subjects receiving 90 mg twice daily.
In the 23 pediatric subjects receiving the 2 mg/kg twice daily dose, the mean SD steady-state AUC was 56.3  22.3 gh/mL, Cmax was 6.3  2.4 g/mL, Ctrough was 3.1  1.5 g/mL, and apparent clearance was 40  17 mL/h/kg .
The pharmacokinetics of enfuvirtide have not been studied in patients over 65 years of age.