(17.5%)
 77/334

(22.4%)
 22/183
(12.0%)
1Discontinuations or virological failures considered as failures.
2Based on GSS score.
5.2 Pharmacokinetic properties
The pharmacokinetic properties of enfuvirtide have been eva luated in HIV-1-infected adult and paediatric patients.
Absorption: The absolute bioavailability after subcutaneous administration of enfuvirtide 90 mg in the abdomen was 84.3 ± 15.5%. Mean (± SD) Cmax was 4.59 ± 1.5 μg/ml, AUC was 55.8 ± 12.1 μg*hr/ml The subcutaneous absorption of enfuvirtide is proportional to the administered dose over the 45 to 180 mg dose range. Subcutaneous absorption at the 90 mg dose is comparable when injected into abdomen, thigh or arm. In four separate studies (N = 9 to 12) the mean steady state trough plasma concentration ranged from 2.6 to 3.4 μg/ml.
Distribution: The steady state volume of distribution with intravenous administration of a 90 mg dose of enfuvirtide was 5.5 ± 1.1 l. Enfuvirtide is 92% bound to plasma proteins in HIV infected plasma over a plasma concentration range of 2 to 10 μg/ml. It is bound predominantly to albumin and to a lower extent to α-1 acid glycoprotein. In in vitro studies, enfuvirtide was not displaced from its binding sites by other medicinal products, nor did enfuvirtide displace other medicinal products from their binding sites. In HIV patients, enfuvirtide levels in the cerebrospinal fluid have been reported to be negligible.
Biotransformation: 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. In vitro human microsomal studies and in in vivo studies indicate that enfuvirtide is not an inhibitor of CYP450 enzymes. In in vitro human microsomal and hepatocyte studies, hydrolysis of the amide group of the C-terminus amino acid, phenylalanine results in a deamidated metabolite and the formation of this metabolite is not NADPH dependent. This metabolite is detected in human plasma following administration of enfuvirtide, with an AUC ranging from 2.4 to 15% of the enfuvirtide AUC.
Elimination: Clearance of enfuvirtide after intravenous administration 90 mg was 1.4 ± 0.28 l/h and the elimination half-life was 3.2 ± 0.42 h. Following a 90 mg subcutaneous dose of enfuvirtide the half-life of enfuvirtide is 3.8 ± 0.6 h. Mass balance studies to determine elimination pathway(s) of enfuvirtide have not been performed in humans.
Hepatic impairment: The pharmacokinetics of enfuvirtide have not been studied in patients with hepatic impairment.
Renal impairment: Analysis of plasma concentration data from patients in clinical trials indicated that the clearance of enfuvirtide is not affected to any clinically relevant extent in patients with mild to moderate renal impairment. In a renal impairment study AUC of enfuvirtide was increased on average by 43-62% in patients with severe or end stage renal disease compared to patients with normal renal function. Haemodialysis did not significantly alter enfuvirtide clearance. Less than 13% of the dose was removed during haemodialysis. No dose adjustment is required for patients with impaired renal function.
Elderly: The pharmacokinetics of enfuvirtide have not been formally studied in elderly patients over 65 years of age.
Gender and Weight: Analysis of plasma concentration data from patients in clin