Chemical formula: C₂₀₄H₃₀₁N₅₁O₆₄ Molecular mass: 4,491.193 g/mol
Enfuvirtide is a member of the therapeutic class called fusion inhibitors. It is an inhibitor of the structural rearrangement of HIV-1 gp41 and functions by specifically binding to this virus protein extracellularly thereby blocking fusion between the viral cell membrane and the target cell membrane, preventing the viral RNA from entering into the target cell.
The susceptibility to enfuvirtide of 612 HIV recombinants containing the env genes from HIV RNA samples taken at baseline from patients in Phase III studies gave a geometric mean EC50 of 0.259 µg/ml (geometric mean + 2SD = 1.96 µg/ml) in a recombinant phenotype HIV entry assay. Enfuvirtide also inhibited HIV-1 envelope mediated cell-cell fusion. Combination studies of enfuvirtide with representative members of the various antiretroviral classes exhibited additive to synergistic antiviral activities and an absence of antagonism. The relationship between the in vitro susceptibility of HIV-1 to enfuvirtide and inhibition of HIV-1 replication in humans has not been established.
Incomplete viral suppression may lead to the development of drug resistance to one or more components of the regimen.
HIV-1 isolates with reduced susceptibility to enfuvirtide have been selected in vitro which harbour substitutions in amino acids (aa) 36-38 of the gp41 ectodomain. These substitutions were correlated with varying levels of reduced enfuvirtide susceptibility in HIV sitedirected mutants.
In phase III clinical studies HIV recombinants containing the env genes from HIV RNA samples taken up to week 24 from 187 patients showed >4 fold reduced susceptibility to enfuvirtide compared with the corresponding pre-treatment samples. Of these, 185 (98.9%) env genes carried specific substitutions in region of aa 36-45 of gp41. The substitutions observed in decreasing frequency were at aa positions 38, 43, 36, 40, 42 and 45. Specific single substitutions at these residues in gp41 each resulted in a range of decreases from baseline in recombinant viral susceptibility to enfuvirtide. The geometric mean changes ranged from 15.2 fold for V38M to 41.6 fold for V38A. There were insufficient examples of multiple substitutions to determine any consistent patterns of substitutions or their effect on viral susceptibility to enfuvirtide. The relationship of these substitutions to in vivo effectiveness of enfuvirtide has not been established. Decrease in viral sensitivity was correlated to the degree of pre-treatment resistance to background therapy.
Due to its novel viral target enfuvirtide is equally active in vitro against both wildtype laboratory and clinical isolates and those with resistance to 1, 2 or 3 other classes of antiretrovirals (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors). Conversely, mutations in aa 36-45 of gp41 which give resistance to enfuvirtide would not be expected to give cross resistance to other classes of antiretrovirals.
The pharmacokinetic properties of enfuvirtide have been evaluated in HIV-1-infected adult and paediatric patients.
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.
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.
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.
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.
The pharmacokinetics of enfuvirtide have not been studied in patients with hepatic 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.
The pharmacokinetics of enfuvirtide have not been formally studied in elderly patients over 65 years of age.
Analysis of plasma concentration data from patients in clinical trials indicated that the clearance of enfuvirtide is 20% lower in females than males irrespective of weight and is increased with increased body weight irrespective of gender (20% higher in a 100 kg and 20% lower in a 40 kg body weight patient relative to a 70 kg reference patient). However, these changes are not clinically significant and no dose adjustment is required.
Analysis of plasma concentration data from patients in clinical trials indicated that the clearance of enfuvirtide was not different in Afro-Americans compared to Caucasians. Other PK studies suggest no difference between Asians and Caucasians after adjusting exposure for body weight.
The pharmacokinetics of enfuvirtide have been studied in 37 paediatric patients. A dose of 2 mg/kg bid (maximum 90 mg bid) provided enfuvirtide plasma concentrations similar to those obtained in adult patients receiving 90 mg bid dosage. In 25 paediatric patients ranging in age from 5 to 16 years and receiving the 2 mg/kg bid dose into the upper arm, anterior thigh or abdomen, the mean steady-state AUC was 54.3 ± 23.5 μg*h/ml, Cmax was 6.14 ± 2.48 μg/ml, and Ctrough was 2.93 ± 1.55 μg/ml.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and late embryonal development. Long-term animal carcinogenicity studies have not been performed.
Studies in guinea pigs indicated a potential for enfuvirtide to produce delayed contact hypersensitivity. In a rat model on the resistance to influenza infection, an impairment of IFN-γ production was observed. The resistance to influenza and streptococcal infection in rats was only weakly compromised. The clinical relevance of these findings is unknown.
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