Enfuvirtide: PHARMACOKINETICS

In: Drug

9 Jun 2010

Enfuvirtide is a synthetic peptide and is thus not bioavailable orally. Following a twice-daily subcutaneous injection of 30 to 90 mg, its bioavailability is approximately 84.3%. Comparable absorption of the 90-mg dose has been reported in different injection sites of the abdomen, thigh, and arm.

The time to maximum concentration (Tmax) ranges from four to eight hours. The volume of distribution (Vd) is 5.5 liters, and the clearance (Cl) rate is 1.4 liters/hour. The area under-the-concen-tration-time curve (AUC) ranges from 25 to 113 mcg/ml, and the elimination half-life (T1/2) is 3.5 to 4 hours. canadian cialis

Enfuvirtide is bound predominantly to plasma albumin (approximately 92%) and, to a lesser extent, to alpha1-acid glycoprotein. The drug undergoes hydrolysis to form a deaminated metabolite at the C-terminal phenylalanine residue (Table 1). In clinical trials, enfuvirtide’s clearance was not affected when the patient’s creatinine clearance was 35 ml/minute or more; however, the effect of the drug’s clearance in patients with a creatinine clearance lower than 35 ml/minute is not known.

Table 1    Pharmacokinetic Parameters of Enfuvirtide

Parameter

Value

Cmax (mcg/ml) T    (hours)

max *          ‘

AUC (hours/mcg/ml)

5.0-1.7

4-8 25-113

Elimination half-life (hours)

3.5-4

Clearance (liter/hour)

1.44

Vd (liters)

5.5

It is recognized, however, that enfu-virtide’s clearance is affected by weight and gender. A 20% decrease in total clearance has been reported in low-weight patients (below 40 kg). Conversely, females have been shown to exhibit a 20% decrease in clearance, compared with their male counterparts.

CLINICAL TRIALS

The regulatory submission for enfuvirtide was based on data from two 24-week phase III trials of approximately 1,000 patients. One of these studies, TORO-1 (T-20 versus Optimized Regimen Only, study 1) was a multicenter, randomized, controlled, open-label trial in North and South America. Patients who had at least six months of previous treatment with agents in the three currently available classes of antiretrovirals— nucleoside reverse-transcriptase inhibitors (NRTIs), non-nucleoside reverse-transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs)—whose infection showed resistance to agents in these classes were included in the study. The enrolled patients also had median viral loads of 5.2 log10 and median CD4 counts of 75.5 cells/mm3.

Similarly, TORO-2 (T-20 versus Optimized Regimen Only, study 2) enrolled similar patients from Europe and Australia. Participants had to have only a minimum of three months of prior experience with antiretroviral agents and median viral loads of 5.1 log10 copies/ml and median CD4 counts of 98 cells/mm3.
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In both clinical trials, patients were randomly assigned, in a 2:1 ratio, to receive 90 mg of enfuvirtide subcuta-neously twice daily plus an optimized background regimen consisting of three to five antiretroviral agents or an optimized background regimen only. During the study, the investigational drugs tenofovir (Viread®, Gilead) and lopinavir-ritonavir (LPV/RTV) (Kaletra®, Abbott) were allowed as part of the optimized background regimen. The primary efficacy endpoint was a significant change in the viral load from baseline evaluation at the end of the 24thweek.


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