Pharmacokinetics of enfuvirtide in pediatric human immunodeficiency virus 1-infected patients receiving combination therapy

Roche, Nutley, NJ 07110, USA.
The Pediatric Infectious Disease Journal (Impact Factor: 2.72). 01/2005; 23(12):1137-41. DOI: 10.1097/01.inf.0000145476.97866.60
Source: PubMed


Enfuvirtide is the first of a new class of antiretroviral agents, the fusion inhibitors.
The primary objective of this analysis was to evaluate the pharmacokinetics of 2.0 mg/kg enfuvirtide in human immunodeficiency virus 1 (HIV-1)-infected children and adolescents when administered in combination with at least 3 other antiretrovirals.
Twenty-five HIV-1-infected pediatric patients (5-16 years of age) enrolled in an ongoing phase I/II study were included in this analysis. Patients received enfuvirtide 2.0 mg/kg sc twice daily (bid) for at least 7 days. Blood samples were collected on day 7, and plasma concentrations of enfuvirtide and its metabolite were measured by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetics measures [Cmax, tmax, Ctrough, and area under the concentration time curve time 0 to 12 hours (AUC12 hours)] were calculated from plasma concentration-time data by standard noncompartmental methods.
There was no significant difference between children and adolescents for enfuvirtide Cmax (6.43 versus 5.88 microg/mL), Ctrough (2.87 versus 2.98 microg/mL) and AUC12 hours (56.1 versus 52.7 hours . microg/mL). Similarly no significant differences were found when the pharmacokinetic measures were compared based on sexual maturity stages. A post hoc regression analysis based on AUC12 hours showed that body weight-adjusted dosing of enfuvirtide provides drug exposure that is independent of age group, body weight and body surface area.
Body weight-adjusted dosing of enfuvirtide, at a dose of 2.0 mg/kg sc bid, in HIV-1-infected pediatric patients at least 5 years of age, provides drug exposure comparable with that previously observed in HIV-1-infected adults after 90 mg sc bid dosing. Drug exposure in children and adolescents is independent of age group, body weight, body surface area and sexual maturity stage.

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    ABSTRACT: Enfuvirtide, the first fusion inhibitor approved for the treatment of HIV-1 infection, is a synthetic peptide that binds to HIV-1 glycoprotein 41, blocking the fusion of viral and cellular membranes. When administered subcutaneously at the recommended dose of 90mg twice daily with optimised background antiretroviral therapy, enfuvirtide significantly reduces plasma HIV-1 RNA levels up to 48 weeks compared with optimised background therapy alone. Enfuvirtide exhibits a small volume of distribution (5.48L), low systemic clearance (1.4 L/h) and high plasma protein binding (92%). Less than 17% of enfuvirtide is converted to a minimally active deaminated form of the parent drug. Both enfuvirtide and its metabolite are primarily eliminated via catabolism to amino acid residues. Following subcutaneous administration, enfuvirtide is almost completely absorbed, and exposure increases almost linearly with dose over the range 45–180mg. When administered at the recommended dose in adults, subcutaneous absorption is slow and protracted, resulting in relatively flat steady-state plasma concentration-time profiles. Bioavailability is high (84.3%) and the elimination half-life (3.8 hours) supports twice-daily administration. Comparable absorption was observed from three different anatomical injection sites. The pharmacokinetic-pharmacodynamic relationship indicates that the recommended dose, in combination with other active antiretrovirals, is optimal. Enfuvirtide clearance is influenced to a small extent by sex and bodyweight but this does not necessitate dosage adjustment. In vitro and in vivo studies indicate that enfuvirtide has a low potential to interact with concomitantly administered drugs. Enfuvirtide did not influence concentrations of drugs metabolised by cytochrome P450 (CYP) 3A4, CYP2D6 or N-acetyltransferase, and had only minimal effects on those metabolised by CYP1A2, CYP2E1 or CYP2C19. Coadministration of ritonavir, ritonavir-boosted saquinavir or rifampicin (rifampin) did not result in clinically significant changes in enfuvirtide pharmacokinetics. In HIV-1-infected paediatric patients, subcutaneous dosages based on bodyweight (2 mg/kg twice daily) produce pharmacokinetics broadly similar to those observed in adults administered 90mg twice daily.
    No preview · Article · Feb 2005 · Clinical Pharmacokinetics
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    ABSTRACT: Current therapeutic intervention in HIV infection relies upon 20 different drugs. Despite the impressive efficacy shown by these drugs, we are confronted with an unexpected frequency of adverse effects, such as mitochondrial toxicity and lipodystrophy, and resistance, not only to individual drugs but to entire drug classes. Thus, there is now a great need for new antiretroviral drugs with reduced toxicity, increased activity against drug-resistant viruses and a greater capacity to reach tissue sanctuaries of the virus. Two different HIV molecules have been selected as targets of drug inhibition so far: reverse transcriptase and protease. Drugs that target the interactions between the HIV envelope and the cellular receptor complex are a ‘new entry’ into the scenario of HIV therapy and have recently raised great interest because of their activity against multidrug-resistant viruses. There are several compounds that are at different developmental stages in the pipeline to counter HIV entry, among them: (i) the attachment inhibitor dextrin-2-sulfate; (ii) the inhibitors of the glycoprotein (gp) 120/CD4 interaction PRO 542, TNX 355 and BMS 488043; (iii) the co-receptor inhibitors subdivided in those targeting CCR5 (SCH 417690 [SCHD], UK 427857 GW 873140, PRO 140, TAK 220, AMD 887) and those targeting CXCR4 (AMD 070, KRH 2731); and (iv) the fusion inhibitors enfuvirtide (T-20) and tifuvirtide (T-1249). The story of the first of these drugs, enfuvirtide, which has successfully completed phase III clinical trials, has been approved by the US FDA and by the European Medicines Agency, and is now commercially available worldwide, is an example of how the knowledge of basic molecular mechanisms can rapidly translate into the development of clinically effective molecules.
    No preview · Article · Feb 2005 · Drugs
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    ABSTRACT: A preliminary open-label study on the administration of the novel, parenteral HIV fusion inhibitor enfuvirtide as a part of a salvage antiretroviral treatment in a cohort of hardly pretreated and multiresistant patients with advanced HIV disease followed until 30 consecutive months of therapy is presented, and discussed on the ground of available experiences, and an update of literature evidences in this field. Expectations and concerns on the use of this novel anti-HIV compound (belonging to an innovative pharmacological class) in daily practice are debated, since no specific recommendations have been produced until now, and enfuvirtide administration appears significantly more effective when made in conjunction with at least one or two other active antiretroviral agents. The management of the very frequent site injection reactions represents an adjunctive problem in the treatment of these multi-problematic patients.
    No preview · Article · Apr 2005 · Recenti progressi in medicina
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