Half-life antivirals

Polyethylene glycol (PEG) consists of repeating units of ethylene glycol forming linear or branched polymers with different molecular masses. Pegylation is the process by which PEG chains are covalently attached to lEN molecules. Pegylation confers a number of properties on lEN-a molecules, such as sustained blood levels that enhance antiviral effectiveness and reduce adverse reactions, as well as a longer half-life and improved patient compliance (Kozlowski et al. 2001). 

Fig. 5.1 Regulators of pre- and post-integration latency. Pre-integration latency is regulated as the viral RNA is reverse transcribed into the proviral DNA (A). This is controlled by the avaUabdity of the nucleotide pool, half life of the forming proviral cDNA copy, and the interaction of the viral protein Vif with the cellular antiviral protein APOBEC, espedaUy family members 3G and 3R It is also regulated at the step of transport across the nuclear membrane through the availability of ATP as the process requires energy (B). Post-integration, the proviral DNA copy of the viral genome, is regulated maiiily by the avadabdity of host transcription factors, especially NF-kB and NFAT (C)...

Alemtuzumab is the antibody to the CD52 receptor present on B and T lymphocytes. The pharmacokinetics of alemtuzumab demonstrate a terminal half-life of 7 days. Alemtuzumab has shown clinical activity in the treatment of chronic lymphocytic leukemia. Severe and prolonged (6 months) immunosuppression may result, which necessitates prophylaxis with cotrimox-azole and antivirals to prevent opportunistic infections. 

Elvitegravir (18, GS-9137, JTK-303, EVG) is the second IN strand transfer inhibitor to advance into phase III clinical trials (Figure 7). EVG was derived from the quinolone antibiotics which do not show IN activity [39-41]. Through careful optimization, this work resulted in EVG displaying enzyme and antiviral activity of 7.2 and 0.9 nM, respectively. EVG has moderate bioavailability in preclinical species (29 and 34%), low clearance (Qp 0.5 and l.OL/h/kg) and a moderate half-life of 2.3 and 5.2h in rats and dogs, respectively [42]. It is primarily metabolized via CYP450 oxidation and shows a marked increase in human exposure with RTV boosting. 

Anthelmintic, antiprotozoal, anti-neoplastic, and antiviral agent Binds many proteins, i.e., cytokines. epidermal growth factor, and members of the FGF family inhibits dengue virus infec-tivity of host cells very long in vivo half-life, exhibits a wide range of toxic side effects 40-47... 

Hudarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine. Its cytotoxicity is not well understood. It is rapidly dephospho-rylated at the cell membrane level and then rephos-phorylated intracellularly by deoxycytidine kinase to the active triphosphate derivative. It inhibits DNA polymerase and DNA primase. It is also incorporated into DNA and RNA. Hudarabine is administered intravenously by infusion over 30-120 min. It is eliminated by renal excretion with a terminal half life 10 hours. Adverse effects include myelosuppres-sion, nausea, vomiting, chills and fever. The number of CD4 positive cells is reduced and the incidence of opportunistic infections is increased. 

Mechanism of Action Avirustatic antiviral that is converted to acyclovir triphosphate, becoming part of the viral DNA chain. Therapeutic Effect Interferes with DNA synthesis and replication of herpes simplex virus and varicella-zoster virus. Pharmacokinetics Rapidly absorbed after PO administration. Protein binding 13%-18%. Rapidly converted by hydrolysis to the active compound acyclovir. Widely distributed to tissues and body fluids (including cerebrospinal fluid CSF ). Primarily eliminated in urine. Removed by hemodialysis. Half-life 2.5-3.3 hr (increased in impaired renal function). 

Pharmacokinetics, safety, and antiviral effects of hypericin were studied in patients with chronic hepatitis C infection (Fig. 4) (71). The patients received an eight-weeks course of 0.05 and 0.10 mg/kg hypericin orally once a day. The pharmacokinetic data revealed a long elimination half-life (mean values of 36.1 and 33.8 hours, respectively, for the doses of 0.05 and 0.10 mg/ kg) and mean AUC determinations of 1.5 and 3.1 pg/mL/hr, respectively. Because relatively high doses of 0.05 and O.lOmg/kg/day were given, which will probably be not reached after oral intake of recommended doses of SJW extract preparations, it is not surprising that hypericin caused a considerable phototoxicity in this study. 

Other close structural analogues of saquinavir (17) incorporating the hydroxyethylamine isostere have been developed to provide potent inhibitors of HIV-1 protease. For example, palinavir (21) (Table III) inhibits the enzyme with a Kj of 0.03 nM and blocks viral replication with an EC50 of 7 nM This antiviral potency was not substantially affected by the addition of oci-acid glycoprotein at physiological concentrations however, 21 did show reduced activity against HIV-1 variants with active site mutations, including valine-32 to isoleucine and isoleucine-84 to valine (Lamarre et al., 1997). Pharmacokinetics in rats have been reported for palinavir. The compound exhibited an oral bioavailability of 20 to 30%, with a plasma half-life of 30 to 50 minutes. 

Antiviral Drug Mechanism of Action Viruses Affectedt Plasma Half-life (hours)... 

Systemic antiviral therapy promotes resolution of HZO skin lesions and reduces the incidence and severity of dendriform keratopathy, anterior uveitis, and stromal keratitis by decreasing the rate of virus replication. All patients with acute HZO should receive antiviral therapy with the goal of minimizing ocular complications. Acyclovir, valacyclovir, and femciclovir are FDA approved for management of herpes zoster. Acyclovir usually is administered orally in dosages of 800 mg five times per day far 7 days. Valacyclovir has better bioavailability when taken orally and can be used with a recommended dosage of 1 g three times a day for 7 days. Famciclovir, which has bioavailability similar to valacyclovir, has an increased half-life and also has the advantage of less frequent administration than acyclovir 500 mg three times a day for 7 days. 

Interferons (IFN) are glycoproteins which possess antiviral, antiproliferative and immunomodulatory properties. Besides the main types a, P and y, other forms are available (lymphoblastoid IFNa, consensus IFNa). Administration is subcutaneous. Bioavailability is about 90%. The serum peak is reached by using IFNa2a after 6-8 hours with a half-life period of 5 hours or by using IFNa2b after 3-12 hours with a half-life of 3 hours. Elimination is primarily via the kidneys. Interferons inhibit CYPIA2. There is no development of resistance. (158, 160, 182) (see chapter 40.5.1.1)... 

Amantadine The antiviral efficacy of amantadine was first reported by w. Davies et al. in 1964. The mode of action consists in preventing uncoating and viral maturation (inhibition of the release of the nucleic acids that have already penetrated the host cell). The active substance is almost completely absorbed following oral intake. It is eliminated unchanged via the kidneys. Half-life is about 16 hours. So far, it has been used to combat influenza virus type A. Tolerance is good. Amantadine on its own is only minimally effective against HCV it is therefore not suitable for initial monotherapy. 

Ribavirin This guanosine analogue was first used experimentally by o. Reichard et al. (1991) and in chronic hepatitis C by J. Andersson et al. (1991). It is rapidly absorbed and distributed in the body, but is excreted slowly (half-life 79 hours). The bioavailability is 45-65%. As a monotherapy, it only leads to a decrease in transaminases and a slight improvement in histological activity. Ribavirin may not exhibit a direct antiviral effect, but can trigger a favourable response to interferon. When combined with IFN, ribavirin proved far more efficacious in chronic hepatitis C (immunomo-dulation ) without any increase in the typical side effects of IFN. (49, 51, 53) (s. p. 707)... 

Trade names Amixx Endantadine Grippin-Merz Mantadix PK-Merz Protexin Symmetrel (Endo) Tregor Indications Parkinsonism, influenza A viral infection Category Adamantane Antiviral Half-life 10-28 hours... 

Category Antiviral, nucleotide analog Half-life 2.6 hours... 

Category Antimetabolite Antineoplastic Antiviral Half-life initial 10-15 minutes... 

Indications Chronic hepatitis B virus infection Category Antiviral Guanosine nucleoside analog Half-life 24 hours... 

Indications Acute herpes zoster, recurrent genital herpes Category Antiviral Guanine nucleoside analog Half-life 2-3 hours... 

Trade names Foscavir (AstraZeneca) Foscovir Indications Cytomegalovirus retinitis in patients with AIDS Category Antiviral DNA RNA polymerase inhibitor Half-life 3 hours... 

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