Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

Clinical Uses

Oral acyclovir has multiple uses (Table 49–1). In primary genital herpes, oral acyclovir shortens by approximately 5 days the duration of symptoms, the time of viral shedding, and the time to resolution of lesions; in recurrent genital herpes, the time course is shortened by 1–2 days. Treatment of primary genital herpes does not alter the frequency or severity of recurrent outbreaks. Long-term chronic suppression of genital herpes with oral acyclovir decreases the frequency both of symptomatic recurrences and of asymptomatic viral shedding in patients with frequent recurrences, thus decreasing sexual transmission. However, outbreaks may resume upon discontinuation of suppressive acyclovir. In recurrent herpes labialis, oral acyclovir reduces the mean duration of pain but not the time to healing. Oral acyclovir decreases the total number of lesions and duration of varicella (if begun within 24 hours after the onset of rash) and cutaneous zoster (if begun within 72 hours). However, because VZV is less susceptible to acyclovir than HSV, higher doses are required (Table 49–1). A meta-analysis suggested that acyclovir was superior to placebo in reducing the duration of "zoster-associated pain," a continuous variable combining acute and chronic pain. When given prophylactically to patients undergoing organ transplantation, oral acyclovir (200 mg every 8 hours or 800 mg every 12 hours) or intravenous acyclovir (5 mg/kg every 8 hours) prevents reactivation of HSV infection. The benefit of acyclovir for prevention of CMV infections in transplant patients is controversial.

Table 49–1. Agents to Treat or Prevent Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV) Infections.

1Dosage must be reduced in patients with renal insufficIency.

Intravenous acyclovir is the treatment of choice for herpes simplex encephalitis, neonatal HSV infection, and serious HSV or VZV infections (Table 49–1). In immunocompromised patients with zoster, intravenous acyclovir reduces the incidence of cutaneous and visceral dissemination.

Topical acyclovir is much less effective than oral therapy for primary HSV infection. It is of no benefit in treating recurrences.

Resistance

Resistance to acyclovir can develop in HSV or VZV through alteration in either the viral thymidine kinase or the DNA polymerase. Infections that are clinically resistant to acyclovir have been reported in immunocompromised hosts. Most clinical isolates are resistant on the basis of deficient thymidine kinase activity and thus are cross-resistant to valacyclovir, famciclovir, and ganciclovir. Agents such as foscarnet, cidofovir, and trifluridine do not require activation by viral thymidine kinase and thus have preserved activity against the most prevalent acyclovir-resistant strains.

Adverse Reactions

Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have occasionally been reported. Intravenous infusion may be associated with reversible renal dysfunction due to crystalline nephropathy or neurologic toxicity (eg, tremors, delirium, seizures); however, these are uncommon with adequate hydration and avoidance of rapid infusion rates. Chronic daily suppressive use of acyclovir for more than 10 years has not been associated with untoward effects. High doses of acyclovir cause testicular atrophy in rats, but there has been no evidence of teratogenicity to date in a cumulative registry and no effect on sperm production was demonstrated in a placebo-controlled trial of patients receiving daily chronic acyclovir.

Valacyclovir

Valacyclovir is the L-valyl ester of acyclovir. It is rapidly converted to acyclovir after oral administration, resulting in serum levels three to five times greater than those achieved with oral acyclovir and approximating those resulting from intravenous acyclovir administration. Oral

bioavailability is about 48%. As with acyclovir, uses of valacyclovir include treatment of first atacks or recurrences of genital herpes, suppression of frequently recurrent genital herpes, treatment of herpes zoster infection, and, recently, as a 1-day treatment for orolabial herpes (Table 49–1). Valacyclovir has also been shown to be effective in preventing cytomegalovirus disease after organ transplantation when compared with placebo. In general, comparative studies have shown similar or slightly improved efficacy of valacyclovir versus acyclovir for all indications; furthermore, valacyclovir therapy was associated with a shorter duration of zoster-associated pain than acyclovir in one study, as well as a lower frequency of postherpetic neuralgia. Once-daily dosing of valacyclovir (500 mg) as chronic suppression in persons with recurrent genital herpes has recently been shown to markedly decrease the risk of sexual transmission. Valacyclovir is generally well tolerated, although nausea, diarrhea, and headache may occur. AIDS patients receiving high-dosage valacyclovir chronically (ie, 8 g/d) had an increased incidence of gastrointestinal intolerance as well as thrombotic microangiopathies such as thrombotic thrombocytopenic purpura and hemolyticuremic syndrome. In transplant patients receiving valacyclovir (8 g/d), non-dose-limiting confusion and hallucinations were the most frequent side effects.

Famciclovir

Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, an acyclic guanosine analog (Figure 49–2). After oral administration, famciclovir is rapidly converted by first-pass metabolism to penciclovir, which shares many features with acyclovir. It is active in vitro against HSV-1, HSV- 2, VZV, EBV, and HBV. Activation by phosphorylation is catalyzed by the virus-specified thymidine kinase in infected cells, followed by competitive inhibition of the viral DNA polymerase to block DNA synthesis. Unlike acyclovir, penciclovir does not cause chain termination. Penciclovir triphosphate has lower affinity for the viral DNA polymerase than acyclovir triphosphate, but it achieves higher intracellular concentrations and has a more prolonged intracellular effect in experimental systems. The most commonly encountered clinical mutants of HSV are thymidine kinase-deficient and are cross-resistant to acyclovir and famciclovir.

Pharmacokinetics

The bioavailability of penciclovir from orally administered famciclovir is 70%; less than 20% is plasma protein-bound. A peak serum concentration of 2 g/mL is achieved following a 250 mg oral dose. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-infected cells, 20 hours in HSV-2-infected cells, and 7 hours in VZV-infected cells in vitro. Penciclovir is excreted primarily in the urine.

Clinical Uses

Oral famciclovir is effective for the treatment of first and recurrent genital herpes attacks and for chronic daily suppression (Table 49–1). It is also used to treat acute herpes zoster (shingles). In controlled trials in immunocompetent patients with zoster, famciclovir was similar to acyclovir in rates of cutaneous healing but was associated with a shorter duration of postherpetic neuralgia. Comparison of famciclovir to valacyclovir for treatment of herpes zoster in immunocompetent patients showed similar rates of cutaneous healing and pain resolution. However, neither drug decreased the incidence of postherpetic neuralgia.

Adverse Reactions

Oral famciclovir is generally well tolerated, although headache, diarrhea, and nausea may occur. As with acyclovir, testicular toxicity has been demonstrated in animals receiving repeated doses.

However, men receiving daily famciclovir (250 mg every 12 hours) had no changes in sperm morphology or motility. The incidence of mammary adenocarcinoma was also increased in female rats receiving famciclovir for 2 years.

Penciclovir

The guanosine analog penciclovir is the active metabolite of famciclovir (see above). Topical application of 1% penciclovir cream is effective for the treatment of recurrent herpes labialis in immunocompetent adults (Table 49–1). When therapy was initiated within 1 hour after the onset of signs or symptoms and continued every 2 hours during waking hours for 4 days, treatment with topical penciclovir resulted in a shortening of the mean duration of lesions, lesion pain, and virus shedding by approximately one-half day compared with placebo. Side effects are uncommon.

Trifluridine

Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis. The compound has in vitro activity against HSV-1, HSV-2, vaccinia, and some adenoviruses. It is phosphorylated intracellularly to its active form by cellular enzymes, then competes with thymidine triphosphate for incorporation by the viral DNA polymerase. Incorporation of trifluridine triphosphate into both viral and cellular DNA prevents its systemic use. Application of a 1% solution is effective in treating primary keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 and HSV-2. Topical application of trifluridine solution, alone or in combination with interferon alfa, has been used successfully in the treatment of acyclovir-resistant HSV infections.

Katzung PHARMACOLOGY, 9e > Section VIII. Chemotherapeutic Drugs > Chapter 49. Antiviral Agents >

Agents to Treat Cytomegalovirus (CMV) Infections

Ganciclovir

Ganciclovir is an acyclic guanosine analog (Figure 49–2) that requires triphosphorylation for activation prior to inhibiting the viral DNA polymerase. Initial phosphorylation is catalyzed by the virus-specified protein kinase phosphotransferase UL97 in CMV-infected cells. The activated compound competitively inhibits viral DNA polymerase and causes termination of viral DNA elongation. Ganciclovir has in vitro activity against CMV, HSV, VZV, EBV, and HHV-8. Its activity against CMV is up to 100 times greater than that of acyclovir.

Pharmacokinetics

Ganciclovir may be administered intravenously, orally, or via intraocular implant.

A 5 mg/kg dose of ganciclovir administered intravenously over 1 hour produces serum concentrations averaging 6–10 g/mL, with trough levels of approximately 1 g/mL. Cerebrospinal fluid concentrations are approximately 50% of those in serum. Intravitreal concentrations following intravenous administration average 1 g/mL. The half-life is 2–4 hours with normal renal function. Clearance of the drug is linearly related to creatinine clearance. Ganciclovir is readily cleared by hemodialysis. The bioavailability of oral ganciclovir is poor (6–9% when taken with food).

In patients with an intraocular implant, ganclovir is released into the vitreous cavity at a rate of

approximately 1.4 g/h.

Clinical Uses

Intravenous ganciclovir has been shown to delay progression of CMV retinitis in patients with AIDS when compared with no treatment (Table 49–2). Dual therapy with foscarnet and ganciclovir has been shown to be more effective in delaying progression of retinitis than either drug administered alone (see Foscarnet, below), although side effects are compounded. Intravenous ganciclovir is also used to treat CMV colitis and esophagitis. Intravenous ganciclovir, followed by either oral ganciclovir or high-dose oral acyclovir, reduces the risk of CMV infection in transplant recipients. Use of intravenous ganciclovir to treat CMV pneumonitis in immunocompromised patients may be beneficial, particularly in combination with intravenous cytomegalovirus immunoglobulin. Oral ganciclovir is indicated for prevention of end-organ CMV disease in AIDS patients and as maintenance therapy of CMV retinitis following induction. Although less effective than intravenous ganciclovir, the risk of myelosuppression and of catheter-related complications is diminished.

Table 49–2. Agents to Treat Cytomegalovirus (CMV) Infection.

1Dosage must be reduced in patients with renal insufficiency.

Ganciclovir may also be administered intraocularly to treat CMV retinitis, either by direct intravitreal administration or via an intraocular implant. The implant, which achieves high and prolonged intraocular levels of ganciclovir, has been shown to delay progression of retinitis to a greater degree than systemic therapy with ganciclovir. Surgical replacement is required at intervals of 5–8 months. Owing to the lack of systemic protection against end-organ CMV disease (eg, colitis, esophagitis, ventriculitis) in patients treated with the ganciclovir implant alone—as well as the absence of protection against contralateral retinal CMV infection—concurrent therapy with a systemic anti-CMV agent is recommended. A recent study showed that the combination of either intravenous or oral ganciclovir and the ganciclovir intraocular implant in AIDS patients with CMV retinitis resulted in a decreased incidence of Kaposi's sarcoma over 6 months compared with those treated with the implant alone.

Resistance

Sporadic cases of ganciclovir-resistant CMV infection have been reported since the introduction of ganciclovir in the late 1980s; clinical manifestations may include progressive disease or prolonged viremia. Until recently, the majority of resistant cases were in patients with AIDS receiving prolonged therapy with ganciclovir. However, with the advent of more widespread use of oral ganciclovir, often in combination with more intensive immunosuppressive therapies, an increased frequency of ganciclovir-resistant CMV infection has been noted in organ transplant recipients. The most common mechanisms of resistance are mutations in UL97, resulting in decreased levels of the triphosphorylated (ie, active) form of ganciclovir; mutations in UL54, which result in a mutant DNA polymerase, occur less frequently. Isolates with mutations in UL97 are not cross-resistant with cidofovir or foscarnet, while mutations in UL54 may confer cross-resistance to cidofovir (and, less frequently, foscarnet). Performance of antiviral susceptibility testing is recommended in patients in whom resistance is suspected clinically, as is the substitution of alternative therapies (eg, foscarnet), and concomitant reduction in immunosuppressive therapies, if possible. The addition of CMV hyperimmune globulin may also be considered.

Adverse Reactions & Drug Interactions

The most common side effect of systemic ganciclovir treatment (more common with intravenous than with oral administration) is myelosuppression, particularly neutropenia (20–40% of patients). Myelosuppression may be additive in patients receiving ganciclovir in combination with zidovudine, azathioprine, or mycophenolate mofetil. Central nervous system toxicity (headache, changes in mental status, seizures) has been rarely reported. Other potential adverse effects include fever, rash, abnormal liver function, and retinal detachment in patients with CMV retinitis. The drug is mitogenic in mammalian cells and carcinogenic and embryotoxic at high doses in animals and causes aspermatogenesis; the clinical significance of these preclinical data is unclear.

The primary potential adverse effects associated with the intraocular implant are vitreous

hemorrhage and retinal detachment.

Levels of ganciclovir may rise in patients taking concurrent probenecid. Concurrent use of ganciclovir with didanosine may result in increased levels of didanosine.

Valganciclovir

Mechanism of Action

Valganciclovir is a monovalyl ester prodrug that is rapidly hydrolyzed to the active compound ganciclovir (see Ganciclovir) by intestinal and hepatic esterases when administered orally.

Pharmacokinetics

Valganciclovir is well absorbed and rapidly metabolized in the intestinal wall and liver to ganciclovir. The absolute bioavailability of oral valganciclovir is 60%, and steady state AUC

increases by 30% with a high-fat meal. The AUC0–24hr resulting from valganciclovir (900 mg once daily) is similar to those noted after 5 mg/kg/d of intravenous ganciclovir. As with ganciclovir, the

major route of elimination is renal, through glomerular filtration and active tubular secretion. Plasma concentrations of valganciclovir are reduced by approximately 50% by hemodialysis.

Clinical Uses

Valganciclovir is indicated for the treatment of CMV retinitis in patients with AIDS (Table 49–2). A randomized, open-label study demonstrated similar efficacy of oral valganciclovir and intravenous ganciclovir for induction therapy. Although clinical data assessing maintenance therapy with valganciclovir are not yet available, the pharmacokinetic profile would suggest similarity with intravenous ganciclovir. Potential side effects and drug interactions are those associated with ganciclovir (see Ganciclovir).

Cidofovir

Cidofovir is a cytosine nucleotide analog with in vitro activity against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxviruses, polyomaviruses, and human papillomavirus. In contrast to ganciclovir, phosphorylation of cidofovir to the active diphosphate is independent of viral enzymes. After phosphorylation, cidofovir acts both as a potent inhibitor of and as an alternative substrate for viral DNA polymerase, competitively inhibiting DNA synthesis and becoming incorporated into the viral DNA chain. Isolates with resistance to cidofovir have been selected in vitro; these isolates tend to be cross-resistant with ganciclovir but retain susceptibility to foscarnet. Clinically significant resistance to cidofovir has not been reported to date.

Pharmacokinetics

Although the terminal half-life of cidofovir is about 2.6 hours, the active metabolite, cidofovir diphosphate, has a prolonged intracellular half-life of 17–65 hours, thus allowing widely spaced administration. A separate metabolite, cidofovir phosphocholine, has a half-life of at least 87 hours and may serve as an intracellular reservoir of active drug. Peak serum concentrations when administered with probenecid (see Clinical Uses) are about 19 g/mL. Cerebrospinal fluid penetration is poor after intravenous administration. Elimination involves active renal tubular secretion. High-flux hemodialysis has been shown to reduce the serum levels of cidofovir by approximately 75%.

Clinical Uses

Intravenous cidofovir is effective for the treatment of CMV retinitis. Intravenous cidofovir must be administered with probenecid (2 g at 3 hours prior to the infusion and 1 g at 2 and 8 hours after), which blocks active tubular secretion and decreases nephrotoxicity. Cidofovir dosage must be adjusted for alterations in the calculated creatinine clearance or the presence of urine protein prior to each infusion, and aggressive adjunctive hydration is required. Initiation of cidofovir therapy is contraindicated in patients with existing renal insufficiency. Direct intravitreal administration of cidofovir is not recommended due to ocular toxicity.

Other potential uses of cidofovir that are currently under investigation include treatment of the polyomavirus-associated progressive multifocal leukoencephalopathy syndrome in patients with AIDS, postexposure prophylaxis against smallpox, and topical treatment of molluscum contagiosum. Topical cidofovir is not currently available in a standardized preparation.

Adverse Reactions

The primary adverse effect of intravenous cidofovir is a dose-dependent nephrotoxicity. Concurrent administration of other potentially nephrotoxic agents (eg, amphotericin B, aminoglycosides, nonsteroidal anti-inflammatory drugs, pentamidine, foscarnet) should be avoided. Prior administration of foscarnet may increase the risk of nephrotoxicity. Other potential side effects include uveitis, decreased intraocular pressure, and probenecid-related hypersensitivity reactions. Neutropenia and metabolic acidosis are rare. The drug caused mammary adenocarcinomas in rats and is embryotoxic.

Foscarnet

Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate compound (Figure 49–2) that inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly, without requiring activation by phosphorylation. It has in vitro activity against HSV, VZV, CMV, EBV, HHV-6, HHV-8, and HIV. Resistance to foscarnet in HSV and CMV isolates is due to point mutations in the DNA polymerase gene and is typically associated with prolonged or repeated exposure to the drug. Mutations in the HIV-1 reverse transcriptase gene have also been described. Although foscarnet-resistant CMV isolates are typically cross-resistant to ganciclovir, activity is usually maintained against ganciclovirand cidofovir-resistant isolates of CMV.

Pharmacokinetics

The drug is available in an intravenous formulation only; poor oral bioavailability and gastrointestinal intolerance preclude oral use. Peak serum concentrations averaging 80–100 g/mL are achieved following an infusion of 60 mg/kg. Cerebrospinal fluid concentrations are 43–67% of steady state serum concentrations. Although the mean plasma half-life is 4.5–6.8 hours, up to 30% of the drug may be deposited in bone, with a half-life of several months. The clinical repercussions of this are unknown.

Clearance of foscarnet is primarily by the kidney and is directly proportionate to creatinine clearance. Serum drug concentrations are reduced by approximately 50% following a 3-hour hemodialysis.

Clinical Uses

Foscarnet is effective treatment for CMV retinitis, with an efficacy approximately equal to that of ganciclovir (Table 49–2). Foscarnet is also used for treatment of CMV colitis, CMV esophagitis, acyclovir-resistant HSV infection, and acyclovir-resistant VZV infection. The dose of foscarnet must be titrated according to the patient's calculated creatinine clearance prior to each infusion. Use of an infusion pump to control the rate of infusion is important to avoid toxicity, and relatively large volumes of fluid are required because of the drug's poor solubility. The combination of ganciclovir and foscarnet is synergistic in vitro against CMV and has been shown to be superior to either agent as monotherapy in delaying progression of retinitis. Foscarnet has been administered intravitreally for the treatment of CMV retinitis in patients with AIDS, but data regarding efficacy and safety are lacking.

As with ganciclovir, a decrease in the incidence of Kaposi's sarcoma has been observed in patients who have received foscarnet. However, treatment of patients with Kaposi's sarcoma using antiherpes agents has not been successful.

Adverse Reactions

Potential adverse effects of foscarnet include renal insufficiency, hypoor hypercalcemia, and hypoor hyperphosphatemia. Saline preloading helps to prevent nephrotoxicity, as does avoidance of concomitant administration of drugs with nephrotoxic potential (eg, amphotericin B, pentamidine, aminoglycosides). The risk of severe hypocalcemia is increased with concomitant use of pentamidine. Penile ulcerations associated with foscarnet therapy may be due to high levels of ionized drug in the urine. Nausea, vomiting, anemia, and fatigue have been reported; the risk of anemia may be additive in patients receiving concurrent zidovudine. Central nervous system toxicities include headache, hallucinations, and seizures. The drug caused chromosomal damage in preclinical studies.

Fomivirsen

Fomivirsen is an oligonucleotide that inhibits human CMV through an antisense mechanism. Binding of fomivirsen to target mRNA results in inhibition of immediate early region 2 protein synthesis, thus inhibiting virus replication. Although resistant isolates have been induced under selection pressure in vitro, clinical resistance has not been observed to date. Cross-resistance between fomivirsen and other anti-CMV agents (ganciclovir, cidofovir, foscarnet) would not be expected. Fomivirsen is injected intravitreally for the treatment of CMV retinitis in patients with AIDS and is indicated for patients who are intolerant of or unresponsive to alternative therapies. The drug is slowly cleared from vitreous with a half-life of approximately 55 hours in humans and is subsequently cleared from the retina. Measurable concentrations of drug are not detected in the systemic circulation following intravitreal administration. Immediate therapy of CMV retinitis with fomivirsen was more effective in delaying progression than deferred treatment in a recent clinical trial. Concurrent systemic anti-CMV therapy is recommended to protect against extraocular and contralateral retinal CMV disease. Potential side effects include iritis and vitreitis as well as increased intraocular pressure and changes in vision. An interval of at least 2–4 weeks is recommended between cidofovir administration and use of fomivirsen because of the risk of ocular inflammation.

Katzung PHARMACOLOGY, 9e > Section VIII. Chemotherapeutic Drugs > Chapter 49. Antiviral Agents >

Antiretroviral Agents

A large and increasing number of antiretroviral agents are currently available for treatment of HIV- 1-infected patients (Table 49–3). When to initiate therapy is controversial, but it is clear that monotherapy with any one agent should be avoided because of the need for maximal potency to durably inhibit virus replication and to avoid premature development of resistance. A combination of agents (highly active antiretroviral therapy; HAART) is usually effective in reducing plasma HIV RNA levels and in gradually increasing CD4 cell counts, particularly in antiretroviral-naive patients. Also important in selection of agents is optimization of adherence, tolerability, and convenience. Given that many patients will ultimately experience at least one treatment failure, close monitoring of viral load and CD4 cell counts is critical to trigger appropriate changes in therapy. The judicious use of drug resistance testing should be considered in selecting an alternative regimen for a patient who is not responding to therapy.

Table 49–3. Currently Available Antiretroviral Agents.