Acyclovir (Acyclovir) - Description and Clinical Pharmacology

DESCRIPTION

Acyclovir is an antiviral drug active against herpes viruses. Acyclovir Injection is a formulation for intravenous administration. Acyclovir Injection is a sterile solution containing acyclovir 25 mg/mL. Acyclovir Injection is available in 20 mL and 40 mL vials, with each mL containing acyclovir sodium equivalent to 25 mg acyclovir. The pH has been adjusted with sodium hydroxide and if necessary, hydrochloric acid to fall in the range of 10.7 to 11.7. Dilution in any appropriate intravenous solution must be performed before infusion (see DOSAGE AND ADMINISTRATION: Method of Preparation and Administration). Each 20 mL vial contains 500 mg of acyclovir and 49 mg of sodium, and each 40 mL vial contains 1000 mg acyclovir and 98 mg of sodium.

The chemical name of acyclovir is 9-[(2-Hydroxyethoxy)methyl]guanine sodium. The molecular formula of acyclovir is C₈H₁₀N₅O₃ Na and it has the following structural formula:

Acyclovir sodium is a white, crystalline powder with a molecular weight of 247.19, and solubility in water at 25°C exceeding 100 mg/mL. At physiologic pH, acyclovir exists as the un-ionized form with a molecular weight of 225.21 and a maximum solubility of 2.5 mg/mL in water at 37°C. The pka’s of acyclovir are 2.27 and 9.25.

VIROLOGY

Mechanism of Antiviral Action

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV).

The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in three ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared to VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activities

The quantitative relationship between the in vitro susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus-sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC₅₀) vary greatly depending upon a number of factors.

Using plaque-reduction assays, the IC₅₀ against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC₅₀ for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC₅₀ of 1.35 mcg/mL.

Drug Resistance

Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from such patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK-negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.

CLINICAL PHARMACOLOGY

Pharmacokinetics

The pharmacokinetics of acyclovir after intravenous administration have been evaluated in adult patients with normal renal function during Phase 1/2 studies after single doses ranging from 0.5 to 15 mg/kg and after multiple doses ranging from 2.5 to 15 mg/kg every 8 hours. Proportionality between dose and plasma levels is seen after single doses or at steady state after multiple dosing. Average steady-state peak and trough concentrations from 1-hour infusions administered every 8 hours are given in Table 1.

Table 1: Acyclovir  Peak and Trough Concentrations at Steady State

Dosage Regimen	CSS max	CSS trough
5 mg/kg q 8 hr (n = 8)	9.8 mcg/ml range: 5.5 to 13.8	0.7 mcg/ml range: 0.2 to 1.0
10 mg/kg q 8 hr (n = 7)	22.9 mcg/ml range: 14.1 to 44.1	1.9 mcg/ml range: 0.5 to 2.9

Concentrations achieved in the cerebrospinal fluid are approximately 50% of plasma values. Plasma protein binding is relatively low (9% to 33%) and drug interactions involving binding site displacement are not anticipated.

Renal excretion of unchanged drug is the major route of acyclovir elimination accounting for 62% to 91% of the dose.

The only major urinary metabolite detected is 9-carboxymethoxymethylguanine accounting for up to 14.1% of the dose in patients with normal renal function.

The half-life and total body clearance of acyclovir are dependent on renal function as shown in Table 2.

Table 2: Acyclovir Half-life and Total Body Clearance

Creatine Clearance (mL/min/1.73 m2)	Half-Life (h)	Total Body Clearance
		(mL/min/1.73 m2)	(mL/min/mg)
>80	2.5	327	5.1
50 - 80	3.0	248	3.9
15 - 50	3.5	190	3.4
0 (Anuric)	19.5	29	0.5

Special Populations

Adults With Impaired Renal Function

Acyclovir was administered at a dose of 2.5 mg/kg to 6 adult patients with severe renal failure. The peak and trough plasma levels during the 47 hours preceding hemodialysis were 8.5 mcg/mL and 0.7 mcg/mL, respectively.

Consult DOSAGE AND ADMINISTRATION section for recommended adjustments in dosing based upon creatinine clearance.

Pediatrics

Acyclovir pharmacokinetics were determined in 16 pediatric patients with normal renal function ranging in age from 3 months to 16 years at doses of approximately 10 mg/kg and 20 mg/kg every 8 hours (Table 3). Concentrations achieved at these regimens are similar to those in adults receiving 5 mg/kg and 10 mg/kg every 8 hours, respectively (Table 1). Acyclovir pharmacokinetics were determined in 12 patients ranging in age from birth to 3 months at doses of 5 mg/kg, 10 mg/kg, and 15 mg/kg every 8 hours (Table 3).

Table 3: Acyclovir Pharmacokinetics in Pediatric Patients (Mean ± SD)

Parameter	Birth to 3 Months of Age (n = 12)	3 Months to 12 Months of Age (n = 16)
CL (mL/min/kg)	4.46 ± 1.61	8.44 ± 2.92
VDSS (L/kg)	1.08 ± 0.35	1.01 ± 0.28
Elimination Half-life (h)	3.80 ± 1.19	2.36 ± 0.97

Geriatrics

Acyclovir plasma concentrations are higher in geriatric patients compared to younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric Use).

Drug Interactions

Coadministration of probenecid with acyclovir has been shown to increase the mean acyclovir half life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced.

Clinical Trials

Herpes Simplex Infections in Immunocompromised Patients

A multicenter trial of acyclovir injection at a dose of 250 mg/m² every 8 hours (750 mg/m²/day) for 7 days was conducted in 98 immunocompromised patients (73 adults and 25 children) with orofacial, esophageal, genital, and other localized infections (52 treated with acyclovir and 46 with placebo). Acyclovir decreased virus excretion, reduced pain, and promoted healing of lesions.

Initial Episodes of Herpes Genitalis

In placebo-controlled trials, 58 patients with initial genital herpes were treated with intravenous acyclovir 5 mg/kg or placebo (27 patients treated with acyclovir and 31 treated with placebo) every 8 hours for 5 days. Acyclovir decreased the duration of viral excretion, new lesion formation, and duration of vesicles, and promoted healing of lesions.

Herpes Simplex Encephalitis

Sixty-two patients ages 6 months to 79 years with brain biopsy-proven herpes simplex encephalitis were randomized to receive either acyclovir (10 mg/kg every 8 hours) or vidarabine (15 mg/kg/day) for 10 days (28 were treated with acyclovir and 34 with vidarabine). Overall mortality at 12 months for patients treated with acyclovir was 25% compared to 59% for patients treated with vidarabine. The proportion of patients treated with acyclovir functioning normally or with only mild sequelae (e.g., decreased attention span) was 32% compared to 12% of patients treated with vidarabine.

Patients less than 30 years of age and those who had the least severe neurologic involvement at time of entry into study had the best outcome with treatment with acyclovir. An additional controlled study performed in Europe demonstrated similar findings.

Neonatal Herpes Simplex Virus Infection

Two hundred and two infants with neonatal herpes simplex infections were randomized to receive either acyclovir 10 mg/kg every 8 hours (n = 107) or vidarabine 30 mg/kg/day (n = 95) for 10 days. Outcomes are presented in Table 4.

Table 4: Mortality at 1 Year

HSV Disease Classification	Treatment Group
*SEM refers to localized infection with disease limited to skin, eye, and/or mouth.
+CNS refers to infection of the central nervous system with compatible neurologic and CSF findings.
++DISS refers to visceral organ involvement such as hepatitis or pneumonitis with or without CNS involvement.
	Acyclovir (n = 107)	Vidarabine (n = 95)
SEM* (n = 85)	0/54	0/31
CNS+ (n = 71)	5/35	5/36
DISS++ (n = 46)	11/18	14/28

Rates of neurologic sequelae at 1 year were comparable between the treatment groups.

Varicella-Zoster Infections in Immunocompromised Patients

A multicenter trial of acyclovir injection at a dose of 500 mg/m² every 8 hours for 7 days was conducted in immunocompromised patients with zoster infections (shingles). Ninety-four (94) patients were evaluated (52 patients were treated with acyclovir and 42 with placebo). Acyclovir was superior to placebo as measured by reductions in cutaneous dissemination and visceral dissemination.