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)
range: 5.5 to 13.8
range: 0.2 to 1.0
|10 mg/kg q 8 hr|
(n = 7)
range: 14.1 to 44.1
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
|Half-Life (h)||Total Body Clearance|
|50 - 80||3.0||248||3.9|
|15 - 50||3.5||190||3.4|
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.
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|
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).
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.
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.|
(n = 107)
(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.