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Clinical Pharmacokinetics of Acyclovir

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Summary

Acyclovir is a selective anti-herpes virus agent. At present it is available in topical and intravenous formulations; an oral formulation is currently being developed.

Absorption of acyclovir after oral administration is slow, variable and incomplete. The bioavailability of oral acyclovir is low and decreases with increasing dosage. The average time to peak concentrations is approximately 2 hours and achievable peak concentrations following oral administration (600mg every 4 hours) are less than 6 μmol/L with current oral dosage forms.

Acyclovir tissue and fluid concentrations can be determined accurately and sensitively by high-performance liquid chromatography, radioimmunoassay, and by virus inhibition (bioassay). Acyclovir demonstrates biexponential elimination, with a terminal plasma half-life of 2 to 3 hours in patients with normal renal function. The volume of the central compartment (21 L/1.73m2) and the apparent volume of distribution at steady-state (48 L/1.73m2) are approximately that of extracellular fluid and total body water, respectively. The drug is distributed into all tissues, with concentrations in the kidney being the highest (10 times the simultaneous plasma concentration) and in central nervous tissue the lowest (25 to 70% of the corresponding plasma concentration). Acyclovir enters the cerebrospinal fluid, saliva and vaginal secretions at concentrations inhibitory to herpes simplex virus. The drug is poorly protein bound, in the range of 9 to 22%.

Acyclovir is eliminated mainly via the kidney by glomerular filtration and renal tubular secretion, with only a small percentage of the dose being oxidised to 9-carboxymethoxy-methylguanine (which is the only significant metabolite of acyclovir in man). Acyclovir has dose-independent kinetics. The renal clearance of acyclovir is about 75 to 80% of the total body clearance and approximately 3-fold greater than creatinine clearance. Probenecid reduces acyclovir renal clearance by 32%, presumably by inhibiting tubular secretion of the drug.

In anuric patients, acyclovir is slowly eliminated with a terminal plasma half-life of approximately 20 hours. The acyclovir total body clearance (29 ml/min/1.73m2) is only 10% of that seen in patients without renal impairment. Acyclovir is readily haemodialysable with an extraction coefficient of 0.45 and a dialysis clearance of 82 ml/min using a hollow fibre single-pass dialyser. A single haemodialysis (6h) reduces acyclovir concentrations by 60%.

The pharmacokinetics of acyclovir in children (greater than 1 year of age) are similar to those in adults. In neonates, the total body clearance is about one-third of that found in children and adults. The terminal plasma half-life is slightly longer in the neonate.

The toxicity of acyclovir appears to be minimal and consists of local irritation after extravasation, phlebitis, and occasionally reversible elevations in serum creatinine, especailly after intravenous bolus doses. Other adverse effects remain to be established. Acyclovir plasma concentrations of 50 to 100 μmol/L are easily achievable by slow intravenous administration without significant adverse effects. Dosage reduction is recommended in patients with impaired renal function, in order to achieve effective concentrations without concomitant drug accumulation.

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  1. Division of Clinical Pharmacology, Department of Medicine and Pharmacology, Cornell University Medical College, 1300 York Ave., New York, New York, 10021, USA

    Oscar L. Laskin

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Laskin, O.L. Clinical Pharmacokinetics of Acyclovir. Clin Pharmacokinet 8, 187–201 (1983). https://doi.org/10.2165/00003088-198308030-00001

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