Pharmacokinetics of Acyclovir and Its Metabolites in Cerebrospinal Fluid and Systemic Circulation after Administration of High-Dose Valacyclovir in Subjects with Normal and Impaired Renal Function

Abstract

Valacyclovir, the L-valyl ester prodrug of acyclovir (ACV), is widely prescribed to treat infections caused by varicella-zoster virus or herpes simplex virus. Rarely, treatment is complicated by reversible neuropsychiatric symptoms. By mechanisms not fully understood, this occurs more frequently in the setting of renal impairment. We characterized the steady-state pharmacokinetics of ACV and its metabolites 9-[(carboxymethoxy)methyl]-guanine (CMMG) and 8-hydroxy-acyclovir (8-OH-ACV) in cerebrospinal fluid (CSF) and the systemic circulation. We administered multiple doses of high-dose valacyclovir to 6 subjects with normal renal function and 3 subjects with chronic renal impairment (creatinine clearance [CrCl], ϳ15 to 30 ml/min). Dosages were 2,000 mg every 6 h and 1,500 mg every 12 h, respectively. Indwelling intrathecal catheters allowed serial CSF sampling throughout the dosing interval. The average steady-state concentrations of acyclovir, CMMG, and 8-OH-ACV were greater in both the systemic circulation and the CSF among subjects with impaired renal function than among subjects with normal renal function. However, the CSF penetration of each analyte, reflected by the CSF-to-plasma area under the concentration-time curve over the 6-or 12-h dosing interval (AUC ) ratio, did not differ based on renal function. Renal impairment does not alter the propensity for ACV or its metabolites to distribute to the CSF, but the higher concentrations in the systemic circulation, as a result of reduced elimination, are associated with proportionally higher concentrations in CSF.Valacyclovir, the L-valyl ester of the antiviral drug acyclovir (ACV), is widely prescribed for varicella-zoster virus and herpes simplex virus infections. Following oral administration, valacyclovir is rapidly and nearly completely hydrolyzed to acyclovir by first-pass intestinal and hepatic metabolism (13,27). Acyclovir crosses the blood-brain barrier, a desirable quality for the treatment of herpes encephalitis, neonatal herpes simplex virus infections, and, possibly, multiple sclerosis (7, 28). Acute, reversible neuropsychiatric symptoms were first associated with acyclovir therapy in the early 1980s (26), and similar adverse effects have been reported for the use of valacyclovir (1, 2, 10, 12, 15, 21, 24). Symptoms include ataxia, involuntary movements, dysarthria, disturbed consciousness, hyperreflexia, and deranged cerebral functions (hallucinations, confusion, and lethargy). Neuropsychiatric symptoms with valacyclovir are infrequent, but the risk increases with acute or chronic renal dysfunction, concomitant neurotoxic drugs, and advanced age (5, 11). The underlying mechanism for these side effects is unknown, and attempts to relate central nervous system (CNS) symptoms and systemic concentrations of acyclovir have been inconsistent (3,5,6,9), suggesting that a metabolite of acyclovir may be responsible or contributory (11).The major route of acyclovir elimination is the renal excretion of unchanged drug. Urinary recovery data after acyclovir a...

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Role of PhaseIMetabolism in Drug Activation and Clinical Treatment Outcomes

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