Aciclovir-induced Neuropsychiatric Symptoms- a Clinical Pharmacology Study

Aciclovir (ACV) and its prodrug valacyclovir (VACV) are used to treat infections caused by herpes simplex virus (HSV) and varicella zoster virus (VZV), and as prophylaxis against cytomegalovirus (CMV) infections in immunocompromised patients. Treatment with ACV has decreased the mortality in herpes simplex encephalitis (HSE) from about 70 % to less than 30 %, and has also reduced the morbidity. ACV is excreted mainly by the kidneys, while a minor proportion is metabolized to 9-carboxymethoxymethylguanine (CMMG) and 8-hydroxy-ACV. It has been found that CMMG concentrations increase if renal function is decreasing. ACV is considered to have low toxicity and benign side effects. However, increasing serum creatinine and acute renal failure have been reported, and in rare cases aciclovir-induced neuropsychiatric symptoms (AINS) have developed. The mechanism behind AINS is unknown. The aim of this thesis was to investigate if there is a correlation between increased serum and cerebrospinal fluid (CSF) concentrations of CMMG, and the development of AINS. In paper I we studied the ACV and CMMG serum concentrations in 44 asymptomatic patients and 49 patients with AINS. The CMMG concentration was significantly higher in AINS patients than in the asymptomatic group (p<0.001). A ROC analysis showed that a cut-off value of 11 μmol/L had the highest sensitivity and specificity to predict AINS compared to other predictors, such as ACV exposure, ACV concentrations and renal function tests. The hypothesis that CMMG is directly involved in AINS implies that it is present in the CNS. In paper II we did find measurable concentrations of CMMG in CSF, but only in subjects with AINS. Asymptomatic control subjects had CSF CMMG levels below the limit of detection. Paper III is a description of two cases developing Cotard’s syndromea delusion of being deadas a result of ACV treatment. Both patients had high serum concentrations of ACV and CMMG. In paper IV the signs and symptoms pattern of AINS were analyzed in a larger group of patients. We retrieved data from published case reports, ADR cases reported to the Swedish Medical Products Agency and from our own Therapeutic Drug Monitoring database, in all 275 cases. We also compared AINS with signs and symptoms from herpes encephalitis (HSE). The study confirmed that altered level of consciousness, confusion, and hallucinations were the most frequent clinical characteristics of AINS, while HSE patients presented with high fever, altered level of consciousness, focal neurological signs, and headache. Paper V is a single-dose, open-label pharmacokinetic crossover study with one intravenous part and one oral part. We found that CMMG levels in hemodialysis patients were more than 10 times higher than in healthy volunteers. Subjects with normal and moderately impaired renal function had CMMG levels close to, or below, measurable concentrations. The results of this thesis support the hypothesis that CMMG is a useful predictor of AINS and that it may be mechanistically involved. Symptoms of AINS cannot always be reliably discriminated from symptoms of HSE, and vice versa. Determination of serum and CSF CMMG concentrations may be a useful tool to diagnose AINS and when distinguishing between AINS and HSE. Dose regimens aimed to minimize CMMG exposure can be developed based on the PK results. LIST OF PUBLICATIONS This thesis is based on the following publications and manuscripts, referred to in the text by their Roman numerals: I. Helldén A, Odar-Cederlöf I, Diener P, Barkholt L, Medin C, Svensson J-O, Säwe J, Ståhle L. High serum concentrations of the acyclovir main metabolite 9-carboxymethoxymethylguanine in renal failure patients with acyclovirrelated neuropsychiatric side effects. Nephrol Dial Transplant. 2003 Jun;18(6):1135-41 II. Helldén A, Lycke J, Vander T, Svensson JO, Odar-Cederlöf I, Ståhle L. The aciclovir metabolite CMMG is detectable in the CSF of subjects with neuropsychiatric symptoms during aciclovir and valaciclovir treatment. J Antimicrob Chemother. 2006 May;57(5):945-9. Epub 2006 Mar 15. III. Helldén A, Odar-Cederlöf I, Larsson KA, Fehrman-Ekholm I, Lindén, T. Death delusion. BMJ. 2007 Dec 22;335(7633):1305 IV. Helldén A. Lindén T, Odar-Cederlöf I, Bergman U, Ståhle L. Clinical characteristics of aciclovir-induced neuropsychiatric symptoms in 275 patients. (In manuscript) V. Helldén A, Odar-Cederlöf I, Pohanka A, Ståhle L. Single-dose pharmacokinetics of acyclovir and its principal metabolite 9carboxymethoxymethylguainine (CMMG) in subjects with normal and impaired renal function and in hemodialysis patients. (In manuscript)