Parkinsonism and Related Disorders 15 (2009) 351353

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Parkinsonism and Related Disorders

journal homepage: www.elsevier.com/locate/parkreldis

Plasma amantadine concentrations in patients with Parkinsons disease

N. Nishikawa, M. Nagai, T. Moritoyo, H. Yabe, M. Nomoto*
Department of Medicine (Neurology), Ehime University Graduate School of Medicine, Shitsukawa Tohon, Ehime 791-0295, Japan

a r t i c l e i n f o
Article history: Received 15 April 2008 Received in revised form 31 July 2008 Accepted 8 August 2008 Keywords: Amantadine Parkinsons disease Plasma concentration Side effects Renal function Creatinine clearance

a b s t r a c t
We determined plasma amantadine concentrations in patients with Parkinsons disease (PD) in daily clinical practice and investigated the relationship between plasma concentration and adverse reactions to clarify the safe therapeutic range. Seventy-eight consecutive PD patients on stable amantadine treatment were recruited. Plasma concentration of amantadine was measured 3 h after the administration of morning amantadine dose. Serum creatinine was measured to estimate renal function. The mean daily dose of amantadine was 135.1 62.3 mg/day, and the mean plasma amantadine concentration was 812.5 839.5 ng/ml (range, 914400 ng/ml). Plasma amantadine concentration increased according to increasing renal dysfunction. Three patients exhibited adverse reactions, such as myoclonus, hallucinations, and delirium, and all of them showed plasma amantadine concentration >3000 ng/ml. None of the three cases had previously shown such side effects. PD patients who have not developed any psychiatric symptoms as adverse reactions to the treatment may develop myoclonus, hallucination, or delirium when the plasma concentration of amantadine exceeds 3000 ng/ml. It is therefore recommended to use amantadine at the plasma concentration of less than 3000 ng/ml in the treatment of Parkinsons disease, especially in elderly patients. 2008 Published by Elsevier Ltd.

1. Introduction Amantadine was developed for the prevention of type A inuenza and has been found to have an anti-Parkinsonian effect in daily clinical practice [1]. It is frequently used for the treatment of Parkinsons disease (PD) or Parkinsons syndrome, alone or in combination with L-dopa or dopamine agonists. In elderly individuals, however, it may cause delirium and the development of hallucinations and excitation at high amantadine plasma concentrations (10005000 ng/ml) [2,3]. Although these symptoms are suspected as being related to overdose or elevated plasma amantadine concentration, there would appear to be no published data on the relationship between plasma concentration and adverse effects of amantadine during treatment of PD. L-dopa is used early, following the onset of symptoms, in the treatment of PD and is known to cause motor uctuation in the later stages of the disease. Recently, high-dose administration of amantadine (!300 mg/day) has been investigated for management of levodopa-induced dyskinesias (LID) and was reported to be effective in improving PD symptoms as well as inhibiting LID at a high concentration of amantadine of >6 mM (1126 ng/ml) [4]. The majority of amantadine is excreted unchanged in urine, so amantadine accumulates in the body and gives rise to increased plasma concentrations in the

presence of impaired renal function [5]. In our study, we measured plasma amantadine concentrations in PD patients in daily clinical practice and investigated the relationship between plasma concentration and renal function, as well as the relationship between plasma concentration and adverse reactions to clarify the safe therapeutic range.

2. Patients and methods The conduct of this study was reviewed and approved by the Clinical Research Ethics Review Committee of Ehime University Hospital. Consecutive patients with PD consulting the Neurology Department at Ehime University Hospital were employed and, in this study, we included those who had been treated with amantadine hydrochloride for at least 2 weeks at a constant dose. Patients were evaluated using the Hoehn and Yahr score at on-time. Plasma amantadine concentration was measured from blood samples taken 3 h after oral administration in the morning. Blood samples (5 ml) were collected into EDTA-2Na tubes and centrifuged for 10 min at 1000 G. Plasma was obtained and stored at the temperature of 80  C until measurement. Plasma amantadine concentration was measured by gas chromatography [6]. Sodium hydroxide 6 mol/L 0.5 ml and chloroform 0.5 ml were added to 2 ml of plasma, followed by shaking. After centrifugation for 10 min with 3000 G at 4  C, the chloroform layer was collected and injected into a gas chromatography analyzer (Shimazu GC-2010AF/ AOC, Kyoto). Amantadine was detected as a peak appearing 10.5 min after injection. The relationship between plasma amantadine concentration and the occurrence of adverse reactions was investigated in those patients who experienced serious adverse events, such as myoclonus, hallucination, excitement, or delirium. Renal function was determined by measuring serum creatinine concentration and concurrent body weight using the CockcroftGault formula to calculate creatinine clearance (Ccr). Data are presented as mean SD. Calculation of the Pearson

* Corresponding author. Tel.: 81 89 960 5095; fax: 81 89 960 5938. E-mail address: nomoto@m.ehime-u.ac.jp (M. Nomoto). 1353-8020/$ see front matter 2008 Published by Elsevier Ltd. doi:10.1016/j.parkreldis.2008.08.005

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correlation coefcients was used for comparison of the relationship between plasma amantadine concentration and Ccr.

3. Results Plasma amantadine concentration was investigated in 78 PD patients. Their ages ranged from 38 to 78 years (mean 66.6 10.3) and included 39 males and 38 females. The duration of PD ranged from 3 to 16 years (mean 6.8 2.3 years) and the severity of PD ranged from II to IV (mean 3.2 1.1) on the Hoehn and Yahr classication. The mean daily dose of amantadine was 135.1 62.3 mg/ day (range, 50300 mg/day). Mean plasma amantadine concentration ranged from 91 to 4400 ng/ml (mean 812.5 839.5 ng/ml) (Fig. 1). A plasma amantadine concentration of 2000 ng/ml or less was observed in 72 patients (94%). A plasma amantadine concentration of 3000 ng/ml or more was observed in 4 patients, of whom 3 showed adverse reactions, such as myoclonus, hallucinations, and delirium, all of which resolved after discontinuation of amantadine in 35 days (Table 1). In cases 1 and 2, marked and tremorous myoclonus was observed in all extremities and the trunk, which was asymmetrical and worsened on activity. One of these 3 cases showed a serum creatinine concentration of 1.1 mg/dl, which is within the normal reference range. She did not show any abnormal ndings on routine urine or blood tests. One of the other cases showed an increased serum creatinine concentration (5.4 mg/dl), which was caused by bladder cancer expanding to the kidneys. The three cases were followed long-term after the cessation of amantadine for up to 5 years, and none of them showed any signs of myoclonus, hallucination, delerium, or alien hand suggestive of other than parkinsonian conditions, such as corticobasal ganglionic degeneration or dementia with Lewy bodies. Renal function was also studied. Mean body weight was 54.9 10.4 kg, mean serum creatinine concentration 0.95 0.83 mg/ dl, and mean Ccr 66.8 22.9 ml/min in all cases. The relationship between plasma amantadine concentration and Ccr was examined in 20 patients who received amantadine twice daily after morning and

evening meals at a xed dosage of 100 mg/day. Plasma amantadine concentration exhibited a signicant negative correlation with Ccr (r 0.543; P < 0.05; n 20). Plasma amantadine concentration was studied in 14 patients who were treated with amantadine twice daily after morning and evening meals at a xed dose of 100 mg/day and who exhibited Ccr !60 ml/min. Plasma amantadine concentration in this population ranged from 191 to 800 ng/ml (mean 475.3 205.2 ng/ml), thus showing a 4-fold difference between minimum and maximum concentrations. 4. Discussion We determined plasma amantadine concentrations in a large cohort of Japanese PD patients attending a single institute who received amantadine for treatment of their disease. Mean plasma concentration at 3 h after oral administration was 812.5 ng/ml, and 93% of the patients exhibited a concentration of 2000 ng/ml or less. The dose of amantadine commonly used in the treatment of PD was within the range of 100200 mg/day, which was expected to produce a plasma concentration of less than 2000 ng/ml when using a twice daily regimen. However, 5 of the 78 patients exhibited a plasma concentration of more than 2000 ng/ml, and 3 of 4 patients with a plasma concentration of more than 3000 ng/ml experienced adverse reactions involving the CNS. All of the adverse reactions were reversible and resolved after discontinuation of amantadine within a few days. Since that time, symptoms such as myoclonus, hallucination, or delirium have not been observed longterm. Investigation of the relationship between plasma amantadine concentration and Ccr revealed that plasma amantadine concentration signicantly increased with decreasing renal function. Amantadine is excreted as intact drug from the kidney and should therefore be used at a reduced dose in the presence of impaired renal function [5]. In this study, we assessed renal function based on the estimated glomerular ltration rate obtained by calculating Ccr from gender, body weight, age, and serum creatinine concentrations using the CockcroftGault formula [7]. Our results are consistent with these ndings. In daily clinical practice, serum creatinine concentration obtained by routine laboratory blood investigation is commonly used for assessment of renal function. Since PD patients are generally middle-aged or older, it is possible that even those patients with a normal serum creatinine concentration may have a decreased Ccr if they are aged and have a low body weight. For example, for a 70-year-old woman weighing 50 kg with a serum creatinine concentration of 0.9 mg/dl suggests normal renal function according to the serum creatinine value, although her Ccr is calculated to be 46 ml/min using the CockcroftGault formula. Thus, serum creatinine concentration may be within the normal reference range even when glomerular ltration rate is low. Consequently, the plasma amantadine concentration may increase to higher levels than expected and subsequently cause adverse reactions. One of the 3 cases with side effects from amantadine showed a serum creatinine concentration of 1.1 mg/kg, which is within the normal reference range. According to reports on patients who developed CNS symptoms due to amantadine, oral administration of amantadine 100200 mg resulted in increased plasma amantadine concentration (1500 4400 ng/ml) due to severe renal function impairment, causing hallucinations and excitation [810]. In our study, a plasma amantadine concentration of >1500 ng/ml was observed in 8 patients, but patients with CNS symptoms exhibited a plasma concentration of over 3000 ng/ml. Since these 3 patients had not previously developed CNS disorders associated with anti-PD drugs, 3000 ng/ml might be the threshold plasma concentration at which amantadine may cause CNS symptoms. If symptoms such as

Fig. 1. Plasma amantadine concentration: 812.5 839.5 ng/ml (mean SD, n 78).

N. Nishikawa et al. / Parkinsonism and Related Disorders 15 (2009) 351353 Table 1 Three cases showing amantadine-related adverse effects Case Age (yr) Gender Body weight (kg) F F M 32.5 42.8 44.0 Amantadine Plasma Serum dose amantadine creatinine (mg/day) concentration (mg/dl) (ng/ml) 200 150 100 4400 3500 3690 1.1 5.4 1.4 Ccr (ml/min) Adverse effects Disease duration (yr) H&Y stage Other drug therapy (mg/day)

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Duration of amantadine therapy (yr) 1 8 2

1 2 3

62 55 78

27.2 7.9 27.1

Myoclonus, hallucination 3 delirium Myoclonus, delirium, 8 hallucination Hallucination, delirium 2

III III IV

LD/CD 300/30 LD/CD 300/30; trihexy-phenidyl 6 LD/CD 300/30

Ccr, creatinine clearance; M, male F, female; H&Y, Hoehn and Yahr; and LD/CD, levodopa/carbidopa.

hallucinations or delirium are observed with the use of other antiPD drugs, it is possible that they will be induced at lower amantadine concentrations. Myoclonus has been observed in cases with high concentrations of amantadine and disappeared after cessation of amantadine [10,11]. Amantadine is a type of NMDA antagonist such as ketamine, phencyclidine, and MK801, which are also known to induce myoclonus or head-twitch response [12,13]. It was therefore concluded that amantadine was a principal factor in the precipitation myoclonus in our 3 cases. We also investigated the variation in plasma amantadine concentration for the patient subgroup with Ccr ! 60 ml/min. The maximum plasma amantadine concentration following administration of amantadine 100 mg/day as a twice daily regimen ranged from 191 to 800 ng/ml, indicating a 4-fold range for the interindividual difference. Most amantadine is excreted into urine as unchanged drug, and the variation in plasma concentration may be attributable to individual differences in the absorption and excretion of the drug. Similar interindividual differences have been documented for a variety of other drugs. L-dopa, a basic anti-PD drug, exhibits an approximately 10-fold range for interindividual difference among healthy subjects [14]. There are generally significant interindividual differences in the clinical efcacy of therapeutic drugs and the incidence of adverse events associated with them. It is believed that this can be handled with the provision of good and appropriate treatment. While results of studies on the pharmacokinetics of amantadine in healthy subjects or patients with impaired renal function are available [15,16], the level of plasma amantadine concentrations that causes psychosis has not been claried in clinical practice for PD patients. Recently, treatment of LID by administration of amantadine at a dose of !300 mg/day has been proposed. Highdose amantadine was effective in LID and the effects showed a positive correlation with plasma amantadine concentration [4]. Therefore, when administering amantadine at high doses, it is recommended to monitor renal function and to simulate the pharmacokinetics of the drug, to avoid adverse reactions. PD patients who have not developed psychiatric symptoms as adverse reactions to drug treatment may develop CNS symptoms when the plasma concentration of amantadine exceeds 3000 ng/ ml. It is therefore recommended to apply amantadine at less than 3000 ng/ml of the plasma concentration, especially in elderly patients. Acknowledgements This work was supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health,

Labour and Welfare of Japan and SRFJ, and a Grant from Ehime University.

Appendix A. Supplementary material Supplementary material for this article can be found, in the online version, at doi:10.1016/j.parkreldis.2008.08.005

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