This question concerns the treatment with levodopa in patients with renal failure. To what extent i

Fråga: This question concerns the treatment with levodopa in patients with renal failure. To what extent is levodopa bound to plasma proteins? How much levodopa is eliminated by dialysis? Background: Uremic patients suffer frequently from neurological symptoms, for example restless legs. In some patients this symptom is treated empirically with Madopark (levodopa/benserazide) 100 mg/25 mg at night. In patients with renal failure this medication is not used, because according to FASS severe renal failure is a contraindication to the use. We would like to try the administration of Madopark (levodopa/benserazide) 100 mg/25 mg at night in patients with chronic renal failure, including patients on dialysis, who suffer from restless legs.

Sammanfattning: Information on the disposition of levodopa and the effects of decarboxylase inhibition on levodopa pharmacokinetics is currently incomplete. Plasma binding of L-dopa is low, 5 to 8 per cent. Pharmacokinetic data of levodopa alone or in combination with benserazide during kidney failure, acute or chronic or during hemodialysis is lacking as are pharmacokinetic data of the decarboxylase inhibitor during these conditions. Based on the few available data and some reasoning, hemodialysis is not thought to disturb treatment attempts with L-dopa/benserazide, and particularly not if the dialysis is performed several hours after the drug intake. We think that a therapeutic trial could be done in these patients with careful monitoring of possible side effects.

Svar: The treatment of restless legs syndrome with levodopa has been previously discussed by the Drug Information Center (1). Two placebo-controlled studies (2,4) and two uncontrolled studies (3,5) report amelioration of restless legs symptoms and improvement of sleep. These studies encompass treatment durations from a few days up to three months. The dose of L-dopa given varies from 50 mg at night up to 250 mg twice daily, always together with a peripheral decarboxylase inhibitor.

In one of these studies, Sandyk and colleagues 5) report a satisfactory relief of restless legs syndrome during a 3 months follow up in six out of eight uremic patients on maintenance hemodialysis treated with levodopa/carbidopa in doses ranging from 100/25 mg to 250/25 mg twice daily. One of these patients had to discontinue therapy due to intolerable gastrointestinal andCNS side effects. This study was open and not placebo controlled (5).

Levodopa is extensively metabolised to several active and inactive metabolites (6). In the presence of a decarboxylase inhibitor, levodopa is converted to homovanillic acid by a process which does not involve decarboxylation to dopamine (7).

Relatively little basic pharmacokinetic data on levodopa exist (8-10). Its volume of distribution is moderate, 0.65 l/kg. The protein binding is very low, 5-8 percent. The elimination half life is short, 1-2 hours (8-10). Pharmacokinetic data of levodopa alone or in combination with decarboxylase inhibitor during kidney failure or during hemodialysis are lacking. Information on the disposition of the decarboxylase inhibitor benserazide (in Madopark) is currently incomplete. Pharmacokinetic data of benserazide during kidney failure or hemodialysis is lacking.

In the lack of data, the following reasoning could be used. L-dopa is eliminated by metabolic conversion and the end products excreted in urine are inactive (Leif Bertilsson, personal communication). Kidney dysfunction is therefore not a problem with regard to accumulation and hence dosage of L-dopa. The text in FASS under contraindications, "severe liver- and kidney disease" is probably a safety precaution generalisation and not based on scientific data. No more information could be obtained from the manufacturer (11).

L-dopa being a small acid molecule, with a moderate volume of distribution and a negligible binding in plasma is likely to be dialysable and to the same extent as other amino acids. Although hard data on the plasma clearance of L-dopa during decarboxylase inhibition in man are not available in kidney insufficiency or during dialysis, it is probably still higher than the maximal clearance obtainable by hemodialysis. Therefore, a certain, but nota great increase in total clearance of L-dopa can be expected during the dialysis hours. Since however the half life of L-dopa still is so short this possibly increased total clearance would have no practical consequence unless the dialysis is performed shortly after the drug is given.

The dose intended (100 mg L-dopa daily) is low compared to what is common in the treatment of Parkinson disease (average daily dose 600 mg).