What doses of quinagolide should be given in the presence of renal failure and haemodialysis? Can p

Fråga: What doses of quinagolide should be given in the presence of renal failure and haemodialysis? Can plasma concentrations of quinagolide be monitored?

A man with a large prolactinoma has been treated with bromocriptin (Pravidel). He has developed retroperitoneal fibrosis with renal failure (S-creatinine 900 umol/L) and is planned to have haemodialysis. The questioner intends to treat with quinagolide (Norprolac).

Sammanfattning: We have not found any studies in the literature on the pharmacokinetics of quinagolide in renal function impairment. Theoretically renal failure and haemodialysis are expected to have only minor influence on the pharmacokinetics of quinagolide. As far as can be judged from theoretical considerations there should be no major risk involved with the use of ordinary doses. Closer clinical observation than usual may be required since the clinical experience is limited.

We have not been able to find a laboratory that determines plasma concentrations of quinagolide and its metabolites.

Svar: Quinagolide is, contrary to bromocriptin, a non-ergot drug, which was registered in Sweden in 1993. Pituitary prolactin secretion is under the tonic inhibitory control of dopamine through stimulation of dopamine D2-receptors on the lactotrophs. Quinagolide acts as a dopamine agonist specific for D2-receptors (1).

Quinagolide is rapidly and well absorbed. In the blood stream it is highly protein bound (> 90 %). Quinagolide undergoes more than 95% presystemic metabolism in the liver to two active metabolites, the N-desethyl and N, N-didesethyl compounds, that both have effects similar to that of the parent compound but they are less potent. These metabolites are conjugated to sulphate- and glucuronide conjugates, which are excreted in the urine. Unconjugated metabolites are found in faeces. More than 90 % of the dose is excreted as metabolites and studies with radiolabeled drug showed equal amounts in faeces and in urine. Animal studies suggest enterohepatic recirculation. The plasma half-life in steady state is 17.5 hours and the overall plasma half-life of the metabolites 23.7 hours (1). Distribution studies have shown that quinagolide and its metabolites concentrate in the pituitary, salivary glands, liver and kidneys.

We have not been able to find a laboratory that performs analyses of plasma concentrations of quinagolide or its metabolites. According to the manufacturer it has not been possible to determine serum concentrations of the metabolites, because they are very low (2).

No studies on the pharmacokinetics of quinagolide in renal failure and haemodialysis have been found in a thorough literature research, including Medline, Embase, Drugline and common pharmacological handbooks as well as personal communication with the manufacturer (2). Theoretically the following can be expected. The metabolism is presumably little affected or not at all. The unconjugated, pharmacologically active metabolites are excreted via faeces, a process which is not expected to be altered by renal failure. The renal excretion of the conjugated metabolites will be impaired and their blood levels will reach higher levels than normal. It is not known if these conjugated metabolites are active. If the experimental observation of enterohepatic recirculation holds true for humans, this process may be enhanced in renal failure. Conjugated metabolites accumulated to higher than normal levels may be excreted via the bile to the intestine, where they may be partly deconjugated and the parent compound will be reabsorbed more than usual. This would prolong and increase the effect but probably only to a minor extent. However, this theory has not been evaluated by studies.

Haemodialysis is not likely to affect the elimination rate of quinagolide, which is highly protein bound and extensively metabolised. The unconjugated metabolites may be dialyzable, but they are present in the blood in very low concentrations (not measurable) and hence hemodialysis is not expected to increase their elimination significantly. Haemodialysis is likely to increase the elimination of conjugated metabolites and may thus reduce the increased serum levels of these metabolites to levels closer to normal.

As far as can be deduced from these theoretical considerations there should be no major risks involved with using ordinary doses in the presence of renal failure and haemodialysis.

The most common (> 10 %) side effects nausea, vomiting and dizziness are also symptoms of uremia and may be more easily evoked in patients with renal failure. There are no reports of adverse effects on the kidneys to the Swedish adverse drug reaction register (3). The WHO adverse drug reaction-monitoring centre has received one report of acute renal failure in connection with quinagolide (4). The reports to the WHO register are, however, not evaluated as to the cause relationship. No long-term adverse events have been seen according to an international textbook (1). Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999 Personlig kontakt med Christina Lloyd, Ferring Swedis (The Swedish Drug Information System) (2004-04-01) Vigibase: WHO:s adverse drug reactions database (2004-04-01)