Levodopa + enzyme inhibitor (benserazide, carbidopa, entacapone)

Additional information

The reported incidence and prevalence of Parkinson’s disease (PD) is slightly higher in men than in women. It seems that men develop PD earlier in life compared to women. Several possible explanations behind these sex differences have been suggested; the protective role of estrogens in premenopausal women, and different profiles of risk factors (environmental and/or genetic). Sex differences in clinical presentations of PD have also been reported. Since the activities of daily living might differ between men and women with PD, different treatment strategies can be recommended to men and women with PD [1].

Pharmacokinetics and dosing

Several studies have shown that women have a higher levodopa AUC than men when receiving a standard dose of 250 mg levodopa corrected as mg/kg body weight, leading to a higher bioavailability of levodopa. This may be explained by the generally lower body weight of women [2-4]. Contrary to these findings, other studies have shown greater bioavailability in women even after adjustment for body weight [5-7]. In these studies, patients received an oral dose of 100 mg levodopa plus 25 mg benserazide or 10 mg carbidopa. Also, levodopa AUC adjusted for body weight were higher in women [5-7].

In a Swedish registry study, women used a lower mean daily dose of levodopa than men [8]. Similar findings were observed in a clinic-based studies from the US and Brazil [9, 10]. A reason behind this sex difference could be the metabolic differences and the risk of side effects such as dyskinesia (see Adverse effects).

Effects

No studies with a clinically relevant sex analysis regarding effects of levodopa + enzyme inhibitors have been found.

Adverse effects

Women with PD seem to be at higher risk of dyskinesia, due to pharmacokinetic factors. This is, however, not confirmed in other reports where patient’s sex has been studied as a risk factor [3]. In one clinical study (67 men, 49 women) no difference in the proportion of men and women experiencing dyskinesias was observed [6]. Female sex is associated with a significantly shorter time to occurrence of levodopa-induced dyskinesia (LID) [11, 12].  The median time to LID was 4 years for women and 6 years for men. The reason for the sex difference is unclear. It has been suggested that hormonal status may underlie this susceptibility, possibly by modifying the individual dyskinetic sensitivity to levodopa through estrogens [11, 12]. Women have a lower expression of dopamine receptor genetic polymorphism (DRD2) which seems to exert a protective role in men against dyskinesia [3]. Women with PD have an 87% higher binding capacity of levodopa in the prefrontal cortex compared to men [13].

Dopaminergic medication is also used as a treatment for RLS (Restless Legs Syndrome) and PLMS (Periodic Leg Movement Syndrome). For nightly treatments, a problem with morning end-of-dose rebound increase in leg movements are reported to occur in about 25% of the patients. In one study (25 men, 21 women), patients with either RLS or PLMS were given 0.5-1 tablet levodopa/carbidopa 100/25 mg 20–30 minutes before bedtime. The dose was increased by 0.5 tablet every 3 days until satisfactory sleep occurred for the first 3 hours or the dose reached a maximum of 4 tablets. Augmentation (increased symptoms over time) was greater for patients with more severe RLS symptoms and for patients on higher doses (>200/50 mg) but was unrelated to patient’s sex or age [14].

Studies report that the increase in serum prolactin after receiving carbidopa or benserazide is larger in women than in men. In one study, healthy young men and women were given a single 125 mg oral dose benserazide inducing a larger percent increase of serum prolactin in women compared to men. In the general population, prolactin secretion is more affected by various stimuli in women [15]. In a similar study, benserazide was given in doses ranging between 10–125 mg and carbidopa was given in doses ranging between 10–250 mg to different groups of women [16]. Two different groups of men were given 125 mg of benserazide and 250 mg of carbidopa, respectively. Significant prolactin rises were observed in both men and women for all doses tested. Secretion areas were lager in women than in men and peak values were higher in women than in men. This sex-related finding is not unexpected considering the well-known sex-related differences in both spontaneous blood levels and responses to various stimuli. Sex differences may also influence serotonergic regulation of prolactin secretion  [16]. For entacapone, pre-marketing clinical trials did not note any differences in the rate of adverse events attributable to entacapone by patient’s sex [17].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).