The effect of mild and moderate renal impairment on the pharmacokinetics of pridopidine, a new drug for Huntington's disease.

AIM: Pridopidine, a new oral drug for treatment of patients with motor symptoms associated with Huntington's Disease (HD) is currently under development. In steady-state conditions, pridopidine elimination is mediated primarily through renal excretion. This study evaluated single dose and steady-state pharmacokinetics (PK) of a daily dose of pridopidine in subjects with mild and moderate renal impairment and matched healthy subjects. METHODS: Subjects with mild renal impairment (n = 12), moderate impairment (n = 12), or their matched healthy controls (n = 25) participated in this study. Subjects received a single dose of pridopidine (45 mg) on day 1 and a multiple dose cycle of 45 mg once daily on days 5-18. Blood and urine samples were collected on days 1 and 18 for PK analysis. RESULTS: Mild renal impairment did not affect the PK of pridopidine whilst an increase in exposure was seen in subjects with moderate renal impairment. Subjects with moderate impairment showed reduced plasma clearance (by 44%) and had 68% higher AUC (90% CI 1.22, 2.30) and 26% higher Cmax (90% CI 1.02, 1.56) values than those with normal renal function at steady-state. Pridopidine was safe and well tolerated in healthy subjects and in subjects with mild and moderate renal impairment. CONCLUSIONS: Mild renal impairment has no impact on exposure to pridopidine while moderately impaired renal function resulted in higher pridopidine concentrations.

Pharmacokinetic and tolerability profile of pridopidine in healthy-volunteer poor and extensive CYP2D6 metabolizers, following single and multiple dosing.

Pridopidine is being developed for the treatment of impaired motor function associated with Huntington's disease and belongs to a new class of compounds known as dopidines, which act as dopaminergic stabilizers. In vitro studies have shown that pridopidine is a substrate for the P450 cytochrome 2D6 enzyme (CYP2D6), and clinical data show that the half-life of pridopidine is different following single dosing versus at steady state. To further investigate the pharmacokinetic profile of pridopidine and to establish whether dose adjustment is needed in poor CYP2D6 metabolizers, a single-centre, open-label, multiple-dose study in healthy volunteers was performed. In total, 24 extensive CYP2D6 metabolizers (EMs) and 12 poor CYP2D6 metabolizers (PMs) were enrolled. Both groups received 45 mg pridopidine twice daily (b.i.d.). Plasma samples were taken during the first day of b.i.d. dosing (Day 1) and at steady state, following 14 days of b.i.d. dosing. At Day 1, total exposure in PMs was almost three times higher than those in EMs (AUC0-∞ = 11,192 and 3,782 h·ng/mL, respectively; PM/EM ratio = 2.96; p < 0.001). However, at steady state, PMs and EMs had comparable exposure due to a reduction in pridopidine elimination in EMs over time. Thus, at steady-state peak (C max) and total (AUC0-24) exposures were only 1.24 and 1.29 times higher, respectively, in PMs than EMs. These results support that pridopidine is a CYP2D6 auto-inhibitor. Pridopidine was well tolerated in both EMs and PMs. The slightly higher exposure level in PMs at steady state does not indicate a need for dose adjustment or genotyping for CYP2D6 metabolizer status.

Desmopressin treatment in nocturia; an analysis of risk factors for hyponatremia.

AIMS: To explore the incidence, severity, time course, and risk factors of clinically significant hyponatremia in desmopressin treatment for nocturia. METHODS: Data from three multi-center phase III trials were pooled. Hyponatremia was categorised as borderline (134-130 mmol/L) or significant (<130 mmol/L). Risk factors were explored with logistic regression and subgroup analysis performed to explore threshold values for contra-indication. RESULTS: In total 632 patients (344 men, 288 women) were analyzed. During dose-titration, serum sodium concentration below normal range was recorded in 95 patients (15%) and 31 patients (4.9%) experienced significant hyponatremia. The risk increased with age, lower serum sodium concentration at baseline, higher basal 24-hr urine volume per bodyweight and weight gain at time of minimum serum sodium concentration. Age was the best single predictor. Elderly patients (>or=65 years of age) with a baseline serum sodium concentration below normal range were at high risk (75%). Limiting treatment in elderly with normal basal serum sodium concentration to those below 79 years and with a 24-hr urine output below 28 ml/kg would reduce the risk from 8.1% to 3.0% at the cost of 34% fulfilling the contra-indication. CONCLUSIONS: The majority of nocturia patients tolerate desmopressin treatment without clinically significant hyponatremia. However, the risk increases with increasing age and decreasing baseline serum sodium concentration. Treatment of nocturia in elderly patients with desmopressin should only be undertaken together with careful monitoring of the serum sodium concentration. Patients with a baseline serum sodium concentration below normal range should not be treated.

Nocturia and associated morbidity in a community-dwelling elderly population.

OBJECTIVE: To investigate the association between nocturia and selected concomitant diseases and medications in a community-dwelling elderly population. SUBJECTS AND METHODS: Data were obtained with a validated questionnaire mailed to all inhabitants aged >or= 65 years in Tierp, Sweden. Descriptive statistics on age, gender, concomitant diseases and medications were calculated for non-nocturics (subjects reporting a mean of < 1 void/night), intermediate (reporting a mean of 1-2 voids/night) and nocturics (reporting a mean of >or= 2 voids/night). Correlations between the number of nocturnal voids/week and concomitant diseases/medications were investigated with logistic regression, controlling for age and gender. RESULTS: Of the 4264 questionnaires sent, 67% (2866) were returned, of which 73% (2081) were fully evaluable on nocturia and incorporated in the analysis. Of these, 62% reported >or= 1 void/night and 29%>or= 2 voids/night. The median (range) age of the respondents was 74 (65-99) years. The prevalence of nocturia increased with age and men reported more nocturia than women. The nocturic group had the highest percentage of reported disease and medication on each question. In the logistic regression, controlling for age and gender, there was no significant correlation between the number of nocturnal voids and hypertension, angina pectoris or diabetes mellitus, nor with treatment of these diseases. Neither was there any correlation for congestive heart failure, snoring, use of diuretics or hypnotics. There were highly statistically significant correlations (P < 0.001) between the increase in number of nocturnal voids and incontinence, daytime urge and nocturnal thirst. The increase in number of nocturnal voids was negatively correlated with good sleep and with feeling in good health (P < 0.001). CONCLUSION: There was no correlation between the number of nocturnal voids and a known and treated hypertension, angina pectoris, congestive heart failure or diabetes mellitus. The number of nocturnal voids was highly correlated with urge and incontinence.

Desmopressin in elderly patients with nocturia: short-term safety and effects on urine output, sleep and voiding patterns.

OBJECTIVE: To investigate the short-term safety of desmopressin in elderly patients with nocturia, with special focus on the risk of hyponatraemia, and to assess the short-term effects on urine output, sleep and voiding patterns. PATIENTS AND METHODS: Patients (72) were recruited from a study using frequency-volume charts, which in turn was preceded by a questionnaire study. Each patient took one 0.2 mg desmopressin tablet at bedtime for three consecutive nights and kept a frequency-volume chart. Serum sodium was assessed in the morning after the first and the third dose. Patients with a mean serum sodium level during treatment deviating more than five units from baseline were considered sensitive to change in serum sodium. Potential predictors for sodium sensitivity and response were investigated with logistic and multiple regression. RESULTS: All 72 enrolled patients completed the trial; no serious adverse events occurred and no adverse events of severe intensity were recorded. Six patients were sensitive to change in serum sodium. The risk (odds ratio, 95% confidence interval) increased with increasing age (1.3, 1.1-1.6), concomitant cardiac disease (10.0, 0.9-105.8) and increasing baseline 24-h urine output (1.2, 1.0-1.5). Patients sensitive to change in serum sodium were pharmacological responders and desmopressin had a greater effect on their 24-h diuresis, indicating that the drug effect was not limited to the night only. CONCLUSION: Desmopressin was well tolerated in elderly patients with nocturia, but the results suggest that serum sodium should be measured before and after a few days of treatment.

Differences between nocturics and non-nocturics in voiding patterns: an analysis of frequency-volume charts from community-dwelling elderly.

OBJECTIVE: To evaluate differences between elderly people with and without nocturia (waking up in the night to void) in terms of voiding habits, urine production and voided volumes. SUBJECTS AND METHODS: Nocturics or= two voids/night) and non-nocturics (< one void/night) were recruited from a questionnaire survey. Subjects were asked to complete a 3-day frequency-volume chart, including time and volume of each void, and their bedtime and waking time. Diaries from 108 non-nocturics and 116 nocturics were analysed. The number of voids, urine production, largest and average voided volumes were analysed using repeated-measures analysis of variance models, controlling for variables such as age, gender, body weight and gender-diagnosis interaction. RESULTS: Nocturnal urine volume was higher in nocturics than in non-nocturics. The difference between the groups was larger among the men (estimated difference 384 mL) than among the women (227 mL), but highly statistically significant (P < 0.001) in both genders. Among the men the diurnal urine and 24-h urine volumes were significantly higher in nocturics (difference, diurnal 131 mL, 24-h 462 mL, both P < 0.001). In the women the diurnal urine volume was lower in nocturics than in non-nocturics (difference 147 mL P = 0.0022) with no difference detected in 24-h urine volume. The largest voided volume was significantly less in nocturics than in non-nocturics; the difference was larger in women (128 mL, P < 0.001) than in men (42 mL, P = 0.0027). The average voided volume was 85 mL less (P < 0.001) in nocturics. The overlap between the groups in nocturnal urine and voided volumes was substantial and several significant covariates identified. The ratio between nocturnal urine volume and largest voided volume was the most statistically significant predictor of the number of nocturnal voids. CONCLUSION: Elderly nocturics had a higher nocturnal urine production and lower volume per void than non-nocturics. Differences between nocturics and non-nocturics in urine production and largest voided volume did not follow the same pattern in men and women. Nocturia was a result of a mismatch between nocturnal urine volume and largest voided volume, rather than abnormal values in either. The treatment of nocturia should be directed at one or both of these factors, depending on the findings from the 3-day frequency-volume chart of the individual.

Renal concentrating capacity test using desmopressin at bedtime.

A crossover trial was undertaken to evaluate the bedtime administration of desmopressin (Minirin) as a renal concentrating capacity test (RCCT). Medication was given intranasally as a single 20-microgram dose to 58 children ranging from 3 to 15 years of age with suspected or known renal impairment. The night-time test was shown to be a simple and effective means of assessing renal concentrating capacity. Comparison with the standard daytime test resulted in a 60 mosmol/kg higher mean osmolality in the night-time test. The results were reproducible, with a 95% confidence interval of -26 to 43 mosmol/kg. The procedure was easy to perform, with 51 of 52 patients (or their parents) preferring the night-time regimen compared with the daytime test. Night-time desmopressin therefore offers the potential of a user-friendly RCCT in patients with suspected impairment of renal tubular function.