Single dose methodology to assess the influence of an α1-adrenoceptor antagonist on uroflowmetric parameters in patients with benign prostatic hyperplasia
Dr Sean P. Curtis, Division of Clinical Pharmacology, RY 32–633, Merck Research Laboratories, 126 E. Lincoln Ave, Rahway NJ 07065, USA. Tel: 732 594 8416; Fax: 732 594 8140; E-mail: email@example.com
Aims To establish methodology which rapidly and reliably assesses the effect of an α1-adrenoceptor antagonist on peak urine flow rates in men with benign prostatic hyperplasia (BPH). This methodology could then be applied to screening new drugs to treat BPH.
Methods Twenty-five patients with BPH enrolled in a double-blind, placebo-controlled, two-period crossover study. Patients were either withdrawn from their current α1-adrenoceptor antagonist therapy (n = 22) or were untreated prestudy (n = 3) and all met prespecified uroflowmetric criteria including: (1) a peak urine flow rate (Qmax) < 12 ml s−1 off therapy (or < 10 ml s−1 if untreated prestudy) and (2) a decrease in peak urine flow rate (Qmax) of > 2 ml s−1 after withdrawal from therapy. Study treatment consisted of tamsulosin 0.4 mg (or matching placebo) once daily for 8 days in a two-period crossover. Uroflowmetry was performed predose and once postdose (4.5–5.5 h postdose) on day 1, and once postdose (4.5–5.5 h postdose) on day 8 of each treatment period.
Results After a single dose of tamsulosin, the least-square mean difference between tamsulosin and placebo in the change from baseline Qmax was 2.8 ml s−1 (P = 0.017 vs placebo). After 8 days dosing of tamsulosin, the least-square mean difference between tamsulosin and placebo in the change from baseline Qmax was also 2.8 ml s−1 (P = 0.044 vs placebo). Additionally, there was no significant difference observed between the single and multiple dose results (P > 0.200 for between group difference).
Conclusions Both single and multiple doses of tamsulosin 0.4 mg increased Qmax in men with BPH. A single dose produced a comparable response to multiple dose administration. The magnitude of the effect was greater than the effect generally seen in longer term clinical trials, but this difference may be explained by the patient population in this study which was preselected for ‘responsiveness’ to an α1-adrenoceptor antagonist. These results support the utility of single dose uroflowmetric measurements in rapidly providing preliminary data on new investigational agents, specifically agents which act to increase urine flow in men with BPH. However, clinical efficacy would still need to be confirmed with longer term clinical trials.
Although the cause of benign prostatic hyperplasia (BPH) is unknown, current models postulate two components to the disease process; a static and a dynamic component. The static component involves hyperplasia of the epithelial and stromal components of the prostate, and the dynamic component is due to adrenergic tone mediated by α1-adrenergic receptors in the smooth muscle of the bladder, prostate capsule and prostate stroma. α1-adrenoceptor antagonists are currently an integral part of the medical management of BPH, targeting the dynamic component, and are known to improve peak urine flow rates in men with this condition [1–7].
Clinical trials to assess the efficacy of α1-adrenoceptor antagonists based on uroflowmetric criteria have differed in design and, depending on the study design, may require a relatively large sample size to identify a clinically meaningful effect on uroflowmetric parameters, due largely to the variability in response .
While most studies assess uroflowmetric parameters following chronic dosing, there are limited data suggesting that an improvement in peak urine flow rate may be seen following a single dose of an α1-adrenoceptor antagonist [8, 9]. Single doses of alfuzosin (either 1.25 mg, or 2.5 mg) were administered to symptomatic patients with BPH, and the effects on urine flow parameters were assessed 1.5 h after administration . The increase in Qmax (mean [s.e. mean]) in the patients receiving alfuzosin (n = 62) was 2.31[0.5] ml s−1, and was significantly greater (P = 0.041) than the 0.53[0.5] ml s−1 increase seen in patients who received placebo (n = 31) in this study. For tamsulosin, the data suggest that the magnitude of the improvement in peak urine flow rates seen following a single dose of tamsulosin 0.4 mg is similar to the effect seen following 13 weeks of treatment . Expressed as the difference from placebo, the mean increase in Qmax was approximately 1.2 ml s−1 after the initial single dose of tamsulosin 0.4 mg, as well as after 13 weeks of treatment. These data for alfuzosin and tamsulosin suggest that a study design based on assessing uroflowmetric parameters following a single dose of an α1-adrenoceptor antagonist might be useful in evaluating new investigational agents.
Therefore, the current investigation was designed as a methodology study to measure the effect of single and multiple doses (8 days) of tamsulosin 0.4 mg compared with placebo on peak urine flow rates in men with BPH.
This multicentre, double-blind, placebo-controlled, two-period crossover study was conducted at the Leeds Urology clinic and at Hammersmith Medicines Research in London between January 1998 and July 1998. The study was authorized by the Ethical Review Committees of both centres and written informed consent was obtained from all patients prior to undergoing a screening evaluation to determine their eligibility.
To be eligible, patients must have met both general and uroflowmetric criteria. The general criteria called for men age 45 years and above, with a clinical diagnosis of BPH based on the presence of signs and/or symptoms of bladder outlet obstruction and a digital rectal examination consistent with prostatic enlargement, who were currently being treated with an α1-adrenoceptor antagonist at the time of study screening and who were willing to withdraw from the medication for the short duration of the study. Patients were required to be on a stable, therapeutic dose of an α1-adrenoceptor antagonist for at least 1 month prior to study screening. Following a screening physical examination, urinalysis, and prostate specific antigen (as well as complete blood count and chemistry panel in all patients above the age of 65 years), and measurement of uroflowmetric parameters, patients were instructed to discontinue their current α1-adrenoceptor antagonist for a minimum of 7 days. Following the washout period, patients returned for repeat measurement of uroflowmetric parameters. Uroflowmetric inclusion criteria for this study were a peak urine flow rate (Qmax) after washout of < 12 ml s−1, and > 2 ml s−1 decrease in Qmax from that measured while on α1-adrenoceptor antagonist therapy. Three patients were also enrolled who were not on α1-adrenoceptor antagonist therapy at the time of study screening, but had a Qmax of < 10 ml s−1 (range 3.5 ml s−1 to 5.0 ml s−1).
Twenty-five eligible patients were randomly assigned to one of two possible treatment sequences (i.e. tamsulosin/placebo or placebo/tamsulosin): each treatment period consisted of 8 days administration of a single daily dose of tamsulosin 0.4 mg or matching placebo. Urine flow parameters (peak flow rate, voided volume, time and calculated mean flow rate) were measured pre and postdose (∼4.5–5.5 h postdose) on the first day and postdose (∼4.5–5.5 h postdose) on the eighth day of both treatment periods. This postdose time interval was chosen to correspond to the time of peak tamsulosin plasma concentration. Orthostatic vital signs (supine and standing HR and BP) were measured pre and postdose (4 h postdose) on the first day of both treatment periods. Upon completion of the first treatment period, patients underwent a 7 day washout period, and then entered the second treatment period.
The uroflowmetry strips were manually read in a blinded fashion by an independent investigator without knowledge of treatment or time of measurement. To be considered valid, a flow reading required a total voided volume of at least 125 ml with the peak rate maintained for at least 2 s .
Baseline Qmax was defined as the predose value on the first day of dosing of each treatment period. The change from baseline Qmax following single and multiple doses of tamsulosin or placebo was analysed using an analysis of variance ( anova) model containing factors for sequence, subject within sequence, period and treatment. Statistical significance was considered for P < 0.050 (two-tailed test). All data are reported as the mean (least square) + s.e. mean, or differences from placebo as mean (least square) with 95% confidence intervals.
Baseline data and patients included in the analysis
Twenty-five patients were randomized. Patient ages ranged from 46 to 71 years (mean 58.6 years). Data for two patients were excluded from both the day 1 and the day 8 analysis. For one of these patients, the day 1 void was outside of the allowed time interval, and the patient withdrew from the study prior to registering a valid void on day 8. For the second patient, the day 1 voided volume was inadequate, and the day 8 data were uninterpretable. Of the remaining 23 patients, data for 21 patients are included in both the day 1 and day 8 analysis. Data for an additional patient were available for the day 1 analysis, but were excluded from the day 8 analysis due to an uninterpretable uroflow reading. A different patient was excluded from the day 1 analysis but included in the day 8 analysis: the patient voided outside of the allowed time interval.
For the total of 22 patients included in the analysis as accounted for above, baseline urine flow parameters for each of the two crossover treatment periods are listed in Table 1.
Table 1. Baseline uroflowmetry (mean (s.e. mean)).
|Tamsulosin (n = 22) 1||7.7 (0.7)||307.2 (26.2)|
|Placebo (n = 22) 1||8.3 (0.8)||317.1 (26.4)|
Baseline uroflowmetric parameters between treatment periods were similar with respect to peak urine flow rate (Qmax) and voided volume.
Effect of single and multiple doses of tamsulosin
Following both single (day 1) and multiple (day 8) doses of tamsulosin 0.4 mg, postdose peak urine flow rates increased in a statistically significant manner, with a value of 2.8 ml s−1 compared with placebo observed after both single and multiple doses ( Table 2). There was no significant difference between the effect observed following single and multiple doses (P > 0.200 for between-group and within group differences).
Table 2. Change from baseline Qmax (ml s−1)
|Tamsulosin (n = 22) 3||2.6 (0.9)||2.8 (0.6, 5.0)||2.9 (0.9)||2.8 (0.1, 5.4)|
|Placebo (n = 22) 3||−0.2 (0.8)||–||0.2 (0.9)||–|
|1P = 0.017 || ||2P = 0.044 || |
Analysis of the data for the 21 patients for whom data exist for both day 1 and day 8 was consistent with these results.
Following both single (day 1) and multiple (day 8) doses of tamsulosin 0.4 mg, the change in voided volume was numerically greater than the change following placebo ( Table 3). There was no significant difference between the effects observed following single and multiple doses (P > 0.200).
Table 3. Change from baseline voided volume (ml)
|Tamsulosin (n = 22) 3||44.0 (35.8)||53.2 (−11.6, 118.1)||68.4 (21.9)||54.0 (−4.2, 112.2)|
|Placebo (n = 22) 3||−9.2 (22.7)||–||14.4 (22.1)||–|
|1P = 0.103 || ||2P = 0.067 || |
Prior studies have, in general, required large numbers of patients in parallel groups to demonstrate significant effects of α1-adrenoceptor antagonists on uroflowmetric parameters, though single dose effects have been evident when studied in this manner [8, 9]. It would clearly be beneficial if study designs permitted a more rapid assessment of the potential for an agent to increase urine flow, and thus allow a timely decision whether resources are warranted to develop further a new compound. The present trial demonstrates that such issues can be addressed efficiently using a crossover design and selecting study patients with prespecified uroflowmetric criteria.
In this methodology study, the improvement in peak urine flow rate obtained with tamsulosin 0.4 mg was numerically similar following both single and multiple doses and was significantly different from placebo on both occasions. These results are generally consistent with previous clinical study results, namely that an improvement in peak urine flow rate can be measured following a single dose of an α1-adrenoceptor antagonist and that the magnitude of the effect of a single dose on peak urine flow rates is similar to the effect following chronic dosing [8, 9].
The magnitude of the effect seen in this study was larger than the effect measured in certain clinical trials with other α1-adrenoceptor antagonists [1, 5, 7]. This difference is likely explained by the patient population studied. The majority of the population in this study (i.e. 22 of 25 patients) represents a subset of BPH patients; specifically, BPH patients who had been clinically stable on an α1-adrenoceptor antagonist prior to enrolment and who met predetermined uroflowmetric inclusion criteria upon withdrawal (i.e. they may be considered as ‘α1-adrenoceptor antagonist-responsive’). Therefore, it is not unreasonable to obtain a larger mean response from such a group compared with the response from a nonpreselected patient population.
Additionally, this approach has proven to be relatively safe. The single episode of acute urinary retention which occurred during this study was treated promptly, and resolved fully following temporary placement of a urinary catheter and reinitiation of prestudy α1-adrenoceptor antagonist therapy.
Given how these patients were selected, this methodology may be considered to apply most directly to the preliminary evaluation of other α1-adrenoceptor antagonists. However, single dose experiments conducted in this manner might also be useful for other agents which could alter the dynamic component of prostatic obstruction, or to assess whether in fact a novel agent has any influence on this component (such as antagonizing the action of endothelin ). Extrapolation of results obtained with this methodology should be done with caution, as only results from longer term clinical trials will more accurately reflect a compound’s individual pharmacokinetics and pharmacodynamic effects. One would not anticipate that patients would respond to finasteride after a single dose, given finasteride’s mechanism of action on the static component of BPH to reduce obstruction (i.e. to decrease prostatic volume and fundamentally alter the prostatic architecture, thereby reducing obstruction and altering the natural history of the disease [12, 13]).
The results of the present study suggest that this methodology can document clear improvements in peak urine flow rates with relatively small numbers of patients following single doses of an α1-adrenoceptor antagonist. Although results using this single dose methodological approach would require confirmation in longer term efficacy studies, this approach could prove useful as a rapid, dose-range finding method in the investigation of novel urologic agents designed to improve uroflowmetric parameters.
This study was funded by Merck and Co., Inc.