a 1 -adrenoceptor antagonist on uro owmetric parameters in patients with benign prostatic hyperplasia

Transcription

1 Single dose methodology to assess the in uence of an a 1 -adrenoceptor antagonist on uro owmetric parameters in patients with benign prostatic hyperplasia S. P. Curtis, 1 I. Eardley, 2 M. Boyce, 3 P. Larson, 1 R. Haesen, 1 K. Gottesdiener 1 & B. J. Gertz 1 1 Division of Clinical Pharmacology, Merck and Co., Rahway, NJ, USA, 2 Department of Urology, Leeds University Hospital, Leeds and 3 Hammersmith Medicines Research, London, UK Aims To establish methodology which rapidly and reliably assesses the effect of an a 1 - adrenoceptor antagonist on peak urine ow rates in men with benign prostatic hyperplasia (BPH). This methodology could then be applied to screening new drugs to treat BPH. Methods Twenty- ve patients with BPH enrolled in a double-blind, placebocontrolled, two-period crossover study. Patients were either withdrawn from their current a 1 -adrenoceptor antagonist therapy (n=22) or were untreated prestudy (n=3) and all met prespeci ed uro owmetric criteria including: (1) a peak urine ow rate (Q max )<12 ml s x1 off therapy (or <10 ml s x1 if untreated prestudy) and (2) a decrease in peak urine ow rate (Q max )of>2mls x1 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. Uro owmetry 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 Q max was 2.8 ml s x1 (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 Q max was also 2.8 ml s x1 (P=0.044 vs placebo). Additionally, there was no signi cant 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 Q max 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 a 1 - adrenoceptor antagonist. These results support the utility of single dose uro owmetric measurements in rapidly providing preliminary data on new investigational agents, speci cally agents which act to increase urine ow in men with BPH. However, clinical ef cacy would still need to be con rmed with longer term clinical trials. Keywords: a 1 -adrenoceptor antagonist, benign prostatic hyperplasia, uro owmetry Introduction Although the cause of benign prostatic hyperplasia (BPH) is unknown, current models postulate two components to the disease process; a static and a Correspondence: Dr Sean P. Curtis, Division of Clinical Pharmacology, RY 32± 633, Merck Research Laboratories, 126 E. Lincoln Ave, Rahway NJ 07065, USA. Tel: ; Fax: ; sean_curtis@merck.com Received 8 April 1999, accepted 16 November 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 a 1 -adrenergic receptors in the smooth muscle of the bladder, prostate capsule and prostate stroma. a 1 -adrenoceptor antagonists are currently an integral part of the medical management of BPH, targeting the dynamic component, and are known to improve peak urine ow rates in men with this condition [1±7]. f 2000 Blackwell Science Ltd Br J Clin Pharmacol, 49, 269±

2 S. P. Curtis et al. Clinical trials to assess the ef cacy of a 1 -adrenoceptor antagonists based on uro owmetric 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 uro owmetric parameters, due largely to the variability in response [8]. While most studies assess uro owmetric parameters following chronic dosing, there are limited data suggesting that an improvement in peak urine ow rate may be seen following a single dose of an a 1 -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 ow parameters were assessed 1.5 h after administration [8]. The increase in Q max (mean [s.e. mean]) in the patients receiving alfuzosin (n=62) was 2.31[0.5] ml s x1, and was signi cantly greater (P=0.041) than the 0.53[0.5] ml s x1 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 ow rates seen following a single dose of tamsulosin 0.4 mg is similar to the effect seen following 13 weeks of treatment [9]. Expressed as the difference from placebo, the mean increase in Q max was approximately 1.2 ml s x1 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 uro owmetric parameters following a single dose of an a 1 -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 ow rates in men with BPH. Methods This multicentre, double-blind, placebo-controlled, twoperiod crossover study was conducted at the Leeds Urology clinic and at Hammersmith Medicines Research in London between January 1998 and July 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 uro owmetric 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 a 1 -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 a 1 -adrenoceptor antagonist for at least 1 month prior to study screening. Following a screening physical examination, urinalysis, and prostate speci c antigen (as well as complete blood count and chemistry panel in all patients above the age of 65 years), and measurement of uro owmetric parameters, patients were instructed to discontinue their current a 1 -adrenoceptor antagonist for a minimum of 7 days. Following the washout period, patients returned for repeat measurement of uro owmetric parameters. Uro owmetric inclusion criteria for this study were a peak urine ow rate (Q max ) after washout of <12 ml s x1, and >2mls x1 decrease in Q max from that measured while on a 1 -adrenoceptor antagonist therapy. Three patients were also enrolled who were not on a 1 - adrenoceptor antagonist therapy at the time of study screening, but had a Q max of <10 ml s x1 (range 3.5 ml s x1 to 5.0 ml s x1 ). Twenty- ve 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 ow parameters (peak ow rate, voided volume, time and calculated mean ow rate) were measured pre and postdose (y4.5±5.5 h postdose) on the rst day and postdose (y4.5±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 rst day of both treatment periods. Upon completion of the rst treatment period, patients underwent a 7 day washout period, and then entered the second treatment period. The uro owmetry 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 ow reading required a total voided volume of at least 125 ml with the peak rate maintained for at least 2 s [10]. Statistics Baseline Q max was de ned as the predose value on the rst day of dosing of each treatment period. The change from baseline Q max 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 signi cance 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% con dence intervals. 270 f 2000 Blackwell Science Ltd Br J Clin Pharmacol, 49, 269±273

3 Short report Table 1 Baseline uro owmetry (mean (s.e. mean)). period Q max (ml s ±1 ) Voided volume (ml) Tamsulosin (n=22) (0.7) (26.2) Placebo (n=22) (0.8) (26.4) 1 Data for both day 1 and day 8 were available for 21 of these 22 patients. Additional data were available for two patients; one for day 1, and one for day 8, respectively. Results Baseline data and patients included in the analysis Twenty- ve 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 uro ow 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 ow parameters for each of the two crossover treatment periods are listed in Table 1. Baseline uro owmetric parameters between treatment periods were similar with respect to peak urine ow rate (Q max ) 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 ow rates increased in a statistically signi cant manner, with a value of 2.8 ml s x1 compared with placebo observed after both single and multiple doses (Table 2). There was no signi cant difference between the effect observed following single and multiple doses (P>0.200 for betweengroup and within group differences). 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 signi cant difference between the effects observed following single and multiple doses (P>0.200). Discussion Prior studies have, in general, required large numbers of patients in parallel groups to demonstrate signi cant effects of a 1 -adrenoceptor antagonists on uro owmetric parameters, though single dose effects have been evident when studied in this manner [8, 9]. It would clearly be bene cial if study designs permitted a more rapid assessment of the potential for an agent to increase urine ow, 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 ef ciently using a crossover design and selecting study patients with prespeci ed uro owmetric criteria. In this methodology study, the improvement in peak urine ow rate obtained with tamsulosin 0.4 mg was numerically similar following both single and multiple doses and was signi cantly different from placebo on both occasions. These results are generally consistent with previous clinical study results, namely that an improvement in peak urine ow rate can be measured following a single dose of an a 1 -adrenoceptor antagonist and that the magnitude of the effect of a single dose on peak urine ow 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 a 1 -adrenoceptor antagonists [1, 5, 7]. This difference is Table 2 Change from baseline Q max (ml s x1 ). period Day 1 Day 8 placebo 1 (95% CI) placebo 2 (95% CI) Tamsulosin (n=22) (0.9) 2.8 (0.6, 5.0) 2.9 (0.9) 2.8 (0.1, 5.4) Placebo (n=22) 3 x0.2 (0.8) ± 0.2 (0.9) ± 1 P= P= Data for both day 1 and day 8 were available for 21 of these 22 patients. Additional data were available for two patients; one for day 1, and one for day 8, respectively. f 2000 Blackwell Science Ltd Br J Clin Pharmacol, 49, 269±

4 S. P. Curtis et al. period Day 1 Day 8 placebo 1 (95% CI) placebo 2 (95% CI) Table 3 Change from baseline voided volume (ml). Tamsulosin (n=22) (35.8) 53.2 (x11.6, 118.1) 68.4 (21.9) 54.0 (x4.2, 112.2) Placebo (n=22) 3 x9.2 (22.7) ± 14.4 (22.1) ± 1 P= P= Data for both day 1 and day 8 were available for 21 of these 22 patients. Additional data were available for two patients; one for day 1, and one for day 8, respectively. 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; speci cally, BPH patients who had been clinically stable on an a 1 - adrenoceptor antagonist prior to enrolment and who met predetermined uro owmetric inclusion criteria upon withdrawal (i.e. they may be considered as `a 1 -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 a 1 -adrenoceptor antagonist therapy. Given how these patients were selected, this methodology may be considered to apply most directly to the preliminary evaluation of other a 1 -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 in uence on this component (such as antagonizing the action of endothelin [11]). Extrapolation of results obtained with this methodology should be done with caution, as only results from longer term clinical trials will more accurately re ect a compound's individual pharmacokinetics and pharmacodynamic effects. One would not anticipate that patients would respond to nasteride after a single dose, given nasteride'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 ow rates with relatively small numbers of patients following single doses of an a 1 -adrenoceptor antagonist. Although results using this single dose methodological approach would require con rmation in longer term ef cacy studies, this approach could prove useful as a rapid, dose-range nding method in the investigation of novel urologic agents designed to improve uro owmetric parameters. This study was funded by Merck and Co., Inc. References 1 Roehrborn CG, Oesterling JE, Auerbach S, et al. The Hytrin Community Assessment Trial Study: a one-year study of terazosin versus placebo in the treatment of men with symptomatic benign prostatic hyperplasia. Urology 1996; 47: 159± Lepor H, Auerbach S, Puras-Baez A, et al. A randomized placebo-controlled multicenter study of the ef cacy and safety of terazosin in the treatment of benign prostatic hyperplasia. J Urol 1992; 148: 1467± Di Silverio F. Use of terazosin in the medical treatment of benign prostatic hyperplasia: Experience in Italy. Br J Urol 1992; 70(Suppl 1): 22±26. 4 Lloyd SN, Buckley JF, Chilton CP, Ibrahim I, Kaisary AV, Kirk D. Terazosin in the treatment of benign prostatic hyperplasia: a multicenter, placebo-controlled trial. Br J Urol 1992; 70(Suppl 1): 17±21. 5 Gillenwater JY, Conn RL, Chrysant SG, et al. Doxazosin for the treatment of benign prostatic hyperplasia in patients with mild to moderate essential hypertension: a double-blind, placebo-controlled, dose±response multicenter study. J Urol 1995; 154: 110± Fawzy A, Braun K, Lewis GP, Gaffney M, Ice K, Dias N. Doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients: a multicenter study. J Urol 1995; 154: 105± Abrams P, Schulman CC, Vaage S and The European Tamsulosin Study Group. Tamsulosin. A selective alpha 1cadrenoceptor antagonist: a randomized, controlled trial in patients with benign prostatic `obstruction' (Symptomatic BPH). Br J Urol 1995; 76: 325± Teillac P, Delauche-Cavallier MC, Attall P, the DUALF Group. Urinary ow rates in patients with benign prostatic hypertrophy following treatment with alfuzosin. Br J Urol 1992; 78: 58±64. 9 Lepor H. for the Tamsulosin Investigator Group. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Urology 1998; 51: 892± Grino PB, Bruskruitz R, Blaivas JG, et al. Maximum urinary ow rate by uro owmetry; automatic or visual interpretation. J Urol 1993; 149: 339± f 2000 Blackwell Science Ltd Br J Clin Pharmacol, 49, 269±273

5 Short report 11 Imajo C, Walden PD, Shapiro E, Doherty AM, Lepor H. Evaluation of the effect of endothelin-1 and characterization of the selective endothelin-1 receptor antagonist PD in the prostate. J Urol 1997; 158: 253± Gormley GJ, Stoner E, Bruskewitz RC, et al. The effect of nasteride in men with benign prostatic hyperplasia. N Engl J Med 1992; 327: 1185± McConnell JD, Bruskewitz R, Walsh P, et al. The effect of nasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998; 338: 557±563. f 2000 Blackwell Science Ltd Br J Clin Pharmacol, 49, 269±