Long-Term Safety and Efficacy of a Once-Daily Formulation of Alfuzosin 10 mg in Patients with Symptomatic Benign Prostatic Hyperplasia: Open-Label Extension Study

Kerrebroeck, Philip Van; Jardin, A; Cangh, Paul Van; Laval, K. U.

doi:10.1016/s0302-2838(01)00016-1

Cited by 52 publications

(36 citation statements)

References 26 publications

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“…Saturation of P-gp by a substrate for cytochrome P450-mediated gut wall metabolism can lead to nonlinear increases in the extent of absorption (e.g., UK-343,664;Abel et al, 2001). ␣-Adrenergic receptor antagonists as a class are generally administered using a gastrointestinal, modified release formulation to improve the safety and/or pharmacokinetic profile of the drugs (e.g., doxazosin, prazosin, alfuzosin) (Elliott et al, 1988;Cases, 2000;Van Kerrebroeck et al, 2002). The fundamental principle of modified release is to delay the absorption rate of a drug, and therefore, such formulations would attenuate nonlinearity in absorption rate, allowing development of compounds such as 315. It is possible that the variable absorption rate of UK-294,315 in humans is a consequence of transporter proteins other than P-gp.…”

Section: Fig 5 Mean Pharmacokinetic Profiles After Oral Administratmentioning

confidence: 99%

NONLINEAR ORAL PHARMACOKINETICS OF THE Α-Antagonist 4-Amino-5-(4-Fluorophenyl)-6,7-Dimethoxy-2-[4-(Morpholinocarbonyl)-Perhydro-1,4-Diazepin-1-Yl]quinoline IN HUMANS: USE OF PRECLINICAL DATA TO RATIONALIZE CLINICAL OBSERVATIONS

Harrison

Betts²,

Fenner³

et al. 2004

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:4-Amino-5-(4-fluorophenyl)-6,7-dimethoxy-2-[4-(morpholinocarbonyl)-perhydro-1,4-diazepin-1-yl]quinoline (UK-294,315) is an antagonist of the human ␣ 1 -adrenoceptor and exhibits nonlinear oral pharmacokinetics in humans. Superproportional increases in C max occur (220-fold, over a 1-to 50-mg dose range), area under the curve increases linearly, but time to maximum concentration decreases with dose, suggesting variation in rate but not extent of absorption. Oral absorption in humans is extensive, with only 14% of an orally administered (20 mg) radiolabeled dose excreted unchanged in the feces. In rats and dogs, UK-294,315 is partially eliminated as unchanged drug in feces (29 and 14% of an intravenous dose, respectively). Oral bioavailability is low in rats (11%) and high in dogs (71%), in keeping with systemic clearance. Fecal elimination of unchanged drug was 60% after oral administration to rats, indicating incomplete absorption in this species, whereas absorption in dogs is complete. UK-294,315 is a P-glycoprotein (P-gp) substrate (K m , 15 M) exhibiting polarized flux in Caco-2 cell monolayers, saturable across a concentration range of 5 to 200 M. Furthermore, the observations in vitro occurred at similar concentrations to those estimated in the gut lumen in clinical trials (dose range, 1-100 mg). It is considered that P-gp acts as a saturable absorption barrier to UK-294,315, slowing the rate of absorption at low doses, and is responsible for the observed nonlinearity in oral disposition in humans. Rat and dog pharmacokinetic studies offered limited insight into the process(es) driving nonlinear pharmacokinetics in humans. Our current understanding of the functional effects of P-gp in the human intestine, in combination with in vitro studies at clinically relevant concentrations, has helped rationalize the clinical data for UK-294,315.4-Amino-5-(4-fluorophenyl)-6,7-dimethoxy-2-[4-(morpholinocarbonyl)-perhydro-1,4-diazepin-1-yl]quinoline (UK-294,315 1 ) (Fig. 1) is a novel potent antagonist of the human ␣ 1 -adrenoceptor found in the prostate, cardiovascular system, and other tissues. ␣ 1 -Adrenoceptor antagonists are well precedented in the effective treatment of hypertension and benign prostatic hyperplasia [e.g., doxazosin (Fulton et al., 1995) and tamsulosin (Wilde and McTavish, 1996)].Following progression to clinical studies, UK-294,315 exhibited nonlinear behavior in the rate, but not extent, of absorption over the dose range studied (1-100 mg). Nonlinear pharmacokinetics pose a challenge to the successful development of a drug candidate, especially when this behavior occurs across the therapeutic dose range. Such behavior complicates drug therapy due to extensive variability in exposure, which may lead to variable efficacy and narrow therapeutic window over potential adverse events. Indeed, nonlinear oral pharmacokinetics, within the commonly used dose range, of the recreational drug "ecstasy" are thought to result in cases of ...

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Section: Fig 5 Mean Pharmacokinetic Profiles After Oral Administratmentioning

confidence: 99%

NONLINEAR ORAL PHARMACOKINETICS OF THE Α-Antagonist 4-Amino-5-(4-Fluorophenyl)-6,7-Dimethoxy-2-[4-(Morpholinocarbonyl)-Perhydro-1,4-Diazepin-1-Yl]quinoline IN HUMANS: USE OF PRECLINICAL DATA TO RATIONALIZE CLINICAL OBSERVATIONS

Harrison

Betts²,

Fenner³

et al. 2004

Drug Metab Dispos

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“…Sustained efficacy and symptom improvement with alfuzosin therapy for up to 3 years is well established. [16][17][18] The profile of rapid and sustained efficacy with alfuzosin therapy, paired with good tolerability and safety, has positive implications for patient compliance. AEs observed in the present study were similar to those reported previously with alfuzosin.…”

Section: Discussionmentioning

confidence: 99%

Rapid onset of action with alfuzosin 10 mg once daily in men with benign prostatic hyperplasia: a randomized, placebo-controlled trial

Resnick

Roehrborn

2007

Prostate Cancer Prostatic Dis

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This randomized, double-blind, placebo-controlled study was conducted to investigate whether alfuzosin 10 mg once daily improves the maximum flow rate (Q(max)) and lower urinary tract symptoms (LUTS) of benign prostatic hyperplasia (BPH) after 1 week and 1 month of treatment. A total of 372 men aged > or = 50 years with symptomatic BPH received alfuzosin or placebo for 28 days. Q(max) increased significantly from baseline at day 8 with alfuzosin (P<0.001 versus placebo); this improvement was evident within 24 h after the first dose and was maintained at day 29. LUTS improved from baseline with alfuzosin at day 8 (P=0.07 versus placebo) and day 29 (P=0.003 versus placebo). Alfuzosin 10 mg once daily exhibits a rapid onset of action, with improvements in Q(max) and LUTS maintained through 1 month of treatment.

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“…No significant differences were seen in the three groups in terms of EjD, libido, and ED. Rates of EjD were unchanged in the 9-month open-label extension of the ALFORTI trial in which 311 men used daily-dose alfuzosin [11,12].…”

Section: Alfuzosinmentioning

confidence: 96%

Sexual Impact of Treatment of Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia

Wiser

Köhler

2010

Curr Urol Rep

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Long-Term Safety and Efficacy of a Once-Daily Formulation of Alfuzosin 10 mg in Patients with Symptomatic Benign Prostatic Hyperplasia: Open-Label Extension Study

Cited by 52 publications

References 26 publications

NONLINEAR ORAL PHARMACOKINETICS OF THE Α-Antagonist 4-Amino-5-(4-Fluorophenyl)-6,7-Dimethoxy-2-[4-(Morpholinocarbonyl)-Perhydro-1,4-Diazepin-1-Yl]quinoline IN HUMANS: USE OF PRECLINICAL DATA TO RATIONALIZE CLINICAL OBSERVATIONS

NONLINEAR ORAL PHARMACOKINETICS OF THE Α-Antagonist 4-Amino-5-(4-Fluorophenyl)-6,7-Dimethoxy-2-[4-(Morpholinocarbonyl)-Perhydro-1,4-Diazepin-1-Yl]quinoline IN HUMANS: USE OF PRECLINICAL DATA TO RATIONALIZE CLINICAL OBSERVATIONS

Rapid onset of action with alfuzosin 10 mg once daily in men with benign prostatic hyperplasia: a randomized, placebo-controlled trial

Sexual Impact of Treatment of Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia

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