Dose Of Tadalafil Research Articles

Continuing Medical Education: 2009 Update on Phosphodiesterase Type 5 Inhibitor Therapy Part 1: Recent Studies on Routine Dosing for Penile Rehabilitation, Lower Urinary Tract Symptoms, and Other Indications (CME)

Highly selective inhibitors of phosphodiesterase type 5 (PDE5I) have been commercially available for over a decade. Our knowledge of these drugs continues to expand. To review developments within the past 18 months on the utilization of PDE5I in preclinical studies and clinical practice. The focus of this article is on updates on regular dosing regimens of PDE5I other than the newly approved daily dose tadalafil. PubMed search utilizing the terms "phosphodiesterase type 5 inhibitor," PDE5 inhibitor,""sildenafil,""vardenafil," and "tadalafil." Articles were screened based on whether or not they addressed issues of routine dosing of PDE5I. Manuscripts on the newly approved daily dose tadalafil for erectile dysfunction (ED) were deferred for analysis in a separate manuscript in this series. Peer reviewed publications on routine dosing of PDE5I published in the medical literature since 2007. There have been numerous publications in the past 2 years regarding routine dosing of PDE5I for three major urological indications; penile rehabilitation, stuttering priapism, and management of lower urinary tract symptoms (LUTS). Evidence from basic science investigations has indicated that daily dose PDE5I may improve erectile function and exert a number of beneficial tissue effects on the penis. Unfortunately, data from human series of routine dose PDE5I for penile rehabilitation after radical prostatectomy are conflicting, with the two largest studies showing no benefit to daily dose therapy in the post-radical prostatectomy and the general ED populations. PDE5I are generally helpful at reducing symptoms of LUTS, particularly when given in conjunction with alpha blockers. Routine dosing of PDE5I has also been utilized successfully for management of stuttering ischemic priapism and several other medical indications. PDE5I given as routine doses have clinical promise. Further research is required to clarify their safety and efficacy for various indications.

Sildenafil or vardenafil nonresponders' erectile response to tadalafil.

Erectile dysfunction has usually been treated by a phosphodiesterase 5 inhibitor in men, especially in the past decade. Although sildenafil and vardenafil are widely used, there is a high percentage of people who do not respond to these drugs. This study was performed in order to evaluate the efficacy of the lastly presented phosphodiesterase 5 inhibitor, tadalafil, in nonresponder group of patients to sildenafil and vardenafil. Forty married men with erectile dysfunction who had taken sildenafil or vardenafil at the maximum recommended doses and had not responded to the treatment were included. They were treated with tadalafil, 20 mg, at least 4 doses at different days. The effectiveness of the treatment was reviewed by different questionnaires, including the International Index of Erectile Function-5 (IIEF-5), Sexual Encounter Profile (SEP) questions 2 and 3, and the Global Assessment Question (GAQ), at the end of the 12th week. The IIEF-5 scores were 11.90 +/- 4.78 and 12.67+/-6.70, before and after at least 4 doses of tadalafil, respectively (P = .30). The rate of positive responses to SEP2, SEP3, and GAQ questions were also insignificantly different after the treatment. During this period, flushing was seen in 10 and headache was seen in 5 patients. The recommended maximum dose for tadalafil insignificantly improved the IIEF5, SEP2, SEP3, and GAQ scores in patients with erectile dysfunction who had not responded to sildenafil and vardenafil. The other treatment alternatives should be in mind after getting no response to the optimum doses and enough trials of sildenafil or vardenafil before trying a tadalafil regimen.

Tadalafil Administered Once Daily for Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: A Dose Finding Study

Phosphodiesterase type 5 inhibitors are widely used to treat erectile dysfunction. Preliminary data have suggested phosphodiesterase type 5 inhibitor efficacy in men with lower urinary tract symptoms associated with clinical benign prostatic hyperplasia. After a 4-week placebo run-in period 1,058 men with benign prostatic hyperplasia lower urinary tract symptoms were randomly allocated to receive 12-week, once daily treatment with placebo or tadalafil (2.5, 5, 10 or 20 mg). The International Prostate Symptom Score least squares mean change from baseline to end point was significantly improved for 2.5 (-3.9, p = 0.015), 5 (-4.9, p <0.001), 10 (-5.2, p <0.001) and 20 mg (-5.2, p <0.001) tadalafil compared to placebo (-2.3). International Prostate Symptom Score improvements at 4, 8 and 12 weeks were significant for all tadalafil doses and they demonstrated a dose-response relationship. Tadalafil (2.5 mg) significantly improved the International Prostate Symptom Score obstructive subscore and the International Index of Erectile Function-Erectile Function domain, the latter in sexually active men with a history of erectile dysfunction. Statistically significant improvements were noted for 5, 10 and 20 mg tadalafil compared to placebo, as assessed by the International Prostate Symptom Score irritative and obstructive subscores, International Prostate Symptom Score Quality of Life, Benign Prostatic Hyperplasia Impact Index (nonsignificant for 10 mg), Global Assessment Question and International Index of Erectile Function-Erectile Function domain. No statistically significant effect of treatment compared to placebo was noted for peak flow at any tadalafil dose. Treatment emergent adverse events were infrequent in all tadalafil groups. Once daily tadalafil demonstrated clinically meaningful and statistically significant efficacy and it was well tolerated in men with benign prostatic hyperplasia lower urinary tract symptoms. Of the doses studied 5 mg tadalafil appeared to provide a positive risk-benefit profile.

Evaluation of testosterone and prolactin hormones levels in erectile dysfunction patients after single oral dose of Tadalafil

Erectile dysfunction (ED) is defined as a consistent inability to sustain an erection sufficient for sexual intercourse. Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection.Tadalafil has no effect in the absence of sexual stimulation. Erection dysfunction could attribute abnormal levels of testosterone and prolactin levels.&#x0D; Twenty Iraqi patients with different levels of ED were considered in this study treated with 20 mg. of tadalafil coated tablets. All patients considered in this study have been get erection after treatments with tadalafil. Prolactin and testosterone has been determined by radioimmunoassay (RIA). The evaluatedresults indicated significant decrease for prolactin (p&lt;0.01) and significant elevation for the testosterone (p&lt;o.ooo1). The ratio of prolactin/ testosteronewas increased after treatments.In conclusion: prolactin and testosterone hormonal levels must be considered with tadalafil treatments. Tadalafil must be not described to patients with abnormal levels of these hormones. Patients with testosterone and prolactin abnormalities need to take advice from the endocrinologist before use tadalafilwith monitoring of prolactin and testosterone levels.

Stepwise Decline in Visual Field After Serial Sildenafil Use

Stepwise Decline in Visual Field After Serial Sildenafil Use

Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction

Erectile dysfunction (ED) is a common comorbidity in men with diabetes mellitus. Tadalafil 10 or 20 mg taken on demand is efficacious and safe for men with diabetes and ED. Recently, continuous treatment with tadalafil has been proposed, addressing ED management as any other chronic condition. This study examined whether once-daily tadalafil 2.5 and 5 mg is efficacious for men with diabetes and ED. This randomized, double-blind, placebo-controlled, multicentre, 12-week study enrolled 298 men with diabetes and ED to once-daily treatment with placebo, tadalafil 2.5 mg or tadalafil 5 mg. Primary efficacy measures were International Index of Erectile Function Erectile Function (IIEF EF) Domain score, and patient success rates for vaginal penetration and completion of intercourse. Patient satisfaction, endothelial function biomarkers, and safety were also assessed. Patients receiving either dose of tadalafil had clinically and statistically significant improvements in IIEF EF and statistically significant improvements in mean success rates for vaginal penetration, completion of intercourse, and overall treatment satisfaction (P < or = 0.005 tadalafil vs. placebo, all measures). Endothelial dysfunction biomarkers were unchanged. The most common adverse events were headache, back pain and dyspepsia. In this first study of men with diabetes and ED, once-daily tadalafil 2.5 and 5 mg was efficacious and well tolerated, suggesting this may be an alternative to on-demand treatment for some men, eliminating the need to plan sex within a limited timeframe.

The cardiovascular safety of tadalafil

Tadalafil is an inhibitor of phosphodiesterase 5, approved for the treatment of erectile dysfunction. Blood pressure-lowering effects of tadalafil in healthy volunteers are minimal. In patients on a broad spectrum of antihypertensive medication, severe hypotension did not occur in combination with tadalafil; however, a combination of tadalafil with any nitric oxide donor can lead to life-threatening hypotension and is, therefore, absolutely contraindicated (at least 48 h interval after last dose of tadalafil). Combination with α-blocking agents, such as doxazosin, may only be considered when patients are hemodynamically stable for a longer period using the lowest dose of tadalafil and with close blood pressure monitoring. In placebo-controlled trials, severe adverse cardiovascular events were rare in tadalafil users and similar in frequency in comparison to placebo. However, as cardiovascular disease is highly prevalent in patients with erectile dysfunction, a complete diagnostic work up of these patients and potentially optimized cardiovascular treatment may be necessary before sexual intercourse can be recommended and tadalafil may be prescribed.

Chronic daily tadalafil prevents the corporal fibrosis and veno‐occlusive dysfunction that occurs after cavernosal nerve resection

To determine whether a long-term single daily oral dose of a longer half-life phosphodiesterase-5 (PDE5) inhibitor, tadalafil, has a similar effect to that of the shorter half-life PDE5 inhibitors sildenafil and vardenafil, and can prevent the fibrosis and resultant corporal veno-occlusive dysfunction (CVOD) occurring after cavernosal nerve (CN) injury. Male rats (10 per group) had either a sham operation, unilateral CN resection (CNR) or bilateral CNR, and were left untreated or given retrolingually 5 mg/kg per day of tadalafil. After 45 days, CVOD was assessed via cavernosometry, and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry (followed by quantitative image analysis), Western blots, and ad hoc methods. Tadalafil treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after CNR compared with sham-operated rats. Tadalafil also normalized the increase in penile shaft collagen content, and the reduction in corporal smooth muscle cell (SMC) content, SMC/collagen, and replication index, and improved the lower collagen III/I ratio and the increase in apoptotic index, caused by CNR, compared with sham operation. There were no effects of tadalafil on increased transforming growth factor beta1, inducible nitric oxide synthase and xanthine oxidoreductase levels. A long-term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage, as effectively as the previously reported continuous treatment with vardenafil or sildenafil, through a cGMP-related mechanism that appears to be independent of inducible nitric oxide synthase induction.

Efficacy and Safety of Tadalafil in Men With Erectile Dysfunction Following Spinal Cord Injury

To determine the efficacy and safety of tadalafil when taken on demand by men with erectile dysfunction (ED) secondary to traumatic spinal cord injury (SCI). Multicenter, randomized, double-blind, placebo-controlled, flexible dose-titration, parallel-group study in clinical practices in Europe. Patients Enrolled patients had ED secondary to SCI (all spinal levels) and sustained 6 months or longer before visit 1. After a 4-week run-in period, patients were randomly assigned to tadalafil, 10 mg, (n = 142) or placebo (n = 44) for a 12-week, on-demand treatment period with assessments at 4-week intervals. The dose of tadalafil was maintained or titrated (10 or 20 mg) at 4 and 8 weeks. Efficacy was measured using the International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP), and Global Assessment Question (GAQ). Treatment-emergent adverse events and vital signs were collected at each visit. Mean age was 38 years. Mean baseline IIEF erectile function domain score was 13.4, and following 12 weeks of treatment, 22.6 for tadalafil and 13.6 for placebo (P < .001). After treatment, the tadalafil group compared with the placebo group was significantly greater (P < .001) in mean per-patient percentage of successful penetration attempts (SEP question 2; 75.4% vs 41.1%) and intercourse attempts (SEP question 3; 47.6% vs 16.8%); percentage of improved erections (GAQ question 1; 84.6% vs 19.5%); and ejaculatory frequency (IIEF question 9; P = .03). The 2 most common treatment-emergent adverse events in the tadalafil group compared with placebo were headache (8.5% vs 4.5%) and urinary tract infection (7.7% vs 6.8%). Tadalafil (10 mg and 20 mg) improved erectile function and was well tolerated by men with ED secondary to traumatic SCI.

Expression of the PDE5 enzyme on human retinal tissue: new aspects of PDE5 inhibitors ocular side effects

We tested the effect of two phosphodiesterase type-5 (PDE5) inhibitors, sildenafil and tadalafil, on ophthalmic artery (OA) blood flow velocity and investigated the presence of the PDE5 enzyme on human retinal tissue in comparison with the PDE6 enzyme localization. Using Colour Doppler ultrasonography (CDU) we investigated, in 30 healthy young subjects (27.8 years of age; range, 24.3-33.7 years), the effects of a single oral dose of sildenafil (100 mg), tadalafil (20 mg), and placebo on OA blood flow velocity. Western blot for PDE6 and PDE5 protein expression was performed on frozen samples of human retina, testis, sperm, skin, and corpus cavernosum. Immunohistochemistry was performed on two ocular globes from dead donors. CDU showed a relationship between the administration of PDE5 inhibitors and OA blood flow velocity modifications in a time-dependent manner. Western blot and immunohistochemical analysis showed PDE6 and PDE5 presence in human retinal tissue and gave a map of its distribution. We demonstrated that (a) tadalafil and sildenafil are able to modify the OA flux in a time-dependent manner; (b) the PDE5 enzyme is expressed on retinal and choroid vasculature (smooth muscle and endothelial cells), on ganglion and bipolar cells; (c) human retinal tissues express the PDE6 enzyme in the rod and cone photoreceptors; (d) visual side effects after PDE5 inhibitors administration may be linked to a specific effect on the PDE5 enzyme; and (e) the PDE5 enzyme may have a physiologic role on ganglion and bipolar cells that need to be further investigated.

Effect of tadalafil on anaerobic performance indices in healthy athletes

Objective:Given the therapeutic and non-therapeutic use of the tadalafil, (phosphodiesterase-5 inhibitor, PDE-5i), we examined its effects on anaerobic performance indices.Methods:In total, 12 well-trained subjects reported to the laboratory on two...

Alterations in sperm motility after acute oral administration of sildenafil or tadalafil in young, infertile men

To evaluate the acute effect of sildenafil and tadalafil on seminal parameters in young, infertile patients. Prospective, randomized, double-blind, crossover clinical investigation on semen parameters after the administration of a single dose of sildenafil (50 mg) or tadalafil (20 mg). An academic hospital as well as a male infertility center and clinical andrology laboratories. Eighteen young, infertile men. Oral administration of a single dose of sildenafil (50 mg) or tadalafil (20 mg) in a blind, randomized order. The semen samples were collected 1 or 2 hours after each treatment. Changes in sperm parameters after sildenafil and tadalafil administration, compared with the basal conditions. A significant increase in sperm progressive motility (median value, 37.0% vs. 28.5%) was observed after sildenafil administration as compared with baseline; in contrast, a significant decreased value was observed after tadalafil (median value, 21.5% vs. 28.5%). These preliminary results indicate that sperm motility appears to be acutely affected in young, infertile patients by a single dose of sildenafil and tadalafil, with opposite effects: stimulatory by the former and inhibitory by the latter.

Phosphodiesterase-5 Inhibitor in Eisenmenger Syndrome

Phosphodiesterase-5 inhibitors produce a significant decrease in pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension. We studied the effects of tadalafil, a phosphodiesterase-5 inhibitor, on short-term hemodynamics, tolerability, and efficacy over a 12-week period in patients of Eisenmenger syndrome having a pulmonary vascular pathology similar to idiopathic pulmonary arterial hypertension. Sixteen symptomatic Eisenmenger syndrome patients (mean age, 25+/-8.9 years) were assessed hemodynamically at baseline and 90 minutes after a single dose of tadalafil (1 mg/kg body weight up to a maximum of 40 mg). The same dose was then continued daily for 12 weeks, and the patients were restudied. There was a significant decrease in mean pulmonary vascular resistance immediately (24.75+/-8.49 to 19.22+/-8.23 Woods units; P<0.005) and at 12 weeks (19.22+/-8.23 to 17.02+/-6.19 Woods units; P=0.03 versus 90 minutes). Thirteen of 16 patients (81.25%) showed a > or = 20% decrease in pulmonary vascular resistance and were defined as responders. The mean systemic oxygen saturation improved significantly both immediately (84.34+/-5.47% to 87.39+/-4.34%; P<0.005) and at 12 weeks (87.39+/-4.34% to 89.16+/-3.8%; P<0.02 versus 90 minutes) without a significant change in systemic vascular resistance. None of the patients had a fall in systemic arterial pressure, worsening of systemic oxygen saturation, or any adverse reactions to the drug. The mean World Health Organization functional class improved from 2.31+/-0.47 to 1.25+/-0.44 (P<0.0001), and the 6-minute walk distance improved from 344.56+/-119.06 to 387.56+/-117.18 m (P<0.001). Preliminary evaluation of tadalafil has shown efficacy and safety in selected patients with Eisenmenger syndrome, warranting further investigation in this subgroup of patients.

Efficacy and safety of tadalafil 5, 10, and 20 mg in Japanese men with erectile dysfunction: Results of a multicenter, randomized, double-blind, placebo-controlled study

Objectives To investigate the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in Japanese men with erectile dysfunction (ED). Methods This multicenter, randomized, double-blind, placebo-controlled, 12-week study enrolled 343 Japanese men with ED. The men were stratified into those with mild, moderate, or severe ED and then randomly assigned 1:1:1:1 to placebo and 5 mg, 10 mg, and 20 mg tadalafil. Co-primary outcomes were the International Index of Erectile Function erectile function domain score, the percentage of “yes” responses to the Sexual Encounter Profile Diary Questions 2 and 3, and tolerability. Secondary outcomes included the International Index of Erectile Function intercourse satisfaction and overall satisfaction domain scores and the percentage of “yes” responses to a global assessment question. Results The least square mean change from baseline was 7.5, 9.1, and 9.4 for 5, 10, and 20 mg tadalafil versus 2.1 for placebo for the International Index of Erectile Function erectile function domain; 28.5, 36.0, and 36.5 for 5, 10, and 20 mg tadalafil versus 8.6 for placebo for Sexual Encounter Profile question 2; and 34.3, 47.3, and 50.8 for 5, 10, and 20 mg tadalafil versus 12.3 for placebo for Sexual Encounter Profile question 3, respectively ( P <0.001 for all doses and all measures). Patients taking tadalafil had significantly greater changes from baseline for the intercourse satisfaction and overall satisfaction domains compared with patients taking placebo ( P <0.001). Also, 76.5%, 81.4%, and 83.7% of patients taking 5, 10, and 20 mg tadalafil, respectively, reported improved erections (global assessment question) versus 31.4% of patients taking placebo ( P <0.001). Most (98%) treatment-emergent adverse events were mild or moderate in severity. One patient (tadalafil 5 mg) discontinued because of an adverse event (ureteral calculus). Of the 343 patients, 302 (88%) completed the study. No deaths were reported. Conclusions All doses of tadalafil studied were efficacious and well tolerated in Japanese men with ED.

Hemodynamic interaction study between the alpha 1-blocker alfuzosin and the phosphodiesterase-5 inhibitor tadalafil in middle-aged healthy male subjects

Objectives To examine the hemodynamic interactions of the phosphodiesterase type 5 (PDE-5) inhibitor tadalafil with the uroselective alpha 1-blocker alfuzosin (10 mg daily), commonly prescribed for benign prostatic hyperplasia-related lower urinary tract symptoms. Erectile dysfunction is commonly associated with lower urinary tract symptoms. PDE-5 inhibitors are the first-line treatment of choice for erectile dysfunction. When co-administered with alpha 1-blockers, PDE-5 inhibitors could induce orthostatic hypotension. Methods During each of the two periods of a randomized, double-blind, placebo-controlled, crossover study, 18 healthy middle-aged men received alfuzosin 10 mg daily for 7 days and either a single 20-mg dose of tadalafil or placebo on day 7. The blood pressure and heart rate were monitored before and for 24 hours after tadalafil or placebo. Results The combination of tadalafil 20 mg with alfuzosin 10 mg daily elicited a maximal decrease in standing systolic blood pressure that was not significantly different from that after placebo (mean difference 4.35 mm Hg, P = nonsignificant). Analysis of the blood pressure outliers showed that only 1 subject had an asymptomatic standing systolic blood pressure of less than 85 mm Hg. No vasodilatory adverse events were observed with the combined medication. Conclusions In healthy, middle-aged men, tadalafil 20 mg showed no clinically relevant hemodynamic interactions with alfuzosin 10 mg daily.

Influence of a single dose of 20 mg tadalafil, a phosphodiesterase 5 inhibitor, on ambulatory blood pressure in subjects with hypertension

To test the non-inferiority of a single dose of tadalafil 20 mg compared with placebo with respect to 26-h mean ambulatory systolic and diastolic blood pressure in treated and untreated hypertensive subjects. A multicentre, randomized, double-blind, placebo-controlled crossover study in 114 subjects with hypertension (36 subjects on no therapy with daytime mean ambulatory blood pressure >/= 140/85 mmHg; 38 subjects on two to four classes of antihypertensive agents with daytime mean ambulatory blood pressure >/=140/85 mmHg and 40 subjects on two to four classes of antihypertensive agents with ambulatory blood pressure < 140/85 mmHg). Overall tadalafil reduced mean ambulatory blood pressure monitor systolic and diastolic blood pressure by 4.8 mmHg [95% confidence interval (Cl) 3.7, 5.9; P < 0.01] and 2.9 mmHg (95% CI 1.9, 3.6; P < 0.01), respectively, compared with placebo. In hypertensive subjects with uncontrolled blood pressure on two to four classes of antihypertensive agents (n = 36) tadalafil reduced mean ABPM systolic and diastolic blood pressure by 7.5 mmHg (95% CI 5.4, 9.6; P < 0.01) and 4.3 mmHg (95% CI 6.1, 8.9; P < 0.01) compared with placebo. In patients with uncontrolled hypertension on multiple agents the addition of tadalafil 20 mg lowered mean 26-h blood pressure.

Preferencia de Tadalafilo vs Sildenafilo en pacientes españoles con disfunción eréctil: resultados procedentes de un estudio multicéntrico internacional

ObjectiveTo compare patient preference for sildenafil citrate (sildenafil) vs. tadalafil and for their respective dosing instructions in a cohort of Spanish patients with erectile dysfunction (ED) Material and methodsSixty four Spanish patients from a multicenter, two period, cross-over, double-blind study (265 patients enrolled in total) were randomized to receive on-demand sildenafil 50 mg or tadalafil 20 mg for 12 weeks and afterwards were crossed over to the alternate regimen for another 12 weeks to assess drug preference in an extension period of the study. Similarly, to evaluate preference for their respective dosing instructions, 30 patients were randomized to one of the 2 arms treated with tadalafil: one with sildenafil (S) dosing instructions and the other with tadalafil (T) dosing instructions ResultsSeventy percent of 56 patients completing the study chose to receive tadalafil treatment versus sildenafil treatment (30%) in the extension period (p < 0.01). Correspondingly, 73% of 13 evaluating each drug dosing instructions preferred T dosing instructions (p>0.05). Preference did not vary with age, concomitant diseases and previous use of sildenafil ConclusionsIn this study, 7 out of 10 patients preferred tadalafil and its dosing instructions to sildenafil, for the treatment of their ED

Tadalafil pharmacokinetics in healthy subjects.

To characterize tadalafil plasma pharmacokinetics in healthy subjects following single and multiple doses. Noncompartmental parameters were calculated for healthy subjects receiving a single 2.5-20-mg tadalafil dose in 13 clinical pharmacology studies. An integrated statistical analysis of results in 237 subjects provided global averages and an assessment of effects of body mass index (BMI), age, gender and smoking status. Diurnal variation, food effects and proportionality of exposure to dose were analysed in three studies. Multiple-dose pharmacokinetics were evaluated in a separate study in which parallel groups of 15 subjects received 10 or 20 mg tadalafil once daily for 10 days. Tadalafil was absorbed rapidly with mean Cmax (378 microg l-1 for 20 mg) observed at 2 h; thereafter, concentrations declined nearly monoexponentially with a mean (5th, 95th percentiles) t1/2 of 17.5 (11.5, 29.6) hours. Mean oral clearance (CL/F) was 2.48 (1.35, 4.35) l h-1 and apparent volume of distribution (Vz/F) was 62.6 (39.5, 92.1) l. No clinically meaningful effect of BMI, age, gender or smoking was identified. Exposure was not substantially affected by time of dosing. Food had negligible effects on bioavailability as assessed by 90% confidence intervals for Cmax and AUC mean ratios. Parameters were proportional to dose, indicating that doubling the dose doubled exposure. Steady state was attained by day 5 following once-daily administration, and accumulation (1.6-fold) was consistent with the t1/2. Tadalafil pharmacokinetics are linear with respect to dose and time, and are not affected by food. Systemic clearance is low relative to other phosphodiesterase 5 inhibitors.

Time from dosing to sexual intercourse attempts in men taking tadalafil in clinical trials

To determine whether patients with erectile dysfunction (ED) and treated with tadalafil use the 36-h duration of effect of the drug, and to discern if the timing of intercourse attempts is influenced by patient age, baseline severity of ED, or previous experience with sildenafil citrate. In 11 multicentre, double-blind, placebo-controlled studies, 2102 patients with ED were randomized to a maximum of one dose per day of tadalafil 10 or 20 mg (1464 men), or placebo (638 men) with no time restrictions before attempting sexual activity after the dose. A post hoc analysis was used to determine the proportion of men with ED who attempted sexual intercourse during various intervals (>0 to < or = 1, >1 to < or = 4, and >4 to < or = 36, including >12 to < or = 36 h) after dosing with tadalafil or placebo over a 12-week period. Patients were stratified by age, baseline severity of ED, and previous history of sildenafil use. Of patients in different age groups and various ED severity, > or = 79% and > or = 53% chose to attempt sexual intercourse at least once during the 12-week treatment period at 4-36 and 12-36 h, respectively, after taking tadalafil. Regardless of previous experience with sildenafil, about a third of patients using tadalafil attempted intercourse a mean of at least once per week at 4-36 h after the dose over 12 weeks. Furthermore, 58% of patients attempted intercourse at least once during two intervals (>1 to < or = 4 h and >12 to < or = 36 h) after separate doses of tadalafil. Regardless of age, ED severity, or previous experience with sildenafil, most patients attempted sexual intercourse at least once at 12-36 h after one dose of tadalafil over a 12-week treatment period. Furthermore, by engaging in sexual intercourse at both earlier and later intervals after separate doses, most patients on treatment did not adhere to a fixed schedule of intimacy and thus took advantage of the 36-h duration.

Effect of tadalafil on cytochrome P450 3A4?mediated clearance: Studies in vitro and in vivo

Tadalafil was examined in vitro and in vivo for its ability to affect human cytochrome P450 (CYP) 3A-mediated metabolism. Reversible and mechanism-based inhibition of CYP3A by tadalafil was examined in human liver microsomes. The ability of tadalafil to influence CYP3A activity was also examined in primary cultures of human hepatocytes. The effect of tadalafil on the pharmacokinetics of CYP3A probe substrates was evaluated in human volunteers before and after coadministration with either a single dose or multiple doses of tadalafil (10 or 20 mg). Negligible competitive inhibition of CYP3A was observed in vitro. Mechanism-based inhibition of CYP3A was detected, albeit with a low potency. In human hepatocytes, exposure to 1 micromol/L or greater of tadalafil resulted in increased CYP3A protein expression; however, as with a combined effect of induction and inhibition, a corresponding increase in CYP3A activity did not occur. The clinical pharmacokinetics of midazolam and lovastatin, probe substrates of CYP3A, were unaffected by up to 14 days of tadalafil administration (90% confidence intervals for the ratio of least squares means for the pharmacokinetic parameters of tadalafil were contained within the no-effect boundaries of 0.7 to 1.43). In vitro results suggested that tadalafil would have little effect on the pharmacokinetics of drugs metabolized by CYP3A. Clinical studies demonstrated that the pharmacokinetics of 2 different CYP3A substrates, midazolam and lovastatin, were virtually unchanged after tadalafil coadministration. Thus therapeutic concentrations of tadalafil do not produce clinically significant changes in the clearance of drugs metabolized by CYP3A.