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Pharmacology: Pharmacodynamics: Mechanism of action: Tadalafil is a selective, inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP).
Erectile dysfunction and benign prostatic hyperplasia: 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 treatment of erectile dysfunction in the absence of sexual stimulation.
The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The resulting vascular relaxation increases blood perfusion which may be the mechanism by which symptoms of benign prostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition of bladder afferent nerve activity and smooth muscle relaxation of the prostate and bladder.
Pharmacodynamic effects: Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum and pancreas. The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, and PDE4, enzymes which are found in the heart, brain, blood vessels, liver, and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also >10,000-fold more potent for PDE5 than for PDE7 through PDE10.
Clinical efficacy and safety: Tadalafil administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mmHg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mmHg, respectively) and no significant change in heart rate.
In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. Across all clinical studies, reports of changes in colour vision were rare (<0.1%).
Three studies were conducted in men to assess the potential effect on spermatogenesis of Tadalafil 10mg (one 6-month study) and 20mg (one 6-month and one 9-month study) administered daily. In two of these studies decreases were observed in sperm count and concentration related to tadalafil treatment of unlikely clinical relevance. These effects were not associated with changes in other parameters such as motility, morphology and FSH.
Erectile Dysfunction: For Tadalafil on-demand, three clinical studies were conducted in 1,054 patients in an at-home setting to define the period of responsiveness. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients' ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing.
In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with ED secondary to spinal cord injury, Tadalafil significantly improved the erectile function leading to a mean per-subject proportion of successful attempts in patients treated with tadalafil 10mg or 20mg (flexible-dose, on-demand) of 48% as compared to 17% with placebo.
For once-a-day evaluation of tadalafil at doses of 2.5mg, 5mg and 10mg, three clinical studies were initially conducted involving 853 patients of various ages (range 21-82 years) and ethnicities, with ED of various severities (mild, moderate, severe) and etiologies. In the two primary efficacy studies of general populations, the mean per-subject proportion of successful intercourse attempts were 57 and 67% on Tadalafil 5mg, 50% on Tadalafil 2.5mg as compared to 31 and 37% with placebo. In the study in patients with ED secondary to diabetes, the mean per-subject proportion of successful attempts were 41 and 46% on Tadalafil 5mg and 2.5mg, respectively, as compared to 28% with placebo. Most patients in these three studies were responders to previous on-demand treatment with PDE5 inhibitors. In a subsequent study, 217 patients who were treatment-naïve to PDE5 inhibitors were randomised to Tadalafil 5mg once a day vs placebo. The mean per-subject proportion of successful sexual intercourse attempts was 68% for Tadalafil patients compared to 52% for patients on placebo.
Tadalafil at doses of 2mg to 100mg has been evaluated in 16 clinical studies involving 3,250 patients, including patients with ED of various severities (mild, moderate, severe), etiologies, ages (range 21-86 years) and ethnicities. Most patients reported ED of at least 1 year in duration. In the primary efficacy studies of general populations, 81% of patients reported that Tadalafil improved their erections as compared to 35% with placebo. Also, patients with ED in all severity categories reported improved erections whilst taking Tadalafil (86%, 83% and 72% for mild, moderate and severe respectively, as compared to 45%, 42% and 19% with placebo). In the primary efficacy studies, 75% of intercourse attempts were successful in Tadalafil treated patients as compared to 32% with placebo.
Benign Prostatic Hyperplasia: Tadalafil was studied in 5 clinical studies (LVHG, LVHJ, LVHR, LVID of 12 weeks duration and LVIW of 26 weeks duration).
Study LVHG randomised 1,058 patients to receive either Tadalafil 2.5mg, 5mg, 10mg or 20mg for once daily use or placebo. Study LVHJ randomised 325 patients to receive either Tadalafil 5mg for once daily use or placebo. Patients with multiple co-morbid conditions such as diabetes mellitus, hypertension and other cardiovascular disease were included.
In each of these trials (LVHG and LVHJ), Tadalafil 5mg for once daily use resulted in statistically significant improvement in the total International Prostate Symptom Score (IPSS) compared to placebo. Mean total IPSS showed a decrease starting at the first scheduled observation (4 weeks) in Study LVHJ and remained decreased through 12 weeks. In the long-term open-label extension phase of the controlled study LVHG, in which patients received Tadalafil 5mg for up to 1 year after the 12-week double-blind treatment period, the improvement in total IPSS induced by Tadalafil at week 12 of double-blind treatment was maintained over 1 year.
In Study LVHR, Tadalafil for once daily use was also shown to be effective in treating ED and the symptoms of BPH in patients with both conditions based on results from one of the placebo-controlled, double-blind, parallel-arm efficacy and safety studies which specifically assessed the efficacy and safety of Tadalafil for once daily use in this population. In this ED and BPH study, Tadalafil 5mg demonstrated statistical superiority over placebo for total IPSS and for the International Index of Erectile Function Erectile Function (IIEF EF) domain score (mean treatment difference, 4.7; p<0.001). The mean per-subject proportion of successful sexual intercourse attempts in this study was 71.9% for Tadalafil 5mg patients compared to 48.3% patients on placebo.
Study LVID randomised 511 patients to receive either Tadalafil 5mg, tamsulosin 0.4mg or placebo. Tadalafil 5mg resulted in statistically significant improvement in total IPSS. The efficacy of Tadalafil 5mg in treating BPH was observed as early as 1 week of therapy and was maintained through 12 weeks. Tadalafil 5mg for once daily use also improved measures of ED after 12 weeks of treatment compared with placebo in sexually active subjects with ED in the Primary Analysis Population, as demonstrated by statistically significant improvements in IIEF EF domain score (mean difference of the change, 4.0; p<0.001).
Data for Study LVHG, LVHJ, LVHR and LVID are shown as follows. (See Table 1.)
Click on icon to see table/diagram/imageIn Study LVIW, Tadalafil for once daily use initiated together with finasteride was shown to be effective in treating the signs and symptoms of BPH in men with an enlarged prostate (>30cc) for up to 26 weeks. This double-blinded, parallel-design study of 26 weeks duration randomised 696 men to initiate either Tadalafil 5mg with finasteride 5mg or placebo with finasteride 5mg. The study population had a mean age of 64 years (range 46-86). Patients with multiple co-morbid conditions such as ED, diabetes mellitus, hypertension and other cardiovascular disease were included. Tadalafil with finasteride demonstrated statistically significant improvement in the signs and symptoms of BPH compared to placebo with finasteride, as measured by the total IPSS at 12 weeks, the primary study endpoint (see table 2 as follows). Key secondary endpoints demonstrated improvement in total IPSS starting at the first scheduled observation at Week 4 (Tadalafil -4.0, placebo -2.3; p<0.001) and the score remained decreased through 26 weeks (Tadalafil -5.5, placebo -4.5; p=0.022). However, the magnitude of the treatment difference between placebo/finasteride and Tadalafil/finasteride decreased from 1.7 points at Week 4 to 1.0 point at Week 26, as shown in the table and figure below. The incremental benefit of Tadalafil beyond 26 weeks is unknown. (See Table 2 and figure.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageIn the 404 patients who had both ED and BPH at baseline, changes in erectile function were assessed as key secondary endpoints using the EF domain of the IIEF questionnaire. Tadalafil with finasteride (n=203) was compared to placebo with finasteride (n=201). A statistically significant improvement from baseline (Tadalafil/finasteride 13.7, placebo/finasteride 15.1) was observed at Week 4 (Tadalafil/finasteride 3.7, placebo/finasteride -1.1; p<0.001), Week 12 (Tadalafil/finasteride 4.7, placebo/finasteride 0.6; p<0.001) and Week 26 (Tadalafil/finasteride 4.7, placebo/finasteride 0.0; p<0.001).
Pharmacokinetics: Absorption: Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) is achieved at a median time of 2 hours after dosing. Absolute bioavailability of tadalafil following oral dosing has not been determined.
The rate and extent of absorption of tadalafil are not influenced by food, thus it may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.
Distribution: The mean volume of distribution is approximately 63 litres at steady state, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Biotransformation: Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.
Elimination: The mean oral clearance for tadalafil is 2.5 l/h at steady state and the mean half-life is 16 hours in healthy subjects.
Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Linearity/non-linearity: Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5mg to 20mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are attained within 5 days of once-daily dosing. Pharmacokinetics determined with a population approach in patients with ED are similar to pharmacokinetics in subjects without ED.
Elderly: Healthy elderly subjects (65 years or over) had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) relative to healthy subjects aged 19 to 45 years. This effect of age is not clinically significant and does not warrant a dose adjustment.
Renal Insufficiency: In clinical pharmacology studies using single dose tadalafil (5mg-20mg), tadalafil exposure (AUC) approximately doubled in subjects with mild (creatinine clearance 51 to 80ml/min) or moderate (creatinine clearance 31 to 50ml/min) renal impairment and in subjects with end-stage renal disease on dialysis. In haemodialysis patients, Cmax was 41% higher than that observed in healthy subjects. Haemodialysis contributes negligibly to tadalafil elimination. Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil is not recommended in patients with severe renal impairment.
Hepatic Insufficiency: Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh class A and B) is comparable to exposure in healthy subjects when a dose of 10mg is administered.
There is limited clinical data on the safety of tadalafil in patients with severe hepatic insufficiency (Child-Pugh class C). If Zenavil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10mg of tadalafil to patients with hepatic impairment. There are no available data about the administration of once-a-day dosing of tadalafil to patients with hepatic impairment. If Zenavil is prescribed once-a-day, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.
Patients with Diabetes: Tadalafil exposure (AUC) in patients with diabetes was approximately 19% lower than the AUC value for healthy subjects. This difference in exposure does not warrant a dose adjustment.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.
There was no evidence of teratogenicity, embryotoxicity, or foetotoxicity in rats or mice that received up to 1000mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was 30mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18-times the human AUC at a 20mg dose.
There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12 months at doses of 25mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7-18.6] than seen in humans given a single 20mg dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. See also Pharmacology: Pharmacodynamics as previously mentioned.
