Pharmacokinetics Of Tadalafil Research Articles

The place of tadalafil in the treatment of PAH in the light of new clinical guidelines of the Eurasian Association of Cardiologists

Pulmonaryarterialhypertension(PAH)isalife-threateningcardiovascular disease that is characterized by a marked increase in pulmonary vascular resistance and pulmonary artery pressure due to obstructive remodeling of the pulmonary vascular bed with the development of right ventricular heart failure as a cause of premature mortality. Impaired synthesis and reduced bioavailability of nitric oxide is one of the key pathophysiological mechanisms of the development and progression of the disease. The review paper presents key data from the evidence base on the clinical use of tadalafil, a phosphodiesterase type 5 inhibitor (PDE5), which in August 2023 approved by the Pharmaceutical Committee of the Russian Ministry of Health for the indication – treatment of patients with PAH. Tadacardil from Canonpharma Production is the first and only drug in Russian practice today with the active substance tadalafil with the registered indication “PAH”, approved in the Eurasian Guidelines for the diagnosis and treatment of pulmonary hypertension 2023 and available on the territory of the Russian Federation and the EAEU. Tadacardil is indicated for use in adult patients with PAH functional class II and III according to the WHO classification to increase exercise tolerance. The efficacy of tadalafil has been shown in idiopathic PAH and PAH associated with connective tissue diseases. The recommended dose is 40 mg (2 tablets of 20 mg) once a day. The paper describes the mechanism of action and pharmacological effects of PDE5 inhibitors, features of the pharmacokinetics of tadalafil in comparison with other drugs of the class. The advantages of Tadacardil from Canonpharma Production are the proven effecacy of use in patients with PAH, ease of use due to a single dose of 2 tablets of 20 mg once a day in a standard dose; good tolerability and favorable safety profile; proven bioequivalence to the reference drug. In light of the new Eurasian recommendations for the diagnosis and treatment of PH, tadalafil has a wide field for clinical use, which will improve the treatment options for patients with PAH both in mono- and combination therapy.

Food Administration and Not Genetic Variants Causes Pharmacokinetic Variability of Tadalafil and Finasteride.

Tadalafil and finasteride are used in combination for the management of benign prostatic hyperplasia (BPH). Genetic variations in genes involved in the metabolism and transport of tadalafil or finasteride (i.e., pharmacogenes) could affect their pharmacokinetic processes altering their drug exposure, efficacy, and toxicity. The main objective of this study was to investigate the effects of variants in pharmacogenes on the pharmacokinetics of tadalafil and finasteride. An exploratory candidate gene study involving 120 variants in 33 genes was performed with 66 male healthy volunteers from two bioequivalence clinical trials after administration of tadalafil/finasteride 5 mg/5 mg under fed or fasting conditions. Afterwards, a confirmatory study was conducted with 189 male and female volunteers receiving tadalafil 20 mg formulations in seven additional bioequivalence clinical trials. Regarding tadalafil, fed volunteers showed higher area in the time-concentration curve (AUC∞), maximum plasma concentration (Cmax), and time to reach Cmax (tmax) compared to fasting volunteers; male volunteers also showed higher AUC∞ and Cmax compared to female volunteers. Furthermore, fed volunteers presented higher finasteride AUC∞, Cmax and tmax compared to fasting individuals. Variants in ABCC3, CYP1A2, CES1, NUDT15, SLC22A1/A2 and UGT2B10 were nominally associated with pharmacokinetic variation in tadalafil and/or finasteride but did not remain significant after correction for multiple comparisons. Genetic variation did not demonstrate to clinically impact on the pharmacokinetics of finasteride and tadalafil; however, additional studies with larger sample sizes are needed to assess the effect of rare variants, such as CYP3A4*20 or *22, on tadalafil and finasteride pharmacokinetics.

The Effect of Grapefruit Juice on the Pharmacokinetics of Tadalafil in Rats.

We developed and validated a novel, sensitive, selective, and inexpensive high-performance liquid chromatography (HPLC) method for the determination of tadalafil in rats plasma and to investigate the effect of grapefruit juice on the pharmacokinetics of tadalafil in rats. The ZORBAX Eclipse XDB-C18 (4.6 × 150 mm, 5 μm) chromatography column can be used to separate tadalafil and carbamazepine (internal standard, IS). A mixture of acetonitrile-0.2% trifluoroacetic acid-water (48 : 10 : 42, V/V/V) was used as the mobile phase with a flow rate of 1.0 mL/min. The column temperature was set at 35.0°C. The detection wavelength was set at 286 nm. The tadalafil was extracted by ethyl acetate from plasma at the alkaline condition. 12 healthy male Sprague-Dawley (SD) rats were randomly divided into two groups, Group A (experimental group, received grapefruit juice 5 mL/kg for 7 days) and Group B (control group, received normal saline for 7 days). All the rats were given a single dose of tadalafil (5 mg/kg) after the last administration. The main pharmacokinetic parameters were calculated by DAS 2.0 software. Under the conditions of this experiment, the plasma concentrations of tadalafil in the range of 10–2000 ng/ml had a good linear relationship. The intra- and interday precision for tadalafil in plasma were less than 15%, and the relative recovery rate was good at low, medium, and high QC levels. The Cmax of tadalafil in the control group and the experimental group was (725.89 ± 161.59) ng/mL and (1271.60 ± 179.31) ng/mL, t1/2 was (9.28 ± 2.07) h and (11.70 ± 1.47) h, AUC (0-t) was (7399.61 ± 696.85) ng·h/mL and (9586.52 ± 2048.81) ng·h/mL, and AUC(0-∞) was (7995.50 ± 707.23) ng·h/mL and (10639.43 ± 2235.94) ng·h/mL, respectively. Results show that the Cmax of tadalafil in group A was 75.17% higher than that in group B, the Vz/F was also reduced, and the t1/2 was increased by 2.42 h. The developed HPLC–DAD method for the determination of tadalafil in rats plasma was accurate, reproducible, specific, and it was found to be suitable for the pharmacokinetics of tadalafil and food-drug interactions. Grapefruit juice can inhibit the metabolism of tadalafil and increase the exposure of tadalafil in rats.

Effect of Ticagrelor, a Cytochrome P450 3A4 Inhibitor, on the Pharmacokinetics of Tadalafil in Rats

Tadalafil is a cytochrome P450 (CYP) 3A4 substrate. Because there are few data on drug-drug interactions, it is advisable to take sufficient consideration when co-administering tadalafil with CYP3A4 inducers or inhibitors. This study was conducted to assess the effect of ticagrelor, a CYP3A4 inhibitor, on the pharmacokinetic properties of tadalafil after oral administration to rats. A total of 20 Sprague–Dawley male rats were randomly divided into the non-pretreated group and ticagrelor-pretreated group, and tadalafil was orally administered to each group after pretreatment with or without ticagrelor. Blood samples were collected at predetermined time points after oral administration of tadalafil. As a result, systemic exposure of tadalafil in the ticagrelor-pretreated group was significantly increased compared to the non-pretreated group (1.61-fold), and the clearance of tadalafil in the ticagrelor-pretreated group was significantly reduced than the non-pretreated group (37%). The prediction of the drug profile through the one-compartment model could explain the differences of pharmacokinetic properties of tadalafil in the non-pretreated and ticagrelor-pretreated groups. This study suggests that ticagrelor reduces a CYP3A-mediated tadalafil metabolism and that tadalafil and a combination regimen with tadalafil and ticagrelor requires dose control and specific pharmacotherapy.

Plasma concentrations of tadalafil in children with pulmonary arterial hypertension.

There is no report documenting the plasma concentrations of tadalafil in children. This study was performed to evaluate the variability in the pharmacokinetics of tadalafil in children with pulmonary arterial hypertension (PAH) treated routinely with the drug. Plasma samples were taken twice (post- and predose) after repetitive oral administration, and the pharmacokinetic parameters (CL/F and V/F) in individual patients were estimated by the Bayesian method using the nonlinear mixed effects model. We also determined the unbound concentration of tadalafil using ultrafiltration. Tadalafil was administered to 23 children aged between 0.25 and 17.4 years, with a mean age of 3.58 years. The mean (±SD) daily dose of tadalafil was 0.97 ± 0.41 mg/kg. Sixteen of the 23 children received bosentan concomitantly. The mean CL/F and V/F values of tadalafil were 0.149 L·h-1·kg-1 and 1.87 L/kg, respectively, which were higher than those reported in adults. No effects of age, bosentan, or the estimated glomerular filtration rate were observed on the CL/F value, indicating that other residual factors might account for the interindividual variability among children with PAH. The unbound tadalafil concentrations of the postdose samples ranged from 5.9 to 146 (46.9 ± 37.1) nmol/L, higher than the reported IC50 value of this phosphodiesterase-5 drug for humans (2-4 nmol/L, corresponding to 0.8-1.6 ng/mL). We demonstrated variability in the total and unbound plasma concentrations of tadalafil in children. However, all children received the empirical doses of the drug; a mean dose of 0.97 mg·kg-1·d-1 showed sufficient unbound concentrations needed for half-maximal inhibition of human phosphodiesterase-5 in vitro. These observations may provide information for the proper use of tadalafil to treat children with PAH.

Effects of Experimental Hyperlipidemia on the Pharmacokinetics of Tadalafil in Rats

Hyperlipidemia is associated with an increased risk of erectile dysfunction. In this study, we investigated the effects of hyperlipidemia on the pharmacokinetics of tadalafil, a novel therapeutic agent for erectile dysfunction, in rats with experimental hyperlipidemia. Tadalafil (1 mg/kg) was administered to control rats and rats with poloxamer-407-induced hyperlipidemia (1 g/kg, i.p.). In addition, we performed in vitro studies to determine the hepatic metabolism in S9 fractions, intestinal absorption, and plasma protein binding. Hyperlipidemia dramatically increased tadalafil's the total area under the plasma concentration-time curve from time 0 to infinity after intravenous (2.09-fold) and oral (11.9-fold) administration, and decreased total body clearance (0.537-fold) and apparent volume of distribution at the steady state (0.438-fold) after intravenous administration of tadalafil. Further, we observed decreased in vitro hepatic S9 metabolism, intestinal first-pass metabolism, and unbound fraction of tadalafil. The alterations in the pharmacokinetics of tadalafil observed in rats with poloxamer 407-induced hyperlipidemia may be attributable to a decrease in hepatic and intestinal metabolism and unbound fraction of tadalafil in the plasma. These findings have potential therapeutic implications for predicting the pharmacokinetic responses of humans to hyperlipidemia. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Effect of Tipranavir/Ritonavir Combination on the Pharmacokinetics of Tadalafil in Healthy Volunteers

This study evaluated the effects of single-dose administration and steady-state concentrations of tipranavir 500 mg and ritonavir 200 mg (TPV/r) combination on the pharmacokinetics of tadalafil 10 mg (TAD) in an open-label study. Seventeen healthy male volunteers received sequential dosing of the studied product: TAD (day 1) alone in a single dose for 7 days followed by TAD (day 8) in a single dose with TPV/r (500/200 mg twice daily, days 8-18). Pharmacokinetic parameters were determined in a noncompartmental analysis. The geometric mean ratio and 90% confidence interval were used to evaluate drug interactions. The effect of a single dose of TAD on the pharmacokinetics of TPV/r resulted in a small decrease in exposure after either first-dose or steady-state TPV/r (geometric mean ratios [90% confidence interval]: area under the concentration-time curve, 0.85 [0.74-0.97]). In contrast, coadministration of TAD exposure was increased significantly (2.33 [2.02-2.69]) when administered with the first dose of TPV/r but not when TPV/r steady state was reached (1.01 [0.83-1.21]). Antiretroviral activity may not be reduced, but the dose of TAD should be reduced at the start of TPV/r therapy and then a full dose can be resumed after steady state is reached.

Randomized Placebo-Controlled Crossover Trial of Tadalafil in Raynaud's Phenomenon Secondary to Systemic Sclerosis

Conclusion: Tadalafil is well tolerated and safe in patients with systemic sclerosis but lacks efficacy in comparison with placebo. Summary: The endothelial injury of systemic sclerosis is associated with decreased nitric oxide production (Kahaleh et al, Rheum Diseases Clin N Am 2008;34:57-71). Type V cyclic GMP phosphodiesterase (PDE-5) affects the tone of smooth muscle. An intracellular regulator of smooth muscle tone is cyclic nucleotide monophosphate, cGMP. Nitric oxide synthase produces nitric oxide. Through a complex pathway, nitric oxide facilitates conversion of GTP into cGMP. PDE-5 breaks down intracellular cGMP. Therefore, inhibition of PDE-5 results in increased availability of intracellular cGMP and results in vasodilatation. Tadalafil is a PDE-5 inhibitor effective in the use of male erectile dysfunction. However, PDE-5 inhibitors have also been suggested as beneficial in patients with severe Raynaud's syndrome (Fries R et al, Circulation 2005;119:2980-5). Tadalafil is an intriguing PDE-5 inhibitor in that it has a half-life of 17.5 hours and efficacy up to 36 hours. The pharmacokinetics of tadalafil are not affected by food or alcohol, age, diabetes, or moderate hepatic insufficiency. It therefore would seem an ideal drug for facilitating vasodilatation in patients with Raynaud's syndrome. This was a randomized, prospective, double-blind, placebo-controlled, crossover study comparing oral tadalafil with a fixed daily dose of 20 mg for 4 weeks vs placebo. The study was conducted in patients with Raynaud's syndrome secondary to systemic sclerosis. Thirty-nine completed the study. All patients fulfilled American College of Rheumatology classification criteria for systemic sclerosis. All were at least 18 years of age and had evidence of at least six Raynaud's attacks during the 2-week pretreatment period. Patients with unstable angina, congestive heart failure, or use of nitrites for angina pectoris or any other condition as well as those with significant central nervous system disease were excluded. Before enrollment, all patients discontinued any other type of vasodilator. Patients were evaluated for duration and frequency of Raynaud's attacks and Raynaud condition scores (RCS). At the end of the evaluation period, there were no significant statistical differences in RCS scores, frequency of Raynaud's attacks, or duration of Raynaud's attacks between the treatment and placebo groups. Comment: The results of the study are disappointing but not conclusive. The participants in this trial had a longer duration of Raynaud's syndrome than those in other trials. Severity of Raynaud's syndrome secondary to systemic sclerosis often increases over time. Patients here may have had greater endothelial cumulative damage than those in other studies. Other studies have primarily evaluated the effect of PDE-5 inhibitors on ulcer healing. Only two patients in this study had active digital ulcers. However, overall, the current results do not support the use of tadalafil as treatment for Raynaud's syndrome secondary to systemic sclerosis at the dosage of 20 mg/d. The study was also burdened by a large placebo effect.

Tadalafil population pharmacokinetics in patients with erectile dysfunction

The purpose of this study was to characterize pharmacokinetics of tadalafil (Cialis) and potential sources of variability in patients with erectile dysfunction (ED). Population models were developed to describe tadalafil pharmacokinetics in 227 patients with mild to severe ED in a phase III trial. Parallel groups of patients received 2, 5, or 10 mg tadalafil or placebo orally, as needed, for 12 weeks. Tadalafil pharmacokinetics in patients with ED were linear with respect to dose and duration of treatment, and a one-compartment model adequately described the data. The absorption rate was rapid (1.86 h(-1)), and the typical population estimates of the apparent oral clearance (CL/F) and apparent volume of distribution were 1.6 l/h and 63.8 l, respectively. Disposition parameters showed a moderate degree of interindividual variability (39-45%). The value of CL/F decreased slightly with increasing serum gamma-glutamyl transferase (GGT) concentration, the only statistically significant covariate detected. Systemic exposure to tadalafil was not influenced by age, weight, smoking status, alcohol consumption, liver enzyme status, ED severity, cardiovascular condition, or diabetes mellitus. Pharmacokinetics in the efficacy/safety trial population are essentially similar to pharmacokinetics in healthy subjects, and no patient-specific factor warranting clinical consideration of dose regimen adjustment was identified in these analyses.

Dapoxetine, a novel treatment for premature ejaculation, does not have pharmacokinetic interactions with phosphodiesterase-5 inhibitors

Potential pharmacokinetic interactions between dapoxetine, a serotonin transporter inhibitor developed for the treatment of premature ejaculation (PE), and the phosphodiesterase-5 inhibitors tadalafil and sildenafil, agents used in the treatment of erectile dysfunction (ED), were investigated in an open-label, randomized, crossover study (n=24 men) comparing dapoxetine 60 mg, dapoxetine 60 mg+tadalafil 20 mg, and dapoxetine 60 mg+sildenafil 100 mg. Plasma concentrations of dapoxetine, tadalafil, and sildenafil were determined by liquid chromatography-tandem mass spectrometry. Tadalafil did not affect the pharmacokinetics of dapoxetine, whereas sildenafil increased the dapoxetine AUCinf by 22%; these effects were deemed not clinically important. Dapoxetine did not appear to affect the pharmacokinetics of tadalafil or sildenafil. Most adverse events were mild in nature. Thus, dapoxetine has no clinically important pharmacokinetic interactions with tadalafil or sildenafil, and the combinations are well tolerated.

Dose-normalised pharmacokinetics of tadalafil administered as a single dose to healthy volunteers

Dose-normalised pharmacokinetics of tadalafil administered as a single dose to healthy volunteers