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Efficacy of 1, 5, and 20 mg oral sildenafil in the treatment of adults with pulmonary arterial hypertension: a randomized, double-blind study with open-label extension.

In a previous study, 6-minute walk distance (6MWD) improvement with sildenafil was not dose dependent at the 3 doses tested (20, 40, and 80 mg 3 times daily [TID]).

This study assessed whether lower doses were less effective than the approved 20-mg TID dosage. Treatment-naive patients with pulmonary arterial hypertension were randomized to 12 weeks of double-blind sildenafil 1, 5, or 20 mg TID; 12 weeks of open-label sildenafil 20 mg TID followed.

Changes from baseline in 6-minute walk distance (6MWD) for sildenafil 1 or 5 mg versus 20 mg TID were compared using a Williams test. Hemodynamics, functional class, and biomarkers were assessed.

The study was prematurely terminated for non-safety reasons, with 129 of 219 planned patients treated.

At week 12, 6MWD change from baseline was significantly greater for sildenafil 20 versus 1 mg ( P = 0.011) but not versus 5 mg. At week 24, 6MWD increases from baseline were larger in those initially randomized to 20 versus 5 or 1 mg (74 vs 50 and 47 m, respectively). At week 12, changes in hemodynamic parameters were generally small and variable between treatment groups; odds ratios for improvement in functional class were not statistically significantly different.

Improvements in B-type natriuretic peptide levels were significantly greater with sildenafil 20 versus 1 but not 5 mg.

Sildenafil cvs pharmacy viagra 20 mg TID appeared to be more effective than 1 mg TID for improving 6MWD; sildenafil 5 mg TID appeared to have similar clinical and hemodynamic effects as 20 mg TID.

ClinicalTrials.gov NCT00430716 (Registration date: January 31, 2007). Pulmonary arterial hypertension (PAH) is a fatal disease in which increasing pulmonary vascular resistance ultimately culminates in right ventricular failure and death [1, 2]. The phosphodiesterase type 5 (PDE5) inhibitor sildenafil is approved to treat adult patients with PAH [2]; pediatric use is approved in the European Union.

In the 12-week, randomized, double-blind, SUPER-1 study [3], statistically significant improvements in 6-minute walk distance (6MWD) were observed with sildenafil versus placebo in treatment-naive patients at all 3 tested doses (20, 40, and 80 mg 3 times daily

[TID]

However, hemodynamic parameters, including mean pulmonary arterial pressure (mPAP), cardiac index, and pulmonary vascular resistance index (PVRI), appeared to improve dose dependently with sildenafil treatment. Sildenafil 20 mg TID appeared to reach the plateau of the dose-response curve for 6MWD [3] and was confirmed by subsequent population pharmacokinetic and pharmacodynamic analysis [4]. This study was conducted to fulfill a postapproval commitment from the US Food and Drug Administration (FDA) to further explore the sildenafil dose-response curve.

This multinational, randomized, double-blind study investigated whether low doses of sildenafil (1 and 5 mg TID) were less effective in adult patients with PAH than the currently approved 20-mg TID dose. However, before completion of this low-dose study, results from another randomized, double-blind, placebo-controlled study (PACES-1) became available that supported approval of a clinical worsening indication by the FDA [5].

PACES-1 evaluated oral sildenafil in patients with PAH who were receiving stable epoprostenol therapy [6]. In PACES-1, ?75% of patients were titrated from sildenafil 20 mg TID, received during the first 4 weeks, to sildenafil 40 mg TID at week 4, and then to sildenafil 80 mg TID at week 8 (and were maintained on this dose, as patients tolerated). After 16 weeks, 6MWD, hemodynamic parameters, and functional class improved.

There was a significant delay in time to clinical worsening (TTCW) [6], defined as death, lung transplantation, hospitalization due to PAH, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy, with sildenafil compared with placebo. The effect was apparent by week 4, when all patients were receiving sildenafil 20 mg TID ( P = cvs pharmacy viagra 0.0074) [4]. Following approval of the clinical worsening indication in the United States in 2009, the FDA released Pfizer from the postapproval commitment to conduct a low-dose study.

The study was subsequently terminated (June 2010) based on the recommendation of the data monitoring committee (DMC) because sildenafil 20 mg TID had been shown to reduce time to clinical worsening in PACES-1 and also acknowledging that with recruitment issues the study was unlikely to meet original enrollment targets.

The primary objective of the study was to get viagra prescription doctor demonstrate a dose response for 6MWD for 1, 5, and 20 mg TID oral sildenafil.

The hypothesis was that there is a dose that is significantly less effective than sildenafil 20 mg TID.

Secondary objectives included assessment of the safety and tolerability of low-dose sildenafil during the 12 weeks of treatment in patients with PAH and evaluation of the effects of sildenafil on perceived PAH-progression biomarkers (B-type natriuretic peptide [BNP]/pro-BNP levels and tricuspid annular plane systolic excursion [TAPSE]).

The study protocol and amendments were reviewed and approved by the Institutional Review Board and/or Independent Ethics Committee at each participating center (Additional file 1); informed consent was obtained from all patients.

Patients were aged >18 years with idiopathic or heritable PAH or PAH associated with connective tissue disease or surgical repair (?5 years before enrollment) of atrial septal defect, ventricular septal defect, patent ductus arteriosus, or aorto-pulmonary window and 6MWD 100 to 450 m. PAH, defined as mPAP ?25 mmHg and pulmonary artery wedge pressure ?15 mmHg at rest (or a left ventricular end diastolic pressure 3 and 6 h, and >6 and 8 h postdose), week 1 (immediately after BNP/pro-BNP sampling), weeks 4 and 8 (immediately before 6MWD), and week 12 (between 15 min and generic viagra online reviews 3 h and between >3 and 6 h postdose, immediately before 6MWD, between >6 and 8 h postdose, and during RHC assessment). Adverse events (AEs) were monitored throughout the study. Laboratory testing and physical examinations were performed at screening, baseline, and weeks 4, 8, and 12.

The relationship between 6MWD and sildenafil exposure could not be modeled because 6MWD had reached a plateau across all SUPER-1 dose groups [3].

Therefore, the relationship between PVRI and exposure was used to select doses predicting exposures from the population pharmacokinetic/pharmacodynamic model. The average sildenafil plasma concentration required to achieve 50% effect (EC 50 ) on PVRI was approximately 3 ng/mL; at a 20-ng/mL concentration, sildenafil appeared to have a 90% maximal effect (EC 90 ) on PVRI [4]. Therefore, after receipt of 20 mg TID, sildenafil concentrations were anticipated to be > EC 90 for the entire 8-hour dosing interval; for 5 mg TID, above EC 50 for the entire 8-hour dosing interval but. The study was conducted at 34 centers in Europe, Asia, Russia, the United States, and Brazil. Of the planned 219 patients, 169 were screened, 130 were randomized, and 129 were treated (1 patient [sildenafil 1 mg] did not meet entry criteria).

Treated patients were mostly female and mostly Asian; baseline cardiac index was significantly higher in the sildenafil 20-mg group versus the 1- and 5-mg groups ( P = 0.0328 and 0.0030, respectively; Table 1). Two patients died during the double-blind phase (pneumonia [1 mg TID; death was the reason for discontinuation] and acute exacerbation of idiopathic pulmonary fibrosis [5 mg TID; patient was enrolled in error and received 4 days of treatment]), neither of which was considered to be treatment related; no deaths were reported in the open-label phase (Fig.

Legend: TID = 3 times daily; SIL = sildenafil.*Right ventricular failure. † Drug hypersensitivity ( n = 1) and rash ( n = 1) Sildenafil concentration.

Overall, 129 patients provided 1068 sildenafil concentrations.

A pfizer viagra 100mg price in usa 1-compartment pharmacokinetic model adequately described the sparse data. From this model, the estimated apparent clearance was 43.9 (95% CI, 39.3–48.6) L/h, the apparent volume of distribution was 458 (95% CI, 393–523) L, and the absorption rate constant was 2.16 (95% CI, 1.48–2.84) h ?1 .

Coadministration of weak or moderate CYP3A4 inhibitors ( n = 12 patients/110 samples) reduced CL/F by 40.4% (95% CI, 19.2%–61.6%).

The model supported dose proportionality of exposures.

The limit of quantification of the pharmacokinetic assay was 1 ng/mL; 134 samples were below the limit of quantification (BLQ).

The majority of BLQ samples (approximately 75%) were measured at the 1-mg TID sildenafil dose, but had little effect on the

population

Figure 3 represents the sildenafil concentration data. Because a small accumulation existed between the first (at baseline visit) and subsequent doses, only concentrations after the second and subsequent doses are shown (for data including baseline visit, see Additional file 3).

Concentrations after concomitant administration of CYP3A4 inhibitors were adjusted for the estimated effect.

Visual inspection of observed concentration distribution across each dose indicated consistency of the observed data with the model.

In particular, in the 8 h after drug administration, most of the determinations in the 1-mg TID group had a concentration below 3 ng/mL, whereas in the 5-mg TID and 20-mg TID groups, most of the determinations had a concentration above 3 ng/mL, which is the average sildenafil plasma concentration required to achieve 50% effect (EC 50 ) on PVRI [4]. An exploratory assessment (see Additional files 4 and 5) of the relationship between 6MWD, PVR, and steady-state concentrations revealed a significant relationship for 6MWD, whereas only a small trend could be seen for PVR across the concentration range observed (Additional files 6 and 7). Plot of observed plasma sildenafil concentrations vs time after sildenafil dosing. Legend: Plasma sildenafil concentrations ( open circles ), sildenafil doses of 1 mg (left ), 5 mg ( middle viagra overnight no prescription ), and 20 mg ( right ). Median ( solid line ) and 90% prediction intervals ( dashed lines ) from simulations are overlaid.

Tick marks on the horizontal time axis indicate concentration measures below the limit of quantification.

The shaded area shows the concentration range between 3 ng/mL and 20 ng/mL, which are the average sildenafil plasma concentrations required to achieve 50% effect (EC 50 ) and 90% effect (EC90) on PVRI, respectively. At week 12, compared with baseline, the increase in 6MWD was of a

magnitude

Among dose groups, the mean change in 6MWD from baseline was statistically significantly different only for the sildenafil 20- versus 1-mg group (Fig. Legend:

Mean

All patients received sildenafil 20 mg TID in the open-label phase of the study (weeks 13–24).

6MWD = 6-minute walk distance; TID = 3 times daily.

Analysis of change from baseline in 6MWD at week 12 showed a statistically significant ( P = 0.011) difference between sildenafil 1 mg and 20 mg, but not sildenafil 5 mg and 20 mg (Table 2). The results were confirmed by an analysis of variance; the mean treatment difference between sildenafil 20 mg and 1 mg was 23 (3–43) m and between 20 mg and 5 mg was –3 (–23 to 17) m ( P = 0.02 and 0.76, respectively). Mean change from baseline in 6MWD assessed by race.

Legend: Mean (SE) overall change from double-blind baseline in 6MWD in the double-blind (week 12) phase of the study ( a ) and change from baseline to week 12 in 6MWD by baseline 6MWD ( b ) assessed by race (Asian vs non-Asian). 6MWD = 6-minute walk distance; TID = 3 times daily. During the open-label period (weeks 12 to 24), in which all patients received sildenafil 20 mg TID, patients who received sildenafil 1 mg TID during the double-blind phase (weeks 0 to 12) had a larger increase in 6MWD than patients who received sildenafil 5 mg TID (mean change, 31 vs 6 m, respectively); the magnitude of change was similar between patients who received sildenafil 1 mg and 20 mg TID in the double-blind phase (mean change, 31 vs 26 m; Fig. Compared with baseline, there was a trend toward reduction in pulmonary vascular resistance (PVR) at week 12 in all groups; the mean reduction was statistically significantly different from 0 only in the 20-mg TID group (ie, 95% CIs do not include 0). There were no statistically significant differences among treatment groups for change in PVR (Table 3).

Changes at week 12 in the additional hemodynamic parameters were generally small and variable between groups. Most patients in each treatment group remained in the same functional class from baseline to week 12; the same was true through week 24 (Table 4). Odds ratios (ORs) showed no significant differences for functional class between sildenafil 20 mg and the 5-mg (OR, 1.08 [95% CI, 0.35–3.32]; P = 0.897) or 1-mg (OR, 1.55 [95% CI, 0.50–7.78]; P = 0.448) dose at week 12. Similarly, there were no differences between sildenafil 20 mg and the 5-mg (OR, 1.31 [95% CI, 0.42–4.05]; P = 0.639) or 1-mg (OR, 0.93 [95% CI, 0.30–2.91]; P = 0.899) dose at week 24. Four patients (sildenafil 1 mg and 5 mg, n = 1 each; sildenafil 20 mg, n = 2) reported events defined as clinical worsening (initiation of ETRA therapy [sildenafil 5-mg patient] and hospitalization due to PAH [all others]).

Decreases from baseline in BNP occurred in all groups at week 12; the response was dose related (Fig.

The sildenafil 20-mg group was statistically significantly ( P = 0.005) different from the 1-mg but not the 5-mg group ( P = 0.496). At week 24, changes from baseline for sildenafil 20 mg were not significantly different among groups. Changes from baseline in BNP ( a ) and pro-BNP ( b ) during double-blind (week 12) and open-label (week 24) phases of the study.

All patients received sildenafil 20 mg TID in the open-label phase of the study (weeks

13–24

Pro-BNP decreases occurred in all groups at week 12 and were dose related (Fig. Differences were significant when sildenafil 20 mg was compared with 1 but not 5 mg ( P = 0.009 and 0.414, respectively).

At week 24, changes from baseline were not significantly different among groups.

There was a trend toward a mean increase in TAPSE in all groups, but there were no statistically significant differences in mean TAPSE index among groups (mean [95% CI] increases of 0.14 [0.02–0.26], 0.17 [0.06–0.28], and 0.04 [–0.08 to 0.16] cm for sildenafil 1, 5, and 20 mg TID, respectively, at week 12 [LOCF] and 0.21 [0.06–0.37], 0.40 [0.19–0.61], and 0.15 [–0.09 to 0.39] at week 24 [LOCF]). Borg dyspnea scores trended toward reduction in all groups (mean [95% CI] changes of –0.28 [–0.76 to 0.20], –0.89 [–1.35 to –0.43], and –0.43 [–0.94 to 0.08] for sildenafil 1, 5, and 20 mg TID, respectively, at week 12 [LOCF] and –1.10 [–1.75 to –0.46], –1.07 [–1.55 to –0.58], and –0.28 [–0.75 to 0.20] at week 24 [LOCF]), with no significant differences between sildenafil 1- and 5-mg TID groups compared with sildenafil 20 mg TID. Baseline 6MWD was weakly correlated with BNP ( r = –0.19; P = 0.0393) and pro-BNP ( r = –0.22; P = 0.0145). The change in 6MWD at week 12 was also weakly correlated with changes at week 12 in BNP ( r = –0.18; P = 0.0499) and pro-BNP ( r = –0.22; P = 0.0193).

The women viagra pills online overall number of AEs and numbers of patients reporting AEs were similar between treatment groups in the double-blind and open-label portions of the study; treatment-related AEs (number of AEs and patients reporting AEs) increased with increasing dose (Table 5).