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Pharmacokinetics of Sildenafil in Patients with a Left Ventricular Assist Device

A Word of Caution

Sabato, Leah A.*; Johnson, Daniel C.*; Haglund, Nicholas; Keebler, Mary*; Cox, Zachary L.

doi: 10.1097/MAT.0000000000000886
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We compared maximal plasma concentrations (Cmax) of sildenafil and metabolite n-desmethyl sildenafil in 12 inpatients with left ventricular assist devices (LVADs) on sildenafil (60 mg/day) to the reference range. Sildenafil Cmax (156.8 ± 124.5 ng/ml) was elevated in 66% of patients, with a two to fivefold increase over the upper limit of the reference range in 25% of patients. Metabolite Cmax (133.3 ± 102.0 ng/ml) was elevated in 75% of patients, with a three to sevenfold increase over the upper limit of the reference range in 40% of patients. Patients with heart failure and LVADs are at increased risk of concentrated-related sildenafil adverse events.

From the *Vanderbilt University Medical Center, Nashville, Tennessee

University of Kansas Medical Center, Kansas City, Kansas

Lipscomb University College of Pharmacy, Nashville, Tennessee.

Submitted for consideration April 2018; accepted for publication in revised form June 2018.

Disclosure: The authors have no conflicts of interest to report.

This work was supported by CTSA award No. UL1TR000445 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.

Correspondence: Leah A. Sabato, Vanderbilt University Medical Center, Department of Pharmaceutical Services Nashville, TN. Email: leahsabato@gmail.com.

Patients with heart failure have physiologic changes associated with altered drug pharmacokinetics (e.g., hepatic dysfunction, hypoalbuminemia, or drug absorption). Drug pharmacokinetics in the heart failure population with left ventricular assist devices (LVADs) remain unknown.

Sildenafil citrate is a phosphodiesterase-type-5 inhibitor used in patients with LVADs for treatment of pulmonary hypertension. Sildenafil is metabolized by hepatic cytochrome 3A4 (major) and 2C9 (minor) and has an active metabolite (n-desmethyl sildenafil).1 Clinically significant adverse events (syncope, hypotension, visual changes, priapism) are associated with elevated sildenafil maximal plasma concentrations (Cmax).1–3 The purpose of this study was to measure and compare the Cmax of sildenafil and n-desmethyl sildenafil in patients with LVADs relative to the reference range.

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Materials and Methods

This research was approved by the Vanderbilt institutional review board. We prospectively identified adults with LVADs who were hospitalized and prescribed sildenafil 20 mg orally three times daily with four previous doses documented to ensure steady state. Exclusion criteria included hepatic cirrhosis, right ventricular mechanical support, or concomitant interacting medications.1,2 A 5 ml blood sample was drawn to capture maximal plasma concentrations of sildenafil and n-desmethyl sildenafil 60–90 minutes after administration similar to previous methods.4,5 The reference ranges for sildenafil and n-desmethyl sildenafil Cmax were 59.6 ± 31.4 and 34.1 ± 14.1 ng/ml, respectively,4 which were validated in the RELAX trial (sildenafil Cmax 78 [interquartile range{IQR}: 35–130] ng/ml).5 For sildenafil and metabolite concentration assessment, a calibration curve across 2–1000 ng/ml was prepared. Samples were analyzed on a Thermo Quantum Ultra AM mass spectrometer with a Thermo Accela HPLC pump. The high-performance liquid chromatography (HPLC) method used an Acquity BEH C18 1.7 µm 2.1 × 100 mm column at 40°C. Data were processed with a coefficient of variation (CV) not to exceed 20% and a minimum coefficient of determination (r2) of 0.95.

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Results

Patient characteristics are shown in Table 1. The mean age was 55 ± 9 years. Patients were predominantly white (n = 7/12, 58.3%). The average body mass index was 28.8 ± 6.7. The majority of patients were implanted as a bridge-to-transplant (n = 7/12, 58.33%). Sildenafil was initiated post-LVAD in 75% of patients, whereas three patients were treated before and after LVAD for pulmonary hypertension. All patients had continuous flow LVADs (n = 5/12 HeartMate II, n = 7/12 Heartware) implanted a mean of 290 days (range 6–671 days) prior. Two patients were treated with intravenous inotropes at the time of sampling because of right ventricular failure or proximity to surgery.

Table 1

Table 1

Sildenafil Cmax and n-desmethyl sildenafil Cmax exceeded the reference range in 66% and 75% of patients, respectively. Sildenafil Cmax ranged from 37.7 to 467.1 ng/ml, with a two to fivefold increase over the upper limit of the reference range in 25% of patients (Figure 1). The mean sildenafil Cmax was 156.8 ± 124.5 ng/ml. Plasma n-desmethyl sildenafil Cmax ranged from 28.7 to 366.1 ng/ml, with a three to sevenfold increase over the upper limit of the reference range in 40% of patients (Figure 1). The mean n-desmethyl sildenafil Cmax was 133.3 ± 102.0 ng/ml. For the majority of patients (n = 10/12), trends were consistent among sildenafil and n-desmethyl sildenafil. Two patients with low sildenafil concentrations had n-desmethyl sildenafil concentrations within the reference range or greater. Neither age, weight, body mass index (BMI), model for end-stage liver disease (MELD) score, sex, ethnicity, inotrope use, right ventricle (RV) function, tricuspid regurgitation severity, or level of care were associated with sildenafil Cmax greater than the reference value (p > 0.05). Patients who had sildenafil concentrations greater than the reference value had significantly lower creatinine clearance (CrCl; p = 0.028). All patients were tolerating therapy at the time of assessment without reported adverse effects.

Figure 1

Figure 1

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Discussion

The key finding of this study is that two-thirds of sildenafil-treated patients with LVADs had Cmax elevated above the reference range, with one-fourth experiencing more than double the reference upper limit.4 This population may be at increased risk for bothersome and serious concentration-related adverse effects, such as hypotension whose incidence is already increased at standard concentrations.2,3,5 The greatest Cmax (467.1 ng/ml, patient 5) exceeded the literature average by more than sevenfold. Likewise, the Cmax for n-desmethyl sildenafil was higher than reported, and the highest value (366.1 ng/ml, patient 1) exceeded the literature average by more than 10-fold.4 Patients with pulmonary hypertension experience higher sildenafil concentrations compared with healthy volunteers; however, the magnitude of the difference we found was greater.1 Our data suggest that conservative and individualized dosage titration may be warranted in patients with LVADs.

From this single-point assessment, we are unable to determine which specific pharmacokinetic parameters led to the concentration changes. Severe renal dysfunction (CrCl <30 ml/min) has been associated with elevated sildenafil concentrations, but mild or moderate dysfunction has not.1 Creatinine clearance was associated with elevated concentrations in our study. However, the average CrCl was 62.9 ml/min, and only one patient had a CrCl <30 ml/min. Thus, the elevation is greater than expected based on renal function. Hepatic dysfunction is also associated with higher sildenafil plasma concentrations.1 Severe hepatic dysfunction was not present in our study by laboratory assessment. We hypothesize that despite having normal measures of hepatic function, there may have been subclinical dysfunction in hepatic metabolizing capacity. We are unable to discern the relative contributions of LVAD and chronic heart failure to the altered pharmacokinetics.

We collected a single plasma sample for Cmax 60–90 minutes after the sildenafil dose1; however, some may have peaked outside of this window. Additionally, concomitant food can delay or decrease Cmax,1 and we measured plasma concentrations in hospitalized patients without fasting. However, both of these limitations would have diminished the observed Cmax. We lacked a control group, which prohibits distinction between heart failure or LVAD as the primary cause of our findings. Conclusions regarding associations between patient characteristics and sildenafil concentrations are limited in this small sample size. We did not assess patients’ genetic status. Poor metabolizers CYP 3A4 metabolizers display increased sildenafil Cmax; however, that phenotype only affects 14.3% of the population.6 It is possible that genetic polymorphisms contributed to the high concentrations observed in our study. Patients with heart failure and LVADs are at increased risk of concentrated-related sildenafil adverse events. Future research should perform complete pharmacokinetic assessment of drugs commonly administered to patients with LVADs.

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References

1. Pfizer Laboratories Inc: Revatio (sildenafil) package insert. 2014.New York, NY.
2. Schwartz BG, Kloner RA. Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation 2010.122: 88–95.
3. Cheitlin MD, Hutter AM Jr, Brindis RG, et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol 1999.33: 273–282.
4. Spence R, Mandagere A, Dufton C, Venitz J. Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers. J Clin Pharmacol 2008.48: 1451–1459.
5. Redfield MM, Chen HH, Borlaug BA, et al; RELAX Trial: Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: A randomized clinical trial. JAMA 2013.309: 1268–1277.
6. de Denus S, Rouleau JL, Mann DL, et al. CYP3A4 genotype is associated with sildenafil concentrations in patients with heart failure with preserved ejection fraction. Pharmacogenomics J 2018.18: 232–237.
Keywords:

heart-assist device; sildenafil; pharmacokinetics

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