Sildenafil renal-impairment pharmacokinetics is defined by a severity-dependent pattern rather than a simple assumption that lower kidney function always produces proportionally higher exposure. In single-dose studies, mild and moderate renal impairment did not materially alter parent sildenafil pharmacokinetics, while severe impairment was associated with substantially higher exposure.
Current U.S. labeling reports that severe renal impairment with creatinine clearance below 30 mL/min reduces sildenafil clearance and approximately doubles parent-drug AUC and Cmax. N-desmethyl sildenafil changes differently: its AUC increases by approximately 200% and its Cmax by approximately 79% compared with subjects with normal renal function.
These findings are notable because sildenafil itself is cleared predominantly through hepatic metabolism and drug-related material is excreted mainly as metabolites. This page therefore focuses on measured renal-impairment PK findings, parent-versus-metabolite behavior and clearance interpretation rather than individualized dosing.
Renal function influences sildenafil pharmacokinetics in a more complex way than direct urinary clearance of unchanged parent drug. Sildenafil is metabolized predominantly through hepatic CYP pathways, while drug-related material is subsequently eliminated mainly as metabolites.
Current labeling reports that approximately 80% of an administered oral dose is recovered in feces and approximately 13% in urine, predominantly as metabolites. This means renal impairment cannot be interpreted simply as reduced filtration of unchanged sildenafil.
Instead, clinical PK studies directly measure how reduced renal function changes parent-drug clearance, parent exposure and active-metabolite exposure. The broader ADME framework is covered on the sildenafil pharmacokinetics hub.
| PK Feature | Renal-Impairment Context |
|---|---|
| Parent sildenafil clearance | Predominantly metabolic rather than direct renal excretion |
| Major metabolism | CYP3A major pathway; CYP2C9 minor pathway |
| Fecal recovery | Approximately 80% of administered oral dose as metabolites |
| Urinary recovery | Approximately 13% of administered oral dose as metabolites |
| Renal-impairment effect | Must be established from measured PK rather than inferred from urinary recovery alone |
Renal clearance is the portion of drug or metabolite removal attributable to kidney-mediated processes. It should not be confused with total sildenafil clearance, which is dominated by hepatic metabolic pathways for the parent drug.
The severe-renal-impairment finding is nevertheless clear: sildenafil apparent clearance is reduced when creatinine clearance is below 30 mL/min, producing substantially greater parent-drug exposure.
This illustrates an important PK principle. An organ can influence systemic drug disposition even when direct excretion of unchanged parent drug through that organ is not the principal elimination pathway.
A separate hemodialysis study adds another distinction: hemodialysis did not significantly clear either sildenafil or its primary N-desmethyl metabolite under the studied conditions.
| Concept | Sildenafil-Specific Interpretation |
|---|---|
| Renal clearance | Kidney-related contribution to drug or metabolite removal |
| Parent sildenafil clearance | Predominantly hepatic metabolic clearance |
| Severe renal impairment | Associated with reduced sildenafil clearance |
| Hemodialysis | Did not significantly clear sildenafil or its major metabolite in a small clinical PK study |
| Total systemic exposure | Can still increase substantially despite limited direct renal elimination of parent sildenafil |
The main quantitative renal-impairment finding concerns severe renal dysfunction. In subjects with creatinine clearance below 30 mL/min, parent sildenafil clearance was reduced and both AUC and Cmax were approximately doubled relative to age-matched subjects with normal renal function.
This is not a minor fluctuation around the normal concentration-time profile. A roughly twofold AUC means substantially greater integrated systemic exposure, while a roughly twofold Cmax means a substantially higher observed concentration peak.
The two measurements should nevertheless remain distinct. AUC describes exposure integrated across time, while Cmax describes peak concentration. Neither should be converted directly into a proportional clinical-effect prediction.
| PK Parameter | Severe Renal Impairment Finding |
|---|---|
| Creatinine clearance | <30 mL/min |
| Sildenafil clearance | Reduced |
| Parent sildenafil AUC | Approximately 2-fold higher |
| Parent sildenafil Cmax | Approximately 2-fold higher |
| Interpretation | Greater systemic parent-drug exposure |
Sildenafil renal PK does not show a simple linear progression in which every reduction in creatinine clearance produces a measurable proportional increase in exposure.
Current labeling reports that after a single 50 mg oral dose, sildenafil pharmacokinetics were not materially altered in mild renal impairment with creatinine clearance of 50 to 80 mL/min or moderate impairment at 30 to 49 mL/min.
The major exposure shift appeared in the severe category below 30 mL/min, where clearance was reduced and AUC and Cmax approximately doubled.
This severity threshold is one of the most important findings on the page because it demonstrates why renal-function categories should be interpreted from observed PK data rather than from a generic assumption about declining kidney function.
| Renal Category | Creatinine Clearance | Observed Parent-Sildenafil PK |
|---|---|---|
| Normal renal function | Reference group | Reference exposure |
| Mild impairment | 50–80 mL/min | Single-dose PK not materially altered |
| Moderate impairment | 30–49 mL/min | Single-dose PK not materially altered |
| Severe impairment | <30 mL/min | Reduced clearance; AUC and Cmax approximately doubled |
Renal impairment affects the major circulating N-desmethyl metabolite differently from parent sildenafil. This is important because the metabolite remains pharmacologically active and has its own formation and elimination profile.
In severe renal impairment, current labeling reports that N-desmethyl sildenafil AUC increased by approximately 200%, while Cmax increased by approximately 79% compared with subjects with normal renal function.
Those changes are not proportional to the parent-drug findings. Parent AUC and Cmax approximately doubled, whereas metabolite AUC increased threefold relative to baseline while its peak rose by a smaller amount.
This divergence demonstrates why parent and metabolite PK should be examined separately. Detailed metabolite pharmacology remains on the sildenafil active metabolite page.
| Analyte / Parameter | Severe Renal Impairment Finding |
|---|---|
| Parent sildenafil AUC | Approximately 2-fold higher |
| Parent sildenafil Cmax | Approximately 2-fold higher |
| N-desmethyl sildenafil AUC | Approximately +200% |
| N-desmethyl sildenafil Cmax | Approximately +79% |
| Key interpretation | Parent and metabolite exposure do not change by identical proportions |
Renal and hepatic impairment can both increase sildenafil exposure, but the underlying organ-function contexts and observed patterns differ.
Severe renal impairment below 30 mL/min is associated with approximately twofold increases in parent AUC and Cmax. By comparison, Child-Pugh A and B hepatic impairment is associated with an approximately 85% increase in AUC and 47% increase in Cmax.
The hepatic finding has a direct mechanistic connection to sildenafil's predominant CYP-mediated metabolism. The renal finding is more complex because parent sildenafil is not eliminated primarily through unchanged urinary excretion.
These comparisons are useful for understanding organ-function PK but should not be used as dose-equivalence calculations. Hepatic data remain on the sildenafil hepatic impairment pharmacokinetics page.
| Organ-Function Context | Parent AUC | Parent Cmax |
|---|---|---|
| Severe renal impairment | Approximately 2-fold | Approximately 2-fold |
| Child-Pugh A/B hepatic impairment | Approximately +85% | Approximately +47% |
| Primary mechanistic distinction | Renal impairment affects the broader disposition system despite predominantly metabolic parent clearance | Hepatic impairment directly affects a major metabolic organ |
The most robust current label findings in severe renal impairment are reduced clearance and increased AUC and Cmax. The label does not reduce renal impairment to a single new half-life value.
Half-life depends on both clearance and distribution, so increased exposure cannot automatically be translated into a proportional extension of terminal half-life.
A hemodialysis crossover study similarly found that overall elimination half-life was not materially changed by whether sildenafil was administered before or after the dialysis session, even though small differences in peak concentration and peak timing were observed.
The general terminal-phase parameter remains on the sildenafil half-life page.
| Observation | Interpretation |
|---|---|
| Reduced clearance in severe impairment | Supports greater systemic exposure |
| AUC approximately doubled | Documents greater integrated exposure |
| Half-life | Should not be inferred directly from AUC change |
| Hemodialysis timing study | Overall elimination half-life was not materially affected by administration before vs after dialysis |
Renal-impairment PK studies use several parameters because no single measurement describes all changes in sildenafil disposition.
AUC and Cmax provide the clearest quantitative evidence in the current label. Clearance explains the direction of the parent-drug change, while separate parent and metabolite measurements reveal that the two analytes respond differently to severe impairment.
Creatinine clearance is used to classify renal-function groups in the underlying studies, but it should not be confused with sildenafil clearance. One measures renal function; the other describes drug-removal efficiency.
| Measure | Role in Renal PK Interpretation |
|---|---|
| CLcr | Classifies renal-function severity |
| Sildenafil clearance | Describes parent-drug removal efficiency |
| AUC | Measures integrated systemic exposure |
| Cmax | Measures peak observed concentration |
| Metabolite AUC | Shows total N-desmethyl exposure |
| Metabolite Cmax | Shows N-desmethyl peak concentration |
| Half-life | Describes terminal concentration decline |
Renal impairment is one documented source of sildenafil PK variability, but its effect depends strongly on severity and on which analyte or parameter is measured.
The mild and moderate categories demonstrate little change in single-dose parent PK, while severe impairment produces a pronounced shift in both parent and metabolite exposure.
This makes renal function a good example of nonlinear-looking PK variability across clinical categories: a factor can show limited measurable impact across one range and a much larger effect after a severity threshold.
Other sources of variability, including food, age, CYP activity and hepatic impairment, are integrated on the sildenafil PK variability page.
| Variability Source | Representative Sildenafil Finding |
|---|---|
| Mild renal impairment | No material single-dose parent PK alteration |
| Moderate renal impairment | No material single-dose parent PK alteration |
| Severe renal impairment | Parent AUC and Cmax approximately doubled |
| Severe impairment — active metabolite | AUC +200%; Cmax +79% |
| Other PK factors | Sildenafil PK Variability |
The renal PK findings describe exposure differences in defined study populations. They do not by themselves determine what an individual should take.
Product and indication context also matter. Current U.S. ED-oriented sildenafil labeling notes the approximately twofold exposure increase in severe renal impairment and includes a specific dose-management consideration, while current REVATIO PAH labeling states that no renal dose adjustment is required, including in severe impairment.
Those different label instructions exist despite the same underlying renal PK findings. This is an important example of why a PK percentage should not be converted independently into a dose calculation.
This page therefore reports the pharmacokinetic evidence and label-context distinction without providing individualized treatment recommendations. General label-based dosage information belongs on the sildenafil dosage page.
| Evidence Layer | What It Establishes |
|---|---|
| Severe renal PK study | Reduced clearance and approximately 2-fold parent AUC/Cmax |
| ED sildenafil label | Applies its own product-specific management language to severe renal impairment |
| REVATIO PAH label | States that no renal adjustment is required, including severe impairment |
| PK data alone | Do not create a universal dose-conversion rule |
| Detailed dosage resource | Sildenafil Dosage |
The core renal-impairment evidence comes from controlled special-population pharmacokinetic studies rather than from an assumption that sildenafil behaves like a predominantly renally excreted drug.
The classic study compared a single 50 mg oral sildenafil dose across subjects with normal renal function and varying degrees of renal impairment. Significant relationships were observed between creatinine clearance and several parent or metabolite PK measures, with the clearest pairwise differences occurring in severe impairment below 30 mL/min.
A separate crossover study in 15 men receiving maintenance hemodialysis found that dialysis did not significantly clear sildenafil or N-desmethyl sildenafil. Giving sildenafil after dialysis produced a modestly higher Cmax and earlier Tmax than giving it before dialysis, while overall absorption and elimination half-life were not materially affected.
The dialysis study also cautions against assuming that every end-stage-renal-disease population will reproduce the same PK profile seen in the earlier severe-impairment volunteer comparison. Population, dialysis status, study design and timing can all affect the observed data.
For the full context, the sildenafil pharmacokinetics hub connects these renal findings with metabolism, distribution, clearance and systemic exposure.
| Research Finding | Interpretation |
|---|---|
| Mild/moderate renal impairment | Single-dose parent PK not materially altered |
| Severe renal impairment | Reduced clearance and approximately doubled parent AUC/Cmax |
| Severe impairment metabolite | AUC +200%; Cmax +79% |
| Hemodialysis clearance | Neither sildenafil nor its primary metabolite was significantly removed by dialysis in the crossover study |
| Dialysis timing | Post-dialysis administration produced a modestly higher Cmax and earlier Tmax without a material change in overall absorption or half-life |
| Main lesson | Interpret renal PK by severity, analyte, population and study design rather than by one generalized kidney-clearance assumption |
The effect is severity-dependent. Mild renal impairment with creatinine clearance of 50 to 80 mL/min and moderate impairment at 30 to 49 mL/min did not materially alter single-dose parent sildenafil PK, while severe impairment below 30 mL/min reduced clearance and approximately doubled parent AUC and Cmax.
Current labeling reports that in severe renal impairment, N-desmethyl sildenafil AUC increased by approximately 200% and Cmax by approximately 79% compared with subjects with normal renal function.
No. Parent sildenafil is cleared predominantly through hepatic metabolism. Drug-related material is excreted mainly as metabolites, with approximately 80% of an oral dose recovered in feces and about 13% in urine.
In the current U.S. labeling dataset, the pharmacokinetics of a single 50 mg oral dose were not materially altered in mild renal impairment with creatinine clearance of 50 to 80 mL/min or moderate impairment at 30 to 49 mL/min.
A small crossover study in 15 male maintenance-hemodialysis patients found that hemodialysis did not significantly clear sildenafil or its primary N-desmethyl metabolite.
No. PK findings describe exposure, while product labeling can apply those findings differently by indication. Current ED sildenafil and REVATIO PAH labels do not use identical renal-impairment dose-management language.