Hepatic impairment can materially change sildenafil pharmacokinetics because parent sildenafil is cleared predominantly through metabolism. Current U.S. labeling reports that in volunteers with Child-Pugh Class A and B hepatic impairment, sildenafil clearance was reduced, producing approximately 85% higher AUC and 47% higher Cmax than in age-matched volunteers without hepatic impairment.
The underlying pharmacokinetic study used a single 50 mg oral dose in subjects with chronic stable hepatic cirrhosis. Apparent oral clearance, CL/F, was approximately 46% lower, supporting the interpretation that reduced hepatic metabolic capacity and possibly altered first-pass handling increased parent-drug exposure.
Severe hepatic impairment, Child-Pugh Class C, has not been studied in the current sildenafil pharmacokinetic dataset. This page therefore focuses on the measured Child-Pugh A/B findings and their limitations rather than extrapolating unsupported values to more severe hepatic dysfunction.
The liver is central to sildenafil disposition because the parent drug is cleared predominantly through hepatic biotransformation. Current labeling identifies CYP3A4 as the major metabolic pathway and CYP2C9 as a minor pathway.
When hepatic metabolic capacity is reduced, unchanged sildenafil can be removed more slowly from the systemic drug pool. In the studied Child-Pugh A/B population, this was observed directly as reduced clearance together with higher peak and integrated plasma exposure.
The measured effect was substantial rather than merely theoretical: sildenafil AUC increased approximately 85% and Cmax approximately 47% compared with age-matched subjects without hepatic impairment.
| PK Process | Sildenafil Hepatic-Impairment Finding |
|---|---|
| Major metabolic pathway | CYP3A4 |
| Minor metabolic pathway | CYP2C9 |
| Clearance | Reduced in Child-Pugh A/B hepatic impairment |
| AUC | Approximately 85% higher |
| Cmax | Approximately 47% higher |
Sildenafil is metabolized principally through CYP3A4, with CYP2C9 contributing a smaller metabolic route. One important biotransformation produces N-desmethyl sildenafil, the major circulating active metabolite.
Hepatic impairment can influence several parts of this process at once: presystemic metabolism after oral administration, systemic metabolic clearance of parent sildenafil and formation or subsequent disposition of metabolites.
The hepatic-impairment study cannot assign the observed exposure increase to one enzyme or one isolated mechanism. The complete enzyme and metabolite pathway remains on the sildenafil metabolism page.
| Component | Role |
|---|---|
| CYP3A4 | Major pathway in sildenafil metabolism |
| CYP2C9 | Minor metabolic pathway |
| Parent sildenafil | Systemic exposure rises when effective clearance falls |
| N-desmethyl sildenafil | Major circulating active metabolite formed through sildenafil metabolism |
Current sildenafil labeling provides direct quantitative evidence for altered systemic exposure in mild-to-moderate hepatic cirrhosis. In Child-Pugh Class A and B subjects, parent sildenafil AUC increased approximately 85% and Cmax increased approximately 47% compared with age-matched subjects with normal hepatic function.
AUC and Cmax changed by different amounts because they measure different properties of the concentration-time profile. AUC reflects integrated systemic exposure, while Cmax describes the observed peak concentration.
The larger AUC increase indicates that hepatic impairment affected more than the height of the early peak. Parent sildenafil remained systemically available to a greater overall extent across the sampled profile.
| Parameter | Child-Pugh A/B Finding | Interpretation |
|---|---|---|
| AUC | Approximately +85% | Substantially greater integrated systemic exposure |
| Cmax | Approximately +47% | Higher peak plasma concentration |
| Clearance | Reduced | Parent sildenafil removed less efficiently |
| Child-Pugh C | Not studied | No evidence-based PK percentage can be assigned |
The published hepatic-impairment study provides a more specific clearance estimate than the label summary. After a single 50 mg oral dose, apparent oral clearance, CL/F, was approximately 46% lower in subjects with chronic stable Child-Pugh A/B cirrhosis than in subjects with normal hepatic function.
Because the study used oral sildenafil, CL/F is an apparent oral clearance parameter rather than a direct measurement of intravenous systemic clearance. It reflects clearance divided by oral bioavailability and can therefore be influenced by both systemic removal and presystemic availability.
The investigators interpreted the higher Cmax together with reduced CL/F as suggesting reduced first-pass metabolism as well as reduced systemic clearance. The broader distinction between clearance and CL/F remains on the sildenafil clearance page.
| Clearance Concept | Hepatic-Impairment Context |
|---|---|
| CL/F | Apparent oral clearance |
| Study finding | Approximately 46% lower in Child-Pugh A/B cirrhosis |
| F component | Means CL/F can reflect changes in oral availability as well as systemic clearance |
| Exposure consequence | Higher AUC and Cmax |
The available sildenafil hepatic-impairment data do not cover the full severity spectrum. The principal study evaluated subjects with chronic stable hepatic cirrhosis classified as Child-Pugh A or B.
Those categories correspond to mild and moderate hepatic impairment in the current labeling framework. The results from these subjects form the evidence base for the reported 85% AUC increase and 47% Cmax increase.
Severe hepatic impairment, Child-Pugh Class C, has not been studied. Values measured in Child-Pugh A/B should therefore not be extrapolated numerically to Child-Pugh C.
| Hepatic Group | Evidence Status |
|---|---|
| Normal hepatic function | Reference population |
| Child-Pugh A | Included in the hepatic-impairment evidence base |
| Child-Pugh B | Included in the hepatic-impairment evidence base |
| Child-Pugh C | Pharmacokinetics not studied |
Sildenafil metabolism produces the active N-desmethyl metabolite, so hepatic impairment can alter more than parent-drug concentrations. Changes in metabolic formation and subsequent metabolite disposition can modify the metabolite concentration-time profile as well.
In the published hepatic-impairment study, systemic exposure to the N-desmethyl metabolite increased in subjects with cirrhosis, and the increase was reported to be approximately twice the magnitude of the parent sildenafil exposure increase.
That finding should not be converted into a simple percentage contribution to clinical effect because metabolite formation, concentration, potency and further elimination all contribute to its pharmacological role. The metabolite itself is covered on the sildenafil active metabolite page.
| Analyte | Hepatic-Impairment Interpretation |
|---|---|
| Parent sildenafil | AUC and Cmax increase because clearance is reduced |
| N-desmethyl sildenafil | Systemic exposure also increased in the published cirrhosis study |
| Relative metabolite change | Increase in systemic exposure reported as approximately twice the magnitude observed for parent sildenafil |
| Clinical effect | Cannot be calculated directly from metabolite exposure alone |
Hepatic and renal impairment are separate sildenafil PK contexts, but the difference should not be reduced to 'liver metabolism versus renal excretion.' Sildenafil itself is cleared predominantly through metabolism rather than direct urinary elimination of unchanged parent drug.
In Child-Pugh A/B hepatic impairment, reduced clearance was associated with approximately 85% higher AUC and 47% higher Cmax. In contrast, mild and moderate renal impairment did not materially alter single-dose sildenafil pharmacokinetics in labeling studies, while severe renal impairment approximately doubled parent sildenafil AUC and Cmax.
The mechanisms and severity thresholds are therefore different even though both conditions can ultimately change systemic exposure. Kidney-function-specific evidence remains on the sildenafil renal impairment pharmacokinetics page.
| Condition | Sildenafil PK Finding |
|---|---|
| Child-Pugh A/B hepatic impairment | AUC approximately +85%; Cmax approximately +47% |
| Child-Pugh C hepatic impairment | Not studied |
| Mild/moderate renal impairment | Single-dose PK not materially altered in labeling studies |
| Severe renal impairment | Parent AUC and Cmax approximately doubled |
Reduced sildenafil clearance in hepatic impairment can alter the late concentration-time profile, but the reported AUC and Cmax changes should not be converted automatically into a new half-life value.
Half-life is derived from the terminal concentration decline and depends on the relationship between distribution and elimination. A percentage change in AUC therefore does not equal the same percentage change in terminal half-life.
Current labeling emphasizes reduced clearance and increased exposure in Child-Pugh A/B rather than assigning one universal hepatic-impairment half-life. The general approximately 4-hour terminal half-life framework is explained on the sildenafil half-life page.
| Parameter | Hepatic-Impairment Interpretation |
|---|---|
| Clearance | Demonstrably reduced |
| AUC | Approximately 85% higher |
| Cmax | Approximately 47% higher |
| Terminal half-life | Should not be inferred directly from the AUC increase |
The hepatic-impairment dataset is most informative when several parameters are interpreted together. Higher AUC establishes greater integrated exposure, higher Cmax identifies a greater peak and lower CL/F indicates reduced apparent oral clearance.
The pattern is internally consistent: sildenafil is being removed less efficiently and/or experiencing less presystemic loss, producing both greater peak concentration and greater overall systemic exposure.
No single parameter establishes the entire mechanism. In particular, CL/F cannot independently distinguish a change in systemic clearance from a change in oral bioavailability.
| Measure | Observed / Relevant Finding | Research Role |
|---|---|---|
| AUC | Approximately +85% | Integrated systemic exposure |
| Cmax | Approximately +47% | Peak exposure |
| CL/F | Approximately -46% in the published study | Apparent oral clearance |
| Child-Pugh classification | A and B studied; C not studied | Defines the evidence boundary |
| Metabolite exposure | Increased | Shows that hepatic impairment also affects metabolite disposition |
Hepatic impairment is a demonstrated source of sildenafil PK variability rather than merely a theoretical one. The Child-Pugh A/B studies show substantial average changes in parent-drug clearance and exposure.
At the same time, hepatic function is only one determinant of sildenafil concentrations. Age, severe renal impairment, CYP3A4 inhibition or induction, oral bioavailability and other physiological factors can also change systemic exposure.
A high sildenafil AUC in an individual therefore cannot be attributed to liver function without supporting clinical and pharmacokinetic context. The broader framework remains on the sildenafil PK variability page.
| Variability Source | Potential Sildenafil Effect |
|---|---|
| Child-Pugh A/B hepatic impairment | Reduced clearance and increased AUC/Cmax |
| CYP3A4 inhibition | Can markedly increase sildenafil exposure |
| Severe renal impairment | Can approximately double parent AUC and Cmax |
| Age | Can increase total systemic exposure |
| Bioavailability | Changes oral systemic input |
The hepatic-impairment PK findings describe population-level changes in exposure; they are not a formula for mathematically adjusting an individual sildenafil dose. An 85% increase in AUC does not mean that a dose should simply be reduced by 85% or by any other inverse percentage.
Product and indication context also matter. Current ED-oriented sildenafil labeling uses a lower-starting-dose framework in hepatic impairment, while current REVATIO PAH labeling states that no dose adjustment is required for mild-to-moderate hepatic impairment and that severe impairment has not been studied.
That difference illustrates why this page should report the shared PK evidence without turning it into one universal sildenafil dosing rule. General label-based regimen information remains on the sildenafil dosage page.
| Question | PK / Label Interpretation |
|---|---|
| Does Child-Pugh A/B increase sildenafil exposure? | Yes |
| Can AUC percentage be converted directly into a dose reduction? | No |
| Do all sildenafil products use identical hepatic-impairment dosing language? | No |
| Has severe Child-Pugh C PK been studied? | No |
| Where does general dosing information belong? | Sildenafil dosage page and the applicable product label |
The core evidence comes from a single-dose pharmacokinetic comparison involving subjects with chronic stable Child-Pugh A/B cirrhosis and controls with normal hepatic function. The published study included 12 subjects in each hepatic-function group and used a 50 mg oral sildenafil dose.
The findings form a coherent PK pattern: apparent oral clearance was approximately 46% lower, parent sildenafil Cmax approximately 47% higher and AUC approximately 85% higher in hepatic impairment.
The evidence boundary is equally important: Child-Pugh C was not studied, and the measured A/B values should not be extrapolated quantitatively to severe hepatic impairment. For the broader ADME framework, the sildenafil pharmacokinetics hub connects these findings with absorption, distribution, metabolism, clearance and exposure.
| Research Question | Sildenafil-Specific Answer |
|---|---|
| Which hepatic groups were studied? | Chronic stable Child-Pugh A and B cirrhosis |
| What oral dose was used in the published PK study? | Single 50 mg dose |
| How many subjects were in the hepatic and control groups? | 12 with cirrhosis and 12 with normal hepatic function |
| What happened to apparent oral clearance? | Approximately 46% lower |
| What happened to AUC? | Approximately 85% higher |
| What happened to Cmax? | Approximately 47% higher |
| Was Child-Pugh C studied? | No |
In current U.S. labeling, Child-Pugh Class A and B hepatic impairment reduced sildenafil clearance and increased parent sildenafil AUC by approximately 85% and Cmax by approximately 47% compared with age-matched subjects without hepatic impairment.
In the published single-dose study of chronic stable Child-Pugh A/B cirrhosis, apparent oral clearance, CL/F, was approximately 46% lower than in subjects with normal hepatic function.
No. Current labeling states that sildenafil pharmacokinetics have not been studied in severe hepatic impairment, Child-Pugh Class C.
Sildenafil metabolism is mediated principally by CYP3A4, with CYP2C9 providing a minor metabolic pathway.
Yes. The published hepatic-impairment study reported increased systemic exposure to the N-desmethyl active metabolite, with the exposure increase described as approximately twice the magnitude observed for parent sildenafil.
No. AUC, Cmax and clearance changes are population pharmacokinetic findings and do not provide a direct mathematical formula for selecting an individual dose. Product and indication-specific labeling also differs.