High-dose variability describes a PK/PD timing construct in which larger sildenafil doses increase exposure magnitude while the resulting duration remains dependent on the shape and persistence of the concentration-time profile. The relationship is therefore not a simple rule in which more drug automatically produces a proportionally longer interval. high dose variability reflects differences in exposure formation, disposition, and response coupling, while duration variability describes dispersion in how long an exposure-response system remains above a functional region. The resulting duration range depends on interacting duration factors, including absorption, distribution, clearance, and metabolic processing. At higher exposure, metabolism variability can become more visible because concentration declines occur from a different starting level and may traverse multiple kinetic regions. metabolism speed, CYP3A4 variability, and metabolic clearance influence the decline phase rather than simply determining the initial concentration. Consequently, slow metabolizers and fast metabolizers can exhibit different exposure persistence even when dose is identical. High-dose timing is therefore an emergent property of coupled PK and PD processes rather than a deterministic consequence of dose magnitude.
A high dose primarily changes the amount of sildenafil entering and persisting within the systemic compartment, but it does not independently determine how quickly that exposure is absorbed, distributed, metabolized, or cleared. The concentration-time curve can therefore shift upward without preserving the same proportional timing characteristics. metabolism variability changes the rate at which concentration declines, while metabolism speed describes the kinetic component of that decline. Differences in CYP3A4 variability can alter metabolic processing, and metabolic clearance determines how efficiently drug is removed through metabolic pathways. The relative position of a concentration curve to a PD threshold can consequently differ even when exposure magnitude is higher. effectiveness variability emerges when equivalent exposure produces different response trajectories because sensitivity, threshold position, or response efficiency differs. An effectiveness threshold can be crossed later on the descending limb when exposure persists, but the timing of that crossing depends on both PK decline and PD sensitivity. The effectiveness duration link therefore connects exposure persistence to response timing without making duration a direct function of dose.
At high exposure, the descending concentration-time phase becomes especially important for interpreting duration because the relevant timing question concerns when exposure moves through a functional response region rather than simply when concentration reaches zero. A higher starting concentration may increase the time required to cross a fixed threshold under some kinetic assumptions, yet variability in absorption, distribution, metabolic processing, and clearance can alter the trajectory substantially. The PD system can also exhibit an effectiveness plateau, where additional exposure produces relatively little additional response over part of the concentration range. Once exposure declines from that region, effectiveness dropoff depends on threshold position and response sensitivity rather than dose alone. Thus effectiveness variability and duration variability can arise together while representing distinct components of the model. A high-dose profile may have greater exposure magnitude yet show only modest timing changes if clearance is efficient, whereas slower metabolic processing can extend persistence more visibly. The central interpretation is that high-dose outcomes reflect PK/PD coupling: dose establishes exposure magnitude, while disposition and pharmacodynamic response determine how that exposure translates into timing, plateau persistence, and eventual threshold crossing.
High-dose exposure begins with a change in the amount of sildenafil available to generate the systemic concentration-time profile. The immediate consequence is an increase in exposure magnitude, but the magnitude of that change does not uniquely determine the later slope of concentration decline. high dose variability therefore reflects more than dose size because the observed trajectory also depends on absorption, distribution, metabolism, and elimination. duration variability emerges when those processes differ between modeled profiles. The metabolic component is represented by metabolism variability and metabolism speed, which influence how rapidly systemic exposure is transformed and removed. CYP3A4 variability adds another source of between-profile differences because pathway activity can alter the rate of metabolic processing. metabolic clearance then contributes directly to the descending concentration phase. Consequently, two high-dose concentration-time curves can begin at different exposure levels while retaining different decline rates, producing timing differences that cannot be inferred from dose magnitude alone.
A useful PK interpretation separates exposure magnitude from disposition kinetics. Increasing dose can raise the area under the concentration-time curve and can increase the concentration reached during the profile, but those changes do not require a proportional change in elimination rate. high dose variability can therefore coexist with similar terminal slopes when clearance mechanisms remain comparable, or with different slopes when metabolism variability is substantial. metabolism speed determines how quickly metabolic transformation contributes to concentration decline, while CYP3A4 variability can shift that contribution between individuals or modeled states. The resulting metabolic clearance influences exposure persistence, but persistence is not identical to subjective duration or to pharmacodynamic effectiveness. A higher concentration may remain above a modeled threshold for longer, yet threshold position and response sensitivity can change the timing relationship. Thus the PK interpretation of a high dose requires consideration of both the vertical displacement of the curve and its temporal behavior. Dose establishes one boundary condition, whereas metabolic and disposition parameters determine much of the subsequent trajectory.
High-dose concentration profiles can also expose why metabolic processing should not be interpreted as a fixed capacity that automatically expands with dose. The dose increases the quantity presented to the disposition system, while intrinsic pathway characteristics determine how that quantity is processed over time. metabolism variability may therefore produce different concentration declines from the same high dose. metabolism speed can shift the persistence of systemic exposure, and CYP3A4 variability can modify the metabolic component of that persistence. The resulting metabolic clearance interacts with absorption and distribution to define the complete concentration-time curve. high dose variability consequently should be interpreted as variability in a coupled system rather than variability caused by dose in isolation. When concentration begins from a higher level, the same clearance process may require more elapsed time to reach a particular absolute concentration, but the time to a functional PD threshold depends on the threshold itself. duration variability therefore represents the combined consequence of exposure magnitude, kinetic decline, and response coupling rather than a deterministic extension produced by the dose.
The PK–PD interpretation of a high dose begins by distinguishing concentration from response. A higher systemic concentration can move the exposure profile farther above a functional response threshold, but the duration of that separation depends on how concentration subsequently declines and how the PD system translates exposure into effect. metabolism variability changes the decline trajectory, while metabolism speed determines one component of the temporal slope. CYP3A4 variability can modify metabolic processing, and metabolic clearance contributes to exposure persistence. In a high-dose profile, slow metabolizers and fast metabolizers can therefore occupy different modeled regions of the concentration-time curve. The same nominal dose can produce different times to threshold crossing because the initial exposure magnitude and subsequent decline interact. Threshold timing is consequently a coupled PK/PD property: PK determines the concentration available at each time point, while PD determines how that concentration is translated into a response region. High-dose interpretation must preserve both dimensions rather than treating concentration as a direct surrogate for duration.
Plateau behavior adds another layer to high-dose timing because response does not necessarily increase in direct proportion to concentration across the entire exposure range. When a modeled response approaches a plateau, further exposure magnitude can produce relatively little additional response while still altering the concentration reserve above a threshold. metabolism variability can determine how long exposure remains within that higher concentration region, while metabolism speed affects the rate at which the profile leaves it. CYP3A4 variability and metabolic clearance consequently influence the timing of movement from plateau-associated exposure toward lower-response regions. slow metabolizers may be represented by slower concentration decline under a given model, whereas fast metabolizers may show a more rapid decline. These descriptions concern kinetic parameters rather than subjective classifications. High-dose duration therefore depends on how the exposure curve traverses the PD response function. A larger dose can increase the vertical distance from threshold, but the temporal consequence depends on clearance, metabolic processing, threshold position, and the shape of the exposure-response relationship.
Metabolic saturation tendencies can complicate the interpretation when the relationship between exposure and metabolic processing is not adequately represented by a simple linear model. A higher concentration may increase the amount presented to a pathway without necessarily producing a proportional increase in metabolic throughput. In a mechanistic model, metabolism variability can therefore interact with dose-dependent concentration changes to produce different decline patterns. metabolism speed summarizes the temporal component, while CYP3A4 variability identifies variability in a major metabolic pathway. metabolic clearance describes the resulting removal process, and differences between slow metabolizers and fast metabolizers illustrate how clearance-related parameters can alter exposure persistence. However, none of these variables independently defines PD duration. Threshold position, response sensitivity, and plateau behavior determine how the concentration trajectory becomes a response trajectory. A high dose can consequently widen the separation between exposure curves while leaving response duration comparatively similar if the PD system is near a plateau. Conversely, modest PK differences can produce larger timing differences near a steep threshold region. The interaction is therefore nonlinear in interpretation even when individual PK components are modeled systematically.
| PK Factor | Mechanistic Basis | High-Dose Timing Impact |
|---|---|---|
| Metabolism variability | Differences in the rate and extent of metabolic processing alter concentration decline. | Can change how long high-dose exposure remains above a modeled response threshold. |
| Metabolism speed | Represents the temporal rate of metabolic transformation contributing to disposition. | Faster or slower decline changes the timing of threshold crossing after high exposure. |
| CYP3A4 variability | Variation in CYP3A4 pathway activity modifies a major component of sildenafil metabolism. | Can shift exposure persistence and the timing of movement toward lower concentrations. |
| Metabolic clearance | Defines the contribution of metabolic removal to systemic drug elimination. | Changes the descending concentration trajectory and therefore potential threshold-crossing time. |
| Slow metabolic processing | Lower modeled metabolic processing produces more persistent systemic exposure. | Can broaden modeled exposure persistence without guaranteeing a proportional PD duration change. |
| Fast metabolic processing | Higher modeled metabolic processing produces more rapid concentration decline. | Can shorten exposure persistence while PD threshold position still determines response timing. |
High-dose duration variability is best represented as dispersion in the time required for an exposure-response system to move through defined kinetic and pharmacodynamic regions. duration variability can arise even when the administered dose is identical because absorption, distribution, clearance, and metabolic processing differ between modeled profiles. The resulting duration range is therefore generated by a distribution of kinetic parameters rather than by dose magnitude alone. duration factors include the starting exposure level, concentration decline, distributional behavior, metabolic processing, and the PD threshold used to define persistence. duration inconsistency describes the resulting dispersion when those parameters vary, while duration stability refers to a narrower distribution under comparatively consistent kinetic and PD conditions. duration prediction consequently requires assumptions about both PK and PD components. A high dose can increase exposure magnitude and potentially increase the time required to cross an absolute threshold, but it does not specify the threshold, clearance process, or response function. The timing outcome remains a coupled model property.
Exposure persistence is particularly important during the descending portion of a high-dose concentration-time curve. A higher starting concentration creates greater exposure above any fixed concentration reference, but the temporal distance to a PD threshold depends on the slope and curvature of the decline. duration variability therefore reflects variation in both the initial exposure state and the subsequent disposition trajectory. The duration range can broaden when clearance or metabolic parameters vary, while duration factors determine which portions of the concentration-time curve are relevant to the modeled endpoint. duration inconsistency can emerge when small PK differences become amplified near a steep exposure-response transition. In contrast, duration stability can occur when exposure and response parameters remain similar across profiles. duration prediction must therefore distinguish exposure persistence from pharmacodynamic persistence. A concentration can remain measurable after the response has moved below a defined functional threshold, meaning that concentration duration and effect duration are not interchangeable. High-dose analysis is consequently concerned with the interaction between the curve and the endpoint, not simply with how much drug was administered.
The relationship between high dose and duration also depends on whether the modeled endpoint is defined by an absolute concentration, a relative response, or a threshold within an exposure-response function. A higher dose may increase the initial margin above a fixed threshold, yet the same increase may have a smaller timing consequence if the response curve is already near a plateau. duration variability captures differences in this timing across profiles, while duration range summarizes the resulting spread. The relevant duration factors include clearance, distribution, metabolic processing, and PD sensitivity. duration inconsistency can be especially apparent when these parameters interact near the threshold-crossing region. duration stability instead reflects relatively constrained movement through that region. duration prediction therefore has an inherent uncertainty component because the same dose can correspond to multiple plausible concentration-time and response trajectories. High-dose variability is not evidence of a single deterministic duration mechanism; it is the observable result of multiple kinetic and pharmacodynamic determinants acting together. The distinction prevents exposure magnitude from being treated as a standalone timing variable.
An integrated interpretation connects high-dose exposure magnitude with duration and effectiveness through sequential PK/PD relationships. high dose variability establishes differences in the amount of exposure entering the system, while duration variability describes differences in how long a modeled exposure-response state persists. metabolism variability contributes by altering concentration decline, and effectiveness variability captures differences in response timing produced by PD sensitivity and threshold position. The effectiveness duration link connects these domains without treating them as identical variables. A high dose can place concentration farther above a functional threshold, but metabolic clearance determines how the concentration subsequently evolves. At the same time, the PD system determines how much response is associated with each concentration region. Thus the duration of a measurable exposure, the duration of a modeled response, and the magnitude of exposure are separate quantities. Their relationship is established by the exposure-response function and by the kinetic parameters governing absorption, distribution, metabolism, and elimination. High-dose variability consequently represents an integrated timing phenomenon rather than a dose-only effect.
The effectiveness component becomes particularly informative when the concentration-time profile passes through regions with different response sensitivity. effectiveness variability can arise when identical high-dose exposure profiles are paired with different PD thresholds or response efficiencies. The effectiveness duration link then describes how the persistence of exposure within a response-relevant region relates to the duration of modeled effectiveness. high dose variability changes the initial exposure magnitude, while metabolism variability can change the speed of subsequent decline. duration variability is produced when these PK differences combine with PD differences. A high exposure can also create a larger concentration reserve above threshold without proportionally increasing the response if the system approaches a plateau. As the concentration falls, the timing of transition toward lower response depends on threshold location and response curvature. The integrated model therefore treats dose as an input to exposure magnitude, not as a direct duration parameter. Duration emerges from the trajectory generated after that input has passed through absorption, distribution, metabolic processing, clearance, and the exposure-response relationship.
High-dose PK/PD coupling can be represented as a sequence in which exposure magnitude, metabolic processing, concentration persistence, and response timing influence one another without becoming interchangeable. high dose variability changes the starting exposure condition. metabolism variability changes the rate at which that condition evolves, while duration variability captures the resulting spread in threshold-crossing times. effectiveness variability then reflects differences in how those exposure trajectories map onto response. The effectiveness duration link is consequently strongest where exposure persistence and PD threshold behavior jointly determine the response endpoint. If concentration remains within a plateau-associated region, additional exposure magnitude may have limited incremental response while still increasing the distance that must be traversed before threshold crossing. Conversely, near a steep response transition, modest PK differences can create larger timing differences. This explains why high-dose duration outcomes cannot be reduced to dose comparisons alone. The relevant mechanism is the coupled movement of concentration and response through time. A mechanistic model therefore needs both PK parameters describing exposure formation and disposition and PD parameters describing sensitivity, threshold position, plateau behavior, and drop-off.
| PK/PD Component | Interaction Basis | Timing Contribution |
|---|---|---|
| High-dose exposure | Raises the initial systemic exposure magnitude entering the concentration-time profile. | Changes the starting distance from concentration or response thresholds. |
| Metabolism variability | Alters the rate at which high-dose exposure is transformed and removed. | Changes the persistence of exposure and timing of downstream threshold crossing. |
| Duration variability | Combines differences in exposure persistence with the selected PD duration endpoint. | Produces dispersion in modeled duration across otherwise comparable high-dose profiles. |
| Effectiveness variability | Reflects differences in PD sensitivity, threshold position, and response efficiency. | Changes when exposure becomes functionally relevant or falls below the response region. |
| Effectiveness-duration link | Connects exposure persistence with the time spent within a response-relevant PD region. | Determines how concentration decline becomes an effectiveness timing trajectory. |
| Exposure-response coupling | Maps each concentration-time state onto a corresponding response state. | Explains why exposure magnitude alone cannot specify the timing of response persistence. |
High dose alone cannot determine duration because dose specifies an administered amount rather than the complete sequence of processes governing concentration and response. metabolism variability can alter concentration decline, while duration range reflects the spread created by differences in absorption, distribution, clearance, metabolism, and PD thresholds. duration inconsistency occurs when these determinants vary enough to produce different threshold-crossing times. By contrast, duration stability describes comparatively narrow timing dispersion under constrained PK/PD conditions. The same high dose can therefore correspond to different exposure persistence without implying that dose itself changed metabolic capacity. Metabolic processing is a property of the disposition system, whereas dose determines the amount presented to that system. The resulting concentration-time curve is shaped by their interaction. This distinction is essential for duration prediction, because prediction requires assumptions about clearance and response thresholds in addition to dose. High-dose exposure may increase the amount of drug available for processing, but it does not uniquely specify metabolic rate, clearance, or the response level that defines duration.
The analytical distinction between inconsistency and stability is also important because duration is an endpoint generated from a distribution of possible trajectories. duration inconsistency can arise when small changes in metabolic processing, clearance, distribution, or PD sensitivity are amplified near a threshold. duration stability instead reflects relatively similar trajectories and threshold positions across profiles. metabolism variability contributes to this dispersion but does not by itself determine whether the response endpoint remains stable. The duration range depends on how the selected endpoint is defined and on the parameters used to generate the concentration-response trajectories. duration prediction therefore carries uncertainty whenever relevant PK or PD parameters are incompletely known. A high dose can increase exposure magnitude while leaving the width of the duration distribution dependent on metabolic and pharmacodynamic variability. This is why a higher dose should not be treated as a deterministic proxy for a longer response interval in a mechanistic model. The model must track the complete pathway from administered dose through exposure formation, disposition, threshold crossing, and response decline.
High-dose interpretation ultimately requires separating what is directly specified by dose from what emerges after PK/PD coupling. Dose specifies an input magnitude, but metabolism variability affects how the resulting concentration changes over time, and duration range describes how those trajectories translate into a distribution of timing outcomes. effectiveness inconsistency can appear when different PK trajectories interact with different PD sensitivities or threshold positions, while duration inconsistency describes analogous dispersion at the duration endpoint. duration stability can occur when the relevant PK and PD parameters remain comparatively constrained. The central analytical point is that high-dose variability does not identify a single metabolic mechanism and does not establish a fixed duration relationship. Instead, it identifies a setting in which exposure magnitude, metabolic processing, clearance, and PD response may interact across a broader concentration range. duration prediction is therefore a model-based exercise involving assumptions about exposure persistence and threshold behavior. The resulting timing estimate is conditional on those assumptions, rather than being an intrinsic property of the dose itself.
High dose variability describes differences in the timing and shape of exposure-response trajectories associated with higher dose exposure. A high dose primarily increases the amount of drug available to generate systemic exposure, which can raise concentrations and overall exposure. It does not, by itself, determine absorption speed, distribution behavior, metabolic rate, clearance, or pharmacodynamic sensitivity. Consequently, two profiles generated from the same high dose can have different concentration-time curves if their kinetic parameters differ. They can also produce different response trajectories if threshold position or sensitivity differs. The term therefore refers to variability emerging from the interaction between dose-related exposure magnitude and the processes governing exposure persistence and response. It is a mechanistic PK/PD construct rather than a direct description of subjective experience or a deterministic statement that higher dose always produces proportionally longer duration.
A higher dose generally increases exposure magnitude, but duration depends on how the resulting concentration-time profile interacts with pharmacodynamic thresholds. The concentration may begin at a higher level while still declining according to clearance and metabolic processes that are not specified by dose alone. Absorption and distribution also influence the profile before the elimination phase becomes dominant. On the pharmacodynamic side, the concentration-response relationship determines how much response is associated with each exposure region. If the response is near a plateau, additional concentration may produce limited incremental response while still increasing exposure above threshold. If the response curve is steep near a threshold, comparatively small changes in concentration decline can alter timing substantially. Therefore, dose changes the initial exposure condition, whereas duration emerges from the subsequent PK and PD trajectory.
Metabolism variability influences high-dose duration by changing the rate at which systemic exposure declines through metabolic processing. A higher dose creates more exposure to be processed, but it does not automatically change the intrinsic metabolic capacity of the system. Differences in metabolic activity can therefore produce different concentration-time trajectories from the same nominal dose. If metabolic processing is represented as slower, concentration may persist longer before reaching a specified threshold. If it is represented as faster, concentration may decline more rapidly. The resulting duration difference depends on the selected pharmacodynamic endpoint because concentration persistence and response persistence are not identical. Threshold position, response sensitivity, and exposure-response curvature determine when a declining concentration becomes functionally significant. Thus metabolism variability contributes to duration variability through concentration persistence, but it is only one component of the complete PK/PD model.
Threshold timing depends on the relationship between the concentration-time curve and a defined pharmacodynamic threshold. A high dose can increase the initial concentration and therefore increase the distance between the starting exposure and a fixed threshold. However, the time required to cross that threshold depends on the subsequent rate of concentration decline. Clearance, metabolic processing, distribution, and absorption all contribute to the trajectory. The threshold itself is also a PD parameter and may represent a concentration associated with a specified response level rather than a universal biological boundary. If the exposure-response curve has a plateau, additional concentration above the plateau region may have limited effect on response while still increasing the concentration reserve above threshold. Threshold timing is consequently a coupled PK/PD result rather than a direct conversion of dose into elapsed time.
PK describes what the body does to the drug, including absorption, distribution, metabolism, and clearance. PD describes how the biological system responds to the resulting exposure. In high-dose variability, PK determines the concentration-time profile generated after the larger exposure input, while PD determines how that profile maps onto response. A high dose can raise concentrations without necessarily changing the intrinsic pharmacodynamic sensitivity of the system. Conversely, two systems with similar concentrations can produce different responses if their thresholds or response efficiencies differ. Duration therefore cannot be assigned solely from either dose or concentration. The timing of response persistence depends on how the PK concentration trajectory intersects the PD response function. High-dose variability is consequently a coupling phenomenon: dose influences exposure magnitude, PK determines its evolution, and PD determines how that evolving exposure becomes a response trajectory.
Exposure magnitude describes how much systemic drug exposure is present, while exposure timing describes when concentrations rise, peak, decline, and cross specified levels. A higher dose commonly changes magnitude, but it does not uniquely determine timing. Timing depends on absorption, distribution, metabolic transformation, and clearance. Two profiles can therefore have different exposure magnitudes while sharing similar decline rates, or similar exposure magnitudes while having different decline rates. The distinction becomes especially important when interpreting duration because duration depends on when exposure reaches a relevant threshold rather than simply on how high the concentration became. Pharmacodynamic response adds another layer because the same concentration can map to different response levels under different threshold or sensitivity assumptions. Exposure magnitude is thus an input characteristic, whereas exposure timing is an emergent property of the full kinetic trajectory and its relationship to the selected pharmacodynamic endpoint.
Prediction uncertainty arises because dose does not contain enough information to specify every parameter governing the concentration-response trajectory. A high dose can establish a larger initial exposure, but absorption, distribution, metabolic processing, clearance, and pharmacodynamic sensitivity may vary. If any of these parameters are uncertain, the predicted time to a threshold is also uncertain. The width of the resulting duration distribution depends on which parameters vary and how strongly they influence the endpoint. Uncertainty can be especially important near steep exposure-response transitions, where modest concentration differences can produce larger differences in modeled response timing. It can be smaller when the response remains within a broad plateau region. Therefore, a mechanistic prediction should be understood as conditional on its kinetic and pharmacodynamic assumptions. High-dose exposure can constrain part of the problem, but it cannot eliminate uncertainty generated by downstream PK/PD variability.
Duration inconsistency refers to dispersion in modeled duration outcomes when relevant PK or PD parameters vary, whereas duration stability refers to comparatively narrow dispersion under more consistent conditions. In a high-dose setting, inconsistency can arise from differences in absorption, distribution, clearance, metabolic processing, or pharmacodynamic threshold position. Stability does not mean that dose has no effect; it means that the parameters controlling the relationship between exposure and the chosen duration endpoint produce similar trajectories across modeled profiles. A higher exposure magnitude can coexist with either outcome depending on the variability of the underlying system. Near a steep response threshold, small kinetic differences may produce relatively large timing differences. Within a broad plateau region, the same kinetic differences may have less effect on the selected response endpoint. The distinction is therefore statistical and mechanistic rather than subjective.
Exposure-response coupling determines how a changing concentration becomes a changing biological response in the model. The concentration-time profile is generated by PK processes, while the response trajectory is generated by applying a PD relationship to that profile. A high dose can increase the starting exposure and may keep concentration above a response threshold for a longer modeled interval, but the actual timing depends on clearance and on the shape of the exposure-response function. If the response curve approaches a plateau, increased exposure may add little response even while increasing the concentration margin above threshold. During decline, the timing of movement from the plateau toward lower response depends on sensitivity and threshold position. Consequently, high-dose duration is not simply an exposure-duration measure. It is the time during which the evolving exposure produces the response state defined by the model. PK and PD must therefore be interpreted together.
High-dose determinants should be separated into exposure-generating, disposition, and response-related components. Dose primarily changes the amount available to generate systemic exposure. Absorption and distribution shape the early concentration-time profile, while metabolism and clearance shape subsequent concentration decline. Pharmacodynamic parameters then determine how those concentrations map onto response, including threshold position, sensitivity, plateau behavior, and drop-off. A high dose can therefore increase exposure magnitude without establishing a fixed duration or metabolic rate. Differences in disposition can produce different persistence from the same dose, and differences in PD parameters can produce different response timing from similar exposure. The mechanistic interpretation is consequently one of coupling rather than direct causation. High-dose variability emerges when dose-related exposure differences interact with variability in PK and PD parameters. Any duration interpretation must therefore specify the endpoint, the concentration trajectory, and the exposure-response assumptions used to define when the modeled response begins and ends.