What is Noncompartmental Pharmacokinetic Analysis?

Pharmacokinetics (PK) is the branch of pharmacology that explores the effects of the human body on a drug. PK helps us understand how a drug moves into the body, passes through the body, and is eventually cleared from the body in a quantitative way. In other words, PK is used to describe the absorption, distribution, metabolism, and excretion (ADME) of a drug. Insights into a drug’s PK are used to inform the drug development program and are critical for guiding input and decision-making by regulatory authorities like the FDA.

Compartmental vs. Noncompartmental Analysis

There are two common approaches to understanding a drug’s PK. One is compartmental PK analysis and the other is noncompartmental PK analysis (NCA).

Compartmental Analysis

Compartmental modeling methods consider the body to consist of a finite number of interconnected, well-mixed, and kinetically homogeneous compartments (e.g., blood, organs, and other tissues). Based on this view, the pharmacokineticist makes certain assumptions and develops models based upon nonlinear regression analysis to describe the PK of the drug. When using a compartmental approach, there is the potential for variability in the output of the analysis because the assumptions used to build the PK model may be somewhat different from one pharmacokineticist to another.

Noncompartmental Analysis

Noncompartmental analysis (NCA) methods are model-independent, meaning they do not rely upon assumptions about body compartments, and they tend to provide more consistency. In addition, NCA relies almost exclusively upon algebraic equations to estimate PK parameters, making the analysis less complex than compartmental methods. NCAs often prove faster and more cost-efficient to conduct, especially when compared to more complex compartmental analyses (e.g., compartmental models that are applied to population PK analyses and that rely upon sparse sampling techniques).

When to Use Noncompartmental Analysis

Deciding whether to use a noncompartmental analysis versus a compartmental analysis approach is not a function of how sophisticated the method is but depends in large part upon the purpose of the analysis. Compartmental methods have key advantages including:

  • characterizing PK across multiple studies
  • exploring PK variability due to intrinsic factors and extrinsic factors
    • age, sex, race, renal impairment, hepatic impairment
  • informing dosage adjustments based upon these factors

On the other hand, NCAs are typically favored for characterizing PK within a single study, including both final analyses and any interim analyses used to make dose escalation decisions. NCAs are the most commonly used approach for establishing the initial exposure characteristics of a drug prior to entry into the clinic (i.e., during nonclinical PK and toxicology studies).

How is a Noncompartmental Analysis Performed?

In an ideal world, the way a drug moves through the body could be tracked directly in every body fluid and tissue. In the real world, this approach is not practical and we must instead make estimates based upon what can be realistically measured. PK analysis relies on observed drug concentration measurements over time in a relevant, accessible matrix (typically blood or plasma). These measurements are provided to the pharmacokineticist by a bioanalytical lab, where blood or plasma samples (or other appropriate matrix samples) from study subjects are analyzed using sensitive detection techniques. Once the pharmacokineticist receives the drug concentration data, a PK software package is used to construct concentration versus time plots to graphically display the pharmacokinetics of the drug in the given matrix and to estimate relevant PK parameters.

The Concentration Versus Time Plot

From the concentration versus time plot, a pharmacokineticist can begin to understand the absorption and elimination characteristics of the drug. In the example graph below, the time it takes the drug to reach Cmax (Tmax) provides information on how quickly the drug is absorbed. The slope of the elimination provides information on how quickly the drug is cleared from the body. Combining the concentration versus time information from multiple individuals further refines the PK assessment, allowing for a determination of the PK variability across the study population.

Example Concentration Versus Time Plot:

Common PK Parameters for Noncompartmental Analysis

The most common PK parameters described by an NCA are:

  • Maximum concentration (Cmax) and time of maximum concentration (Tmax)
  • Area under the concentration-time curve (AUC)
  • Volume of distribution (Vd)
  • Systemic clearance (CL)
  • Terminal half-life (t1/2)

Maximum Concentration and Time of Maximum Concentration

Maximum concentration (Cmax) is the peak concentration in a matrix. Time of maximum concentration (Tmax) is the time at which that concentration is reached. These parameters are calculated directly from the observed data and do not need equations for their estimation.

Area Under the Concentration-time Curve

Area under the concentration-time curve (AUC) is the definite integral in the plot of the concentration-time curve and a measure of overall drug exposure. The NCA approach estimates AUC parameters using trapezoidal approximations of the integral. Along with Cmax, AUCs are the primary drug exposure parameters. AUC is defined over a given timeframe that can range from:

  • very short periods: from the time of dosing to a few minutes or hours later
  • a full dosing interval: 0-12 hours for twice-daily dosing or 0-24 hours if the drug is given only once daily
  • the last measurable concentration or extrapolated from the time of dosing to infinity

Volume of Distribution

Volume of distribution (Vd) is the theoretical volume necessary to contain the total amount of an administered drug at the same concentration that is observed in the evaluated matrix (typically blood or plasma). This value may exceed the volume of total body water when a drug distributes away from the blood and into body tissues.

Systemic Clearance

Systemic clearance (CL) is a measure of drug removal from the body over time.

Terminal Half-life

Terminal half-life (t1/2) is the time required to clear one half of the drug from the plasma after reaching pseudo-equilibrium.


Among the available strategies for PK analyses, the NCA approach provides a number of advantages. It is a standard, efficient, and effective method for estimating PK parameters and is indispensable for characterizing PK within a single study and for making time-critical dosing decisions (e.g., within dose escalation trials). Parameters from NCAs are also routinely used by regulatory authorities to inform their decision making both during development and during the approval process. Allucent has performed hundreds of NCAs. Contact a consultant to learn more.

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