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What is Noncompartmental PK Analysis?

Pharmacokinetics (PK) is the branch of pharmacology exploring the effects of the body on a drug. In particular, PK helps us to understand in a quantitative way how a drug moves into, passes through, and is eventually cleared from the body. Put another way, PK is used to describe the absorption, distribution, metabolism, and excretion (ADME) of a drug. Importantly, insights into a drug’s PK are used not only to inform the drug development program but are also 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 methods consider the body to consist of a finite number of interconnected, well-mixed, and kinetically homogeneous compartments (e.g., blood and other tissues/organs). Based upon this view, the pharmacokineticist makes certain assumptions and develops models based upon nonlinear regression analysis to describe the PK of the drug. As a result of this approach, there is the potential for variability in the output of the analysis from one analyst to another, since the assumptions used to build the PK model may be somewhat different.

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

Deciding When to Use NCA

Deciding whether to use a noncompartmental analysis versus a compartmental approach is not a function of how sophisticated the method is but really depends in large part upon the purpose of the analysis.

Compartmental methods boast key advantages for characterizing PK across multiple studies, for exploring PK variability due to intrinsic factors (e.g., age, sex, race, renal impairment, hepatic impairment) and extrinsic factors, and for 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. In addition, NCA is 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 an NCA 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, he or she uses a PK software package 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

An example of a concentration versus time plot is provided below:

From the concentration versus time plot, a pharmacokineticist can begin to understand the absorption and elimination characteristics of the drug. In the example shown above, 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.

Common PK Parameters

Among the most common PK parameters described by an NCA are:

Maximum concentration (Cmax) and time of maximum concentration (Tmax):

The peak concentration in a matrix and 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 (AUC):

The definite integral in the plot of the concentration-time curve and a measure of overall drug exposure. AUC is defined over a given timeframe that can range from very short periods (e.g., from the time of dosing to some few minutes or hours later) to a full dosing interval (e.g., 0-12 hours for twice-daily dosing or 0-24 hours if the drug is given only once daily) and beyond (e.g., to the last measurable concentration or even extrapolated from the time of dosing to infinity). The NCA approach estimates AUC parameters using trapezoidal approximations of the integral. Along with Cmax, AUCs are the primary drug exposure parameters.

Volume of distribution (Vd):

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, for example, a drug distributes away from the blood and into body tissues.

Systemic clearance (CL):

A measure of drug removal from the body over time.

Terminal half-life (t1/2):

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.

Nuventra has performed hundreds of NCAs in our 10-year history. Contact a consultant to learn more.

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