Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are

the target patient population receiving clinically relevant doses of a drug of interest.

Certain patient demographical, pathophysiological, and therapeutical features, such as body weight, excretory and metabolic functions, and the presence of other therapies, can regularly alter doseconcentration relationships

Identification of the measurable patho-physiologic factors that cause changes in the dose-concentration relationship and the extent of these changes

Check if such changes are associated with clinically significant shifts in the therapeutic index

Alter the dosage appropriately

The collection of relevant pharmacokinetic information in patients who are representative of the target population to be treated with the drug. The identification and measurement of variability during drug development and evaluation. The explanation of variability by identifying factors of demographic, patho-physiological, environmental, or concomitant drug-related origin that may influence the pharmacokinetic behavior of a drug. The quantitative estimation of the magnitude of the unexplained variability in the patient Population

The magnitude of the unexplained (random) variability is important because the efficacy and safety of a drug may decrease as unexplainable variability increases. In addition to inter individual variability, the degree to which steady-state drug concentrations in individuals typically vary about their long-term average is also important. Concentrations may vary due to inexplicable daytoday or week-to-week kinetic variability and/or due to errors in concentration measurements.

The population approach may be used to estimate population parameters of a response surface model in phases 1 and 2B of clinical drug development, where information is gathered on how the drug will be used in subsequent stages of drug development and after release.

The population approach can also be applied to phases 2A and 3 of drug development to gain information on drug safety (efficacy) and to gather additional information on drugpharmacokinetics (and pharmacodynamics) in special populations, such as the elderly . It is also useful in postmarketing surveillance (phase 4 studies ).

A brief statement of the problem to measurement of drug concentrations

A summary of factors that may influence drug disposition and effects

An assessment of prior and present pharmacokinetic data Recommendations for possible changes in drug therapy and follow-up evaluations

Estimates of this kind of variability (residual intra-subject, inter-occasion variability) are important for therapeutic drug monitoring

In the population pharmacokinetics context, there are two broad approaches for obtaining information about pharmacokinetic variability: (a) trough screen (single or multiple) studies and (b) full pharmacokinetic screen (experimental population pharmacokinetic) studies. (1)the single-trough sampling design, (2) the multiple-trough sampling design, and (3) the full population PK sampling design.

A single blood sample is obtained from each patient at or close to the trough of drug concentrations, shortly before the next dose ,and a frequency distribution of plasma or serum levels in the sample of patients is calculated.

Provided that the sample size is large, that assay and sampling errors are small, and that the dosing regimen and sampling times are identical for all patients, a histogram of such a trough screen gives a fairly accurate picture of the variability in trough concentrations in a target population. If these conditions are not met, such histograms do not represent strict pharmacokinetic variability because the data include many other sources of random fluctuation with significant contribution to the observed spread.
When related with therapeutic outcome and occurrence of side effects, such histograms can be useful to improve the knowledge of the optimal concentration range of a given drug.

The relationships of patient characteristics to the trough levels can be explored by simple statistical procedures such as multiple linear regression. Although simple, the trough (pharmacokinetic) screen will only yield information about oral clearance and no other parameters of interest (e.g., apparent volume of distribution, half-life). Only qualitative, not quantitative, information will be obtained. Components of variability interindividual and residual variability cannot be separated. This method will identify, qualitatively, pharmacokinetically relevant factors and their differences among subgroups (subpopulations). When implementing this sampling strategy, the difficulty of getting patients and physicians to adhere to the sampling strategy should be kept in mind. Compliance with at least the last two doses before trough level measurement is adequate for this type of study, but the drug should be dosed to steady state.

Because of uncertainty in doses and samples, the method can only reasonably be applied to drugs dosed at intervals less than or equal to one elimination half-life unless timing of dose and of level can be assured, as in inpatient studies . Large numbers of subjects would be needed for this type of study because the data would be noisy. With this design, it is not advisable to contemplate measuring peak observations unless the drug is given intravenously or is a certain type of sustained release formulation. The time for achieving maximum concentration depends on rates of all processes of drug disposition and may vary among subjects. Thus, the simple estimation of peak levels is subject to large uncertainty. Sampling peak levels also yields information on variability of largely irrelevant kinetic processes for drugs for which effects relate to steady-state mean concentrations, or the area under the concentration curve.

In this design, two or more blood samples are obtained near the trough of steadystate concentrations from most or all patients. In addition to relating blood concentrations to patient characteristics, it is possible now to separate interindividual and residual variabilities. Since patients are studied in greater detail, this design requires fewer subjects, and the relationships to patient characteristics can be evaluated with higher precision. To estimate interindividual variability of the oral clearance, nonlinear mixed-effects modeling should be used.

When using pharmacokinetic models for parameter estimation, a sensitivity analysis should be required to fix a parameter such as absorption rate constant to estimate other parameters and to determine the fixed parameter value that has the least effect on the estimation of the remaining parameters.
The drawbacks of the single-trough screen design apply here. Although the estimates of intersubject and residual variability may or may not be biased, they may not be precise unless a large number of patients are studied.

With this approach, blood samples are drawn from subjects at various times (typically 1 to 6 time points) following drug administration . The objective is to obtain, where feasible, multiple drug levels per patient at different times. This approach permits an estimation of pharmacokinetic parameters of the drug in the study population and an explanation of variability using the nonlinear mixed-effects modeling approach. The full pharmacokinetic screen (experimental population pharmacokinetic) study should be designed to explore the relationship between the pharmacokinetics of a drug and demographic/patho-physiological features of the target population (with its subgroups) for which the drug is being developed. A full pharmacokinetic screen study requires careful design considerations.

The variance of an individuals PK observations about the individual-specific PK model on a given occasion (i.e., the intra-individual variability) can conceptually be factored into two components: #1)variability of PK observations due to variability of the PK model from occasion to occasion (interoccasion variability), and #2) variability of PK observations about the individual PK model appropriate for the particular occasion (noise; PK model misspecification).

Simulation of a planned study offers a powerful tool for evaluating and understanding the consequences of different study designs. Shortcomings in study design result in the collection of uninformative data.

Simulation can reveal the effect of input variables and assumptions on the results of a planned population pharmacokinetic study.
Simulation allows study designers to assess the consequences of the design factors chosen and the assumptions made. Thus, simulation enables the pharmacometrician to better predict the results of a population study and to choose the study design that will best meet the study objectives. It is important to simulate a population pharmacokinetic study using alternative study designs to determine the most informative design, given the study objectives, before initiating such studies. Simulation is a useful tool to provide convincing objective evidence of the merits of a proposed study design and analysis.

Two types of protocol may be considered depending on the setting in which a population pharmacokinetic study is to be performed. If it is added on to a clinical trial (as can be envisaged in most situations), the population study should be carefully interwoven with the existing clinical protocol to ensure that it does not compromise the primary objectives of the study. Every effort should be made to convince investigators of the relevance of including a population pharmacokinetic study. Graphical displays of simulation results may help to achieve this objective. In addition, a population pharmacokinetic study protocol should be written since a population study can also be defined as evaluating data from existing data and/or data coming from more than one study. When a population study is a stand alone study, a comprehensive protocol should be prepared. The population pharmacokinetic study as part of the clinical protocol and the population pharmacokinetic study protocol are discussed briefly.

The objectives of the population pharmacokinetic study should be clearly defined.

These objectives, should be secondary to the primary clinical study objectives or primary when they would not compromise the study in question.
The criteria for sampling subjects and methods for data analysis (described in the population pharmacokinetic study protocol) should be clearly stated. The data to be used for population analysis should be defined, including patients and subgroups to be used and covariates to be measured. The sampling design should be specified and any subgroup stratification should be defined .

In a multicenter trial, it may sometimes be necessary to obtain extensive data from some centers and sparse data from others . This type of data collection can be useful for informative data analysis protecting against model misspecification and it should be specified in the protocol. The data analysis plan should be described in advance in the protocol as accurately as possible. Statements such as a pharmacokinetic screen will be performed or data will be analyzed using NONMEM are inappropriate because they do not convey information on the study objective or how the analysis will be carried out. If possible, special case report forms that can be easily understood by investigators should be designed to meet the needs of the pharmacokinetic evaluation.

The practical details of the pharmacokinetic evaluation should be described in a population pharmacokinetic study protocol, although the principles may be specified in the clinical study protocol in a general way. The primary (same as that in the clinical protocol) and secondary objectives should be clearly stated. The secondary objectives should be those that enable the data analyst to search for the unexpected, after the primary objectives have been addressed. The sampling design, data assembly, data checking procedure, and procedures for handling missing data and data anomalies should be clearly spelled out in the protocol. The data to be used for population analysis should be defined, including patients and subgroups to be used and covariates to be measured. The sampling design should be specified and any subgroup stratification should be defined . Real-time data assembly (see Data Assembly) would permit population pharmacokinetic data analysis to be performed before the end of a clinical trial and would make it possible to include the results in the filing of the new drug application (NDA).

If drug-drug interactions are to be characterized, the protocol should pre-specify whether to determine

(1) the effect of the presence or absence of a specific concomitant medication or (2) the total daily dose of the concomitant medication or

(3) the plasma concentration of the potentially interacting medication. If food effect is to be evaluated, the time of sampling in relation to food intake, and the composition of food, should be specified in the protocol.

Also, the procedure for analyzing the data (and validation when appropriate) should be specified.

Distinguishing between clinically relevant and statistically significant covariates is important. The protocol should include study objectives; Patient inclusion/exclusion criteria and pharmacokinetic evaluability criteria; Sampling design; Data handling and checking procedures; Initial assumptions for modeling; A list of possible covariates to be investigated and the rationale for choosing them; and whether a sensitivity analysis and A validation procedure is envisaged.

A population pharmacokinetic study should be conducted according to current good clinical practice and good laboratory practice standards.

The sampling strategy and the recording of samples should be part of good clinical practice and the handling of samples part of good laboratory practice.
Error in recording sampling times relative to dosing history could result in biased and imprecise parameter estimates, depending on the nature and degree of the error . Every effort should be made to ensure that study subjects and clinical investigators comply with study protocol. To improve compliance, the protocol should not be overly complicated and blood sampling times should be convenient to both clinical staff and patients.

The necessity of blood sampling should be carefully explained to patients and investigators. Instructions provided to the investigators should be clear and concise. These measures should be backed up by adequate monitoring by the sponsor while the study is ongoing. Adequate resources should be available for optimal sample preparation, storage at the investigator site, and transportation and storage of biological samples prior to analysis. Noncompliance with drug intake can be a source of confounding and lead to inappropriate interpretation of study results . Special care should be taken to use methodologies that are as objective as possible to reconstruct dosage history. Communication between all parties involved is essential for the successful conduct of a population study, especially if the study is part of a large scale clinical trial.

Correct evaluation of pharmacokinetic data depends on the accuracy of the analytic data obtained. Clinical investigators and their staff should be educated on the importance of sample timing, recording, proper labeling, and handling of samples. The accuracy of analytical data depends on the criteria used to validate the method. Consequently, drug and/or metabolite(s) stability, assay sensitivity, selectivity, recovery, linearity, precision, and accuracy should be carefully scrutinized before samples are analyzed. The importance of using validated assay methods for analyzing pharmacokinetic data cannot be over emphasized.

1.Objectives, Hypotheses, and Assumptions

The objectives of the analyses should be clearly stated. The hypotheses being investigated should be clearly articulated. It is recommended that all known assumptions inherent in the population analysis be explicitly expressed.

2. Population Model Development

The steps taken (i.e., sequence of models tested) to develop a population model should be clearly outlined to permit the reproducibility of the analysis. The criteria and rationale for model building procedures dealing with confounding, covariate, and parameter redundancy should be clearly stated.

The criteria and rationale for model reduction to arrive at the final population model should also be clearly explained.

3. Reliability of Results

The reliability of the analysis results should be checked using diagnostic plots; confidence intervals (standard errors) for key parameters should be checked using nonparametric techniques and the profile likelihood plot (mapping the objective function ) This is appropriate because the possibility of biased results is increased by the complexity of the population models and by the sparse individual data available. The nonlinearity of the statistical model and ill-conditioning of a given problem can produce numerical difficulties and force the estimation algorithm into a false minimum.

Because the maximum likelihood procedure is sensitive to bizarre observations, it may be necessary to check the stability of the model .
It is important to evaluate the quality of the results of a population study/analysis for robustness. Evaluation for robustness may be approached by sensitivity analysis the use of case deletion diagnostics is also encouraged. Evidence of robustness renders the results reasonable and independent of the analyst.

The concept of feedback control methods for drug dosage optimisation is described from the viewpoint of control theory.

The control system consists of 5 parts: (a) patient (the controlled process); (b) response (the measured feedback); (c) model (the mathematical description of the process); (d) adaptor (to update the parameters); and (e) controller (to determine optimum dosing strategy). In addition to the conventional distinction between open-loop and closed-loop control systems, a classification is proposed for dosage optimisation techniques which distinguishes between tight-loop and loose-loop methods depending on whether physician's interaction is absent or included as part of the control step. Unlike engineering problems where the process can usually be controlled by fully automated devices, therapeutic situations often require that the physician be included in the decision-making process to determine the 'optimal' dosing strategy. Tight-loop and loose-loop methods can be further divided into adaptive and nonadaptive, depending on the presence of the adaptor.

The main application areas of tight-loop feedback control methods are general anaesthesia, control of blood pressure, and insulin delivery devices. Loose-loop feedback methods have been used for oral anticoagulation and in therapeutic drug monitoring. The methodology, advantages and limitations of the different approaches are reviewed. A general feature common to all application areas could be observed: to perform well under routine clinical conditions, which are characterised by large interpatient variability and sometimes also intrapatient changes, control systems should be adaptive.

Apart from application in routine drug treatment, feedback control methods represent an important research tool.
They can be applied for the investigation of pathophysiological and pharmacodynamic processes.

A most promising application is the evaluation of the relationship between an intermediate response (e.g. drug level), which is often used as feedback for dosage adjustment, and the final therapeutic goal.