If the IND is metabolised by CYP450, its systemic exposure may be changed when coadministered with drugs that induce or inhibit CYP450. A DDI study design should include drugs that inhibit or induce the major CYP450 involved in the IND metabolism (Table 15.1).
Excretion-Based Drug Interactions
These interactions occur mostly at the level of the kidney when two drugs compete for the same elimination pathway. The interaction can also occur by inhibiting or inducing a protein transporter found in the kidney. Not all excretion-based interactions are deleterious. In fact, inhibiting the tubular secretion of penicillin by probenecid is considered to be beneficial since concomitantly administered probenecid decreases the required dose of penicillin.
Another mechanism by which a drug interaction can occur at the level of the kidney is by a drug altering the urinary pH, thus affecting the excretion of anionic and cationic drugs.
Protocol
Title: Metabolic DDI study
Research Topic
A single oral dose study to determine pharmacokinetic interactions between drug A, a potent inhibitor of CYP3A4, and midazolam, a known prototype substrate of CYP3A4, in healthy volunteers.
Objectives
The inhibitory effect of drug A on midazolam, the substrate for CYP3A4, is evaluated by studying the PKs of both drugs.
Hypothesis
In vitro studies have demonstrated drug A to be a potent inhibitor of CYP3A4 at clinically relevant concentrations. A potential drug interaction exists when drug A is given with midazolam, a substrate for CYP3A4. Drug A increases the plasma concentrations of the substrates of CYP3A4.
Research Questions
Should drug A be contraindicated in the presence of substrates or inhibitors of CYP3A4? Are any dosing adjustments warranted when drug A is coadministered with substrates or inhibitors of CYP3A4?
Study Design
Study population: This section specifies the following:
Study Procedure
This section should specify in detail all study-related procedures including drug administration, PK sample draws, sample handling and storage, bio-analytical method and planned laboratory tests.
Data Analysis
PK parameters of interest should be estimated using a non-compartmental approach. The estimated parameters can then be compared to determine if dosing adjustments are required in the presence of the two drugs as compared when they are administered alone. A BE approach could be used to test whether an interaction exists or not. The 90% confidence interval for the log transformed ratio of Cmax and AUC for the two treatments (both drugs coadministered together compared to each drug administered alone) is within prespecified criteria.
Pharmacokinetic/Pharmacodynamic Relationship Studies
In order to understand the safety and efficacy of a new molecular entity, it is essential to establish its PK/PD or exposure–response relationship. It also serves as a useful tool that can help optimise the dose and dose rate to the individual patient. Historically, because the systemic concentration–response relationships were assumed to be unaltered in various populations, dosing adjustments in the various populations with different disposition characteristics were based on exposure or plasma levels alone. However, in recent years it has been recognised that the exposure–response relationship can be different from one population to the other. Therefore, the ability to determine the exposure–response relationships in the different demographic groups and subgroups will enhance the decision-making ability on dosing adjustments and optimise the therapeutic benefit to patients.
General Categories of Pharmacological Responses
Survival Analysis
Survival analysis is one type of failure-time analysis or a subset of time-to-event analysis. PK/PD modelling has little to no value in relating temporal drug concentration profiles with survival or time-to-event analyses.
Categorical Variables
Categorical variables are discrete. In its simplest case, they can be termed binary 0 or 1 response (yes or no). Nominal variables also qualify as categorical responses that can be classified as whole numbers between 0 and 5.
Frequency Distributions
Frequency distributions are also discrete rather than continuous variables; they are also known as counts during predefined interval.
Graded Responses
Graded responses are the simplest and most convenient in the context of biomarkers. Both drug concentrations and biochemical biomarkers behave as graded, continuous responses. Biomarkers which are measured on a continuous scale (e.g. heart rate, blood pressure) have widespread acceptance and general application.
Scope of PK/PD Study
In general, PK/PD studies should have the following criteria:
Designing/Planning PK/PD Studies
When designing PK/PD studies both PK as well as PD considerations have to be taken into account to optimise the outcome and success of the study.
Pharmacokinetic Considerations
PK variables that can affect the design and outcome are as follows:
Generally one is interested not only in the change in plasma drug concentrations but also in the temporal relationship between drug concentration and biomarker or clinical endpoint response. Biomarker responses do not parallel drug concentrations and that is why models are used to better understand the relationship and how it might change as a function of drug input and other variables.5,6 Therefore, one might want to create an optimum sampling strategy to compare drug concentrations and biomarker responses across the entire population over the entire course of therapy. The optimally designed composite PK/PD profile resulting from all sampling times should provide this insight.7 Alternatively, extensive sampling during a dosing interval after the first dose, after the first month of drug administration and after the sixth month of administration during a 6-month study should also provide tremendous insight into the concentration–response relationship.
Pharmacodynamic Considerations
PD considerations primarily relate to the endpoint that is under study. However, the following points should be considered when designing and conducting the study.
PK/PD Studies in the Different Phases of Drug Development
PK/PD studies can be conducted during any phase of the clinical drug development process.
Phase I
Integration of PK/PD in early development helps with compound selection and guides creation of an efficient clinical development programme.8–11 In addition to providing valuable information on the tolerability and PK of a drug in humans, Phase I studies can explore the relationship between exposure (whether dose or concentration) and response (e.g. nonclinical biomarkers, potentially valid surrogate endpoints, or short-term clinical effects). The purpose of these studies is to provide evidence that the hypothesised mechanism of action is affected by the drug and that the effect on the mechanism leads to a desired short-term clinical outcome.12 Also, they may provide guidance for designing initial clinical endpoint trials that use a plausibly useful dose range. Both the magnitude of an effect and the time course of effect are important in choosing the dose, the dosing interval, and monitoring procedures, and in some cases in the selection of the type of dosage form (e.g. controlled-release dosage form) to be developed. Exposure–response and PK data can also define the changes in dose and dosing regimens that account for intrinsic and extrinsic patient factors.13,14
Phase II
At this stage it is important to characterise the relationship between drug exposure and response. The information that is gathered during this phase provides the basis to decide whether the proper balance between the safety and efficacy of the drug exists to continue to the much more expensive Phase III programme.5 A key feature of this approach is to use previous clinical trial information in the same disease with prior PK/PD information on the new compound to better predict the most probable trial outcome.
Phase III and Beyond
At this stage, the exposure–response data can support whether a drug is safe and effective and also provide information on how to best optimise the benefit to the patient by determining the optimal dose and the optimal dosing interval.
If the mechanism of action is well understood, PK/PD studies may add to the weight of evidence supporting efficacy. When the effectiveness is already established in one setting and the study demonstrates a PK/PD relationship that is similar, or different, in an interpretable way from the established setting, the PK/PD information may provide primary evidence for safety and efficacy for different doses, dosing regimens, or dosage forms or use of the drug in different populations.
Strategic PK/PD Study Designs
Cascade Design
There is a ramp-up and a ramp-down function. This approach can be used to evaluate carryover effects, reversibility and reproducibility of placebo responses in a single small study. The cascade design usually starts with a placebo phase followed by a dose escalation and de-escalation phase followed by another placebo phase.
Sequential Design
Sequential dose–response designs are common in first-in-human safety, tolerability and PK/PD studies as well as in first-in-patient safety and proof-of-principle studies. In most cases, the dose is escalated in independent cohorts. Once a dose level is adequately tolerated, the next cohort is randomised and treated. Patients in each cohort are randomly assigned to receive active or placebo treatment.
Variations on sequential designs can be used to a final dose period to evaluate a safe intravenous dose level based on oral administration and PK/PD experience. Intra-subject/inter-occasion variability can be evaluated by bringing one cohort back to give the same dose under the same conditions on a second occasion. Potential food effects can be evaluated by bringing one cohort back to give the same dose with food that had been given in the fasting state. The most critical variables for drug success can be evaluated earlier in using this type of approach.
Crossover Design
Crossover designs can be used to obtain PK/PD data. Crossover designs are usually not implemented until safety and tolerability testing has been completed on each dose level that is to be included in the study.15 The crossover design can be replicated within a study to evaluate more than one dose level in each cohort. Therefore, PK/PD comparisons can be made while knowing the amount of drug being delivered to the systemic circulation according to a predetermined input function. For example this design can be useful in determining whether protracted absorption from a subcutaneous injection site will alter the PK/PD relationship of a drug. Crossover designs can be used for PK/PD studies by combining placebo and active treatments in a variety of ways to accomplish the desired objectives. Each design provides some information that an alternative design does not, but generally at the expense of some other information.
Replicate Design
Replicate study designs can be used to evaluate reproducibility of PK profiles, PD profiles and/or concentration–response relationships on two or more occasions under similar conditions.15
Protocol
Title: PK/PD relationship study
Research Topic
To determine the PK/PD of a single oral dose of MR formulation of an antihypertensive drug.
Objectives
To characterise the plasma concentration-effect relationship and to determine whether it is affected by the rate of drug delivery.
Hypothesis
A relationship exists between plasma concentrations and blood pressure-lowering effect of an antihypertensive agent. In addition, the reflex tachycardia correlates with the rate of drug delivery.
Research Questions
What is the optimal plasma concentration that needs to be achieved to maintain the blood pressure-lowering effect and what is the best input rate to minimise the incidence of side effects?
Study Design
This section specifies the following:
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