In the drug development process, especially the early non-clinical or clinical studies, it is critical to understand the DMPK. DMPK, or Drug Metabolism and Pharmacokinetics, is an important part of studies often referred to as ADME (Absorption, Distribution, Metabolism, and Elimination).
- Absorption (how much and how fast, often referred to as the absorbed fraction or bioavailability)
- Distribution (where the drug is distributed, how fast and how extensive)
- Metabolism (how fast, what mechanism/route, what metabolite is formed, and whether they are active or toxic)
- Elimination (how fast, which route)
In clinical pharmacology studies, the purpose of the study is to characterize the pharmacokinetics profile to assess the bioavailability and bioequivalence. In clinical pharmacology studies, usually, the series of blood samples will be collected for measuring the concentration of the study drug and its metabolites. Based on the measured concentrations from the series blood samples, pharmacokinetics parameters can be calculated. The common pharmacokinetics parameters are AUC (area under the time-concentration curve), Cmax (maximum concentration), Tmax (time to maximum concentration), T1/2 (half life),…
When designing a clinical pharmacology study, it is critical to decide and select adequate time points for blood sampling. The ideal blood sampling scheme will include the time points close to the Tmax (so that we can get a good estimate for Cmax and Tmax) and have good spaced time points to characterize the elimination phase (so that we can get a good estimate for T1/2).
From the practicality standpoint, it is not easy to draw the blood samples at the exact time according to the sampling scheme specified in the study protocol. For the phase I study using healthy volunteers at confined clinical research unit, the time windows can be easily controlled. However, for PK studies in patients across many investigational sites, it was very difficult to keep all blood draws within the narrow windows.
It is very common that time windows are allowed for these blood sampling time points. For example, for sampling time at 1 hour (60 minutes) after the study drug administration, we may add a time window to allow the 1-hour sample to be drawn any time between 55 – 65 minutes after the study drug administration, denotes as 60 +/- 5 minutes. A time window of 5 minutes is allowed for this time point. If the blood drawn is outside the time window (for example outside 55 - 65 minutes), a protocol deviation will be recorded. If the data entry is through an EDC (electronic data capture) system, the edit checks are usually built in to track the deviations for sampling time outside windows.
There are some articles arguing the necessity of the time windows.
- Using Sampling “Windows” for PK Blood Samples
- Should you Include a +/- Time Window Around Collection of PK/PD Samples in a Clinical Trial?
The arguments are 1) when we calculate the pharmacokinetic parameters, the actual sampling times are used. The deviations from the nominal time or pre-specified time point have little impact on the calculation of the PK parameters. 2) if the time windows are set too tight and any outside time windows are recorded as protocol deviation, there will be a lot of unnecessary protocol deviations being recorded. If any outside time window is flagged/alerted during the data entry in EDC, it can be very annoying to the data entry person.
My experience is that we can keep the time windows in the study protocol, but not set the time windows too tight. The sites usually need to have some instructions about the time windows, not purely for the PK parameter calculations, but more for operations. The time windows can be set up as a suggestion and we can use the word ‘should’, not ‘must’ for following the time windows. In this way, not any out of window blood drawn will be automatically recorded as a protocol deviation.
5 comments:
Agree with you that a PK time window is still necessary in study protocol. Even for a small study with a single arm of, let's say 12 subjects, in a well-established CRU, it won't be feasible and practical there to have 12 study nurses who will start to perform the 1:1 blood draws at a calibrated same time. Not to mention usually there will be other tests around those nominal PK time points to perform, e.g. ECG. On the other hand, no matter what mitigation approaches will be implemented, people still could make mistakes. In that case, it's better to have a pre-defined PD criterion in protocol than nothing to follow from regulation perspective.
Very well-written. Thanks for the post.
Very well-written piece. In the early stages of drug development, especially non-clinical or clinical trial studies, it is critical to understand the DMPK. In studies often referred to as ADME (Absorption, Distribution, Metabolism, and Elimination), Drug Metabolism and Pharmacokinetics are integral.
I'm working on my master degree my study point is measuring drug peak concentration (cmax) from plasma samples and correlating it with another genetic marker
I made a mistake that i could't draw all blood samples for patients at the same time interval as i'm working on a large number of patients but i recorded each patient real sampling time is there any way that i can correct my readings and still use them in my analysis
Thanks in advance for your help
it is ok not to have all blood samples drawn at the same time intervals. You can still obtain the Cmax and Tmax based on the actual time the blood samples are drawn.
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