drug discovery & Cp-time curves

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Drug concentration graphs display Cp (plasma concentration) versus time. One type of curve corresponds to an intravenous (IV) bolus - injection directly into the circulatory system. The concentration of the drug is immediately high at the time of injection and then the concentration decreases as the drug is broken down or removed by different processes in the body. Another type of Cp-time curve is for an oral drug. The curve shows the Cp of a drug that has been dosed so that Cp at time 0 rises rapidly before the curve peaks and then falls. The drug enters a patient’s mouth. Cp rises quickly (but not immediately) as the drug is absorbed along the gastrointestinal tract and then Cp falls. The study of how a drug or other molecule behaves within a living organism is called pharmacokinetics, or simply PK. Pharmacokinetics has many aspects but includes the mathematical modeling of these curves. One of the terms commonly associated with PK is half-life, which provides a general sense of how long a drug will persist in the body. Since this course emphasizes oral drugs, let’s look at a Cp-time curves for a multidose oral drug.
Curves for multiple oral doses shows a rise and fall for each dose. The number of peaks is the number of doses. Part of being safe and effective requires the drug to be dosed in a manner that allows the drug to achieve “efficacious exposure” in a patient. Drug exposure is another aspect of pharmacokinetics. The patient needs enough drug to realize the therapeutic benefit of the drug, but not too much drug which may cause safety risks that outweigh any benefit. How does one gather evidence that a molecule will have a favorable pharmacokinetic profile during the discovery process? We use a combination of in vitro assays and in vivo studies.
In vitro assays are used to understand a molecule’s ADME properties. ADME stands for absorption, distribution, metabolism, and excretion. These are properties that affect the PK of a molecule. While understanding ADME properties is helpful, promising compounds will be subsequently studied in animals for their PK properties. These are in vivo studies and provide more data for predicting human PK. If the molecule is advanced into the clinic, the human PK properties will be confirmed. Understanding human PK begins with the very first phase I trials.