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Pharmacokinetics

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Pharmacokinetics is the study of the absorption, distribution, metabolism, and excretion of drugs. Simply put, pharmacokinetics is what the body does to the drug, which is opposed to pharmacodynamics, which is what the drug does to the body. This review will introduce pharmacokinetics as a science showing how biochemistry, biology, pharmacology, and physiology interact to explain how a drug ‘works’. Pharmacokinetics is becoming increasingly quantitative with population pharmacokinetics–pharmacodynamics, which uses nonlinear mixed effects model methodology, becoming more and more commonplace and acting as the core to model‐based drug development. This review will show how statistics is becoming increasingly more important in pharmacokinetic analysis and provide an introduction to statistical analysis of pharmacokinetic data. WIREs Comp Stat 2011 3 332–342 DOI: 10.1002/wics.153

Figure 1.

Drug absorption after oral administration. Drugs are absorbed in the gastrointestinal tract after first disintegrating and then dissolving into the gastrointestinal (GI) fluid. Drugs that do not dissolve in the GI fluids are not absorbed and a primary chemical property affecting dissolution is a drug's solubility. Once dissolved in GI fluids, drug can be decomposed, excreted into the feces, or be available for absorption. Absorption across the membranes of the GI tract is influenced by the permeability of the drug and the presence of transporters that absorb the drug into cells or excrete the drug from cells. Once a drug is absorbed into the blood of the GI tract it must first pass through the liver where it could be metabolized or excreted back into the GI tract via biliary excretion. This process is generally referred to as the first‐pass effect. The influence of solubility and permeability form the basis of the Biopharmaceutics Classification System,6 which is used by the FDA to issue waivers clinical bioequivalence studies for high permeability, high solubility drugs.

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Figure 2.

Schematic of the blood flow and distribution of drugs in the body. Once a drug is absorbed from the GI tract and passes through the liver it travels to the heart by the venous circulation, goes to the lungs (where it could possibly be further metabolized), travels back to the heart, and then is distributed to the organs via the arterial circulation.

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Figure 3.

An example metabolic scheme. Clofarabine is a purine nucleoside used for the treatment of acute lymphocytic leukemia. Shown is the metabolic scheme in rats.18 Clofarabine is metabolized to variety of different metabolites, the most abundant being 6‐ketoclofarabine. In human plasma samples, 6‐ketoclofarabine, which is inactive pharmacologically, accounts for <10% of circulating moieties in plasma.19

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Figure 4.

Scatter plot illustrating the pharmacokinetic parameters calculation using noncompartmental analysis. Top: Cmax, Tmax, and AUC(0 − ∞); bottom: half‐life.

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Figure 5.

Scatter plot of effect as a function of drug concentration. An Emax model (Eq. (3)) without baseline was fit to the data and shown as the solid blue line.

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