Anyone who has ever taken a medicine is aware of the balance between efficacy and adverse effects. Efficacy cannot be obtained unless the dose is high enough, but if the dose is too high, adverse effects will kick in and may outweigh the positive impact of the drug. To assure that the patient’s dose is within this therapeutic window, a prescriber must rely on information provided by the manufacturer in the form of the package insert.

While pharmacology and toxicology address the impact of a drug at the site of action or site of adverse effect, how the drug gets to and leaves the site of efficacy or toxicity is the realm of pharmacokinetics and its related disciplines. DMPK (drug metabolism and pharmacokinetics) and ADME (adsorption, disposition, metabolism, and excretion) are two other terms that are commonly used to describe the study of how drugs get to their targets and are cleared from the body. Scientist in this field utilize a variety of in vitro and in vivo data and rely heavily on statistics and computer modeling with the overall goal of being able to predict as accurately as possible what dose and dosing regimen will provide the optimal balance of efficacy and side effects for a given patient.

Various factors determine the pharmacokinetics of a given drug in a given body, and all of these are studied in detail by pharmacokineticists to understand not only how the drug will act in an average body but also what factors will influence the amount of drug that reaches the active site and how long it stays there. Before drug taken in a pill can reach its target tissue in the body, the pill must first fall apart and the drug dissolve in the gastrointestinal tract. Some of the drug may be metabolized at the intestinal membrane and some of it may simply not be absorbed and will pass out of the body into the stool. Drug that is absorbed can be pushed back out into the intestine by efflux pumps in the intestinal cells, and lipophilic drugs may enter the lymphatic system rather than the bloodstream. Drug that does enter the bloodstream will go directly to the liver, where it can be metabolized or excreted into the bile. Once in the bloodstream, the drug can bind to proteins such as albumin, which protect it from excretion and metabolism but also make it less available to its target receptors. It can also be cleared by the kidneys, either by passive filtration (glomerular filtration) or by active transport and can distribute into tissue or into the central nervous system across the blood-brain barrier. All of this and more is under the purview of pharmacokinetics.

With all the different variables involved, the complexity of pharmacokinetics becomes quite clear. Yet this science is critical to establishing the working parameters of all medicines and determining what subclasses of patients should take higher or lower doses or avoid the medicine altogether. For example, if a drug is metabolized by a particular enzyme and a patient has abnormally low levels of that enzyme, less of the drug will be metabolized, meaning that more of the drug will accumulate in the bloodstream, quite possibly to toxic levels. The same applies if a drug is primarily cleared by the kidneys and a patient has impaired renal function. Pharmacokinetics must address all of these aberrations as well as the norm.

A central pharmacokinetic concept that applies to all routes of administration other than intravenous is bioavailability. This is an expression of the percentage of the total dose that reaches the bloodstream. Since an intravenous drug is injected directly into the bloodstream, its bioavailability by definition is 100%. The bioavailability of other dosage forms, such as oral tablets and capsules, topically administered drugs, and even intramuscular and subcutaneous injections, is calculated as the total amount of drug that reaches the bloodstream divided by the total amount of drug that would reach the bloodstream if the drug was injected directly into it. Pharmacokineticists calculate this number by determining the total “exposure” or “area under the curve” (AUC) following intravenous and oral (or other route of administration) dosing. AUC is essentially the concentration of the drug in the blood multiplied by time, but since the concentration of the drug is constantly changing, it is the sum of many small increments of time multiplied by the drug concentration at each time increment.

In addition to bioavailability and AUC, key pharmacokinetic parameters include clearance, half-life, percent of drug that is bound to protein, and various kinetic constants that describe the rates of absorption, metabolism, renal clearance, and redistribution. One approach to obtaining some of these constants is what is called “non-compartmental analysis,” wherein no assumptions are made about the mechanisms of delivery and disposition and key pharmacokinetic parameters are determined directly from the data. A more sophisticated means of modeling is called “compartmental analysis” in which drug is assumed to move from one box to another and this movement is described by a series of kinetic constants and differential equations. Using a reiterative process the kinetic constants are solved for to give the best fit to available data.

Ideally, one would like to have very large sets of data for every subset of patients under every condition, but such extensive data is seldom available, at least until the conclusion of Phase 3 clinical studies. At early stages of development, pharmacokineticists may need to rely on very small sets of human data or perhaps animal data alone. Even after thousands of patients have been dosed, not every possible combination of variables can be covered in a large enough group to be statistically significant. This is where mechanistic pharmacokinetics becomes especially important. Using very sophisticated computer models that contain multiple compartments and multiple functionalities, pharmacokineticists can gradually elucidate not only the rates of different processes but the mechanisms behind them. This allows them to make predictions that can extend beyond the species or patient groups for which data is available, and this is where the role of the pharmacokineticist becomes especially crucial.

Developing mechanistic pharmacokinetic models requires mastery of not only mathematics and statistics but also biochemistry, physiology, and cell biology, among other disciplines. Given this broad range of required knowledge, the work is typically done best by a multidisciplinary team rather than a by a single expert. Smaller companies can gain access to such expert teams by working with an organization specializing in collaborative pharmaceutical consulting. Such organizations may also be able to provide the project management resources to organize all these activities and keep them on track.

For all its complexity, pharmacokinetics is an extremely crucial science which allows drugs to be used in accordance with the central tenet of medical practice, to cure and to do no harm. Every time a parent measures out an antibiotic for a sick child or a cancer patient is administered chemotherapy, someone somewhere has labored to understand the pharmacokinetics of that drug so that the optimal balance of benefit against adverse effects is most likely to be achieved.

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Bruce Rehlaender, Ph.D., Principal, Formulation Development, PharmaDirections, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We direct development for virtual biotechs.

Bruce Rehlaender, Ph.D., Principal, Formulation Development at http://www.PharmaDirections.com, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We design and direct preclinical programs for biotech.

Author Bio: Bruce Rehlaender, Ph.D., Principal, Formulation Development, PharmaDirections, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We direct development for virtual biotechs.

Category: Medical Business
Keywords: Pharmaceutical Consulting, Project Management, Formulation Development, Preclinical, CMC