Clinical Pharmacokinetics Related terms: Clinical pharmacokinetics is the discipline that applies pharmacokinetic Pharmacokinetics, principles to individualize dosage regimens, optimize the therapeutic effects of Pharmacodynamics, Bioavailability, Volume of Distribution, Drug Concentration, Elimination Drug, Animal, Toxicity, Human ‘a medication, and minimize the chances of an adverse drug reaction. From: Fetal and Neonatal Physiology (Fifth Edition), 2017 View full index > Clinical Pharmacokinetics Edward Flynn, in xPharm: The Comprehensive Pharmacology Reference, 2007 Clinical pharmacokinetics provides the rational basis for administering the appropriate amount of drug for a reasonable length of time to achieve the desired beneficial effects while minimizing adverse events. In obtaining this therapeutic goal, it is assumed that there is an appropriate target concentration that will produce the desired pharmacodynamic response. Furthermore, this target concentration is controlled by the concentration of drug in the bloodstream, which is, in turn, determined by its pharmacokinetic parameters (half-life, apparent volume of distribution, clearance, and bioavailability). Clearance is often the pharmacokinetic parameter affected by changes caused by disease states, enzyme induction, altered glomerular filtration, or aging. Each of these processes can contribute to an altered response in individual patients. In addition, as dearance is the volume of plasma per time interval that is cleared of drug by all routes of administration, the drug must be administered at a dose and time calculated to replace the amount of drug that has, been cleared. The aim is to maintain a steady-state concentration of drug in plasma within the therapeutic window. Clinical Pharmacokinetics ARTHUR J. ATKINSONJr., in Principles of Clinical Pharmacology (Second Edition), 2007 Publisher Summary This chapter discusses various aspects of clinical pharmacokinetics (PK). PK is an important tool when conducting both basic and applied research and is an essential component of the drug development process. PK is a valuable adjunct for prescribing and evaluating drug therapy. The rationale for measuring concentrations of drugs in plasma, serum, or blood is that concentration=response relationships are often less variable than dose-response relationships. Additional dinical information is often necessary to interpret drug-concentration measurements that are otherwise equivocal. Drug- concentration monitoring is most helpful for the drugs that have a low therapeutic index and that have no clinically observable effects that can be easily monitored to guide dose adjustment. PK provides the scientific basis of dose selection, and the process of dose regimen design can be used to illustrate with a single-compartment model the basic concepts of apparent distribution volume, elimination half-life, and elimination clearance. Laplace transform methods are also helpful in PK when convolution/deconvolution methods are used to characterize drug absorption processes. Clinical PharmacokineticsArthur J. Atkinsonjr., in Principles of Clinical Pharmacology (Third Edition), 2012 Elimination Clearance Just as creatinine dearance is used to quantitate the renal excretion of creatinine, the removal of drugs eliminated by first-order kinetics can be defined by an elimination clearance (Cl,). In fact, elimination clearance is the primary pharmacokinetic parameter that characterizes the removal of drugs that are eliminated by first-order kinetics. When drug administration is by intravenous infusion, the eventual steady-state concentration of drug in the body (C,,) can be calculated from the following equation, where the drug infusion rate is given by : 22) When intermittent oral or parenteral doses are administered at a dosing interval, r, the corresponding equation is: 23) where is the mean concentration during the dosing interval. Under conditions of intermittent administration, there is a continuing periodicity in maximum ("peak") and minimum ("trough") drug levels so that only a quasi-steady state is reached. However, unless particular attention is directed to these peak and trough levels, no distinction generally is made in clinical pharmacokinetics between the true steady state that is reached when an intravenous infusion is administered continuously and the quasi-steady state that results from intermittent administration. Because there is a directly proportionate relationship between administered drug dose and steady-state plasma level, Equations 2.2 and 2.3 provide a straightforward guide to dose adjustment for drugs that are eliminated by first-order kinetics. Thus, to double the plasma level, the dose simply should be doubled. Conversely, to halve the plasma level, the dose should be halved. It is for this reason that Equations 2.2 and 2.3 are the most clinically important pharmacokinetic equations. Note that, as is apparent from Figure 2.6, these equations also stipulate that the steady-state level is determined only by the maintenance dose and elimination clearance. The loading dose does not appear in the equations and does not influence the eventual steady-state level. In contrast to elimination clearance, elimination half-life (ty2) is not a primary pharmacokinetic parameter because itis determined by distribution volume as well as by elimination clearance: (24) The value of Vsin this equation is not Vainirapy ut represents a second estimate of distribution volume, referred to as Vigor) Of Vay that generally is estimated from measured elimination half-life and clearance. The similarity of these two estimates of distribution volume reflects the extent to which drug distribution is accurately described by a single compartment model, and obviously varies from drug to drug [16] Figure 2.7 illustrates how differences in distribution volume affect elimination half-life and peak and trough plasma concentrations when the same drug dose is given to two patients with the same elimination clearance. If these two hypothetical patients were given the same nightly dose of a sedative-hypnotic drug for insomnia, would be the same for both. However, the patient with the larger distribution volume might not obtain sufficiently high plasma levels, to fall asleep in the evening, and might have a plasma level that was high enough to cause drowsiness in the morning. Pharmacokinetics Terry P. Kenakin PhD, in A Pharmacology Primer (Fourth Edition), 2014 9.4.8 Bioavailability ‘An important concept in clinical pharmacokinetics is the bioavailability of a drug. This is the actual fraction of drug that enters the central systemic circulation upon administration via the chosen therapeutic route. For example, drugs taken by the oral route must be absorbed either through the stomach or, most likely, the small intestine, into the bloodstream. The blood preferentially flows through the liver from the Gl tract; thus, the drug is subjected to metabolism before itenters the general circulation. This first barrier of metabolism is reterred to as the first pass effect. Bioavailability is calculated as the ratio of area under the curves when the drug is given intravenously (assume 100% bioavailability) versus the chosen route of administration; see Figure 9:30 Drugs given by the oral route must pass through the liver before they emerge in the circulation. This “first pass effect” can be devastating for highly metabolized drugs, such as for organic nitrates (i-e., glycerol trinitrate F=196); for this reason these are given sublingually, because they can be so completely cleared by first pass metabolism that they are ineffective by the oral route. Drugs subject to high first pass extraction are more dependent on liver function, causing drug levels to be much more variable (ie., verapamil). High first pass drugs are more subjectto enzyme induction and/or inhibition and liver disease. Intravenous and oral doses of drugs with high bioavailability are comparable. In contrast, a drug with 10% bioavailability will require 10 times more drug orally than when given iv. The maximal total bioavailability (Fofa drug can be predicted from the expression: (9.25) where fis the fraction of drug absorbed by the gut, and fy isthe fraction escaping the liver (f,=1~ Eu, where Eyis the hepatic extraction ratio). If it is assumed that the drug is completely absorbed from the gut (fg=1), then the maximal bioavailability Fry) is given by: (9.26) where CL is the intrinsic hepatic clearance and Qu liver blood flow. In general, a value of F>0.2 is preferred, but there are exceptions to this rule. For example, the bisphosphonate used for stabilizing bone matrix in osteoporosis is given by the oral route, yet for this drug F=0.08. Low metabolic clearance is a good predictor of good oral bioavailability and long halflife, while high clearance leads to high rate of elimination and lack of oral bioavailability. There are many other factors involved in oral bioavailability. These involve drug dissolution (chemical properties of drug, crystal form{s], dosage form [sustained release, coated tablets], pH of stomach and intestine), the gastric emptying rate (stability of drug at stomach pH, solution-solid form [liquids empty more quickly}, effects of food, antacids, drugs [opiates], disease), intestinal motility (mainly affects slowly soluble drugs [i-e., sustained release], degradation andjor metabolism in gut microflora), drug interactions in gut lumen (complexation [i-e.,tetragyclines+divalent metal ions), adsorption [ie., anion exchange resins), food interactions [ie., antibiotics)) and passage through the gut wall (chemical properties [.e., quarternary ammonium compounds}, and metabolism by ‘enzymes in intestinal epithelium [ie., CYP3A4 in the Gl tract leading to poor oral bioavailability)). Some other factors which affect oral bioavailability are given in Table 9.12. Table 9.12, some Factors afeaing On Blcaalabilty Increased Decreased Stomach i.e, hunger, exercise, metoclopramide Increased hot meals, pain, narcotics, antidepressants Decreased Emptying absorption absorption Intestinal gastroenteritis / decreased transit time Decreased narcotics, anticholinergics, tricyclics Increased Motility absorption absorption Chemical chelation of tetracyclines with metal ions Decreased Interaction absorption Finally, some drug absorption is affected by the enterohepatic cycle, specifically the secretion of some drugs into the bile for subsequent reabsorption in the Gl tract. Many drugs (i. high molecular weight drugs (approx. 500], large polar molecules, glucuronide conjugates, ie., chloramphenicol) are secreted into the bile unchanged, and these are available for reabsorption via the Gl tract. Some other drugs that are reabsorbed via the enterohepatic cyde are reabsorbed as