Clinical Pharmacokinetics PDF

VM508 Lauver, Puschner, Hegg CLINICAL PHARMACOKINETICS OVERVIEW Pharmacokinetics describes the absorption, distribution, metabolism and excretion of drugs. When new drugs are developed, principles of pharmacokinetics are used to develop appropriate dosing regimens -- the d...

VM508 Lauver, Puschner, Hegg CLINICAL PHARMACOKINETICS OVERVIEW Pharmacokinetics describes the absorption, distribution, metabolism and excretion of drugs. When new drugs are developed, principles of pharmacokinetics are used to develop appropriate dosing regimens -- the dose and formulation of the drug, route of administration, and dosing interval. In clinical practice, principles of pharmacokinetics are used to make adjustments in the dosing regimen of patients who have altered elimination mechanisms due to disease, genetic, or environmental factors. THE CONCEPT OF COMPARTMENTS A pharmacokinetic compartment is a collection of organs, tissues, and body fluids that have the same pharmacokinetic properties; that is, they all appear the same to the drug. In the simplest case, the entire body functions as “one compartment.” The drug distributes freely throughout the body and all tissues and organs reach equilibrium at the same time. A compartment is not an actual anatomical site, however. For example, a highly polar drug bound to plasma proteins might distribute within one compartment (blood). On the other hand, a small, water-soluble drug could distribute within one compartment, but this compartment would be total body water. The number of compartments can often be estimated from the shape of a drug’s plasma concentration time curve. One-Compartment Model When a drug’s kinetics are said to follow a one-compartment model, the drug is confined to plasma and to a few highly perfused and rapidly equilibrating organs like the liver, kidneys, lungs and heart (together called the central compartment). In this case the plasma concentration time curve has a single slope. For extravascular administration, the number of slopes should be assessed after Cmax. Two-Compartment Model When a drug’s kinetics are said to follow a two-compartment model, the drug distributes from plasma (central compartment) to a second compartment (peripheral compartment, tissue compartment), which is made up of more slowly equilibrating tissues like muscle. 1 VM508 Lauver, Puschner, Hegg In this case the plasma concentration time curve is biphasic, meaning it has 2 slopes. For extravascular administration, the number of slopes should be assessed after C max. Three-Compartment Model When a drug’s kinetics are said to follow a three-compartment model, the drug distributes from plasma (central compartment) to a second compartment (peripheral compartment, tissue compartment) and also to a third “deep compartment.” Deep compartments are generally poorly perfused tissues such as bone and adipose tissue and therefore accumulate drug slowly. The levels of drug released back into the central compartment from deep compartments are often below the threshold level for pharmacological activity. Deep compartments generally are not clinically significant and may not even be detectable when single doses of a drug are given. However, when deep compartments become saturated following chronic administration, they act like large reservoirs for the drug and may release drugs from their stores for a long, long time. In this case the plasma concentration time curve has 3 slopes. For extravascular administration, the number of slopes should be assessed after Cmax. Absorbed Drug Instantaneous Distribution Central Peripheral Deep Compartment Compartment Compartment nt slow slower distribution distribution Elimination 2 VM508 Lauver, Puschner, Hegg Ln Cp Time THE THERAPEUTIC WINDOW The aim in drug therapy is to produce drug concentrations within a therapeutic window -- a range of drug concentrations above the threshold concentration (the minimum effective drug concentration) and below the toxic threshold (the concentration at which serious side-effects begin to occur). Fortunately, the dosing regimen for most drugs consists of administering a pill or tablet orally once or twice a day. Some drugs, however, must be specially formulated or given by parenteral routes. Finally, there are a few drugs for which an individualized dosing regimen must be calculated for each patient and the concentrations of drug in the plasma measured periodically, called therapeutic drug monitoring. The Plateau Principle When a drug is administered chronically (by either constant rate infusion (CRI) or consecutive oral dosing) at a rate faster than it can be eliminated from the body, the plasma drug concentration will rise steadily, but eventually will reach a “plateau” or 3 VM508 Lauver, Puschner, Hegg “steady-state” concentration. This occurs when the rate of drug entering the body equals its rate of elimination from the body. The graph above shows what happens when a drug is administered intravenously by constant infusion. The plasma drug concentration increases continuously until the steady state is reached which is 4-5 elimination half-lives. Time to steady state is 4-5 half-lives When a drug is administered orally, the plasma drug levels fluctuate between peak and trough levels, but steadily increase until they reach an equilibrium state where the amount of drug entering the body equals the amount leaving the body. This is at 4-5 elimination half-lives. At steady state, the drug concentrations fluctuate about a mean = steady state drug level (Css). The following principles apply to drugs at equilibrium or at steady-state: 1. The concentration of the drug at steady-state (mean concentration if the drug is given orally) is determined by: Dose (corrected for fraction absorbed F) 4 VM508 Lauver, Puschner, Hegg Dose interval (DI) Distribution of the drug in the body (VD) Drug elimination rate (kel) 2. Time to reach steady state depends only upon the rate of elimination. After 1 half-life, 50% of the steady-state concentration is reached. After 2 half-lives, 75% of the steady- state concentration is reached. Although it takes an infinite time to reach equilibrium, by convention steady-state is said to be reached within 4 to 5 half-lives (93.75% - 96.88% of the final equilibrium concentration). 3. Fluctuations in drug concentrations about the steady-state mean are dependent upon: dose interval The shorter the dose interval, the smaller the fluctuations in drug concentrations. The smallest fluctuation occurs with an IV infusion (no dose interval = no fluctuations). Slow drug absorption minimizes fluctuations. Timed-release medications may release drugs so slowly that they act like a sustained infusion and produce minimal fluctuations in drug concentrations. BASIC CLINICAL PHARMACOKINETIC CALCULATIONS Calculating Time to Reach Steady State Calculate time to steady state by using the rule-of-thumb that equilibrium is achieved after 4 -5 half-lives. For a drug with an elimination half-life of 24 hours, time to steady state is: Time to steady state = 4 − 5 × t1/2 = 4− 5 × 24 hr = 96− 120 hr This drug will take 96-120 hours to reach a steady-state plateau. Since the steady state concentration is the targeted therapeutic concentration, this may be too long and a loading dose (LD) might be warranted. Calculating a Loading Dose A loading dose is a large dose given initially to achieve a therapeutic drug concentration quickly. It is important to note that a loading dose does NOT mean steady state is achieved. Steady state is a time and only occurs after 4-5 elimination half-lives. Without a loading dose, it may take an unacceptably long time to reach the therapeutic drug concentration. A loading dose may be given by any route of administration. This depends on the particular drug being administered. In some cases (especially with drugs with a narrow therapeutic window) in order to prevent an overshoot in plasma drug concentrations that may lead to toxicity, it may be prudent to divide the loading dose into multiple smaller doses separated by a short interval. For example, a potassium bromide loading dose is often split into 4 doses and administered at 6 hour intervals over 24 hours. 5 VM508 Lauver, Puschner, Hegg The animal is monitored during administration of the loading dose for any adverse or undesirable effects. To calculate a loading dose, use the formula: LD = (TDC×VD)/F If the TDC is 10 mg/L, the VD = 0.5 L/Kg and F=1 (100%) LD = 10 mg/L×0.5 L/kg = 5 mg/kg *Remember F=bioavailability A loading dose of 5 mg/kg of this drug should result in a plasma concentration of 10 mg/L. Calculating a Maintenance Dose The loading dose must be followed by a maintenance dose to maintain what the loading dose has achieved. Before calculating an oral maintenance dose, the dosing interval must first be specified. Remember, the dose interval determines the magnitude of the fluctuations about the mean steady-state concentration. Calculating a Dosing Interval (DI) For a drug with a narrow therapeutic window it is desirable to minimize fluctuations in the plasma drug concentrations. A dosing interval that will keep the fluctuations in plasma drug concentrations within a desired range can be calculated from the general formula: Tmax = ln (Cmax/Cmin)/Kel If Cmax and Cmin are 10 and 5 ug/mL, respectively and Kel = 0.087 hour-1 Tmax = ln(10/5)/0.087 = 8 hours 6 VM508 Lauver, Puschner, Hegg Tmax is the maximum amount of time that can elapse and allow drug concentrations to remain between Cmax and Cmin. The dosing interval is also called tau. In clinical practice it is best to round off the dose interval to convenient times (DI = 12 or 24 hours) in order to promote owner compliance. The dose interval can then be used to calculate a maintenance dose. Maintenance Dose = (CL * TDC * DI)/F If the TDC is 7.5 ug/mL (or 7.5 mg/L), CL is 0.04 L/hr/kg, F=100% and DI is 8 (from calculation above) = (0.04 L/hr/kg * 7.5 mg/L * 8 hr)/1 = 2.4 mg/kg A note about “slow-release” oral preparations: The steady-state plasma levels would be nearly the same, but there will be less fluctuation in plasma concentrations. Slow release preparations are designed to act much like a constant infusion; however, they are affected by food in the GI tract, other drugs, and disease states and don’t always produce completely predictable plasma concentrations. ADJUSTING DOSING REGIMENS Dosing regimens must sometimes be adjusted such as when disease affects a patient’s organs of elimination (liver and kidneys) or concurrent drugs are administered. Information about the patient’s hepatic and renal function can be used to adjust the dosing regimen. Then, after administering the drug and waiting for steady-state to be reached, therapeutic drug monitoring (more later) can be used to further adjust the patient’s dosing regimen. Example: How to adjust the maintenance dose if metabolism is altered Induction of metabolism increases total body clearance of a drug. Consider an increase in total body clearance of 1.5 times. An adjusted maintenance dose can be calculated using the formula: Adjusted Dose = TDC * DI * CL * 1.5 F If the TDC is 7.5 ug/mL, normal CL is 0.04 L/hr/kg and DI is 8 = 7.5 ug/mL * 8 * 0.04 L/kg * 1.5 = 3.6 mg/kg If the drug’s clearance is increased 1.5 times, then the maintenance dose must be increased 1.5 times. What would be an appropriate loading dose for the patient with altered 7 VM508 Lauver, Puschner, Hegg metabolism? The loading dose would remain the same, as this does not rely on clearance. An adjusted dosing regimen for this patient would be 5 mg/kg initially followed by 3.6 mg/kg every 8 hours. This would result in a therapeutic concentration of 10 mg/L. However, because the drug’s clearance has gone up, its half-life has decreased; therefore, the fluctuations in plasma drug concentrations will now be greater than for the patient with normal metabolic function as long as the same dosing interval is utilized. A dose of 2.4 mg/kg every 8 hours produces a plasma drug concentration of 10 mg/L at steady-state. How would you adjust the dose to achieve a new steady-state concentration of 5 mg/L? To achieve a 50% reduction in the steady-state plasma concentration, reduce the dose proportionally by 50%. Adjusted Dose = 50% Normal Dose = 0.5× 2.4 mg/kg every 8 hr =1.2 mg/kg 8 hr How long will it take to reach the new steady-state concentration of 5 mg/L? It takes 4 - 5 half-lives to reestablish any new steady-state. Remember steady state starts over when you change the dose. 8