Therapeutic Drug Monitoring Lecture 1 PDF

Therapeutic Drug Monitoring Lecture 1 Department of Clinical Pharmacy/fifth stage AIMS: To revise the concepts of clinical pharmacokinetics and the meaning and relevance of volume of distribution to loading dose calculation OBJECTIVES: By the end of the session you should be able to: Explain the ter...

Therapeutic Drug Monitoring Lecture 1 Department of Clinical Pharmacy/fifth stage AIMS: To revise the concepts of clinical pharmacokinetics and the meaning and relevance of volume of distribution to loading dose calculation OBJECTIVES: By the end of the session you should be able to: Explain the terms “pharmacokinetics and pharmacodynamics” Explain the term “volume of distribution” Calculate a drug loading dose from a target concentration and an estimate of volume of distribution. Basic Principles of Clinical Pharmacokinetics: Pharmacokinetics: “What the body does to the drug” Absorption (input) Distribution Metabolism (liver) Excretion (kidneys) Pharmacodynamics: “What the drug does to the body” Therapeutic effects Toxic effects PK/PD relationships determine drug dosage regimens LINEAR VERSUS NONLINEAR PHARMACOKINETICS When drugs are given on a constant basis, such as a continuous intravenous infusion or an oral medication given every 12 hours, serum drug concentrations increase until the rate of drug administration equals the rate of drug metabolism and excretion. when the rate of drug administration equals the rate of drug removal, the amount of drug contained in the body reaches a constant value. This equilibrium condition is known as steady state and is extremely important in clinical pharmacokinetics ???? because usually steady-state serum or blood concentrations are used to a/ assess patient response b/ and compute new dosage regimens. If a plot of steady state concentration versus dose yields a straight line, the drug is said to follow linear pharmacokinetics??? In this situation, steady-state serum concentrations increase or decrease proportionally with dose. Therefore, EX. if a patient has a steady-state drug concentration of 10 μg/mL at a dosage rate of 100 mg/h, the steady-state serum concentration will increase to 15 μg/mL if the dosage rate is increased to 150 mg/h (e.g., a 50% increase in dose yields a 50% increase in steady-state concentration). Nonlinear Pharmacokinetics While most drugs follow linear pharmacokinetics, in some cases drug concentrations do not change proportionally with dose. When steady-state concentrations change in a disproportionate fashion after the dose is altered, a plot of steady-state concentration versus dose is not a straight line and the drug is said to follow nonlinear Pharmacokinetics??. ## When steady-state concentrations 1- increase more than expected after a dosage increase, the most likely explanation is that the processes removing the drug from the body have become saturated. This phenomenon is known as saturable or Michaelis-Menten pharmacokinetics??. ex: Both phenytoin and salicylic acid follow Michaelis-Menten pharmacokinetics. ## When steady-state concentrations increase 2- less than expected after a dosage increase, there are two typical explanations??. Ex: Some drugs, such as valproic acid and disopyramide a/ saturate protein binding sites so that as the dosage is increased steady-state serum concentrations increase less than expected. Other drugs, such as carbamazepine, b/ increase their own rate of metabolism (autoinduction ) from the body as dose is increased so steady-state serum concentrations increase less than anticipated. CLEARANCE: (Volume of serum or blood completely cleared of drug per unit time) Clearance (Cl) is the most important pharmacokinetic parameter because it determines the maintenance dose (MD) that is required to obtain a given steadystate serum concentration MD = Css ⋅ Cl If one knows the clearance of a drug, and wants to achieve a certain steady-state serum concentration, it is easy to compute the required maintenance dose. This range of steady-state concentrations is known as the therapeutic range?? for the drug. (Minimum and maximum serum or blood concentrations that produce the desired pharmacological effect without producing unwanted adverse effects ) ## For example, the therapeutic range for theophylline is generally accepted as 10– 20 μg/mL for the treatment of asthma with concentrations of 8–12 μg/mL considered as a reasonable starting point. If it were known that the theophylline clearance for a patient equaled 3 L/h and the desired steady-state theophylline serum concentration was 10 μg/mL, the theophylline maintenance dose to achieve this concentration would be 30 mg/h, 10 μg/mL = 10 mg/L; MD = Css ⋅ Cl; MD = 10 mg/L ⋅ 3 L/h = 30 mg/h. VOLUME OF DISTRIBUTION (Proportionality constant that relates serum concentrations to amount of drug in the body) Volume of distribution (V) is an important pharmacokinetic parameter because it determines the loading dose (LD) that is required to achieve a particular steady-state drug concentration immediately after the dose is administered: LD = Css ⋅ V The volume of distribution (V) is a hypothetical volume that is relates the concentration of drug in the blood or serum (C) and the amount of drug in the body. ## If 100 mg of drug is given to each patient, the resulting concentration will be 10 mg/L in the patient with the smaller volume of distribution, but 1 mg/L in the patient with the larger volume of distribution. Ex: very small if the drug is primarily contained in the blood (warfarin V = 5–7 L), or very large if the drug distributes widely in the body and is mostly bound to bodily tissues (digoxin V = 500 L). Why?? How the drug binds in the blood or serum compared to the binding in tissues is also an important determinate of the volume of distribution for a drug. For example, the reason: warfarin has such a small volume of distribution is that it is highly bound to serum albumin so that the free fraction of drug in the blood is very small. Digoxin has a very large volume of distribution because it is very highly bound to tissues (primarily muscle) HALF-LIFE AND ELIMINATION RATE CONSTANT HALF-LIFE is (Time required for serum concentrations to decrease by one-half after absorption and distribution phases are complete) When drugs that follow linear pharmacokinetics are given to humans, serum concentrations decline in a curvilinear fashion. When the same data is plotted on a semilogarithmic axis, serum concentrations decrease in a linear fashion after drug absorption and distribution phases are complete. This part of the curve is known as the elimination phase.?? Another Common measurement used to denote how quickly drug serum concentrations decline in a patient is ## the elimination rate constant (ke). Terminal slope of the serum concentration/time curve after absorption and distribution phases are complete The dimension for the elimination rate constant is reciprocal time (hour−1, minute−1, day−1, etc.). The half life and elimination rate constant are related to each other by the following equation, so it is easy to compute one once the other is known: t1/2 = 0.693/ke Importance of half life: The half-life is important because it determines the time to a/ steady state during the continuous dosing of a drug and the b/ dosage interval. The approach to steady-state serum concentrations is an exponential function. If a drug is administered on a continuous basis for 3 half-lives, serum concentrations are ~90% of steady-state values; on a continuous basis for 5 half-lives, serum concentrations equal ~95% of steady-state values; or on a continuous basis for 7 half-lives, serum concentrations achieve ~99% of steady-state values Dose intervals: The dosage interval for a drug is determined by the half-life of the agent. In this case, Ex: the half-life of the drug is 8 hours, and the therapeutic range of the drug is 10–20 mg/L. In order to ensure that maximum serum concentrations never go above and minimum serum concentrations never go below the therapeutic range, it is necessary to give the drug every 8 hours (τ = dosage interval). The half-life and elimination rate constant are known as dependent parameters?? because their values depend on the clearance (Cl) and volume of distribution (V) of the agent: t1/2 = (0.693 ⋅ V)/Cl , ke = Cl/V The half-life and elimination rate constant for a drug can change either because of a change in clearance or a change in the volume of distribution. Because the values for clearance and volume of distribution depend solely on physiological parameters and can vary independently of each other, they are known as independent parameters??. 5- MICHAELIS-MENTEN OR SATURABLE PHARMACOKINETICS This is the type of nonlinear pharmacokinetics that occurs when the number of drug molecules saturates the enzyme’s ability to metabolize the drug When this occurs, steady-state drug serum concentrations increase in a disproportionate manner after a dosage increase , the clinical implication of Michaelis-Menten pharmacokinetics is that: ## the clearance of a drug is not a constant???? as it is with linear pharmacokinetics, but is concentration- or dose-dependent. As the dose or concentration increases, the clearance rate (Cl) decreases as the enzyme approaches saturable conditions: For example, phenytoin follows saturable pharmacokinetics with average Michaelis-Menten constants of Vmax = 500 mg/d and Km = 4 mg/L. The therapeutic range of phenytoin is 10–20 mg/L. As the steady-state concentration of phenytoin increases from 10 mg/L to 20 mg/L, clearance decreases from 36 L/d to 21 L/d Cl = Vmax/(Km + C); Cl = (500 mg/d) / (4 mg/L + 10 mg/L) = 36 L/d Cl = (500 mg/d)/(4 mg/L + 20 mg/L) = 21 L/d. ## The volume of distribution (V) is unaffected by saturable metabolism and is still determined by the a/ physiological volume of blood and tissues as well as the b/ unbound concentration of drug in the blood and tissues. Also, ## half-life (t1/2) is still related to clearance and volume of distribution using the same equation as for linear pharmacokinetics: t1/2 = (0.693 ⋅ V)/Cl However, since clearance is dose- or concentration-dependent, half-life also changes with dosage or concentration changes. As doses or concentrations increase for a drug that follows MichaelisMenten pharmacokinetics, clearance decreases and half-life becomes longer for the drug: ↑t1/2 = (0.693 ⋅ V)/↓Cl BIOAVAILABILITY The fraction of the administered dose that is delivered to the systemic circulation is known as the bioavailability for the drug and dosage form. When medications are given orally, intramuscularly, subcutaneously, or by other extravascular routes, the drug must be absorbed across several biologic membranes before entering the vascular system. In these cases, drug serum concentrations rise while the drug is being absorbed into the bloodstream, reach a maximum concentration (Cmax): when the rate of drug absorption equals the rate of drug elimination, and eventually decrease according to the half-life of the drug. For drugs that follow linear pharmacokinetics, bioavailability is measured by comparing serum concentrations achieved after extravascular and intravenous doses in the same individual. the bioavailabilty (F) would be computed by dividing the AUC after oral administration (AUCPO) by the AUC after intravenous administration (AUCIV): F = AUCPO/AUCIV