CLINICAL PHARMACOKINETICS INDEPENDENT LEARNING MODULE Joseph K. Ritter, Ph.D. Assoc. Professor, Pharmacology and Toxicology MSB 536, 828-1022, jritter@vcu.edu This self study module will reinforce the principles taught in the class about clinical pharmacokinetics with a focus on continuous dosing regimens. The goal of a continuous dosing regimen is to maintain plasma drug levels in the effective range, above the minimum effective concentration [MEC] but below the minimum toxic concentration. If the plasma drug level is too high (toxic) or too low (no response) the patient will not respond appropriately to administered drug. Many patient characteristics (age, weight, kidney function, liver function, etc.) can influence the dose of drug required to produce the appropriate response. Another goal of this module is to help you understand how to calculate the loading dose (LD), maintenance dose (MD) and plasma plateau level (C SS ) of drugs cleared by first-order and zeroorder kinetics, and the influence of changes in dose or dose interval (i.e., dosing rate) on Css. Take a minute to review the following equations for the LD, MD, and Css for drugs eliminated by first order kinetics of elimination. In addition, this study guide includes equations for calculating LD, MD, and Css for drugs that are eliminated by zero order kinetic processes. Although few drugs are eliminated by zero order processes, several that are such as the anticonvulsant drug, phenytoin, emphasize the need to understand the important differences in principles between the two types of elimination kinetics. Note that the zero order equations appear to be related to the Michaelis-Menten kinetic model which equates the rate of metabolism (elimination) of a drug at concentration Css with the Vmax and the Km of the enzyme system that eliminates the drug. FIRST-ORDER ZERO-ORDER LD = (Vd x C) / F (Vd x C) / F MD = (Css x CL x T)/F DR = (Css x Vm)/(Css + Km) Css = (F x D)/(CL x T) (Km x DR)/(Vm DR) Vd = volume of distribution; C = peak plasma level of drug; F = bioavailability; T = dose interval; CL = total body clearance; D = dose of drug; DR = dose rate; Vm = maximum rate; Km = dose of drug that produces 50 % maximum rate (Vm). To review, the plateau principle states that the plasma level of all first-order cleared drugs will rise and eventually reach a plateau as long as the drug is repeatedly administered at intervals shorter than 4 half-lives. If the drug is administered at intervals longer than 4 half life intervals,
100 (MTC) [plateau] = Css = F D CL T CSS by F or D, or by CL or T CSS by F or D, or by CL or T 50 (MEC) Time course of plateau is by CL [ t 1 / 2 ] or by CL [ t 1 / 2 ] 0 0 1 2 3 4 5 6 7 1t 1 / 2 = 50% 2t 1 / 2 = 75% 3t 1 / 2 = 88% 4t 1 / 2 = 94% 5t 1 / 2 = 97% 6t 1 / 2 = 99% 7t 1 / 2 = 100% Half-life intervals minimal accumulation of the drug will occur because the drug will be essentially completely eliminated after each dose prior to administering the next dose. A. What factors influence the magnitude of the plateau (i.e., the Css)? Circle correct answers: Dose Dose interval Half life Vd CL F B. What factors alter the time to reach the plateau? Circle correct answers: Dose Dose interval Half life Vd CL F Whether the clearance (CL) or rate of elimination of a drug is affected by age, liver or kidney function, exposure to hepatic inducing agents (cigarette smoking, chronic alcohol intake, phenobarbital intake) or hepatic enzyme inhibitors (cimetidine), secretion inhibitors, blood flow to the organ of elimination depends on characteristics of the drug s elimination. For example, a drug that is predominantly eliminated by renal excretion mechanisms will not be subject to processes or factors that alter hepatic elimination mechanisms, or a drug that is a low hepatic extraction drug will not be decreased in patients with decreased hepatic blood flow. In this self learning module, we will work through examples provided by two drugs. The first of these is digoxin, a drug used to treat congestive heart failure. Digoxin is predominantly eliminated by the kidneys and follows first order kinetics of elimination (rate of elimination proportional to C). The second is phenytoin, which exhibits saturable hepatic metabolism resulting In zero-order elimination kinetics (rate of elimination independent of C). For the following series of questions, consider the drug digoxin which has the following pharmacokinetic parameters:
DIGOXIN (used to treat congestive heart failure [CHF]) A. Bioavailability (oral) [F] 0.5 B. Fraction excreted as unchanged drug f e 0.88 C. Volume of Distribution (L/kg) [Vd] 8.6 D. Clearance (L/hr/kg) [NORMAL] 0.1 E. Clearance (L/hr/kg) [CHF, elderly, kidney disease] 0.05 F. Half-life (hours) [t ½] [NORMAL] 60 G. Half-life (hours) [t1/2] (CHF, Elderly, Kidney Disease) H. Effective Concentrations (mg/l) [MEC].001 I. Toxic Concentrations (mg/l) [MTC].002 C. Calculate the intravenous loading dose of digoxin that is necessary to bring the plasma drug concentration (C) to the desired concentration of 0.0015 mg/l. Assume that the patient is a 100 kg adult with normal renal function. Circle the correct answer: 1290 mg 129 mg 12.9 mg 1.29 mg 0.00129 mg D. Calculate the oral loading dose necessary to bring the plasma digoxin concentration (C) to the desired concentration of 0.0015 mg/l in the 100 kg patient with normal renal function. Circle the correct answer: 2580 mg 2.58 mg 0.00258 mg 0.645 mg 645 mg 0.000645 mg E. Given the pharmacokinetic kinetic parameters stated above for digoxin, would you expect compromised renal function to have a significant effect on the clearance of this drug? Circle the correct answer: Yes No Not enough information is given Justify your reasoning: F. If the 100 kg patient has reduced renal function and their digoxin clearance is reduced to 0.05 L/hr/kg, will this affect the size of the loading dose of digoxin? Circle the correct answer: Yes No Why or why not?
G. Now let s calculate the oral maintenance dose rate required to maintain the plasma drug concentration at a plateau concentration of 0.0015 mg/l in the two different cases. The first patient (100 kg) has normal renal function (digoxin CL = 0.1 L/hr/kg). Circle the correct answer: 0.0075 mg/hr 0.015 mg/hr 0.030 mg/hr 0.060 mg/hr H. Now calculate the oral maintenance dose rate to maintain the plasma drug concentration at a plateau concentration of 0.0015 mg/l in the patient with reduced renal function (elderly, renal disease, CHF) (digoxin CL = 0.05 L/hr/kg). Circle the correct answer: 0.0075 mg/hr 0.015 mg/hr 0.030 mg/hr 0.060 mg/hr What was the effect of having a 50% lower clearance on the plasma drug concentration at steady state Css? I. If no loading dose was used and the administration of digoxin was initiated in the patient with normal digoxin CL (0.1 L/hr/kg), how long would it take to attain 94% of the desired C of 0.0015 mg/ml? Circle all correct answers: 60 hrs 120 hrs 240 hrs 480 hrs 960 hrs Would having an reduced digoxin clearance alter the time it takes to reach the steady state? Why or why not? J. If no loading dose was used and the administration of the drug was initiated in the young adult patient at the maintenance dose rate you calculated above, how long would it take to reach the MEC of 0.001 mg/l? Circle the best answer: Less than 1 half life Between 1 and 2 half lives Between 2 and 4 half lives > 4 half lives Justify your reasoning: K. In the patient with reduced digoxin CL (0.05 L/hr/kg), if the oral maintenance dose rate is doubled (from 0.015 mg/hr to 0.030 mg/hr), what will the new plateau plasma drug concentration be? Circle the best answer: 0.00075 mg/l 0.0015 mg/l 0.00225 mg/l 0.003 mg/l
Now let s turn to the anticonvulsant drug phenytoin which is eliminated by saturable CYP450-mediated metabolism and has the following pharmacokinetic parameters: PHENYTOIN A. Bioavailability (F) 1 B. Fraction excreted as unchanged drug (fe) 0.02 C. Clearance (dose-dependent) zero order kinetics D. Volume of distribution (L/kg) [Vd}.65 E. Half-life (dose-dependent) [t ½ ] Var. F. Effective Concentrations (mg/l) [MEC] 10 G. Toxic Concentrations (mg/l) [MTC] 20 H. Km (mg/l) 5.7 I. Vmax (mg/kg/24 h) [NORMAL] 7.5 J. Vmax (mg/kg/24 h) [LIVER CIRRHOSIS] 3.75 K. Vmax (mg/kg/24 h) [SMOKER] 15 L. Vmax (mg/kg/24 h) [ELDERLY] 3.75 L. Calculate the oral loading dose of phenytoin necessary to bring the plasma drug concentration (C) to the desired concentration of 15 mg/l in a 100 kg patient. Circle the correct answer: 975 mg 0.975 mg 487 mg 0.487 mg 9750 mg M. If the patient is a smoker with increased liver enzyme activity (Vmax = 15 mg/kg/24 hrs), will this affect the size of the loading dose? Circle the correct answer: Yes No Explain: N. Would you expect compromised renal function to have a significant effect on the elimination of phenytoin and the LD, MD, or Css of phenytoin? Circle the correct answer: Yes No Explain: O. Calculate the oral maintenance dose rate required to maintain the plasma phenytoin concentration at a plateau concentration of 15 mg/l assuming that the patient is 100 kg and has a normal phenytoin elimination rate (7.5 mg/kg/24 hrs).
Circle the correct answer: 239 mg/24 hr 302 mg/24 hr 543 mg/24 hr 1087 mg/24 hr Justify your response: P. If the oral dose rate of phenytoin in this patient is increased from 543 mg/24 hr to 650 mg/ 24 hrs (normal phenytoin elimination rate of 7.5 mg/kg/24 hrs), what will the new Css of phenytoin be? Circle the correct answer: 15 mg /L 20 mg /L 25 mg /L 37 mg /L Was the increase in Css proportional to the increase in dose rate? Circle the correct answer: Yes No Why or why not? Q. Now calculate the oral maintenance dose rate required to maintain the plasma phenytoin concentration at a plateau concentration of 15 mg/l assuming that the patient is 100 kg and is a two pack a day cigarette smoker (Vmax = 15 mg/kg/24 hrs). Circle the correct answer: 543 mg/24 hr 814 mg/24 hr 1086 mg/24 hr 1207 mg/24 hr What effect did having a 2-fold higher Vmax have on the size of the maintenance dose? R. Which of the following agents might increase the elimination of phenytoin? Circle correct answers: phenobarbital alcohol (chronic/acute) phenytoin rifampin smoking S. Which of the following agents might reduce the clearance of phenytoin? Circle correct answers: cimetidine chloramphenicol alcohol (acute) disulfiram In summary, a number of factors (age, weight, drugs, smoking, liver disease, chronic alcohol intake, kidney disease, heart disease, etc) influence the dose of drug required to maintain plasma drug levels in the therapeutic range. Appropriate use of drugs is only possible when one understands that drug doses must be adjusted when you treat patients with different characteristics. Failure to understand basic pharmacokinetic concepts results in giving too much or too little drug to patients and both situations result in inappropriate drug therapy. The elderly patient is at increased risk of inappropriate drug therapy as a result of age-associated changes in drug pharmacokinetics, pharmacodynamics and the high rate of use of prescription and over the counter drugs.