The predicted creatinine production rate in women is 85% of the calculated value because they have a smaller muscle mass per kilogram, and it is muscle mass that determines creatinine production. Muscle mass as a fraction of body weight decreases with age, which is why age appears in the Cockcroft-Gault equation. *
The decrease of renal function with age is independent of the decrease in creatinine production. Because of the difficulty of obtaining complete urine collections, creatinine clearance calculated in this way is at least as reliable as estimates based on urine collections. The fat-free mass (equation [14]) should be considered rather than total body weight for obese patients, and correction should be made for muscle wasting in severely ill patients.
Revising Individual Estimates of Volume of Distribution & Clearance
The commonsense approach to the interpretation of drug concentrations compares predictions of pharmacokinetic parameters and expected concentrations to measured values. If measured concentrations differ by more than 20% from predicted values, revised estimates of V or CL for that patient should be calculated using equation (1) or equation (2). If the change calculated is more than a 100% increase or 50% decrease in either V or CL, the assumptions made about the timing of the sample and the dosing history should be critically examined.
For example, if a patient is taking 0.25 mg of digoxin a day, a clinician may expect the digoxin concentration to be about 1 ng/ mL. This is based on typical values for bioavailability of 70% and total clearance of about 7 L/h (CLrenal 4 L/h, CLnonrenal 3 L/h). If the patient has heart failure, the nonrenal (hepatic) clearance might be halved because of hepatic congestion and hypoxia, so the expected clearance would become 5.5 L/h. The concentration is then expected to be about 1.3 ng/mL. Suppose that the concentration actually measured is 2 ng/mL. Common sense would suggest halving the daily dose to achieve a target concentration of 1 ng/mL. This approach implies a revised clearance of 3.5 L/h. The smaller clearance compared with the expected value of 5.5 L/h may reflect additional renal functional impairment due to heart failure.
This technique will often be misleading if steady state has not been reached. At least a week of regular dosing (four half-lives) must elapse before the implicit method will be reliable.
Benet LZ, Hoener B: Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002;71:115. Holford NHG: Pharmacokinetic and pharmacodynamic principles, 2013. http:// holford.fmhs.auckland.ac.nz/teaching/pharmacometrics/advanced.php. Holford NHG: Target concentration intervention: Beyond Y2K. Br J Clin
Pharmacol 1999;48:9. Holford N, Heo YA, Anderson B: A pharmacokinetic standard for babies and adults. J Pharm Sci 2013;102:2941. Holford NHG, Sheiner LB: Understanding the dose-effect relationship. Clin
Pharmacokinet 1981;6:429.
* The Cockcroft-Gault equation is given in Chapter 60.
CHAPTER 3 Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action