Clinical
Pharmacokinetics
Equations and
Calculations (II)
Department of Clinical Pharmacy
Faculty of Pharmacy
Northern Border University
Average Steady-State
Concentration
• If the drug is administered as a sustained-release dosage form or the
half-life is long compared to the dosage interval, it is possible to use the
average steady-state concentration equation to individualize doses. The
dosage regimen is computed using the following equation:
• D = (Css Cl τ)/F = (Css keVτ)/F, where D is the dose, Css is the steady-
state drug concentration, Cl is the drug clearance, τ is the dosage
interval, ke is the elimination rate constant, and V is the volume of
distribution.
• A loading dose (LD) is computed using the following expression: LD =
(CssV)/F.
Average Steady-State Concentration
(cont.)
• An example of this technique is a patient with an atrial
arrhythmia needing treatment with procainamide sustained-
release tablets (clearance equals 24 L/h based on current
procainamide continuous infusion; F = 0.85, τ = 12 h for
sustained-release tablet) and an average steady-state
procainamide concentration equal to 5 mg/L: D = (Css Cl τ)/F =
(5 mg/L ⋅ 24 L/h ⋅ 12 h) / 0.85 = 1694 mg, round to a practical
dose of 1500 mg. The patient would be prescribed procainamide
sustained-release tablets 1500 mg orally every 12 hours.
MICHAELIS-MENTEN EQUATIONS FOR
SATURABLE
PHARMACOKINETICS
• When the dose of a drug is increased and steady-state serum
concentrations do not increase in a proportional fashion, but instead
increase more than expected, Michaelis-Menten or saturable
pharmacokinetics may be taking place.
• This situation occurs when the serum concentration of the drug
approaches or exceeds the Km value for the enzyme system that is
responsible for its metabolism.
• The Michaelis-Menten expression describes the dose required to
attain a given steady-state drug concentration:
• D = (Vmax ⋅ Css) / (Km + Css), where D is the dose, Css is the steady-
state drug concentration, Vmax is the maximum rate of drug
metabolism, and Km is the concentration where the rate of
metabolism equals Vmax/2. Phenytoin is an example of a drug that
MICHAELIS-MENTEN EQUATIONS FOR
SATURABLE
PHARMACOKINETICS
• Computing the Michaelis-Menten constants for a drug is not as straight
forward as the calculation of pharmacokinetic parameters for a one-
compartment linear pharmacokinetic model. The calculation of Vmax and
Km requires a graphical solution.
• The Michaelis-Menten equation is rearranged to the following formula:
• D = Vmax − [Km(D/Css)].
• This version of the function takes the form of the equation of a straight
line: y = y-intercept + [(slope)x]. A plot of dose (D) versus dose divided by
the steady-state concentration (D/Css) will yield a straight line with a
slope equal to −Km and a y-intercept of Vmax.
MICHAELIS-MENTEN EQUATIONS FOR
SATURABLE
PHARMACOKINETICS
• In order to use this approach, a patient is placed on an initial
dose (D1) of the medication, a steady-state concentration is
obtained (Css1), and the dose/steady-state concentration ratio
determined (D1/Css1). The dose of the medication is changed
(D2), a second steady-state concentration is measured (Css2),
and the new dose/steady-state concentration ratio is
computed (D2/Css2). The dose and dose/steady-state
concentration pairs are plotted on a graph so that Vmax (the
y-intercept) and Km (the -slope) can be determined
MICHAELIS-MENTEN EQUATIONS FOR
SATURABLE
PHARMACOKINETICS
Example:
A patient receiving phenytoin for the treatment of tonic-clonic seizures. The
patient received a dose of 300 mg/d with a steady-state concentration of 8
mg/L and a dose of 500 mg/d with a steady-state concentration equal to 22
mg/L.
The dose/steady-state concentration ratios are 37.5 L/d and 22.7 L/d for the
first and second doses, respectively ([300 mg/d] / 8 mg/L = 37.5 L/d; [500
mg/d] / 22 mg/L = 22.7 L/d).
A plot of this data yields a Vmax = 807 mg/d and a Km = 13.5 mg/L.
The phenytoin dose to reach a steady-state concentration equal to 13 mg/L is:
D = (Vmax ⋅ Css) / (Km + Css) = (807 mg/d ⋅13 mg/L) / (13.5 mg/L + 13 mg/L)
= 396 mg/d, rounded to a practical dose of 400 mg/d.
