A 37-year-old man comes to the emergency department due to fever, chills, and malaise. He has no significant medical history but he uses illicit intravenous drugs on a regular basis. The patient is febrile, tachycardic, and hypotensive. Auscultation reveals a heart murmur. A preliminary diagnosis of infective endocarditis is established. Blood cultures grow methicillin-resistant Staphylococcus aureus, and the patient is prescribed an intravenous antibiotic administered every 12 hours. Calculation of the maintenance dose will most likely require which of the following parameters?
Pharmacokinetic parameter | Formula | Note |
Half life | Vd × 0.7 / CL | Steady-state concentration is achieved in 4-5 half-lives. |
Maintenance | Css × CL × dosing interval | Maintenance dose is decreased in patients with renal or hepatic impairment. |
Loading dose | Vd × Css | Loading dose is affected by body weight and composition. |
| CL = drug clearance; Css = steady-state plasma concentration; Vd = volume of distribution. | ||
Most drugs are administered in the form of repetitive, intermittent doses designed to achieve a steady-state plasma concentration within a targeted therapeutic range. The amount of each dose is calculated so that the administered dose is just enough to replace the amount of drug eliminated by the body since the last dose. This replacement dose (maintenance dose) depends on both of the following:
Steady-state plasma concentration (Css)
Drug clearance (CL), or volume of plasma cleared of drug per unit time (eg, mL/min)
Multiplying these two parameters gives the elimination rate, or the amount of drug eliminated from the body per unit of time:
Elimination rate = CSS × CL
The maintenance dose can then be calculated for the appropriate dosing interval (eg, 12 hr) by multiplying the elimination rate (CSS × CL) by the time between doses:
Maintenance dose = CSS × CL × dosing interval
(Choice B) When a drug is administered more quickly than it can be eliminated from the body, it accumulates until a steady-state level is reached; as plasma concentration increases, the amount of drug eliminated also increases until the amount administered equals the amount eliminated. When a drug is administered at regular intervals, the time needed to reach the steady state level depends only on the drug half-life (ie, it takes 5 half-lives to reach 97% of the steady-state level); the exact size of each dose or interval between doses does not matter.
(Choices C, D, and E) Loading doses are larger than maintenance doses and can be used during treatment initiation to shorten the time needed to reach target steady-state plasma concentrations. They are most useful when an immediate therapeutic response is needed (eg, life-saving antibiotics) or when using drugs with large volumes of distribution (eg, amiodarone). Total body weight influences the volume of distribution and is often used when calculating the loading dose. However, these parameters are not needed when calculating the maintenance dose because the amount of drug lost per unit of time depends only on the steady-state plasma concentration and drug clearance.
Educational objective:
Clearance (CL) determines the dose rate required to maintain a given steady-state plasma concentration (Css):
Maintenance dose = CSS × CL × dosing interval