When should a plasma sample be obtained to reflect a trough drug level in a patient at steady state during a course of medication?

From the Guidelines

A plasma sample to reflect a trough drug level in a patient at steady state should be obtained immediately before the next scheduled dose of medication. This approach is supported by the principles of pharmacokinetics, where the trough concentration is the lowest level of the drug in the patient's system during the dosing interval 1. For medications administered on a regular schedule, such as twice daily, the blood sample should ideally be drawn just before the next dose, for example, just before the 8 AM or 8 PM dose if the medication is taken at those times. Similarly, for once-daily medications, the sample should be collected within a short timeframe before the next scheduled dose, typically within 30 minutes, to accurately capture the trough level. It is crucial that the patient has reached steady state, which usually occurs after 4-5 half-lives of the drug, to ensure that the trough level reflects the drug's stable concentration in the body. Consistency in the timing of sample collection is vital for the accurate interpretation of trough levels, as deviations from this timing can result in misleading values. The importance of accurately measuring trough levels is particularly pronounced for drugs with narrow therapeutic indexes, such as vancomycin, where the trough concentration has traditionally been a target for therapeutic drug monitoring, although recent studies suggest that the area under the curve (AUC) may be a better predictor of efficacy and safety 1. Key considerations include:

• The timing of the sample in relation to the dosing schedule
• The drug's half-life and the time to reach steady state
• The therapeutic index of the drug and the implications for toxicity and efficacy
• The use of advanced modeling techniques for predicting trough concentrations and other pharmacokinetic parameters, as outlined in recent studies on population pharmacokinetic modeling and precision dosing 1.

From the FDA Drug Label

To allow adequate time for equilibration of digoxin between serum and tissue, sampling of serum concentrations should be done just before the next scheduled dose of the drug. If this is not possible, sampling should be done at least 6 to 8 hours after the last dose, regardless of the route of administration or the formulation used

A plasma sample should be obtained to reflect a trough drug level just before the next scheduled dose of the medication, or at least 6 to 8 hours after the last dose if sampling before the next dose is not possible, in a patient at steady state during a course of medication 2.

From the Research

Trough Drug Level Sampling

To reflect a trough drug level in a patient at steady state during a course of medication, a plasma sample should be obtained at a specific time. The following points outline the key considerations:

• The patient should have achieved a steady-state condition, which typically occurs when the patient has been taking the same dose for 5 to 7 days (i.e., 5 x the half-life) for drugs with a half-life of 24 hours 3.
• The time between when the last dose was taken and the sample was obtained is crucial. Ideally, for most drugs, this interval should be 10 to 12 hours after the last dose was taken, assuming the patient is taking the dose daily 3.
• This interval is chosen because it best reflects the average concentration that the patient achieves over the daily dosing interval on that drug, and it is not influenced by differences in the absorption of the drug 3.
• For depot medications, the results should be obtained at the end of the dosing cycle, just before the administration of the drug, and after the patient has ideally received 4 to 5 injections at equal intervals (e.g., monthly) to be near steady-state 3.

Specific Considerations for Digoxin

• For digoxin, a cardiac glycoside with a narrow therapeutic range, trough plasma concentrations should be measured to prevent toxicity, especially in older adults 4.
• The therapeutic ranges of digoxin trough plasmatic concentration (C0) are: 1 to 2.5 ng.mL-1 in children, 0.8 to 2 ng.mL-1 in adults, and 0.5 to 0.9 ng.mL-1 in older adults (≥ 65 years) in atrial fibrillation and heart failure 4.
• Studies have shown a linear relationship between oral doses of digoxin and steady-state digoxin plasma concentration in patients with and without renal impairment 5.
• The ratio of given dose and trough concentration of digoxin is mainly predicted by clearance creatinine, and to a lesser extent by patient's ideal body weight 6.