Redefining normal variability of drug disposition

The pharmacokinetics of many drugs are said to be predictable. This is often used to imply the ease of dosing or dose-adjustments. However, predictability requires both accuracy (lack of bias) and precision (reproducibility). In the context of pharmacokinetics, precision refers to the ability to achieve a specified target concentration in different individuals. Precision is the inverse of the variance between-subjects, i.e. the greater the between subject variability (BSV) the less precise/predictable a parameter is across a patient population. BSV in PK parameters is quantified by the coefficient of variation (CV%). The current convention is that BSV in PK parameters is considered “low” (CV% ≤ 10%), “moderate” (CV% ~ 25%), or “high” (CV% > 40%). [1]

To explore the range of BSV values in population PK parameters

A literature review of population PK studies from various data sources was conducted. Drug classes studied included psychotropics, immunosuppressants, cardiovascular drugs, and antibiotics. Estimates of clearance (CL) and volume of distribution (V) and their corresponding CV% were recorded.

A total of 181 studies involving 95 drugs were reviewed. The mean CV% in CL/F was 40.3% and in V/F was 51.3%. The mean CV% in CL/F in predominately renally cleared drugs was 31% (after accounting for renal function) and those predominately hepatically cleared drugs was 47.4%. Age, sex, weight, and renal function were among the most significant covariates reported across the drug classes.

According to the current convention most drugs show “moderate” to “high” BSV. The current convention needs to be recalibrated to consider that a low BSV in CL is 50% is high. Clinically, this means that a normal level of variability in CL would result in a 5- to 6-fold variability in steady state average plasma concentrations (the 95% interval of steady state average concentrations) and therefore for all drugs with a low therapeutic index, monitoring plasma concentration or response and dose-individualisation will be essential.

[1] Rowland M, Tozer TN. Variability. Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2011. p. 333-55.

Hesham Al-Sallami