A simplified account of drug accumulation and steady-state dose equivalences

The accumulation of medication taken regularly can influence its clinical effects, cumulative toxicities and steady-state equivalent doses to similar agents, and the elimination of concurrent medications. A basic expression of drug accumulation, the Unit Dose Accumulation Ratio (UDAR), is defined as the ratio of the day-average blood drug concentration at steady-state to the peal blood drug concentration after one dose. In a single-compartment analysis the UDAR is found to equal 0.0601 multiplied by the elimination half-life (in hours). The UDARs estimated in this way approximate those found from measurements of valproic acid, desipramine, and reboxetine. Further modeling reveals that in common situations graduality of release has only small effects on UDARs. Extension to multiexponential elimination is described by simple expressions in terms of ratios of kinetic coefficients. Modeling of accumulation with biexponential elimination is depicted on a graph. Several applications of the UDAR are illustrated. The UDAR permits determination of steady-state dose equivalences from single dose equivalences and vice-versa. This facilitates medication interchange, as in clinical withdrawal management by replacement of short-acting sedative-hypnotics with long-acting agents, e.g., alprazolam with clonazepam. The UDAR reflects tolerance, e.g., if 30-mg flurazepam equals 4-mg lorazepam, the UDAR indicates that at steady-state, 30 mg/day of flurazepam approximates 21 mg/day of lorazepam. The UDAR can estimate total exposure, e.g., to organic chlorine. The UDAR complements methods described previously for drug dose prediction and blood drug level monitoring that were simplified by expressing blood levels as averages over the day.