A nomogram to predict the best biological half-life values for candidates for oral prolonged-release formulations

It is sometimes possible to maintain plasma concentrations between desired maximum and minimum limits by repetitively administering a drug in an oral prolonged-release formulation when this goal cannot be achieved with a rapid-release formulation. However, this approach does not work with all drugs. The biological half-life value of the drug can be one cause for failure of this approach. Although it is recognized that a half-life may be too long or too short, neither the criteria for determining these values nor the consequences of failing to meet them have been established. The best half-life values for prolonged-release candidates were found by simulating once-a-day and twice-a-day administration of formulations and examining the capacity of these formulations to maintain steady-state plasma concentrations between various selected limits. These observations were used to establish criteria to judge the acceptability of half-lives. Half-life values were considered too long if drugs were self-sustaining and simulations of their rapid-release formulations were also successful. Half-life values were considered too short if minor variability in prolonged-release rates resulted in plasma concentrations above and/or below the selected limits. The actual half-life values that were considered too long or too short depended on the dosing interval and the selected maximum and minimum plasma concentrations. A nomogram was constructed to assess the acceptability of the biological half-life of a candidate for once-a-day or twice-a-day prolonged-release formulations. The nomogram employs the user-selected limits for the desired plasma concentrations to predict whether the half-life of a candidate is (1) too long, (2) too short, or (3) acceptable (i.e., between 1 and 2).