Rapid Attainment of Successively Higher Steady-State Plasma Levels Using the Wagner Two-step Infusion Method

Abstract

The Wagner equation describing the plasma concentration-time relationship for the two-step infusion method is presented in general form for application to both the fast and slow infusion phases of single- and multiple-cycle infusions. The generalized parameters C (steady-state concentration), Q (infusion rate), A (amount of drug), and t′ (time) are defined for each case. Plasma concentrations are simulated for a hypothetical two-compartment drug, X, to illustrate the uses of the equat.ion and to examine error effects in the QF/QS ratio, T, and kel. For the single-cycle case, it is shown that positive or negative (±) errors in QF/QS and T delay the approach to the steady-state plasma value, Clss, but such errors would not be of clinical importance when they are ≤ ±2.5%. Errors in kel prevent attainment of Clss and more greatly affect the plasma concentration at the end of the dose cycle, ClT, than do the same errors in QF/QS or T. Therefore, the use of an average population value for kel instead of the actual patient value is more likely to produce large deviations from Clss than experimental errors in flow rate and T. The utility of the two-step infusion method in reaching successively higher steady-state values, Cl,(n)ss, for drugs with a high therapeutic index is also demonstrated for drug X over a range of multiple cycles. The examination of error effects for the multiple-cycle case revealed that errors in QF/QS and T yield Cl,(n)T values that tend to converge toward the desired value of Cl,(n)ss as the dose cycle increases, while such errors in k0 yield Cl,(n)T values that increasingly diverge from Cl,(n)ss as dosing increases. Thus, individual patient differences as reflected in kel become increasingly more important as a source of error in Cl,(n)T with successively higher dosing, while experimental errors in QF/QS become less important.