Exact dosing times calculations in linear pharmacokinetics.
The problem of determining the particular dosing time, tau, that results in a certain ratio between peak and trough drug levels at steady state (ss) is addressed. Calculation of tau in combination with simple dose linearity principles ensures constraint on the drug level variations at ss, contrary to calculations based on only clearance principles. It is shown that the dosing time problem is solved using a nested, single-variable rootsolving. Using a derivative-free, robust, single-variable rootsolver enables automatic, reliable calculations of tau. An algorithm and computer program, SSTATE, for the automatic calculation of tau in intra- and extravascular dosings are presented. Contrary to various approximation formulae proposed in the past, SSTATE provides solutions that are exact. SSTATE provides additional ss parameters such as time to peak, and maximum, minimum, and mean levels, and can also be executed in a simulation mode to explore various practical dosage regimen schemes. Dosage regimen calculations for quinidine are presented to demonstrate the practical utility of the proposed approach. It is also demonstrated by simulation studies that some approximation formulae previously proposed may produce excessive errors, especially when applied to extravascular dosings.
Veng-Pedersen
P
P
College of Pharmacy, University of Iowa, Iowa City 52242.
Wagner
J G
JG
D000465:Algorithms; D006801:Humans; D010599:Pharmacokinetics; D011802:Quinidine / Q000493:pharmacokinetics; D012984:Software
D011802:Quinidine