Willi Weber, Lutz Harnisch
Aventis Pharma, Frankfurt, Germany
Sodium-proton-exchange inhibition is a promising novel approach to achieve cardioprotection in patients at risk of myocar dial necrosis. A large combined phase II/III study in 11,590 patients investigated this hypothesis in patients with either unstable angina p ectoris, need for percutanuous revascularization, or need for coronary artery bypass surgery (CABG). Population pharmacokinetic (PK) paramet ers were determined in a subgroup of 269 patients. Based upon phase I data, a PK model was developed and its predictability confirmed in thi s Phase III substudy. These data together with the dose history and demographic variables relevant to the PK profile of the compound were us ed to predict individual PK profiles for the total study population.
In patients undergoing CABG surgery, a reduction in the risk of death or myocardial infarction was observed, and a co ncentration-efficacy analysis pursued. Predicted plasma concentrations were used to calculate the mean concentration during CABG surgery con sidered to represent the period of highest risk. This calculated mean concentration during the acute risk period was used as a predictor var iable in a time-to-event analysis.
RESULTS Without using the information on individual concentration measurements, this model adequately predicte d the individual concentration data obtained from the Population Pharmacokinetic substudy. The measured concentrations and the correspondin g predicted values were symmetrically distributed around the line of unity, indicating an unbiased prediction. However, the between subject variability was larger in patients than in healthy volunteers.
A mixture of two Weibull functions adequately described the time course of the observed sum of the acute and chronic haza rd rate. The calculated mean concentration during the period of surgery was an adequate predictor variable for the probability of an event i n the acute risk period. A steep relationship was found between the reduction of the event rate and the mean concentration during the acute risk period.
Based upon these findings, a modified dosing regimen was recommended that would both achieve optimized concentrations during the period of highest risk and would also account for uncertainties regarding the total duration of the period of risk. Accordingly, a dosing regimen consisting of a loading dose followed by a continuous infusion was designed that is expected to yield plasma concentration s above the estimated threshold level in more than 95% of patients throughout the treatment period, and that will be investigated in future studies with this compound.
Reference: PAGE 9 (2000) Abstr 99 [www.page-meeting.org/?abstract=99]
Poster: poster