Title: Rapid Repeat Dosing of Zolpidem - Apparent Kinetic Change Between Doses
M.G. Spigarelli (1, 2), D. Healy (3, 4), W. Buterbaugh (3), M. Gottschlich (4), R.J. Kagan (4, 5) and C.M.T. Sherwin (1, 2)
(1)Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA (2) Clinical Trials Office, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA, (3) James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, USA (4)The Shriners Hospitals for Children«, Cincinnati, Ohio, USA (5)Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
Objectives: Zolpidem, a common sleep inducing imidazopyridine, that has been the subject of recent regulatory dosing adjustments. This project sought to evaluate rapid repeat (single dose followed by second equal dose four hours later) zolpidem dosing in pediatric burn patients.
Methods: Zolpidem was administered to paediatric patients (2 controls and 9 cases) at a mean dose of 0.22+0.1 mg/kg in either tablet or suspension as tolerated by the patient under an IRB approved protocol. Each participant was taking the drug for clinical purposes, informed consent and assent obtained and the drug was given in either 1 episode per day (control) or twice separated by a period of four hours. PK samples were obtained at 0, 1, 2, 4, 5, 6 and 8 hours after the first dose. Analysis of the resulting concentration time curves was performed utilizing NONMEM 7.2 and Prism Graph 6.0b.
Results: First order elimination modeling was obtained for the 1, 2 and 4 hour time points and residual concentration of drug were estimated and subtracted from the combined, overlying curves to produce two distinct concentration time curves for each dose administered. This technique was used to estimate the concentrations from the later time points for the control subjects which were strongly in agreement. In six of nine cases, the algorithm was able to fit the individual data and produce clearance equation with an r2 > 0.951 and in each case the calculated half-life for the second curve was significantly shorter than the first curve and demonstrated an appropriately increase in k.
Conclusions: Rapid repeat zolpidem dosing, on the order of four hours, is associated with a predictable change in elimination phase kinetics for the second dose as compared to the first. This technique has application to other similar situation in which a second dose is given while there is still residual from previous dosing to determine the relative concentration by dose.