Francis Hsuan

Single- vs multiple-dose pharmacokinetics of clozapine in psychiatric patients

AbstractClozapine plasma levels were monitored in 16 patients during a series of three consecutive treatments (single dose–multiple dose–single dose). Each patient received a single 75-mg dose (3 × 25 mg) with clozapine tablets, and serial plasma samples were collected over 48 hr after the dose. At 48 hr, a multiple-dose regimen was started, consisting of an initial dose escalation period followed by dosing at a constant regimen for at least 6 days. After the last dose, serial plasma samples were again obtained over 72 hr. Drug was then withheld for at least 7 days, a final single 75-mg dose was given, and plasma sampling was repeated. A subset of the patient population (N = 7) was used to test for a food effect during the single-dose treatments. The pharmacokinetic parameters between the initial and the final single dose periods were not significantly different. Similarly, there were no differences within patients when given the dose after fasting (fed 1 hr after dose) or with a meal. In contrast, the terminal elimination rate differed between the single-dose and the multiple-dose treatments (t

{2}-Inverses and Their Statistical Application

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The {2}-inverse with applications in statistics

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A METHOD FOR ESTIMATING AND TESTING AREA UNDER THE CURVE IN SERIAL SACRIFICE, BATCH, AND COMPLETE DATA DESIGNS

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Some statistical considerations on the FDA draft guidance for individual bioequivalence

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A likelihood ratio test and its modifications for the homogeneity of the covariance matrices of dependent multivariate normals

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A moment-based criterion for determining individual bioequivalence

m3 = 7.9 hr single dose and 14.2 hr multiple dose) (P < 0.05) and the dose-normalized area under the plasma concentration/time curves increased 27% with multiple dosing. Since a previous study in patients (Choc et al., Pharm. Res. 4:402–405, 1987) showed dose proportionality of clozapine plasma concentrations during multiple-dose regimens, the present results cannot be described by Michaelis–Menten kinetics.

Ridge regression from principal component point of view

We propose an adaptive procedure for dose-finding in clinical trials when the primary efficacy endpoint is continuous. We model the mean of the efficacy endpoint, given the dose, as a four-parameter logistic function. The efficacy endpoint at each dose is distributed according to either a normal or a gamma distribution. We consider the cases of fixed variance and fixed coefficient of variation assuming them to be both known and unknown. The analytic formulae for the Fisher information matrix are obtained, which are used to build the locally and adaptive D -optimal designs.