A 1-step Bayesian predictive approach for evaluating in vitro in vivo correlation (IVIVC).

IVIVC (in vitro in vivo correlation) methods may support approving a change in formulation of a drug using only in vitro dissolution data without additional bioequivalence trials in human subjects. Most current IVIVC methods express the in vivo plasma concentration of a drug formulation as a function of the cumulative in vivo absorption. The absorption is not directly observable, so is estimated by the cumulative dissolution of the drug formulation in in vitro dissolution trials. The calculations conventionally entail the complex and potentially unstable mathematical operations of convolution and deconvolution, or approximations aimed at omitting their need. This paper describes, and illustrates with data on a controlled-release formulation, a Bayesian approach to evaluating IVIVC that does not require convolution, deconvolution or approximation. This approach incorporates between- and within-subject (or replicate) variability without assuming asymptotic normality. The plasma concentration curve is expressed in terms of the in vitro dissolution percentage instead of time, recognizing that this correspondence may be noisy because of the various sources of error. All conventional functions of the concentration curve such as AUC, C(max) and T(max) can be expressed in terms of dissolution percentage, with uncertainties arising from variability in measuring absorption and dissolution accounted for explicitly.

Metabolism and disposition of a potent and selective GABA-Aalpha2/3 receptor agonist in healthy male volunteers.

[14C]7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine ([14C]-TPA023; 99 microCi/dose) was administered to five young, healthy, fasted male subjects as a single oral dose (3.0 mg) in solution (propylene glycol/water, 10:90 v/v). The parent compound was rapidly absorbed (plasma Tmax approximately 2 h), exhibited an apparent terminal half-life of 6.7 h, and accounted for approximately 53% of the total radioactivity in plasma. After 7 days of collection, the mean total recovery of radioactivity in the excreta was 82.6%, with 53.2% and 29.4% in urine and feces, respectively. Radiochromatographic analysis of the excreta revealed that TPA023 was metabolized extensively, and only trace amounts of unchanged parent were recovered. Radiochromatograms of urine and feces showed that TPA023 underwent metabolism via three pathways (t-butyl hydroxylation, N-deethylation, and direct N-glucuronidation). The products of t-butyl hydroxylation and N-deethylation, together with their corresponding secondary metabolites, accounted for the majority of the radioactivity in the excreta. In addition, approximately 10.3% of the dose was recovered in urine as the triazolo-pyridazine N1-glucuronide of TPA023. The t-butyl hydroxy and N-desethyl metabolites of TPA023, the TPA023 N1-glucuronide, and the triazolo-pyridazine N1-glucuronide of N-desethyl TPA023 were present in plasma. In healthy male subjects, therefore, TPA023 is well absorbed and is metabolized extensively (t-butyl hydroxylation and N-deethylation > glucuronidation), and the metabolites are excreted in urine and feces.

Chiral separation of labetalol stereoisomers in human plasma by capillary electrophoresis.

A newly derivatized cyclodextrin [octakis-(2,3-diacetyl-6-sulfato)-gamma-cyclodextrin] was investigated as a chiral selector in capillary zone electrophoresis in a study of the chiral separation of labetalol stereoisomers. Heptakis(2,3-diacetyl-6-sulfato)-beta-cyclodextrin (HDAS-beta-CD) and octakis(2,3-diacetyl-6-sulfato)-gamma-cyclodextrin (ODAS-gamma-CD) were shown to be effective in separating labetalol stereoisomers. Optimal separating conditions of the four stereoisomers of labetalol were achieved with 10 mM HDAS-beta-CD and 10 mM ODAS-gamma-CD in an acidic pH buffer of low molarity. Data illustrating the effects of capillary length and cyclodextrin concentration on the separation are presented. The longer capillary length and high voltage enabled the baseline separation of all isomers in less than 15 min. The optimized method was applied to the analysis of human control plasma containing labetalol utilizing solid-phase extraction (SPE) in the 96-well format.