TPA023, a GABA(A) alpha2,3 alphasubtype-selective partial agonist, is expected to have comparable anxiolytic efficacy as benzodiazepines with reduced sedating effects. The compound lacks efficacy at the alpha1 subtype, which is believed to mediate these effects. This study investigated the effects of 0.5 and 1.5 mg TPA023 and compared them with placebo and lorazepam 2 mg (therapeutic anxiolytic dose). Twelve healthy male volunteers participated in this placebo-controlled, double-blind, double-dummy, four-way, cross-over study. Saccadic eye movements and visual analogue scales (VAS) were used to assess the sedative properties of TPA023. The effects on posturaL stability and cognition were assessed using body sway and a standardized battery of neurophysiological memory tests. Lorazepam caused a significant reduction in saccadic peak velocity, the VAS alertness score and impairment of memory and body sway. TPA023 had significant dose dependent effects on saccadic peak velocity (85 deg/sec maximum reduction at the higher dose) that approximated the effects of lorazepam. In contrast to lorazepam, TPA023 had no detectabLe effects on saccadic latency or inaccuracy. Also unlike lorazepam, TPA023 did not affect VAS alertness, memory or body sway. These results show that the effect profile of TPA023 differs markedly from that of lorazepam, at doses that were equipotent with regard to effects on saccadic peak veLocity. Contrary to lorazepam, TPA023 caused no detectable memory impairment or postural imbalance. These differences reflect the selectivity of TPA023 for different GABA(A) receptor subtypes.

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TPA023; 99 Ci/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 T max ϳ2 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.

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.