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F17464, a highly potent preferential D3 antagonist, is a novel compound in development for schizophrenia treatment. This phase II, double-blind, randomized, placebo-controlled, parallel-group study in five European countries evaluated the efficacy and safety of F17464, 20 mg twice daily, versus placebo over 6 weeks in patients with acute exacerbation of schizophrenia. Change from baseline to Day 43 of the Positive and Negative Syndrome Scale (PANSS) total score was the primary outcome. The data from 134 randomized patients (67 per group) were analyzed (efficacy/safety). Using analysis of covariance (ANCOVA) after last observation carried forward (LOCF) imputation (primary analysis), the PANSS total score reduction was statistically significantly greater for F17464 than placebo treated subjects at endpoint (p= 0.014); using ANCOVA with Multiple Imputation (MI) method, the between-group difference was in favor of F17464 but did not reach statistical significance. Differences in PANSS positive and general psychopathology subscale score, Marder positive factor score, PANSS response, and PANSS resolution criteria were also statistically significant in favor of F17464 (pvalues < 0.05) using the LOCF method, with similar results as for the primary analysis using the MI method. Treatment-related adverse events (AEs) were reported in 49.3% and 46.3% of patients on F17464 and placebo, respectively. The most common AEs in F17464 group: insomnia, agitation, and increased triglycerides; worsening of schizophrenia/drug ineffective was less frequent in F17464. Interestingly, no weight gain, no extrapyramidal disorder except rare akathisia were observed under F17464. This 6-week trial demonstrated therapeutic efficacy of 40 mg/day F17464 in improving symptoms of acute exacerbation of schizophrenia with a favorable safety profile.

Abstract—Methadone is used as a treatment for opiate detoxification in methadone maintenance programs. Intra‐ and inter‐patient variations in methadone bioavailability have been observed after oral methadone treatment and this makes it difficult to predict a dosing regimen. Intestinal absorption and metabolism could explain these variations. The in vitro gut sac model was used to study the intestinal absorption of methadone, and it confirmed that methadone is a substrate for P‐glycoprotein. The transport of methadone was increased in presence of P‐gp inhibitors verapamil and quinidine. The appearance of a major metabolite of methadone, 2‐ethylidene‐1, 5‐dimethyl‐3, 3‐diphenyl pyrrolidine (EDDP) in the gut sac contents also demonstrated the existence of intestinal metabolism of methadone.

Abstract—Physico‐chemical descriptors of drug molecules are often not adequate in predicting their oral bioavailability. In vitro methods can be useful in evaluating some of the different factors contributing to bioavailability. While physical parameters such as drug solubility may effect oral bioavailability, in most cases, the major determining factors are likely to be metabolism, and absorption at the intestinal level. Metabolism may be preabsorptive, as with peptides, or during absorption, particularly as a result of the activity of the intracellular enzyme CYP3A4. Absorption may be transcellular (membrane diffusion, carrier‐mediated, endocytosis) or paracellular, while p‐glycoprotein activity in the apical cell membrane may limit bioavailability by expelling drugs from the mucosal cells. Knowledge of the absorption mechanism is important in determining formulation strategies. The different in vitro techniques used to study absorption have advantages and disadvantages. Ussing chambers can be useful to measure bidirectional transport, but most studies use simple salt media, and full tissue viability is doubtful. Caco‐2 cell monolayers are human cells, but the system is static, and gives very low rates of transport, and exagerated enhancement of the paracellular route compared with small intestine. The rat everted gut sac incubated in tissue culture medium maintains tissue viability and gives reliable data, although it is a closed system. In situ perfusion gives no information on events at the cellular level, and absorption may be reduced by anaesthesia and surgical manipulation. In vivo perfusion in man, with multichannel tubes, gives valuable data, but is not practical for screening. Pharmacokinetic modelling can also give useful data such as the existence of different absorption sites. Permeability values from the literature show that for small hydrophilic molecules, which pass by the paracellular route, the improved everted sac gives values close to those for humans, while values with Caco‐2 cells are orders of magnitude lower.