Translating pharmacology models effectively to predict therapeutic benefit.

Many in vitro and in vivo models are used in pharmacological research to evaluate the role of targeted proteins in a disease. Understanding the translational relevance and limitation of these models for analyzing a drug's disposition, pharmacokinetic/pharmacodynamic (PK/PD) profile, mechanism, and efficacy, is essential when selecting the most appropriate model of the disease of interest and predicting clinically efficacious doses of the investigational drug. Selected animal models used in ophthalmology, infectious diseases, oncology, autoimmune diseases, and neuroscience are reviewed here. Each area has specific challenges around translatability and determination of an efficacious dose: new patient-specific dosing methods may help overcome these limitations.

Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists.

2-Aminooxazolines were discovered as a novel structural class of TAAR1 ligands. Starting from a known adrenergic compound 1, structural modifications were made to obtain highly potent and selective TAAR1 ligands such as 12 (RO5166017), 18 (RO5256390), 36 (RO5203648), and 48 (RO5263397). These compounds exhibit drug-like physicochemical properties, have good oral bioavailability, and display in vivo activity in a variety of animal models relevant for psychiatric diseases and addiction.

Pharmacokinetics of intravenous, single-dose tiotropium in subjects with different degrees of renal impairment.

Tiotropium, a new potent anticholinergic bronchodilator, is excreted mainly by the kidney. To investigate the pharmacokinetics of tiotropium in renal impairment, the authors evaluated the pharmacokinetics and safety after administration of a single dose of intravenous tiotropium 4.8 microg, given as an infusion over 15 minutes in subjects with normal renal function and a wide range of renal impairment based on measured creatinine clearance (normal: > 80 mL/min, n = 6; mild impairment: > 50-80 mL/min, n = 5; moderate impairment: 30-50 mL/min, n = 7; severe impairment: < 30 mL/min, n =6). As expected for a drug excreted predominantly in unchanged form by the kidneys, tiotropium plasma concentrations increased as renal impairment worsened, with mean values of 55.5 (16.2 percent geometric coefficient of variation [%gCV]), 77.1 (20.1 %gCV), 101 (29.8 %gCV), and 108 (27.3 %gCV) pgh/mL for AUC(0-4h) in the normal renal function and the mild, moderate, and severe renal impairment groups, respectively. The percentage of tiotropium dose excreted unchanged in the urine decreased from 60.1% of dose (17.7 %gCV) to 59.3% (14.4 %gCV), 39.9% (34.5 %gCV), and 37.4% (10.2 %gCV) in the normal renal function and the mild, moderate, and severe renal impairment groups, respectively. Plasma protein binding of tiotropium did not significantly change in the renal-impaired subjects. Two subjects with normal renal function experienced headache 10 hours after the infusion, which was mild and transient. No adverse events occurred in subjects with renal impairment. There were no clinically relevant changes in blood pressure, pulse rate, 12-lead ECG, physical examination, hematology, or clinical chemistry, compared with baseline values, in any subject after intravenous administration of tiotropium. Tiotropium should only be used in patients with moderate to severe renal insufficiency if the potential benefit outweighs the potential risks.

Population pharmacokinetic analysis of meloxicam in rheumatoid arthritis patients.

AIM: To perform a nonlinear mixed effect modelling (NONMEM) population pharmacokinetic analysis of meloxicam plasma concentrations in rheumatoid arthritis (RA) patients participating in three clinical trials, and to evaluate the effects of age, weight, gender and concomitant medications on meloxicam pharmacokinetics. METHODS: Meloxicam was administered to RA patients once daily for 3 weeks or 6 months at doses between 7.5 and 60 mg. Plasma samples were obtained at least 7 days after the first dose and meloxicam plasma concentrations were quantified by h.p.l.c. RESULTS: NONMEM analysis was conducted on plasma samples derived from 586 patients. A one-compartmental model was found to describe the data adequately. For a typical subject in the population, a clearance of 0.377 l h-1 (95% confidence interval (CI) 0.0304-0.449) in males and 0.347 l h-1 (95% CI 0.274-0.419) in females was obtained. The volume of distribution was estimated to be 14.9 l. The findings were corroborated by subsequent analysis using WinBUGS. Analysis of covariates showed that age and gender both significantly (P < 0.005) affected clearance. The effect of age was relatively small and a dose adjustment of <10% was deemed unnecessary. Differences between males and females were attributed to differences in weight. No clinically relevant drug-drug interactions were found, although sulphasalazine and glucocorticoids both significantly (P < 0.005) affected meloxicam clearance (+19% and - 12%, respectively). The mechanisms by which these agents affect meloxicam clearance remain to be elucidated. CONCLUSIONS: The population pharmacokinetic meloxicam data from patients with RA gave similar results to those obtained from phase I trials. However, uncommon drug interactions may not be detected in phase I trials because of the small number of observations made.