Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach.

BACKGROUND AND PURPOSE: Tesofensine is a centrally acting drug under clinical development for Alzheimer's disease, Parkinson's disease and obesity. In vitro, the major metabolite of tesofensine (M1) displayed a slightly higher activity, which however has not been determined in vivo. The aims of this investigation were (i) to simultaneously accomplish a thorough characterization of the pharmacokinetic (PK) properties of tesofensine and M1 in mice and (ii) to evaluate the potency (pharmacodynamics, PD) and concentration-time course of the active metabolite M1 relative to tesofensine and their impact in vivo using the PK/PD modelling approach. EXPERIMENTAL APPROACH: Parent compound, metabolite and vehicle were separately administered intravenously and orally over a wide dose range (0.3-20 mg kg(-1)) to 228 mice. Concentrations of tesofensine and M1 were measured; inhibition of the dopamine transporter was determined by co-administration of [(3)H]WIN35,428 as the pharmacodynamic measure. KEY RESULTS: Pharmacokinetics of tesofensine and M1 were best described by one-compartment models for both compounds. Nonlinear elimination and metabolism kinetics were observed with increasing dose. The PK/PD relationship was described by an extended E(max) model. Effect compartments were used to resolve observed hysteresis. EC(50) values of M1, as an inhibitor of the dopamine transporter, were 4-5-fold higher than those for tesofensine in mice. CONCLUSIONS AND IMPLICATIONS: The lower potency of M1 together with approximately 8-fold higher through steady-state concentrations suggest that M1 did contribute to the overall activity of tesofensine in mice.

Cyclosporine A (CsA) affects the pharmacodynamics and pharmacokinetics of the atypical antipsychotic amisulpride probably via inhibition of P-glycoprotein (P-gp).

The importance of P-glycoprotein (P-gp) in the pharmacokinetics of amisulpride and the effects of a P-gp inhibitor cyclosporine A (CsA) was investigated both, in vitro and in vivo. In vitro and in vivo results indicated amisulpride as a substrate of P-gp. Amisulpride was not metabolized by rat liver microsomes. Open field behavior showed time dependent abolishment in locomotion by amisulpride (50 mg kg(-1)). Co-administration of CsA (50 mg kg(-1)) resulted in a higher and significantly longer antipsychotic effect (24 h after drug administration). Accordingly, the area under concentration-time curve in serum and brain was higher in CsA co-treated rats (13.5 vs. 29.8 micromol h l(-1) for serum and 2.16 vs 2.98 micromol h l(-1) for brain tissue) while renal clearance was not affected. These results pointed to a pharmacokinetic drug interaction between CsA and amisulpride most likely caused by inhibition of P-gp.

Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice.

The cyclooxygenase (COX) product, prostacyclin (PGI(2)), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI(2) biosynthesis substantially in humans. Because deletion of the PGI(2) receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF(1alpha) by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI(2) biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 +/- 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.

Comparison of manual versus ambulatory blood pressure measurements with pharmacokinetic-pharmacodynamic modeling of antihypertensive compounds: application to moxonidine.

OBJECTIVES: To compare the results of the pharmacokinetic-pharmacodynamic analyses of 24-hour ambulatory blood pressure measurements and manual blood pressure data in patients receiving moxonidine. METHODS: 32 patients with borderline to mild-to-moderate hypertension were enrolled in a double-blind, placebo-controlled phase II study. After receiving placebo for 1 week (run-in phase), the patients were randomly allocated to the placebo or the 0.6-, 0.9-, or 1.2-mg dose groups. Placebo and moxonidine were administered once daily for 1 week (drug-treatment phase). Four 24-hour ambulatory blood pressure measurement profiles were obtained for each individual. Plasma samples (n = 9) and four measurements of manual blood pressure were taken at the start and end of the drug-treatment phase. Two additional manual blood pressure measurements were taken during the run-in and drug-treatment phases. RESULTS: Pharmacokinetics was described by a one-compartment model. For the 24-hour ambulatory blood pressure measurements, baseline circadian patterns were described with a two-cosine function model that included interindividual and interoccasion variability. Pharmacodynamics was described with use of an effect-compartment model [k(e0) = 0.37 (1/h)] and an Emax model. For diastolic blood pressure the maximum drug-induced decrease (Emax) was 30.9 mm Hg and the steady-state plasma drug concentration eliciting half of maximum effect (C50) was 1.33 microg/L. Interindividual variability was estimated for ke0 (24.8%) and Emax (33.3%). For the manual blood pressure measurements, data was described by a time-invariant baseline model combined with an effect-compartment model and an Emax model. Mean population estimates were in agreement with those obtained during the analysis of 24-hour ambulatory blood pressure measurements. However, interindividual variability could be estimated for the baseline parameter only. CONCLUSIONS: Although similar typical population estimates for the drug action-related parameters were obtained with use of manual blood pressure data and 24-hour ambulatory blood pressure measurements, the latter allowed for a more detailed description of the individual pharmacodynamic profiles because interindividual variability in pharmacodynamic parameters could be estimated together with increased precision in parameter estimates.