Statistical comparison of dissolution profiles to predict the bioequivalence of extended release formulations.

Appropriate setting of dissolution specification of extended release (ER) formulations should include precise definition of a multidimensional space of complex definition and interpretation, including limits in dissolution parameters, lag time (t-lag), variability, and goodness of fit. This study aimed to set dissolution specifications of ER by developing drug-specific dissolution profile comparison tests (DPC tests) that are able to detect differences in release profiles between ER formulations that represent a lack of bioequivalence (BE). Dissolution profiles of test formulations were simulated using the Weibull and Hill models. Differential equations based in vivo-in vitro correlation (IVIVC) models were used to simulate plasma concentrations. BE trial simulations were employed to find the formulations likely to be declared bioequivalent and nonbioequivalent (BE space). Customization of DPC tests was made by adjusting the delta of a recently described tolerated difference test (TDT) or the limits of rejection of f2. Drug ka (especially if ka is small), formulation lag time (t-lag), the number of subjects included in the BE studies, and the number of sampled time points in the DPC test were the factors that affected the most these setups of dissolution specifications. Another recently described DPC test, permutation test (PT), showed excellent statistical power. All the formulations declared as similar with PT were also bioequivalent. Similar case-specific studies may support the biowaiving of ER drug formulations based on customized DPC tests.

A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery.

Dabigatran etexilate is the orally bioavailable pro-drug of dabigatran, a direct thrombin inhibitor. Using data from eight clinical studies in healthy volunteers and patients with non-valvular atrial fibrillation (AF) or undergoing orthopaedic surgery (OS), population pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to investigate whether the PK and PD of dabigatran differ across different populations. In both healthy volunteers (n=80) and patients (n=1,965), the PK of dabigatran was best described by a two-compartment disposition model with first-order absorption and elimination. Renal function was the only covariate shown to have a clinically relevant impact on dabigatran exposure. The patient PK model was successfully applied in predicting exposure observed in the RE-LY trial evaluating dabigatran treatment in patients with non-valvular AF. The relationship between dabigatran plasma concentrations and activated partial thromboplastin time in healthy volunteers and patients (n=762) was best described with a combination of a linear model and a maximum effect (Emax) model, consistent with previous reports. PK/PD relationships were robust across the various populations tested and were not affected by any of the covariates examined. In summary, the PK of dabigatran is sufficiently consistent to allow extrapolation of data generated in healthy volunteers to patients with AF or undergoing OS.

Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial.

BACKGROUND: Dabigatran etexilate (DE) is an orally absorbed prodrug of dabigatran, a thrombin inhibitor that exerts potent anticoagulant and antithrombotic activity. OBJECTIVES: To characterize the pharmacokinetics of dabigatran in patients with non-valvular atrial fibrillation (AF) from the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial and to quantify the effect of selected factors on pharmacokinetic (PK) model parameters. PATIENTS AND METHODS: A total of 27 706 dabigatran plasma concentrations from 9522 patients who received DE 110 or 150 mg twice daily were analyzed with non-linear mixed-effects modeling. RESULTS: The pharmacokinetics of dabigatran were best described by a two-compartment disposition model with first-order absorption. The covariates creatinine clearance (CRCL), age, sex, heart failure and the ethnic subgroup 'South Asian' exhibited statistically significant effects on apparent clearance of dabigatran. Body weight and hemoglobin significantly influenced the apparent volume of distribution of the central compartment. Concomitant medication with proton-pump inhibitors, amiodarone and verapamil significantly affected the bioavailability. However, all of the statistically significant factors that were identified, except for renal function status, showed only small to moderate effects (< 26% change in exposure at steady state). On the basis of simulations from the final population PK model, a dose of 75 mg twice daily would result in similar exposure for severely renally impaired patients with CRCL of 15-30 mL min(-1) and patients with normal renal function receiving 150 mg twice daily. CONCLUSIONS: The analysis provides a thorough PK characterization of dabigatran in the AF patient population from RE-LY. None of the covariates investigated, with the exception of renal function, warrants dose adjustment.

Population pharmacokinetic modelling and simulation of single and multiple dose administration of meloxicam in cats.

The objectives of these investigations were: first, to describe the pharmacokinetic properties of meloxicam in cats following single and multiple oral administration and secondly, to simulate different oral dosage regimes for meloxicam in cats after multiple dose administration to illustrate and evaluate those dosage regimes for the alleviation of inflammation and pain in cats. Six healthy domestic short hair cats were treated orally with various dosage regimes (0.05-0.2 mg/kg/day). Plasma samples were collected at predefined times and quantitatively analysed using liquid/liquid extraction followed by reverse phase HPLC with UV-detection. Meloxicam plasma concentration data were analysed using the population pharmacokinetic approach (software: NONMEM). The final model was used to simulate different dosage regimes. The plasma concentration-time profiles of meloxicam in cats after oral single and multiple dose administration were best described by an open one-compartment model with first-order absorption and first-order elimination. Pharmacokinetic parameters were estimated to be 0.00656 L/h/kg for the total apparent body clearance (CL/F), 0.245 L/kg for the apparent volume of distribution (V/F), 1.26 1/h for the absorption constant (K(A)) and 25.7 h for the mean plasma terminal half-life. Simulations showed that the median trough steady-state concentrations of 228 ng/mL were reached after five, one or 6 days following a single initial dose of 0.05, 0.1 and 0.2 mg/kg each followed by 0.05 mg/kg/day.

Localization of carbohydrate determinants common to Biomphalaria glabrata as well as to sporocysts and miracidia of Schistosoma mansoni.

The presence of antigenic carbohydrate epitopes shared by Biomphalaria glabrata as well as by the sporocysts and miracidia representing snail-pathogenic larval stages of Schistosoma mansoni was assayed by immunohistochemical staining of paraformaldehyde-fixed tissues. To this end, both polyclonal rabbit antiserum raised against soluble egg antigens (SEA) of S. mansoni and monoclonal antibodies recognizing the carbohydrate epitopes LDN [GalNAc(beta1-4)GlcNAc(beta1-)], F-LDN [Fuc(alpha1-3)GalNAc(beta1-4)GlcNAc(beta1-)], LDN-F [GalNAc(beta1-4)[Fuc(alpha1-3)]GlcNAc(beta1-)], LDN-DF [GalNAc(beta1-4)[Fuc(alpha1-2)Fuc(alpha1-3)]GlcNAc(beta1-)] and Lewis X [Gal(beta1-4)[Fuc(alpha1-3)]GlcNAc(beta1-)] were used. Intriguingly, anti-SEA serum as well as anti-F-LDN antibodies displayed significant binding in the foot region, anterior tissue and the hepatopancreas of uninfected snails, whereas the Lewis X epitope was only weakly detectable in the latter tissue. In contrast, increased binding of antibodies recognizing LDN, LDN-F and LDN-DF was observed in infected snail tissue, in particular in regions involved in sporocystogenesis, in addition to an enhanced binding of anti-SEA serum and antibodies reacting with F-LDN. A pronounced expression of most of these carbohydrate antigens was also observed at the surface of miracidia. Hence, the detection of shared carbohydrate determinants in uninfected snail tissue, sporocysts and miracidia may support the hypothesis of carbohydrate-based molecular mimicry as a survival strategy of S. mansoni.

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.

Origins of a local hospital: the real story.

An examination of the papers that document the creation and development of America's earliest health care and social institutions reveals concerns common to both the mid-nineteenth and the late twentieth centuries. Such sources give invaluable insight into how community leaders reacted to tensions and inequalities that still exist. They explain how some organizations worked to extend the benefits of democracy to the less fortunate. The documents that contain these stories need to be preserved. A group of health care-related archival organizations in Rochester, New York has united to make their documents available to researchers.