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Grasela T.H.,Cognigen Corporation
Clinical Pharmacology and Therapeutics | Year: 2010

The productivity of the pharma enterprise has fallen, as evidenced by a decline in regulatory submissions and less commercial success. Two major impediments to better productivity are an empirical decision-making process and barriers between functional areas. Better integration of the functional areas is a critical missing element. We contend that this integration requires a shift to model-based drug development (MBDD), effective integrated project teams (IPTs), and a structured, disciplined, and continual evaluation of the probability that a new drug will achieve clinical and commercial success. © 2010 American Society for Clinical Pharmacology and Therapeutics. Source

Darwish M.,Science Med Bridge LLC | Megason G.,University of Mississippi | Bond M.,Teva Branded Pharmaceutical Products R and D Inc | Hellriegel E.,Teva Branded Pharmaceutical Products R and D Inc | And 3 more authors.
Current Medical Research and Opinion | Year: 2014

Objective: The pharmacokinetic (PK) profile of bendamustine has been characterized in adults with indolent non-Hodgkin lymphoma (NHL), but remains to be elucidated in pediatric patients with hematologic malignancies. This analysis used data from a nonrandomized pediatric study in patients with relapsed/refractory acute lymphocytic leukemia or acute myeloid leukemia. Methods: Bendamustine 90 or 120mg/m2 (60-minute infusion) was administered on days 1 and 2 of 21 day cycles. The population PK base model was adjusted for body surface area (BSA), and the appropriateness of the final model was evaluated by visual predictive check. A covariate analysis explored PK variability. Bayesian PK parameter estimates and concentration-time profiles for each patient were generated. Bendamustine PK in pediatric patients was compared with that of adults with indolent NHL. PK/pharmacodynamic analyses were conducted for fatigue, nausea, vomiting, and infection. Results: Thirty-eight patients (median age: 7 years; range: 1-19 years) receiving bendamustine 120mg/m2 and an additional five patients receiving bendamustine 90mg/m2 (median age: 12 years; range: 8-14 years) were included in the population PK analysis. Peak plasma concentrations of bendamustine (Cmax) occurred at the end of infusion (about 1h). Decline from peak showed a rapid distribution phase (tα=0.308h) and a slower elimination phase (tβ=1.47h). Model-predicted mean Cmax and area under the curve values from time 0-24h were 6806ng/mL and 8240ng∗h/mL, respectively. When dosed based upon BSA, it appeared that age, body weight, race, mild renal (n=3) or hepatic (n=2) dysfunction, cancer type, and cytochrome P450 1A2 inhibitors (n=17) or inducers (n=3) did not affect systemic exposure, which was comparable between pediatric and adult patients. Infection was the only adverse event associated with bendamustine Cmax. However, due to the small sample size for some subgroups, the observed trends should be interpreted with caution. Conclusions: At the recommended dose (120mg/m2), bendamustine systemic exposure was similar across the pediatric population and comparable to adults. The similarity in exposure despite the large range of BSA across pediatric and adult populations confirms the appropriateness of BSA-based dosing, which was utilized to attain systemic exposures in pediatric patients reflective of the therapeutic range in adults. Probability of occurrence of infection increased with higher bendamustine Cmax. © 2014 Informa UK Ltd. Source

Grasela T.H.,Cognigen Corporation | Slusser R.,Cognigen Corporation
Clinical Pharmacology and Therapeutics | Year: 2014

Scientific advances in specialty areas are proceeding at a rapid rate, but the research and development enterprise seems unable to take full advantage. Harnessing the steady stream of knowledge and inventions from different disciplines is the critical management issue of our time. This article suggests a framework for a management-directed effort to improve productivity by enhancing interdisciplinary collaboration. Source

Flanagan S.,Cubist Pharmaceuticals Inc. | McKee E.E.,Central Michigan University | Das D.,Catholic University of Louvain | Das D.,Novartis | And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [± standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 μMversus 6.4 ± 1.2 μM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedi-zolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies. © 2015, American Society for Microbiology. All Rights Reserved. Source

Darwish M.,Clinical Pharmacology | Bond M.,RandD Company | Ricciotti N.,RandD Company | Hsieh J.,RandD Company | And 2 more authors.
Reproductive Sciences | Year: 2014

Quartette (levonorgestrel [LNG]/ethinyl estradiol [EE] and EE) is an ascending-dose, extended-regimen combined oral contraceptive (COC) that consists of a constant dose of LNG 150 μg on days 1 to 84 with EE 20 μg on days 1 to 42, 25 μg on days 43 to 63, 30 μg on days 64 to 84, and 10 μg of EE monotherapy on days 85 to 91. A population pharmacokinetic (PK) model for EE was developed using nonlinear mixed-effects modeling to characterize the PK profile of EE administered in Quartette and other extended-regimen LNG/EE COCs. Model-predicted plasma concentration - time profiles demonstrated a stepwise increase in systemic exposure to EE during the first 84 days of the cycle following each EE dose change. Lower concentrations of EE were noted during the final 7-day period of EE 10 mg. Gradual increases in EE seen with Quartette may decrease the incidence of unscheduled bleeding frequently observed during early cycles of extended-regimen COCs. © The Author(s) 2014. Source

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