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Darwish M.,Clinical Pharmacology | Bond M.,R and D Inc. | Ricciotti N.,R and D Inc. | Hsieh J.,R and D Inc. | 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.


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.


Burke J.M.,Rocky Mountain Cancer Centers | Burke J.M.,Us Oncology Research | Hellriegel E.,Teva Branded Pharmaceutical Products R and D Inc. | Robertson Jr. P.,Teva Branded Pharmaceutical Products R and D Inc. | And 4 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2014

Purpose: Bendamustine plus rituximab has been reported to be effective in treating lymphoid malignancies. This analysis investigated the potential for drug-drug interactions between the drugs in patients with indolent non-Hodgkin lymphoma or mantle cell lymphoma. Methods: Data were derived from a bendamustine-rituximab combination therapy study, a bendamustine monotherapy study, and published literature on rituximab monotherapy and combination therapy. Analysis of the potential for rituximab to affect bendamustine systemic exposure included comparing bendamustine concentration-time profile following monotherapy to that following combination therapy and comparing model-predicted Bayesian bendamustine clearance in the presence and absence of rituximab. Analysis of the potential for bendamustine to affect rituximab systemic exposure included plotting observed minimum, median, and maximum serum rituximab concentrations at the end of rituximab infusion (EOI) and 24 h and 7 days post-infusion in patients receiving combination therapy versus concentrations reported in literature following rituximab monotherapy. Results: The established population pharmacokinetic model following bendamustine monotherapy was evaluated to determine its applicability to combination therapy for the purpose of confirming lack of pharmacokinetic interaction. The model adequately described the bendamustine concentration-time profile following monotherapy and combination therapy in adults. There was no statistically significant difference in estimated bendamustine clearance either alone or in combination. Also, rituximab concentrations from EOI to 24 h and 7 days demonstrated a pattern of decline similar to that seen in rituximab studies without bendamustine, suggesting that bendamustine does not affect the rituximab clearance rate. Conclusions: Neither bendamustine nor rituximab appears to affect systemic exposure of the other drug when coadministered. © 2014 The Author(s).


PubMed | Teva Pharmaceuticals and Cognigen Corporation
Type: Journal Article | Journal: Journal of clinical pharmacology | Year: 2016

Population pharmacokinetic models for armodafinil and its major metabolites, R-modafinil acid and modafinil sulfone, were developed, and selected covariates were investigated. Data from 583healthy subjects and patients with bipolar I disorder in 11 phase 1-3 studies (8027 concentrations) of armodafinil, given as single or multiple once-daily doses (50- to 400-mg tablet or capsule), were pooled. A previously developed 1-compartment model with first-order absorption without covariate effects was initially applied to pooled phase 1 and 2 data. After covariate analysis, the phase 3 data were pooled with the phase 1 and 2 data set and the model was refined again using a second backward elimination step. Population modeling was performed with NONMEM version 7 with the first-order conditional estimation method. Estimated armodafinil apparent oral clearance (CL/F), volume of distribution (Vc/F), and absorption t


Pai A.B.,Albany College of Pharmacy and Health Sciences | Nielsen J.C.,Cognigen Corporation | Kausz A.,AMAG Pharmaceuticals | Miller P.,AMAG Pharmaceuticals | And 2 more authors.
Clinical Pharmacology and Therapeutics | Year: 2010

Intravenous (IV) iron is used to treat iron-deficiency anemia in patients with chronic kidney disease (CKD). Ferumoxytol is a novel iron formulation administered rapidly as two IV boluses of 510mg each. In this placebo-controlled, double-blind, parallel-group study, 58 healthy volunteers received ferumoxytol in two 510mg doses administered 24h apart. Population pharmacokinetics (PK) analysis was conducted, and a two-compartment open model with zero-order input and Michaelis-Menten elimination was found to best describe the data. The population mean estimates for volume of distribution of the central compartment (V1), maximal elimination rate (V max), and ferumoxytol concentration at which rate of metabolism would be one-half of Vmax (Km) were 2.71l, 14.3mg/h, and 77.5mg/l, respectively. When the effect of body weight on V1 was added in the analysis, interindividual variability was found to be reduced. A noncompartmental analysis of two simulated 510-mg ferumoxytol doses was also performed to provide clinically interpretable data on half life and exposure. Ferumoxytol given as two consecutive 510-mg doses was well tolerated. © 2010 American Society for Clinical Pharmacology and Therapeutics.


Flanagan S.,Cubist | Passarell J.,Cognigen Corporation | Lu Q.,Cognigen Corporation | Fiedler-Kelly J.,Cognigen Corporation | And 2 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

Tedizolid phosphate is a novel antibacterial prodrug that is rapidly and extensively converted to its active moiety, tedizolid. We developed a population pharmacokinetics (PK) model for tedizolid using pooled data from seven densely and sparsely sampled clinical trials evaluating oral and intravenous tedizolid. Model-derived exposure estimates were evaluated for relationships to select efficacy and safety outcomes. A two-compartment model with sigmoidal absorption, absolute bioavailability, and linear elimination described the PK data well. Variability was small (clearance, 31% coefficient of variation; volume, 13.4% coefficient of variation), and absolute bioavailability was high (86%). No clinically significant covariate effects on tedizolid PK were found. Based on phase 3 data evaluating 200-mg once-daily tedizolid for acute bacterial skin and skin structure infections (ABSSSI), no relationships were seen between various efficacy outcomes and estimated tedizolid exposure; the estimated exposure range (free-drug area under the concentration-time curve over 24 h at steady state [AUCss(0-24)], 7 to 50 μg • h/ml) in these patients was modest. Safety data modeling, using once-daily doses of up to 400 mg, showed a small increase in the probability of an adverse event with increasing model-estimated tedizolid exposure; no such relationship was observed when specifically evaluating the 200-mg dose. There were no trends in neutrophil or platelet counts with increasing tedizolid exposure. Target attainment simulations for 200-mg tedizolid indicated a 98.31% probability of attaining the target measure (AUC for the free, unbound fraction of a drug [fAUC]/MIC = 3) against a Staphylococcus aureus strain for which the MIC was ≤0.5 μg/ml. These findings support 200-mg tedizolid once daily as the optimum dose for treatment of ABSSSI. Copyright © 2014, American Society for Microbiology. All Rights Reserved.


Owen J.S.,Cognigen Corporation | Owen J.S.,Union University at Jackson | Melhem M.,Cognigen Corporation | Melhem M.,Eli Lilly and Company | And 4 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2010

Purpose: The pharmacokinetic profiles of bendamustine and active metabolites were defined in patients with rituximab-refractory, relapsed indolent B-cell non-Hodgkin's lymphoma, and supported understanding of exposure-response relationships for efficacy and safety. Methods: Bendamustine was administered as a 60-min 120 mg/m2 intravenous infusion on days 1 and 2 of six 21-day cycles. Pharmacokinetic models were developed, with covariate assessment. Correlations between bendamustine exposure and responder status or occurrence of neutropenia, thrombocytopenia, fatigue, nausea, and vomiting were examined. Results: Following a single dose of bendamustine HCl, concentrations declined in a triphasic manner, with rapid distribution, intermediate, and slow terminal phases. The intermediate t 1/2 (40 min) was considered the pharmacologically relevant (beta elimination) t 1/2 since the initial phases accounted for 99% of the AUC. Age, sex, mild/moderate renal, or mild liver impairment did not alter pharmacokinetics. Metabolite concentrations were low relative to parent. No correlation was observed between exposure and safety or efficacy measures because of the limited range of exposures after 120 mg/m2 administration, except bendamustine C max was a significant (P value = 0.013) predictor of the probability of nausea in patients, most of whom were pretreated with antiemetics. Conclusions: The BSA-based dosing regimen for bendamustine achieved the targeted exposure and was associated with a high incidence of therapeutic response. Given the short t 1/2 and low concentrations of bendamustine observed by 12 h after dosing, the single-dose profile for bendamustine described by these analyses is expected to be representative of the multiple-dose profile. The occurrence of nausea was significantly related to bendamustine exposure, with the probability of nausea increasing as bendamustine C max increases. © 2010 Springer-Verlag.


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.


Grasela T.H.,Cognigen Corporation | Slusser R.,Rancho Palos Verdes
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.


Bihorel S.,Cognigen Corporation | Fiedler-Kelly J.,Cognigen Corporation | Ludwig E.,Cognigen Corporation | Sloan-Lancaster J.,Eli Lilly and Company | Raddad E.,Eli Lilly and Company
AAPS Journal | Year: 2014

Interleukin-1 beta (IL-1β) is an inflammatory mediator which may contribute to the pathophysiology of rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). Population pharmacokinetics (PK) of LY2189102, a high affinity anti-IL-1β humanized monoclonal immunoglobulin G4 evaluated for efficacy in RA and T2DM, were characterized using data from 79 T2DM subjects (Study H9C-MC-BBDK) who received 13 weekly subcutaneous (SC) doses of LY2189102 (0.6, 18, and 180 mg) and 96 RA subjects (Study H9C-MC-BBDE) who received five weekly intravenous (IV) doses (0.02-2.5 mg/kg). Frequency of anti-drug antibody (ADA) development appears dose-dependent and is different between studies (36.7% in Study H9C-MC-BBDK vs. 2.1% in Study H9C-MC-BBDE), likely due to several factors, including differences in patient population and background medications, administration routes, and assays. A two-compartment model with dose-dependent bioavailability best characterizes LY2189102 PK following IV and SC administration. Typical elimination and distribution clearances, central and peripheral volumes of distribution are 0.222 L/day, 0.518 L/day, 3.08 L, and 1.94 L, resulting in a terminal half-life of 16.8 days. Elimination clearance increased linearly, yet modestly, with baseline creatinine clearance and appears 37.6% higher in subjects who developed ADA. Bioavailability (0.432-0.721) and absorption half-life (94.3-157 h) after SC administration are smaller with larger doses. Overall, LY2189102 PK is consistent with other therapeutic humanized monoclonal antibodies and is likely to support convenient SC dosing. © 2014 American Association of Pharmaceutical Scientists.

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