Justification for a Fixed Dose of Eflapegrastim, a Long-Acting G-CSF, in Patients Receiving Docetaxel-Cyclophosphamide Chemotherapy.

Eflapegrastim (Rolontis) is a long-acting granulocyte colony-stimulating factor (G-CSF) produced by conjugating a human G-CSF analogue and a human immunoglobulin G4 Fc fragment, linked via a polyethylene glycol linker. Weight-based doses of 45 to 270 µg/kg eflapegrastim (12.3-73.6 µg/kg as G-CSF) were evaluated in a phase 2 study in patients. Based on these results, a fixed dose of 13.2 mg eflapegrastim (3.6 mg G-CSF) was compared with pegfilgrastim (6 mg G-CSF) in 2 phase 3 studies and in a pharmacokinetic single-arm multicenter study. Absolute neutrophil count (ANC) data from these 3 studies were evaluated in patients with early-stage breast cancer who were treated with docetaxel and cyclophosphamide (n = 669). Serum concentrations of eflapegrastim were determined by enzyme-linked immunosorbent assay. Eflapegrastim systemic exposures were higher in cycle 1 than in cycle 3, likely attributable to the higher ANC in cycle 3, increasing neutrophil-mediated clearance. Eflapegrastim elicited a greater effect on ANC than pegfilgrastim in patients at ∼60% of the G-CSF dose. Body weight had no clinically significant effect on response, justifying administration of a fixed dose of eflapegrastim. The results from 2 phase 3 studies demonstrate that eflapegrastim at a fixed dose of 13.2 mg (3.6 mg G-CSF) administered once per chemotherapy cycle is effective in prophylactic treatment of chemotherapy-induced neutropenia.

Eflapegrastim's enhancement of efficacy compared with pegfilgrastim in neutropenic rats supports potential for same-day dosing.

Eflapegrastim (Rolontis) is a long-acting granulocyte colony-stimulating factor (G-CSF) with an IgG4 Fc fragment and short polyethylene glycol linker. Current G-CSF products are administered 24 hours after chemotherapy. The present study compares the duration of neutropenia (DN) with eflapegrastim or pegfilgrastim at 0, 2, 5, or 24 hours post chemotherapy. Eflapegrastim was evaluated by G-CSF receptor binding and bone marrow cell proliferation assays in vitro. Eflapegrastim-Fc component binding to Fcγ receptors C1q and FcRn was assessed by enzyme-linked immunosorbent assay. Neutropenia was induced in rats via intraperitoneal cyclophosphamide or docetaxel/cyclophosphamide. Rats received chemotherapy followed by vehicle, pegfilgrastim, or eflapegrastim at 2, 5, or 24 hours. The difference in DN after treatment was assessed. In vitro binding to G-CSF receptor of both agents was similar. Binding to FcRn and no binding to Fcγ receptors or C1q were observed with eflapegrastim. Studies in chemotherapy-induced neutropenic rats revealed shorter DN with eflapegrastim versus pegfilgrastim. Increased levels of G-CSF in serum and marrow were observed in groups treated with eflapegrastim versus those treated with pegfilgrastim. Although eflapegrastim and pegfilgrastim have similar in vitro binding affinity, the Fc fragment in eflapegrastim increases the uptake into bone marrow, resulting in increased therapeutic potential for chemotherapy-induced neutropenia. Eflapegrastim's greater marrow resident time provided a pharmacodynamic advantage over pegfilgrastim, translating into shortened duration of neutropenia. Our findings support eflapegrastim same-day administration with chemotherapy, warranting further evaluation in patients undergoing myelosuppressive chemotherapy.

Exposure-Response Analysis for Mogamulizumab in Adults With Cutaneous T-Cell Lymphoma.

Mogamulizumab is a humanized monoclonal antibody against C-C chemokine receptor 4 approved in the United States for the treatment of patients with relapsed/refractory mycosis fungoides or Sézary syndrome, the most common forms of cutaneous T-cell lymphoma (CTCL). The exposure-response relationships for efficacy (progression-free survival [PFS] and overall response rate [ORR]) and safety (the 5 most common treatment-related adverse events by Medical Dictionary for Regulatory Activities [MedDRA] System Organ Class) for 184 patients with CTCL treated with mogamulizumab in a large, registrational clinical trial. Exposure metrics were area under the serum mogamulizumab concentration-time curve over the dose interval at steady state (AUCss ) and minimum serum mogamulizumab concentration after the first dose (Cmin,1st ). PFS by investigator assessment, the primary efficacy objective, and PFS and ORR by independent review were not correlated with exposure metrics; however, there was a statistically significant positive relationship between a secondary objective, ORR by investigator assessment, and AUCss (P = .0168). The frequency of treatment-related adverse events was not related to exposure metrics (Cmin,1st or AUCss ) for any of the MedDRA System Organ Classes examined. Of the covariates that were found to have a statistically significantly effect on the population PK model (ie, albumin, aspartate aminotransferase, body surface area, mild to moderate hepatic impairment, and sex), none was found to impact efficacy or safety, indicating that there is no need to modify dose on the basis of these parameters.

Population Pharmacokinetic Modeling of Mogamulizumab in Adults With Cutaneous T-Cell Lymphoma or Adult T-Cell Lymphoma.

Cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia/lymphoma (ATL) are rare non-Hodgkin lymphomas commonly expressing C-C chemokine receptor 4 (CCR4). Mogamulizumab is a humanized monoclonal antibody against CCR4 approved in the United States for the treatment of patients with relapsed/refractory mycosis fungoides or Sézary syndrome, the most common forms of CTCL. Pharmacokinetic (PK) and clinical study data from 444 adult patients with ATL or CTCL collected during 6 clinical trials of mogamulizumab were used to construct a population PK model, which was best described by a 2-compartment model with linear clearance. Albumin, aspartate aminotransferase, mild-to-moderate hepatic impairment, and sex were statistically significant predictors of clearance; albumin was also a statistically significant predictor of peripheral volume of distribution; and body surface area was a statistically significant predictor for central volume of distribution. None of the other covariates-for example, age, body weight, body mass index, bilirubin, creatinine clearance, disease type (ATL and CTCL), ATL subtype (acute, lymphoma, and chronic), CTCL subtype (mycosis fungoides and Sézary syndrome), CCR4 expression (status or degree), race (Japanese and non-Japanese), renal impairment (normal, mild, moderate, and severe), or performance status-had a statistically significant impact. Performance of the final population PK model was acceptable. This model will be valuable for guiding further studies of mogamulizumab.

Outcome prediction from post-injury resilience in patients with TBI.

PURPOSE/OBJECTIVE: The objective of the study was to evaluate the extent to which 1- and 2-year outcomes after traumatic brain injury (TBI) are predicted by resilience. Research Method/Design: This was an observational, longitudinal study of persons (n = 158) with moderate or severe TBI who completed both 1- and 2-year outcome assessments. Outcomes included anxiety (Generalized Anxiety Disorder-7), depression (Patient Health Questionnaire-9), life satisfaction (Satisfaction with Life Scale), substance misuse, and return-to-work measures. The Connor-Davidson Resilience Scale was used to assess resilience at 3 or 6 months after injury. RESULTS: Greater resilience predicted less anxiety, depression, and substance use and better satisfaction with life and return to work at 1 year after injury for both adjusted and unadjusted models. Standardized regression coefficients were all greater than 0.38 for continuous outcomes, whereas odds ratios were 1.34 and 0.81 for the return to work and substance misuse outcomes, respectively (p < .05). Similar but weaker trends were found at 2 years after injury, with statistical significance no longer met for all outcomes. CONCLUSIONS/IMPLICATIONS: Resilience was shown to have predictive ability for outcomes at 1 and 2 years after TBI. Resilience appears to be a salient and important variable for long-term outcomes in person with TBI after adjusting for injury and demographic characteristics. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Predictive utility of an adapted Marshall head CT classification scheme after traumatic brain injury.

OBJECTIVE: To study the predictive relationship among persons with traumatic brain injury (TBI) between an objective indicator of injury severity (the adapted Marshall computed tomography [CT] classification scheme) and clinical indicators of injury severity in the acute phase, functional outcomes at inpatient rehabilitation discharge, and functional and participation outcomes at 1 year after injury, including death. PARTICIPANTS: The sample involved 4895 individuals who received inpatient rehabilitation following acute hospitalization for TBI and were enrolled in the Traumatic Brain Injury Model Systems National Database between 1989 and 2014. DESIGN: Head CT variables for each person were fit into adapted Marshall CT classification categories I through IV. MAIN MEASURES: Prediction models were developed to determine the amount of variability explained by the CT classification categories compared with commonly used predictors, including a clinical indicator of injury severity. RESULTS: The adapted Marshall classification categories aided only in the prediction of craniotomy or craniectomy during acute hospitalization, otherwise making no meaningful contribution to variance in the multivariable models predicting outcomes at any time point after injury. CONCLUSION: Results suggest that head CT findings classified in this manner do not inform clinical discussions related to functional prognosis or rehabilitation planning after TBI. ABBREVIATIONS: CT: computed tomography; DRS: disability rating scale; EGOS: extended Glasgow outcome scale; FIM: functional independence measure; NDB: National Data Base; PTA: posttraumatic amnesia; RLOS: rehabilitation length of stay; SPOS: semipartial omega squared statistic; TBI: traumatic brain injury; TBIMS: Traumatic Brain Injury Model Systems.

Accuracy of ultrasound-guided versus palpation-based carpometacarpal joint injections: A randomized pilot study in cadavers.

OBJECTIVE: To determine the accuracy of ultrasound guidance compared to palpation in performing carpometacarpal joint injections in cadavers. DESIGN: In all, 36 carpometacarpal joints were randomized to either ultrasound-guided or palpation-based injections, with 1 cc of blue latex solution injected into each joint. The specimens were then dissected and the distribution of the latex was assessed by two independent, blinded raters. Injection accuracy was evaluated on a four-point quartile rating scale of 1-4, corresponding to the amount of the latex solution within the joint (1 = 0-25%, 2 = 26-50%, 3 = 51-75%, 4 = 76-100%). Inter-rater reliability was a secondary measure. RESULTS: The mean rating of accuracy was 2.1 for both palpation-based and ultrasound-guided injections. There was no statistically significant difference in accuracy between the two injectors. Chi-square analysis testing differences in accuracy for the two conditions was not statistically significant. The Cronbach's alpha for rater 2 was 0.74, which represents an acceptable level of reliability. A Friedman's Chi-square for the two raters was 2.3 (p = 0.13), indicating no significant difference between raters. CONCLUSION: Ultrasound guidance did not improve the accuracy of carpometacarpal joint injections in cadavers. However, the high inter-rater reliability attests to the value of the novel assessment scale.

Race/Ethnicity and Retention in Traumatic Brain Injury Outcomes Research: A Traumatic Brain Injury Model Systems National Database Study.

OBJECTIVE: To investigate the contribution of race/ethnicity to retention in traumatic brain injury (TBI) research at 1 to 2 years postinjury. SETTING: Community. PARTICIPANTS: With dates of injury between October 1, 2002, and March 31, 2013, 5548 whites, 1347 blacks, and 790 Hispanics enrolled in the Traumatic Brain Injury Model Systems National Database. DESIGN: Retrospective database analysis. MAIN MEASURE: Retention, defined as completion of at least 1 question on the follow-up interview by the person with TBI or a proxy. RESULTS: Retention rates 1 to 2 years post-TBI were significantly lower for Hispanic (85.2%) than for white (91.8%) or black participants (90.5%) and depended significantly on history of problem drug or alcohol use. Other variables associated with low retention included older age, lower education, violent cause of injury, and discharge to an institution versus private residence. CONCLUSIONS: The findings emphasize the importance of investigating retention rates separately for blacks and Hispanics rather than combining them or grouping either with other races or ethnicities. The results also suggest the need for implementing procedures to increase retention of Hispanics in longitudinal TBI research.

Longitudinal Examination of Resilience After Traumatic Brain Injury: A Traumatic Brain Injury Model Systems Study.

OBJECTIVES: To evaluate (1) the trajectory of resilience during the first year after a moderate-severe traumatic brain injury (TBI); (2) factors associated with resilience at 3, 6, and 12 months postinjury; and (3) changing relationships over time between resilience and other factors. DESIGN: Longitudinal analysis of an observational cohort. SETTING: Five inpatient rehabilitation centers. PARTICIPANTS: Patients with TBI (N=195) enrolled in the resilience module of the TBI Model Systems study with data collected at 3-, 6-, and 12-month follow-up. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Connor-Davidson Resilience Scale. RESULTS: Initially, resilience levels appeared to be stable during the first year postinjury. Individual growth curve models were used to examine resilience over time in relation to demographic, psychosocial, and injury characteristics. After adjusting for these characteristics, resilience actually declined over time. Higher levels of resilience were related to nonminority status, absence of preinjury substance abuse, lower anxiety and disability level, and greater life satisfaction. CONCLUSIONS: Resilience is a construct that is relevant to understanding brain injury outcomes and has potential value in planning clinical interventions.

Effects of Rifampin on the Pharmacokinetics of a Single Dose of Istradefylline in Healthy Subjects.

Istradefylline, a selective adenosine A2A inhibitor, is under development for the treatment of Parkinson's disease. The effect of oral steady-state rifampin 600 mg/day, a potent cytochrome P450 (CYP) 3A4 inducer, on the disposition of a single oral dose of istradefylline 40 mg was determined in a crossover study in 20 healthy subjects by measuring plasma concentrations of istradefylline and its M1 and M8 metabolites and their derived pharmacokinetic parameters. Based on the geometric mean ratio of log-transformed data, rifampin reduced istradefylline exposure: Cmax , 0.55 (90%CI, 0.49-0.62); AUClast , 0.21 (90%CI, 0.19-0.22); and AUCinf , 0.19 (90%CI, 0.18-0.20), indicating nonequivalence. These changes were primarily because of the effect of rifampin on the elimination parameters of istradefylline; mean CL/F was increased from 4.0 to 20.6 L/h, and mean t1/2 was reduced from 94.8 to 31.5 hours. The effect of rifampin coadministration on the disposition of the istradefylline M1 and M8 metabolites was inconsistent and variable. Furthermore, as exposure of the istradefylline M1 and M8 metabolites in plasma was generally <9% of total drug exposure, it would be expected to have a negligible impact on the pharmacodynamic effect of istradefylline. Caution should be exercised when istradefylline is administered concurrently with strong CYP3A4 inducers and dose adjustment considered.

Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study.

OBJECTIVE: Determine incidence of posttraumatic seizure (PTS) following traumatic brain injury (TBI) among individuals with moderate-to-severe TBI requiring rehabilitation and surviving at least 5 years. METHODS: Using the prospective TBI Model Systems National Database, we calculated PTS incidence during acute hospitalization, and at years 1, 2, and 5 postinjury in a continuously followed cohort enrolled from 1989 to 2000 (n = 795). Incidence rates were stratified by risk factors, and adjusted relative risk (RR) was calculated. Late PTS associations with immediate (<24 h), early (24 h-7 day), or late seizures (>7 day) versus no seizure prior to discharge from acute hospitalization was also examined. RESULTS: PTS incidence during acute hospitalization was highest immediately (<24 h) post-TBI (8.9%). New onset PTS incidence was greatest between discharge from inpatient rehabilitation and year 1 (9.2%). Late PTS cumulative incidence from injury to year 1 was 11.9%, and reached 20.5% by year 5. Immediate/early PTS RR (2.04) was increased for those undergoing surgical evacuation procedures. Late PTS RR was significantly greater for individuals who self-identified as a race other than black/white (year 1 RR = 2.22), and for black individuals (year 5 RR = 3.02) versus white individuals. Late PTS was greater for individuals with subarachnoid hemorrhage (year 1 RR = 2.06) and individuals age 23-32 (year 5 RR = 2.43) and 33-44 (year 5 RR = 3.02). Late PTS RR years 1 and 5 was significantly higher for those undergoing surgical evacuation procedures (RR: 3.05 and 2.72, respectively). SIGNIFICANCE: In this prospective, longitudinal, observational study, PTS incidence was similar to that in studies published previously. Individuals with immediate/late seizures during acute hospitalization have increased late PTS risk. Race, intracranial pathologies, and neurosurgical procedures also influenced PTS RR. Further studies are needed to examine the impact of seizure prophylaxis in high-risk subgroups and to delineate contributors to race/age associations on long-term seizure outcomes.

Resilience Following Traumatic Brain Injury: A Traumatic Brain Injury Model Systems Study.

OBJECTIVE: To examine resilience at 3 months after traumatic brain injury (TBI). DESIGN: Cross-sectional analysis of an ongoing observational cohort. SETTING: Five inpatient rehabilitation centers, with 3-month follow-up conducted primarily by telephone. PARTICIPANTS: Persons with TBI (N=160) enrolled in the resilience module of the TBI Model System study with 3-month follow-up completed. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Connor-Davidson Resilience Scale. RESULTS: Resilience scores were lower than those of the general population. A multivariable regression model, adjusting for other predictors, showed that higher education, absence of preinjury substance abuse, and less anxiety at follow-up were significantly related to greater resilience. CONCLUSIONS: Analysis suggests that lack of resilience may be an issue for some individuals after moderate to severe TBI. Identifying persons most likely at risk for low resilience may be useful in planning clinical interventions.

Neuropsychological care and rehabilitation of cancer patients with chemobrain: strategies for evaluation and intervention development.

Malignant tumors and their various treatments such as chemotherapy, radiotherapy and hormonal therapy can deleteriously affect a large number of cancer patients and survivors on multiple dimensions of psychosocial and neurocognitive functioning. Oncology researchers and clinicians are increasingly cognizant of the negative effects of cancer and its treatments on the brain and its mental processes and cognitive outcomes. Nevertheless, effective interventions to treat cancer and treatment-related neurocognitive dysfunction (CRND), also known as chemobrain, are still lacking. The paucity of data on effective treatments for CRND is due, at least partly, to difficulties understanding its etiology, and a lack of reliable methods for assessing its presence and severity. This paper provides an overview of the incidence, etiology, and magnitude of CRND, and discusses the plausible contributions of psychological, motor function, and linguistic and behavioral complications to CRND. Strategies for reliable neuropsychological screening and assessment, and development and testing of effective ways to mitigate CRND are also discussed.

Neuromuscular electrical stimulation efficacy in acute stroke feeding tube-dependent dysphagia during inpatient rehabilitation.

OBJECTIVE: The aim of this study was to compare the efficacy of neuromuscular electrical stimulation (NMES) in addition to traditional dysphagia therapy (TDT) including progressive resistance training (PRT) with that of TDT/PRT alone during inpatient rehabilitation for treatment of feeding tube-dependent dysphagia in patients who have had an acute stroke. DESIGN: This study is an inpatient rehabilitation case-control study involving 92 patients who have had an acute stroke with initial Functional Oral Intake Scale (FOIS) scores of 3 or lower and profound to severe feeding tube-dependent dysphagia. Sixty-five patients, the NMES group, received NMES with TDT/PRT, and 27 patients, the case-control group, received only TDT/PRT. Treatment occurred in hourly sessions daily for a mean ± SD of 18 ± 3 days. χ(2) Analyses/t tests revealed no significant statistical differences between the groups for age (t = -0.85; P = 0.40), sex (χ(2) = 0.05; P = 0.94), and stroke location (χ(2) = 4.2; P = 0.24). A Mann-Whitney U test revealed a statistically significant difference between the groups for the initial FOIS score (z = -2.4; P = 0.015), with the NMES group having worse initial scores with a mean rank of 42.64 and the case-control TDT/PRT group having a mean rank of 55.8. The main outcome measure was the comparison of the FOIS scores after treatment. RESULTS: The mean ± SD FOIS score after NMES with TDT/PRT treatment was 5.1 ± 1.8 compared with 3.3 ± 2.2 in the case-control TDT/PRT group. The mean gain for the NMES group was 4.4 points; and for the case-control group, 2.4 points. Significant improvement in swallowing performance was found for the NMES group compared with the TDT/PRT group (z = 3.64; P < 0.001). Within the NMES group, 46% (30 of 65) of the patients had minimal or no swallowing restrictions (FOIS score of 5-7) after treatment, whereas 26% (7 of 27) of those in the case-control group improved to FOIS scores of 5-7, a statistically significant difference (χ(2) = 6.0; P = 0.01). CONCLUSIONS: This study suggests that NMES with TDT/PRT is significantly more effective than TDT/PRT alone during inpatient rehabilitation in reducing feeding tube-dependent dysphagia in patients who have had an acute stroke.

Satraplatin, an oral platinum, administered on a five-day every-five-week schedule: a pharmacokinetic and food effect study.

PURPOSE: The study aimed to assess the pharmacokinetic behavior of satraplatin under fasted and fed conditions, and its safety and preliminary antitumor activity in adults with advanced solid tumors. EXPERIMENTAL DESIGN: Satraplatin was administered orally at 80 mg/m(2) once daily with prophylactic antiemetics for 5 consecutive days every 5 weeks. Patients were randomized to receive day 1 and day 5 doses of satraplatin in either the fed or fasted state, the order being reversed for cycle 2. Pharmacokinetic sampling was done during the first two cycles. For all subsequent cycles, patients received satraplatin in the fasted state. RESULTS: Seventeen patients were treated with 60 total cycles of satraplatin. There was no dose-limiting toxicity during cycle 1. Severe hematologic toxicity was rare and the hematologic nadir occurred during week 4. Nausea, vomiting, and diarrhea were grade 1/2. No significant cardiac, renal, hepatic, or neurologic toxicity was observed. The hypothesis that food decreased ultrafiltrate platinum bioavailability could not be rejected, as the lower limit of the 90% confidence intervals for peak plasma concentration and area under the concentration-time curve from time 0 to 24 hours were 56.14% and 73.53%, respectively, both below the 80% bioequivalence acceptance criterion. One partial response (hormone refractory prostate cancer) and four durable stable diseases (breast, ovarian, parotid, and hormone refractory prostate cancer) were confirmed. CONCLUSIONS: There is an effect of food on the pharmacokinetics of satraplatin, the clinical significance of which is unclear. It is recommended that satraplatin be administered in the fasting state. This 5-week interval schedule of satraplatin was well tolerated in heavily pretreated patients.

Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion.

OBJECTIVE: To evaluate the impact of prior intensive diabetes therapy on neuropathy among former Diabetes Control and Complications Trial (DCCT) participants. RESEARCH DESIGN AND METHODS: At the conclusion of the DCCT, subjects in the intensive group were encouraged to maintain intensive therapy, and subjects in the conventional group were encouraged to begin intensive therapy. Thereafter, we annually assessed neuropathy as part of the Epidemiology of Diabetes Intervention and Complications (EDIC) study. Neuropathy was defined using the Michigan Neuropathy Screening Instrument (MNSI). We recorded potential adverse consequences of neuropathy. RESULTS: At the first EDIC examination, 1,257 subjects participated in the neuropathy assessment. Consistent with DCCT results, the former intensive group showed a lower prevalence of neuropathy than the conventional group based on positive questionnaire (1.8 vs. 4.7%; P = 0.003) or examination (17.8 vs. 28.0%; P < 0.0001) results. Despite similar levels of glycemic control, symptoms and signs of neuropathy remained less prevalent among the former intensive group compared with the conventional group. At the beginning of the EDIC study, prior intensive therapy reduced the odds of having symptoms and signs of neuropathy using MNSI criteria by 64% (P = 0.0044) and 45% (P < 0.0001), respectively, with similar odds reductions observed for both neuropathic symptoms (51%, P < 0.0001) and neuropathic signs (43%, P < 0.0001) across 8 years of EDIC follow-up. CONCLUSIONS: The benefits of 6.5 years of intensive therapy on neuropathy status extended for at least 8 years beyond the end of the DCCT, similar to the findings described for diabetic retinopathy and nephropathy.

Regulation of the human taurine transporter by oxidative stress in retinal pigment epithelial cells stably transformed to overexpress aldose reductase.

In diabetes, overexpression of aldose reductase (AR) and consequent glucose-induced impairment of antioxidant defense systems may predispose to oxidative stress and the development of diabetic complications, but the mechanisms are poorly understood. Taurine (2-aminoethanesulfonic acid) functions as an antioxidant, osmolyte, and calcium modulator such that its intracellular depletion could promote cytotoxicity in diabetes. The relationships of oxidative stress and basal AR gene expression to Na+-taurine cotransporter (TT) gene expression, protein abundance, and TT activity were therefore explored in low AR-expressing human retinal pigment epithelial (RPE) 47 cells and RPE 47 cells stably transformed to overexpress AR (RPE 75). Changes in TT gene expression were determined using a 4.6-kb TT promoter-luciferase fusion gene. Compared with RPE 47 cells, in high AR-expressing RPE 75 cells, TT promoter activity was decreased by 46%, which was prevented by an AR inhibitor. TT promoter activity increased up to 900% by prooxidant exposure, which was associated with increased TT peptide abundance and taurine transport. However, induction of TT promoter activity by oxidative stress was attenuated in high AR-expressing cells and partially corrected by AR inhibitor. Finally, exposure of RPE 75 cells to high glucose increased oxidative stress, but down-regulated TT expression. These studies demonstrate for the first time that the TT is regulated by oxidative stress and that overexpression of AR and high glucose impair this response. Abnormal expression of AR may therefore impair antioxidant defense, which may determine tissue susceptibility to chronic diabetic complications.

Preclinical pharmacokinetics of a novel HIV-1 attachment inhibitor BMS-378806 and prediction of its human pharmacokinetics.

BMS-378806 is a prototype of novel HIV attachment inhibitors that block the gp120 and CD4 interaction, the first step of HIV-1 entry into cells. The present work investigated the pharmacokinetics of BMS-378806 in rats, dogs and monkeys and assessed its in vitro permeability and metabolism. BMS-378806 exhibited species-dependent oral bioavailability which was 19%-24% in rats and monkeys and 77% in dogs. In rats and monkeys, absorption was prolonged, with an apparent terminal half-life of 2.1 and 6.5 h, respectively. In rats, linear pharmacokinetics was observed between i.v. doses of 1 and 5 mg/kg and between p.o. doses of 5 and 25 mg/kg. The total body clearance was intermediate in rats and low in dogs and monkeys. The steady-state volume of distribution was moderate (0.4-0.6 l/kg), contributing to a short half-life (0.3-1.2 h) after i.v. dosing. Studies in bile-duct cannulated rats together with intraportal infusion studies revealed that the renal and hepatic clearance each accounted for 30% and 70% of the total elimination in rats, with the hepatic clearance largely being oxidative metabolism. In vitro, BMS-378806 was not highly protein bound (44%-73%). The Caco-2 permeability was modest (51 nm/s) and confounded by P-glycoprotein mediated efflux transport. Both of these may contribute to the low brain penetration observed in rats (brain/plasma AUC ratio=0.06). In human liver microsomes BMS-378806 was equally metabolized by cytochrome P450 1A2, 2D6 and 3A4 and did not inhibit major drug-metabolizing enzymes to a significant extent. Based on in vitro and animal data, a mechanistic approach that factors in absorption and first-pass metabolism was employed to predict the human oral bioavailability of BMS-378806 (ca 20%). This, together with the complex Dedrick plot method, was used to simulate human oral profiles and to project an efficacious dose. These study results offer a comprehensive assessment of the developability of BMS-378806 and provide important guidance to improving absorption and half-life of future compounds in the series. The current studies also demonstrate the value and approaches of understanding pharmacokinetic properties in the early stage of drug discovery.