In Vitro Metabolism of Slowly Cleared G Protein-Coupled Receptor 139 Agonist TAK-041 Using Rat, Dog, Monkey, and Human Hepatocyte Models (HepatoPac): Correlation with In Vivo Metabolism.

Hepatic metabolism of low-clearance compound TAK-041 was studied in two different in vitro model systems using rat, dog, monkey, and human suspended cryopreserved hepatocytes and HepatoPac micropatterned coculture model primary hepatocytes. The aim of this work was to investigate the most appropriate system to assess the biotransformation of TAK-041, determine any notable species difference in the rate and in the extent of its metabolic pathways, and establish correlation with in vivo metabolism. TAK-041 exhibited very low turnover in suspended cryopreserved hepatocyte suspensions for all species, with no metabolites observed in human hepatocytes. However, incubations conducted for up to 14 days in the HepatoPac model resulted in more robust metabolic turnover. The major biotransformation pathways of TAK-041 proceed via hydroxylation on the benzene ring fused to the oxotriazine moiety and subsequent sulfate, glucuronide, and glutathione conjugation reactions. The glutathione conjugate of TAK-041 undergoes further downstream metabolism to produce the cysteine S-conjugate, which then undergoes N-acetylation to mercapturic acid and/or conversion to ß-lyase-derived thiol metabolites. The minor biotransformation pathways include novel ring closure and hydrolysis, hydroxylation, oxidative N-dealkylation, and subsequent reduction. The HepatoPac model shows a notable species difference in the rate and in the extent of metabolic pathways of TAK-041, with dogs having the fastest metabolic clearance and humans the slowest. Furthermore, the model shows its suitability for establishing correlation with in vivo metabolism of low-turnover and extensively metabolized compounds such as TAK-041, displaying an extensive and unusual downstream sequential ß-lyase-derived thiol metabolism in preclinical species and human. SIGNIFICANCE STATEMENT: This study investigated the most appropriate in vitro system to assess the biotransformation of the low-turnover and extensively metabolized compound TAK-041, determine any notable species difference in the rate and in the extent of its metabolic pathways, and establish correlation with in vivo metabolism. The HepatoPac model was identified and showed its suitability for species comparison and establishing correlation, with in vivo metabolism displaying an extensive and unusual downstream sequential ß-lyase-derived thiol metabolism in preclinical species and human.

Overall benefit of antiretroviral treatment on the risk of fracture in HIV: nested case-control analysis in a health-insured population.

OBJECTIVES: Fractures are common and associated with multiple risk factors. We assessed the risks of fracture associated with time-dependent, differential antiretroviral drug exposures among a cohort of persons with HIV infection. DESIGN: Nested case-control study from an HIV cohort of 59,594 medically insured persons with HIV infection enrolled in a medical care between January 1997 and March 2008. METHODS: Cases were participants with a low-impact, nontraumatic fracture identified by ICD-9-CM codes; noncases were 1:4 matched and without fracture. RESULTS: Cases included 2,477 persons with HIV infection with fractures, who were risk-set matched to 9,144 persons with HIV infection without fractures. Exposure to antiretroviral therapy by drug class and by duration (any drug/class) was associated with reduced risk for fracture. Drug-specific antiretroviral exposures over time identified an increased risk for fracture associated with darunavir, delavirdine and saquinavir, whereas reduced risk was associated with efavirenz, emtricitabine, lamivudine, tenofovir, and zidovudine. An initial null risk became a reduced risk with increased duration for nevirapine. In a similar pattern, abacavir, didanosine, nelfinavir, ritonavir and stavudine were initially associated with increased risk for fracture, after which the risk became null with increased duration of exposure. Null or uncertain risk for fracture was associated with amprenavir, atazanavir, enfuvirtide, fosamprenavir, indinavir, lopinavir, tipranavir, and zalcitabine. CONCLUSION: Our findings suggest an overall reduced risk for facture in persons treated versus not treated with antiretroviral drugs for HIV infection. Differential drug-specific exposure-response relationships for fracture will need to be further evaluated in other study populations.

Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects.

BACKGROUND: Recently, the Data collection of Adverse events of Anti-HIV Drugs Group (D:A:D) described results from their international observational cohort of 33,347 HIV-1-infected individuals, suggesting unexpected increased risk of myocardial infarction (MI) associated with abacavir (ABC) therapy [relative rate 1.9, 95% confidence interval (CI): 1.47 to 2.45; P = 0.0001]. To contribute to the scientific question, we summarized GlaxoSmithKline HIV clinical trial data to determine if a similar signal emerged. METHODS: We compiled data from GlaxoSmithKline-sponsored clinical trials with > or = 24 weeks of combination antiretroviral therapy comprising 14,174 HIV-infected adults who received ABC (n = 9502; 7641 person-years) or not (n = 4672; 4267 person-years). FINDINGS: Baseline demographics and HIV disease characteristics, including lipids and glucose values, were similar. MI rates were comparable among subjects exposed [n = 16 (0.168%; CI: 0.096 to 0.273; 2.09 per 1000 person-years)] or not [n = 11 (0.235%; CI: 0.118 to 0.421; 2.57 per 1000 person-years)] to ABC-containing therapy. Results of 12 trials with randomization to ABC or not were consistent (2.15 per 1000 person-years vs. 4.10 per 1000 person-years). INTERPRETATIONS: In this pooled summary, we observed few MI events overall and no excess risk of MI with ABC therapy. It is unclear why results from this data set seem discrepant to the Data collection of Adverse events of Anti-HIV Drugs data set, particularly, as the non-ABC MI event rate is similar. Further data are needed to evaluate any association between ABC and increased risk of MI.

Antidiabetic medication use and prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States.

OBJECTIVES: The aims of this study were to estimate the proportion of patients with type 2 diabetes mellitus (DM) in the United States with different stages of chronic kidney disease (CKD) and to describe glycemic control and antidiabetic drug use among them. METHODS: Using data from the Fourth National Health and Nutrition Examination Survey (NHANES IV) for the years 1999 through 2004, we performed a cross-sectional analysis of patients with type 2 DM aged >or=20 years at the time of the survey interview. CKD stages were categorized according to the classification system established by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Anti-diabetic medication use among these patients was described using self-reported survey responses as well as survey medication files. RESULTS: A total of 1462 patients with type 2 DM were included in the analysis. Men and women constituted 48.3% and 51.7% of the study sample, respectively; 15.6% received a DM diagnosis <2 years ago, and 36.2% received their diagnosis >10 years ago. CKD was present in 39.7% of patients with DM. Mean (SE) glycosylated hemoglobin was lower in more advanced CKD stages, from stage 1 (8.35% [0.23%]) to combined stages 4 and 5 (6.63% [0.15%]). Based on the medication file data, the proportion of patients with CKD using 1 antidiabetic medication was higher as CKD progressed, from 36.3% at stage 1 to 62.9% at stages 4 and 5 (P = 0.007). By self-report, the proportion of patients with CKD using insulin alone was 6.7% at stage 1 and 38.8% at stages 4 and 5 (P < 0.001). The proportion of patients using oral antidiabetic agents alone was 69.0% at stage 1 and 43.4% at stages 4 and 5 (P < 0.001). CONCLUSIONS: Our results indicate that 39.7% of adult patients with type 2 DM in the United States had some degree of CKD, as measured in NHANES IV for the years 1999 through 2004. This finding reinforces the need to screen patients with type 2 DM for CKD and to prevent the cascade of events leading to nephropathy by implementing adequate glycemic and blood pressure controls, especially in the early stages of CKD. Our data also reinforce the need for developing more oral antidiabetic therapies for patients with advanced CKD and type 2 DM, because treatment options for this group are limited.