Human mass balance, metabolite profile and identification of metabolic enzymes of [¹4C]ASP015K, a novel oral janus kinase inhibitor.

1. The human mass balance of (14)C-labelled ASP015K ([(14)C]ASP015K), an orally bioavailable Janus kinase (JAK) inhibitor, was characterized in six healthy male subjects after a single oral dose of [(14)C]ASP015K (100 mg, 3.7 MBq) in solution. [(14)C]ASP015K was rapidly absorbed with tmax of 1.6 and 1.8 h for ASP015K and total radioactivity in plasma, respectively. Mean recovery in urine and feces amounted to 36.8% and 56.6% of the administered dose, respectively. The main components of radioactivity in plasma and urine were ASP015K and M2 (5'-O-sulfo ASP015K). In feces, ASP015K and M4 (7-N-methyl ASP015K) were the main components. 2. In vitro study of ASP015K metabolism showed that the major isozyme contributing to the formation of M2 was human sulfotransferase (SULT) 2A1 and of M4 was nicotinamide N-methyltransferase (NNMT). 3. The in vitro intrinsic clearance (CLint_in vitro) of M4 formation from ASP015K in human liver cytosol (HLC) was 11-fold higher than that of M2. The competitive inhibitory effect of nicotinamide on M4 formation in the human liver was considered the reason for high CLint_in vitro of M4 formation, while each metabolic pathway made a near equal contribution to the in vivo elimination of ASP015K. ASP015K was cleared by multiple mechanisms.

Quantification of the spatial distribution of rectally applied surrogates for microbicide and semen in colon with SPECT and magnetic resonance imaging.

AIMS: We sought to describe quantitatively the distribution of rectally administered gels and seminal fluid surrogates using novel concentration-distance parameters that could be repeated over time. These methods are needed to develop rationally rectal microbicides to target and prevent HIV infection. METHODS: Eight subjects were dosed rectally with radiolabelled and gadolinium-labelled gels to simulate microbicide gel and seminal fluid. Rectal doses were given with and without simulated receptive anal intercourse. Twenty-four hour distribution was assessed with indirect single photon emission computed tomography (SPECT)/computed tomography (CT) and magnetic resonance imaging (MRI), and direct assessment via sigmoidoscopic brushes. Concentration-distance curves were generated using an algorithm for fitting SPECT data in three dimensions. Three novel concentration-distance parameters were defined to describe quantitatively the distribution of radiolabels: maximal distance (D(max) ), distance at maximal concentration (D(Cmax) ) and mean residence distance (D(ave) ). RESULTS: The SPECT/CT distribution of microbicide and semen surrogates was similar. Between 1 h and 24 h post dose, the surrogates migrated retrograde in all three parameters (relative to coccygeal level; geometric mean [95% confidence interval]): maximal distance (D(max) ), 10 cm (8.6-12) to 18 cm (13-26), distance at maximal concentration (D(Cmax) ), 3.8 cm (2.7-5.3) to 4.2 cm (2.8-6.3) and mean residence distance (D(ave) ), 4.3 cm (3.5-5.1) to 7.6 cm (5.3-11). Sigmoidoscopy and MRI correlated only roughly with SPECT/CT. CONCLUSIONS: Rectal microbicide surrogates migrated retrograde during the 24 h following dosing. Spatial kinetic parameters estimated using three dimensional curve fitting of distribution data should prove useful for evaluating rectal formulations of drugs for HIV prevention and other indications.

Changes in Health Insurance Coverage Over Time by Immigration Status Among US Older Adults, 1992-2016.

Importance: Disparities in health insurance coverage by immigration status are well documented; however, there are few data comparing long-term changes in insurance coverage between immigrant and nonimmigrant adults as they age into older adulthood. Objective: To compare longitudinal changes in insurance coverage over 24 years of follow-up between recent immigrant, early immigrant, and nonimmigrant adults in the US. Design, Setting, and Participants: This population-based cohort study used data from the nationally representative Health and Retirement Study. Data were collected biennially from 1992 to 2016. The population included community-dwelling US adults born between 1931 and 1941 and aged 51 to 61 years at baseline. Statistical analysis was performed from February 3, 2017, to January 10, 2020. Exposures: Participants were categorized as nonimmigrants (born in the US), early immigrants (immigrated to the US before the age of 18 years), and recent immigrants (immigrated to the US from the age of 18 years onward). Main Outcomes and Measures: Self-reported data on public, employer, long-term care, and other private insurance were used to define any insurance coverage. Longitudinal changes in insurance coverage were examined over time by immigration status using generalized estimating equations accounting for inverse probability of attrition weights. The association between immigration status and continuous insurance coverage was also evaluated. Results: A total of 9691 participants were included (mean [SD] age, 56.0 [3.2] years; 5111 [52.6%] female). Nonimmigrants composed 90% (n = 8649) of the cohort; early immigrants, 2% (n = 201); and recent immigrants, 8% (n = 841). Insurance coverage increased from 68%, 83%, and 86% of recent immigrant, early immigrant, and nonimmigrant older adults, respectively, in 1992 to 97%, 100%, and 99% in 2016. After accounting for selective attrition, recent immigrants were 15% less likely than nonimmigrants to have any insurance at baseline (risk ratio, 0.85; 95% CI, 0.82-0.88), driven by lower rates of private insurance. However, disparities in insurance decreased incrementally over time and were eliminated, such that insurance coverage rates were similar between groups as participants attained Medicare age eligibility. Furthermore, recent immigrants were less likely than nonimmigrants to be continuously insured (risk ratio, 0.89; 95% CI, 0.85-0.94). Conclusions and Relevance: Among community-dwelling adults who were not age eligible for Medicare, recent immigrants had lower rates of health insurance, but this disparity was eliminated over the 24-year follow-up period because of uptake of public insurance among all participants. Future studies should evaluate policies and health care reforms aimed at reducing disparities among vulnerable populations such as recent immigrants who are not age eligible for Medicare.