Population pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes.

Data from five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with type 2 diabetes mellitus (T2DM; N = 974; 1-100 mg q.d.; ≤12 weeks) were used to develop a population pharmacokinetic (PK) model for empagliflozin. The model consisted of two-compartmental disposition, lagged first-order absorption and first-order elimination, and incorporated appropriate covariates. Population estimates (interindividual variance, CV%) of oral apparent clearance, central and peripheral volumes of distribution, and inter-compartmental clearance were 9.87 L/h (26.9%), 3.02 L, 60.4 L (30.8%), and 5.16 L/h, respectively. An imposed allometric weight effect was the most influential PK covariate effect, with a maximum effect on exposure of ±30%, using 2.5th and 97.5th percentiles of observed weights, relative to the median observed weight. Sex and race did not lend additional description to PK variability beyond allometric weight effects, other than ∼25% greater oral absorption rate constant for Asian patients. Age, total protein, and smoking/alcohol history did not affect PK parameters. Predictive check plots were consistent with observed data, implying an adequate description of empagliflozin PKs following multiple dosing in patients with T2DM. The lack of marked covariate effects, including weight, suggests that no exposure-based dose adjustments were required within the study population and dose range.

Facilitating pharmacometric workflow with the metrumrg package for R.

metrumrg is an R package that facilitates workflow for the discipline of pharmacometrics. Support is provided for data preparation, modeling, simulation, diagnostics, and reporting. Existing tools and techniques are emphasized where available; original solutions are provided for otherwise unmet needs. In particular, metrumrg implements an R interface for the NONMEM(®) modeling software, optionally run in a distributed computing environment. The paradigm allows start-to-finish analyses in a single scripting language. Emphasis on text-based formats promotes traceability of results.

Population pharmacokinetics and exposure-response of albinterferon alfa-2b.

Albinterferon alfa-2b (albIFN) has been studied for treatment of chronic hepatitis C virus (HCV). A population pharmacokinetics model was developed using nonlinear mixed-effects modeling. Efficacy/safety exposure-response relationships were assessed for subcutaneous albIFN doses (900-1800 µg once every 2 or 4 weeks) administered for either 24 weeks (HCV genotypes 2/3) or 48 weeks (genotype 1), plus daily oral ribavirin. Sustained virologic response (SVR) exposure-response was modeled using logistic regression. Adverse event incidence was tabulated versus exposure quartiles. First-order absorption rate constant (0.0148 h(-1)), apparent clearance (38.9 mL/h), and apparent volume of distribution (11.6 L) had interindividual variances (coefficient of variation) of 21%, 34%, and 24%, respectively. Residual variance estimates were 27% (coefficient of variation) and 1.51 ng/mL (standard deviation). For the only explanatory covariate-body weight-exposure decreased as weight increased. Important SVR predictors included baseline HCV RNA, fibrosis score, and black race (genotype 1); SVR was minimally related to exposure. Most adverse events had similar incidence rates across exposure quartiles. Some adverse events had a higher incidence in the upper exposure quartile without evidence of exposure-response across the lower quartiles. Given the lack of consistent efficacy/safety exposure-response relationships, further investigation is necessary to optimize albIFN dosing.

Influence of soil moisture and land use history on denitrification end-products.

We investigated the effects of recent moisture history on the relative production of N2O and N2 during denitrification in soil from cropped and successional ecosystems. The soils were pedogenically identical but had been managed differently for the past decade. Sieved soils were amended with nitrate, glucose, and water. Long-wet and short-wet incubations received 80 and 0%, respectively, of prescribed water 2 d before incubation and the rest just before incubation. The N2O and N2 production and N2O mole fraction (N2O/[N2O + N2]) were measured using acetylene inhibition. The N2 production and soil 15N enrichment were measured by 15N-gas evolution. The response of N2O mole fraction to moisture history differed by ecosystem. Mean N2O mole fraction in the successional system was about the same for long-wet and short-wet treatments (0.34 and 0.33, respectively). For the cropped system, however, the N2O mole fraction was 0.36 for the long-wet and 0.90 for the short-wet treatment. Thus, in the cropped system a much smaller proportion of end product was N2O if soil had been wet for 2 d. For N2 fluxes, the isotope method gave the same pattern (r = 0.92) but only about one-third the magnitude, suggesting that N2 derived from two distinct pools. Differences in response of N2O mole fraction for successional and cropped soils may be due to differences in microbial communities. Further knowledge of ecosystem differences with respect to N2O mole fraction and recent moisture history may improve modeled estimates of local and global N2O fluxes.