Background and Objectives Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed as an orally administered treatment for patients with moderate to severe rheumatoid arthritis (RA) and other autoimmune disorders. These analyses characterized the population pharmacokinetics of upadacitinib across phase I–III clinical trials using data for immediate-release (IR) and extended-release (ER) formulations. Methods Pharmacokinetic data from 4170 subjects taking IR doses of 1–48 mg and ER doses of 7.5–30 mg across 12 studies spanning phase I–III clinical trials, with a total of 29,372 upadacitinib plasma concentrations, were analyzed using non-linear mixed-effects modeling. The model was evaluated using bootstrap analyses and visual predictive checks. Results A two-compartment model with first-order absorption with lag time for the IR formulation, mixed zero- and first-order absorption with lag time for the ER formulation, and linear elimination, adequately described upadacitinib plasma concentration–time profiles. Population estimates of upadacitinib apparent oral clearance and steady-state volume of distribution in healthy volunteers for the ER formulation were 53.7 L/h and 294 L, respectively. The relative bioavailability of the ER formulation compared with the IR formulation was estimated to be 76.2%. Statistically significant covariates were patient population (RA subjects vs. healthy subjects), creatinine clearance, and baseline bodyweight on apparent clearance (CL/F) and bodyweight on volume of distribution of the central compartment (Vc/F). The intersubject variability for upadacitinib CL/F and Vc/F were estimated to be 21% and 24%, respectively, in the phase I studies, and 37% and 53%, respectively, in the phase II/III studies. Upadacitinib area under the concentration–time curve (AUC) was estimated to be only 5% higher or lower for RA patients who were < 60 or > 100 kg, respectively, relative to subjects with a bodyweight of 60–100 kg. RA subjects with mild or moderate renal impairment had 13% and 26% higher AUC, respectively, compared with RA subjects with normal renal function. Sex, race, concomitant use of pH-modifying drugs, moderate cytochrome P450 3A inhibitors, or methotrexate use had no effect on upadacitinib exposure. Conclusions A robust population pharmacokinetic model was developed for upadacitinib using a large dataset from phase I–III clinical trials in healthy volunteers and subjects with RA. None of the identified covariates had a clinically meaningful effect on upadacitinib exposures. The model is appropriate to use for simulations and to evaluate the exposure–response relationship of upadacitinib. Electronic supplementary material The online version of this article (10.1007/s40262-019-00739-3) contains supplementary material, which is available to authorized users.
The objective of this research was to characterize the venetoclax exposure‐efficacy and exposure‐safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low‐dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure‐safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure‐efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure‐response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400‐mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure‐response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.
Plants may use different strategies to attract pollinators in long distance (e.g. floral display) and in short distance (e.g. ratio between differentially colored flowers) scales. The Verbenaceae Lantana canescens Kunth is a wide spread species in open sites of the Brazilian Pantanal wetland. Individuals of this generalist species can produce a variable number of open inflorescences with yellow and white flowers that are organized in whorls. In this study we tested the hypothesis that increased floral display (long distance attraction) and the ratio between yellow and white flowers (short distance attraction) enhances the number of pollinator species and individuals. We observed flower visitors and calculated floral parameters in 38 plots of 1 m2 each, that contained a varying number of flowering L. canescens individuals. Non-metric multidimensional scaling and Bray-Curtis distances were used to account for flower visitor composition and the relative visitation rate, respectively. We used a structural equation model to test the power of each predictor variable on the visitation rate and a covariance analysis to disentangle the effect of each independent variable on the frequency of plant-pollinator interactions. We found that the number of flower visitors and the visitation rate increased with increasing number of inflorescences. Disentangling long and short distance attraction indicated that the number of inflorescences (per plot) and the number of yellow flowers (yellowing effect) contributed most to flower visitation at long and short distance, respectively.
1. The oil‐collecting bee Centris analis (Fabricius, 1804) is an important pollinator for the Neotropical region. The species can be attracted to nest in human‐made cavities. Such trap nests or insect hotels offer the opportunity to study the behaviour of populations in semifield conditions. 2. We studied a newly established trap nest aggregation of C. analis in Mato Grosso do Sul, Brazil and tested the effect that differentially painted nesting options have on the rate of nest foundation, and on the ability of relocating the nest when returning from a foraging trip (homing behaviour). Moreover, we tested if the duration of foraging trips decreased with time. 3. We found that females preferred to nest in painted nests compared to unpainted nests, with blue nests being the most occupied ones, followed by purple, yellow, white, and green. Furthermore, bees improved their homing behaviour with time, however, nest colour did not seem to have an effect on this process. Moreover, we found that bees reduce the duration of their foraging trips with time. This could be an indicator of improved foraging efficiency through learning. 4. These findings could inform a new and fruitful line of research on the behaviour and ecology of trap nesting solitary bees.
1. Recent reports on bee health suggest that sublethal doses of pesticides have negative effects on wild bee reproduction and ultimately on their population growth.2. Females of the solitary horned mason bee Osmia cornuta, evaluate thoracic vibrations and odours of males to assess male quality. When certain criteria are met, the female accepts the male and copulates. However, these signals were found to be modified by sublethal doses of pesticides in other hymenopterans. Here, we tested whether sublethal doses of a commonly used fungicide (Fenbuconazole) impact male quality signals and mating success in O. cornuta. Males exposed to fenbuconazole exhibited reduced thoracic vibrations and an al-tered cuticular hydrocarbon profile compared to the control bees. Moreover, males exposed to the fungicide were less successful in mating than control males. Synthesis and applications.Our results indicate that a low toxicity fungicide can negatively affect male reproductive success by altering behavioural and chemical cues. This could explain the decreasing pollinator populations in a pesticidepolluted environment. This study highlights the need for a more comprehensive approach, including behaviour and chemical cues, when testing new pesticides and a more cautionary approach to the pesticides already used on crops.
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