Bioaccumulation of Pyraoxystrobin and Its Predictive Evaluation in Zebrafish

This paper aims to understand the bioaccumulation of pyraoxystrobin in fish. Using a flow-through bioconcentration method, the bioconcentration factor (BCF) and clearance rate of pyraoxystrobin in zebrafish were measured. The measured BCF values were then compared to those estimated from three commonly used predication models. At the exposure concentrations of 0.1 μg/L and 1.0 μg/L, the maximum BCF values for pyraoxystrobin in fish were 820.8 and 265.9, and the absorption rate constants (K1) were 391.0 d−1 and 153.2 d−1, respectively. The maximum enrichment occurred at 12 d of exposure. At the two test concentrations, the clearance rate constant (K2) in zebrafish was 0.5795 and 0.4721, and the half-life (t1/2) was 3.84 d and 3.33 d, respectively. The measured BCF values were close to those estimated from bioconcentration predication models.

Effects of Last Dosing Time on Population Pharmacokinetic Analysis of Tacrolimus Performed using Extracted Data from Electronic Health Records

A tacrolimus population pharmacokinetic (PK) study with 440 subjects was performed using real world data extracted from electronic heath records (EHRs) to identify patient factors affecting variability in tacrolimus PK parameters. Using last-dose times extracted by our own natural language processing system, medExtractR, we assessed the effects of incorporating last-dose times in the data on tacrolimus PK parameter estimates. The estimates of population level PK parameters were Cl = 24.9 L/h [23.5, 26.3] and V = 6310 L [5461, 7159]. There was no appreciable difference in parameters estimates with vs. without last-dose time incorporated in the data. We also investigated the effects of absorption rate constants that are often fixed at a published value in tacrolimus population PK analysis. Our sensitivity analysis revealed little difference between parameters estimated assuming a range of absorption rate constants.

Population Pharmacokinetics of Nevirapine in HIV-1-Infected Pregnant Women and Their Neonates

ABSTRACTThe aim of the present study was to describe the nevirapine (NVP) pharmacokinetics (PK) in pregnant women and their neonates and to evaluate the transplacental drug transfer and administration scheme for the prevention of mother-to-child transmission. Thirty-eight HIV-1-infected pregnant women were administered one tablet of NVP (200 mg) and two tablets of tenofovir-emtricitabine (Truvada) at the initiation of labor. Children were given NVP syrup (2 mg/kg of body weight) as a single dose (sdNVP) on the first day of life. By pair, NVP concentrations were measured in 11 maternal, 1 cord blood, and 2 neonatal plasma samples and analyzed by a population approach. A one-compartment model was used for mothers and neonates; the absorption rate constants for mothers and neonates were 0.95 h−1(intersubject variability, 111%) and 0.39 h−1, respectively; the apparent elimination clearances were 1.42 liter·h−1(intersubject variability, 22%) and 0.035 liter·h−1, respectively; and apparent volumes of distribution were 87.3 liters (intersubject variability, 25%) and 5.65 liters, respectively. An effect compartment was linked to maternal circulation by mother-to-cord and cord-to-mother rate constants of 1.10 h−1and 1.43 h−1, respectively. Placental transfer, expressed as the fetal-to-maternal area under the curve ratio, was 75%. Neonates had a very long half-lives (110 h) compared to adults. In the 38 mothers, the simulated median individual predicted time during which the NVP concentration remained above the half-maximal inhibitory concentration (IC50) was 13.2 days (range, 12 to 19.2 days). Thus, the administration of tenofovir-emtricitabine for at least 3 weeks after delivery should be considered to prevent the emergence of resistant viruses. The neonate must receive sdNVP immediately after birth when the infant is born less than 30 min after maternal drug intake to keep NVP concentrations above the IC50.