The critical role of the routing scheme in simulating peak river discharge in global hydrological models

Global hydrological models (GHMs) have been applied to assess global flood hazards, but their capacity to capture the timing and amplitude of peak river discharge—which is crucial in flood simulations—has traditionally not been the focus of examination. Here we evaluate to what degree the choice of river routing scheme affects simulations of peak discharge and may help to provide better agreement with observations. To this end we use runoff and discharge simulations of nine GHMs forced by observational climate data (1971–2010) within the ISIMIP2a project. The runoff simulations were used as input for the global river routing model CaMa-Flood. The simulated daily discharge was compared to the discharge generated by each GHM using its native river routing scheme. For each GHM both versions of simulated discharge were compared to monthly and daily discharge observations from 1701 GRDC stations as a benchmark. CaMa-Flood routing shows a general reduction of peak river discharge and a delay of about two to three weeks in its occurrence, likely induced by the buffering capacity of floodplain reservoirs. For a majority of river basins, discharge produced by CaMa-Flood resulted in a better agreement with observations. In particular, maximum daily discharge was adjusted, with a multi-model averaged reduction in bias over about 2/3 of the analysed basin area. The increase in agreement was obtained in both managed and near-natural basins. Overall, this study demonstrates the importance of routing scheme choice in peak discharge simulation, where CaMa-Flood routing accounts for floodplain storage and backwater effects that are not represented in most GHMs. Our study provides important hints that an explicit parameterisation of these processes may be essential in future impact studies

Neonatal pain score after use of paracetamol:Is there a relationship with serum trough concentration at steady state in preterm and term neonates?

Objective: An easy to establish and patient-friendly biomarker to guide dosing of paracetamol in neonates is currently not available. The aim of this study was to determine the potential association between the serum trough concentration and area under the curve (AUC) of paracetamol at steady state and differences in pain scores in preterm and term neonates. Materials and methods: A retrospective observational study was performed, using an academic hospital database to identify neonates treated with intravenous or rectal paracetamol for at least 48 hours. At steady state, serum trough concentrations and the 24-hour AUC were determined. Pain was measured by COMFORTneo scores, before the 1st and 6th dose. Linear regression was performed to assess the association between serum trough concentration and 24-hour AUC and differences in pain scores. Subgroup analyses were performed for patients who received paracetamol due to a COMFORTneo score ≥ 14 (group 1) or who received prophylactic paracetamol because of upcoming surgery (group 2). Results: 21 neonates were included. The median (interquartile range (IQR)) serum trough concentration of paracetamol before the 6th dose was 4.5 mg/L (2.7 - 8.5 mg/L). In subgroup 1, the median (IQR) COMFORTneo scores before the 1st and 6th dose were 17 (16.5 - 20) and 12 (11 - 16.5), respectively. In subgroup 2, the median (IQR) scores were 9 (8 - 10) and 11 (9 - 12), respectively. The serum trough concentration and 24-hour AUC were not associated with reduced pain scores (p = 0.12 and p = 0.67, respectively). Conclusion: No association was found between the serum trough concentration and 24-hour AUC of paracetamol at steady state and differences in pain scores in preterm and term neonates. Future research is needed to prospectively determine a patient-friendly biomarker to optimize the treatment with paracetamol.</p

Hepatotoxicity following nevirapine-containing regimens in HIV-1-infected individuals

To determine the incidence of hepatotoxicity and to investigate whether plasma concentrations of nevirapine, in addition to other risk factors, could predict hepatotoxicity during treatment with nevirapine-containing regimens, we conducted a retrospective analysis with data from 174 individuals infected with human immunodeficiency virus-1 (HIV-1). During regular visits to the clinic, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters including liver enzymes (LEs) and total bilirubin (TBR). Severe hepatotoxicity was defined as a grade > or =3 elevation in at least one of the tested LEs or TBR levels while on therapy. Analysis of predictive factors was focused on increases in aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) to grade > or =2. Grade > or =3 elevation developed with an incidence of 0.15 per patient year (PY); only 3.4% of the patients developed grade > or =3 values for ASAT and/or ALAT (incidence 0.03 per PY). We found that patients who use a protease inhibitor (PI) in a nevirapine-containing regimen and patients who have chronic hepatitis B (HBV) infection are at a higher risk for the development of increases in ASAT and/or ALAT to grade > or =2. In contrast, the plasma concentration of nevirapine does not appear to be a predictive factor in this study populatio

The steady-state pharmacokinetics of nevirapine during once daily and twice daily dosing in HIV-1-infected individuals

Objective: To investigate and to compare the steady-state plasma pharmacokinetics of nevirapine in a dosing regimen of 400 mg once daily versus 200 mg twice daily in HIV-1-infected individuals. Design: Open-label, randomized, cross-over study. Methods: Twenty HIV-1-infected individuals who already used nevirapine as part of their antiretroviral regimen were randomized to continue their current regimen (200 mg twice daily) or to switch to the alternate regimen (400 mg once daily). The steady-state plasma pharmacokinetics of nevirapine were assessed after 2 weeks during a 24-h period. Subsequently, patients were switched to the alternate regimen and the pharmacokinetics of nevirapine were assessed again after 2 weeks. Noncompartmental methods were used to calculate the area under the plasma concentration versus time curve (AUC([24 h])), and the maximal (C(max)) and minimal plasma concentration (C(min)), the time to C(max) (t(max)), the plasma elimination half-life (t(1/2)), the apparent oral clearance (Cl/F) and the apparent volume of distribution (V/F). Differences in these pharmacokinetic parameters for the two dosing regimens were tested using ANOVA. Results: The exposure to nevirapine, as measured by the AUC([24 h]), was not significantly different between the 400 mg once daily and 200 mg twice daily dosing regimen (P = 0.60). Furthermore, the values for t(max), t(1/2) Cl/F and V/F were not significantly different between the two dosing regimens (P ≥ 0.08). However, C(max) and C(min) were higher and lower, respectively, when nevirapine was used in the once daily regimen as compared with the twice daily regimen. The median values for C(max) and C(min) as measured for the once daily and twice daily regimens were 6.69 and 5.74 μg/ml, respectively (P = 0.03), and 2.88 and 3.73 μg/ml, respectively (P < 0.01). Conclusion: These data show that the daily exposure to nevirapine, as measured by the plasma AUC([24 h]), is not different between a 400 mg once daily and a 200 mg twice daily dosing regimen. However, C(max) and C(min) are higher and lower, respectively, for the once daily regimen as compared with the twice daily regimen. The clinical implications of these differences remain to be established. (C) 2000 Lippincott Williams and Wilkins

Optimizing Antiviral Dosing for HSV and CMV Treatment in Immunocompromised Patients

Herpes simplex virus (HSV) and cytomegalovirus (CMV) are DNA viruses that are common among humans. Severely immunocompromised patients are at increased risk of developing HSV or CMV disease due to a weakened immune system. Antiviral therapy can be challenging because these drugs have a narrow therapeutic window and show significant pharmacokinetic variability. Above that, immunocompromised patients have various comorbidities like impaired renal function and are exposed to polypharmacy. This scoping review discusses the current pharmacokinetic (PK) and pharmacodynamic (PD) knowledge of antiviral drugs for HSV and CMV treatment in immunocompromised patients. HSV and CMV treatment guidelines are discussed, and multiple treatment interventions are proposed: early detection of drug resistance; optimization of dose to target concentration by therapeutic drug monitoring (TDM) of nucleoside analogs; the introduction of new antiviral drugs; alternation between compounds with different toxicity profiles; and combinations of synergistic antiviral drugs. This research will also serve as guidance for future research, which should focus on prospective evaluation of the benefit of each of these interventions in randomized controlled trials

Optimizing Antiviral Dosing for HSV and CMV Treatment in Immunocompromised Patients

Herpes simplex virus (HSV) and cytomegalovirus (CMV) are DNA viruses that are common among humans. Severely immunocompromised patients are at increased risk of developing HSV or CMV disease due to a weakened immune system. Antiviral therapy can be challenging because these drugs have a narrow therapeutic window and show significant pharmacokinetic variability. Above that, immunocompromised patients have various comorbidities like impaired renal function and are exposed to polypharmacy. This scoping review discusses the current pharmacokinetic (PK) and pharmacodynamic (PD) knowledge of antiviral drugs for HSV and CMV treatment in immunocompromised patients. HSV and CMV treatment guidelines are discussed, and multiple treatment interventions are proposed: early detection of drug resistance; optimization of dose to target concentration by therapeutic drug monitoring (TDM) of nucleoside analogs; the introduction of new antiviral drugs; alternation between compounds with different toxicity profiles; and combinations of synergistic antiviral drugs. This research will also serve as guidance for future research, which should focus on prospective evaluation of the benefit of each of these interventions in randomized controlled trials

Predicting treatment response to vancomycin using bacterial DNA load as a pharmacodynamic marker in premature and very low birth weight neonates: A population PKPD study

Background: While positive blood cultures are the gold standard for late-onset sepsis (LOS) diagnosis in premature and very low birth weight (VLBW) newborns, these results can take days, and early markers of possible treatment efficacy are lacking. The objective of the present study was to investigate whether the response to vancomycin could be quantified using bacterial DNA loads (BDLs) determined by real-time quantitative polymerase chain reaction (RT-qPCR). Methods: VLBW and premature neonates with suspected LOS were included in a prospective observational study. Serial blood samples were collected to measure BDL and vancomycin concentrations. BDLs were measured with RT-qPCR, whereas vancomycin concentrations were measured by LC-MS/MS. Population pharmacokinetic–pharmacodynamic modeling was performed with NONMEM. Results: Twenty-eight patients with LOS treated with vancomycin were included. A one-compartment model with post-menstrual age (PMA) and weight as covariates was used to describe the time PK profile of vancomycin concentrations. In 16 of these patients, time profiles of BDL could be described with a pharmacodynamic turnover model. The relationship between vancomycin concentration and first-order BDL elimination was described with a linear-effect model. Slope S increased with increasing PMA. In 12 patients, no decrease in BDL over time was observed, which corresponded with clinical non-response. Discussion: BDLs determined through RT-qPCR were adequately described with the developed population PKPD model, and treatment response to vancomycin using BDL in LOS can be assessed as early as 8 h after treatment initiation

Predicting treatment response to vancomycin using bacterial DNA load as a pharmacodynamic marker in premature and very low birth weight neonates: A population PKPD study

Background: While positive blood cultures are the gold standard for late-onset sepsis (LOS) diagnosis in premature and very low birth weight (VLBW) newborns, these results can take days, and early markers of possible treatment efficacy are lacking. The objective of the present study was to investigate whether the response to vancomycin could be quantified using bacterial DNA loads (BDLs) determined by real-time quantitative polymerase chain reaction (RT-qPCR). Methods: VLBW and premature neonates with suspected LOS were included in a prospective observational study. Serial blood samples were collected to measure BDL and vancomycin concentrations. BDLs were measured with RT-qPCR, whereas vancomycin concentrations were measured by LC-MS/MS. Population pharmacokinetic–pharmacodynamic modeling was performed with NONMEM. Results: Twenty-eight patients with LOS treated with vancomycin were included. A one-compartment model with post-menstrual age (PMA) and weight as covariates was used to describe the time PK profile of vancomycin concentrations. In 16 of these patients, time profiles of BDL could be described with a pharmacodynamic turnover model. The relationship between vancomycin concentration and first-order BDL elimination was described with a linear-effect model. Slope S increased with increasing PMA. In 12 patients, no decrease in BDL over time was observed, which corresponded with clinical non-response. Discussion: BDLs determined through RT-qPCR were adequately described with the developed population PKPD model, and treatment response to vancomycin using BDL in LOS can be assessed as early as 8 h after treatment initiation