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Limitations of Current Therapies for HIV-1 Infection
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
It is likely that antiretroviral drug activity will prove to be a function of the ratio of drug exposure to viral susceptibility. Parameters requiring better characterization include: 1) what magnitude that ratio needs to be to assure suppression; 2) whether susceptibility should be defined as IC50, IC90, IC95 etc; and 3) whether the concentration used should be the trough level (most likely) or some other pharmacokinetic parameter. For nucleosides, exposure determinations are complicated by the fact the concentrations of the triphosphates of the drug, as well as the physiologic deoxynucleosides within the infected cells is what is important. For compounds not anabolized to active drugs like non-nucleoside reverse transcriptase inhibitors and protease inhibitors, exposure is probably defined by free drug concentration which is determined by plasma level and protein binding. Intracellular transport and efflux, however, may also pose important hurdles (51–53).
Infection
Published in Janet M Rennie, Giles S Kendall, A Manual of Neonatal Intensive Care, 2013
Janet M Rennie, Giles S Kendall
The disadvantage of using an aminoglycoside is the need to monitor plasma levels. Standard practice is to monitor the levels around the third dose, although levels should be checked earlier in babies with poor renal function. The trough level should be taken just before a dose is due and a peak level 1 hour later. Acceptable levels are given in Table 16.4. With once-daily dosing, a pre-dose level is considered clinically adequate. If the trough level is too high, the dose frequency needs to be decreased. The genetic link between gentamicin and sensorineural hearing loss is also of concern, following the finding that approximately 1:500 of the population carry the mitochondrial DNA mutation m.1555A→G. Carriers of this mutation have permanent and profound hearing loss after receiving aminoglycosides even when drug levels are within the therapeutic range (Bitner-Glindzicz et al. 2009; Vandebona et al. 2009).
Laboratory Testing in Pain Disorders
Published in Mark V. Boswell, B. Eliot Cole, Weiner's Pain Management, 2005
In an ideal world, the therapeutic drug specimen should be collected after a steady state has been achieved. For drugs with short half-lives, both a steady-state peak and a trough level should be obtained. Each drug has a different peak collection time, but all trough levels should be taken just prior to the next dose of the drug. A toxic drug evaluation level may be collected at any time.
The clinical relevance of dupilumab serum concentration in patients with atopic dermatitis: a two-center prospective cohort study
Published in Journal of Dermatological Treatment, 2023
Angela L. Bosma, Louise A. A. Gerbens, Hajar El Khattabi, Floris C. Loeff, Michael Duckworth, Richard T. Woolf, Theo Rispens, Catherine H. Smith, Phyllis I. Spuls
Blood samples were collected at baseline (NL + UK), 2 (UK), 12 (NL + UK), 24 (NL), and 48 (NL) weeks. The time point of blood sampling was aspired to be at the trough level, just before a new dose administration. Samples were centrifuged, aliquoted into microtubes, and frozen at −20 °C (NL) and −80 °C (UK). Serum levels were measured using an enzyme-linked immunosorbent assay (ELISA). Maxisorp microtiter plates were coated overnight at room temperature (RT) with 1 μg/mL monoclonal anti-dupilumab (clone 1G11). This is a chimeric antibody of rabbit origin, with a mouse IgG2b Fc, recombinantly expressed as described before (30). After five times washing with PBS/0.02% Tween (PT), plates were incubated for 1 h at RT with patient serum samples, diluted 100-fold, and 2000-fold in high-performance ELISA buffer (HPE, Sanquin). Subsequently, the plates were washed with PT and incubated for 1 h with 0.5 μg/mL mouse monoclonal antihuman IgG4 (clone MH164.4, Sanquin). After washing, the ELISA was developed with 1-step ultra TMB-ELISA Substrate Solution (thermoFischer) diluted with MQ (ratio 3:1). The reaction was stopped with 0.2 M HCl. Delta of the absorption at 450 and 540 nm was determined and compared to a titration curve of dupilumab in each plate. The lower limit of quantification is 0.3 μg/mL; accuracy and precision ranged from 87% to 102% and 4.4% to 12.2% CV (coefficient of variation).
Antimicrobial safety considerations in critically ill patients: part I: focused on acute kidney injury
Published in Expert Review of Clinical Pharmacology, 2022
Foroud Shahbazi, Lida Shojaei, Fakhrossadat Farvadi, Sara Kadivarian
An initial dose of 15–20 mg/kg based on actual body weight (maximum 2 g per dose) every 12 hours is suggested [91]. In addition, a loading dose of 25–30 mg/kg has been suggested to attain rapid serum concentration in seriously ill patients [91,92]. A 30–60 mg/kg maintenance dose is recommended to attain the best trough levels. Vancomycin AUC/MIC ≥400 mg.h/L after two doses has the best correlation with clinical outcome [93]. So, vancomycin monitoring using AUC/MIC is recommended for all patients who are being treated for invasive MRSA infections, especially for those with unstable renal function, those at higher risk of nephrotoxicity, and those receiving a prolonged course (> 3 days) [93]. Most episodes of vancomycin nephrotoxicity occur between days 4–17 after initiation [91].
The value of sorafenib trough levels in patients with advanced hepatocellular carcinoma – a substudy of the SORAMIC trial
Published in Acta Oncologica, 2020
Tim A. Labeur, Quincy Hofsink, R. Bart Takkenberg, Otto M. van Delden, Ron A. A. Mathôt, Regina Schinner, Peter Malfertheiner, Holger Amthauer, Kerstin Schütte, Bristi Basu, Christiane Kuhl, Julia Mayerle, Jens Ricke, Heinz-Josef Klümpen
Median duration of sorafenib administration was 51 weeks (IQR 27–62), which was significantly longer in the sorafenib monotherapy arm compared with the SIRT plus sorafenib arm (53 vs 34 weeks, p = .029). The mean daily dose was 676 mg (IQR 453–782). A total of 154 PK samples were suitable for trough level analysis, ranging between 1 and 6 samples per patient and drawn after a median of 25 weeks (IQR 10–42) after the start of sorafenib treatment. The trough level was determined in a single sample in 30 (41%) patients or, in patients with two (n = 19, 26%) or ≥3 samples (n = 25, 34%), the average and highest value was calculated. Patients had a mean trough level of sorafenib and M2 of 3217 ng/ml (IQR 2166–4526, range 452–11,995) and 360 ng/ml (IQR 190–593, range 27–6272) with CVs of 65% and 146%, respectively. There was no significant correlation between mean daily doses and mean trough levels of sorafenib (ρ = 0.091, p = .439) or M2 (ρ = 0.022, p = .851). The highest measured trough level of sorafenib and M2 in each patient was 3653 ng/ml (IQR 2318–6083, range 491–11995) and 468 ng/ml (IQR 214–871, range 27–6927), respectively. There were no significant differences in mean trough levels of sorafenib (3258 vs 2745 ng/ml, p = .230) or M2 (522 vs 344 ng/ml, p = .089) between patients treated with SIRT plus sorafenib or sorafenib, respectively.