Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy.

Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocrit; this may lead to increased free concentrations, tissue distribution, and clearance during pregnancy. In this paper we highlight the importance and challenges of considering changes in total and free concentrations during pregnancy. For medicines highly bound to plasma proteins, such as tacrolimus, efavirenz, clindamycin, phenytoin, and carbamazepine, differential changes in concentrations of free drug during pregnancy may be clinically significant and have important implications for dose adjustment. Therapeutic drug monitoring usually relies on the measurement of total concentrations; this can result in dose adjustments that are not necessary when changes in free concentrations are considered. We explore the potential of physiologically based pharmacokinetic (PBPK) models to support the understanding of the changes in plasma proteins binding, using tacrolimus and efavirenz as example drug models. The exposure to either drug was predicted to be reduced during pregnancy; however, the decrease in the exposure to the total tacrolimus and efavirenz were significantly larger than the reduction in the exposure to the free drug. These data show that PBPK modelling can support the impact of the changes in plasma protein binding and may be used for the simulation of free concentrations in pregnancy to support dosing decisions.

Unexpectedly high concentrations of 2,4-di-tert-butylphenol in human urine.

Synthetic phenolic antioxidants (SPAs) have received increasing attention due to the reports of toxicity and environmental contamination. Nevertheless, limited information was available on human burdens of these SPAs, with the exception of 2,6-di-tert-butyl-4-methylphenol (BHT). In our study, BHT as well as six other SPAs were analyzed in human urine samples from United States donors. Three SPA congeners were detected in human urine: BHT, 2,4-di-tert-butylphenol (DBP), and 3-tert-butyl-4-hydroxyanisole (BHA). BHT, which is the congener received most concerns, was detected at low concentrations [geometric mean (GM): 0.06 ng/mL], whereas four of its metabolites were detected at relatively high concentrations (GM: 1.68 ng/mL). Surprisingly, DBP was detected at extremely high concentrations (GM: 18.3 ng/mL). The concentrations of DBP (GM: 25.8 ng/mL), BHT (0.853 ng/mL), and metabolites (GM: 10.5 ng/mL) increased significantly after the urine samples were hydrolyzed by ß-glucuronidase (p < 0.01), indicating the prevalence of the conjugated forms of SPAs and their metabolites in human urine. DBP, which has previously received little attention, was the predominant congener, contributing 88.2% and 63.6% to total target concentrations in the urine samples before and after ß-glucuronidase hydrolysis, respectively. Thus, previous studies have vastly underestimated the burdens of SPAs to humans. To our knowledge, this is the first study revealing the presence of DBP in human urine.

Assays for therapeutic drug monitoring of ß-lactam antibiotics: A structured review.

In some patient groups, including critically ill patients, the pharmacokinetics of ß-lactam antibiotics may be profoundly disturbed due to pathophysiological changes in distribution and elimination. Therapeutic drug monitoring (TDM) is a strategy that may help to optimise dosing. The aim of this review was to identify and analyse the published literature on the methods used for ß-lactam quantification in TDM programmes. Sixteen reports described methods for the simultaneous determination of three or more ß-lactam antibiotics in plasma/serum. Measurement of these antibiotics, due to low frequency of usage relative to some other tests, is generally limited to in-house chromatographic methods coupled to ultraviolet or mass spectrometric detection. Although many published methods state they are fit for TDM, they are inconvenient because of intensive sample preparation and/or long run times. Ideally, methods used for routine TDM should have a short turnaround time (fast run-time and fast sample preparation), a low limit of quantification and a sufficiently high upper limit of quantification. The published assays included a median of 6 analytes [interquartile range (IQR) 4-10], with meropenem and piperacillin being the most frequently measured ß-lactam antibiotics. The median run time was 8 min (IQR 5.9-21.3 min). There is also a growing number of methods measuring free concentrations. An assay that measures antibiotics without any sample preparation would be the next step towards real-time monitoring; no such method is currently available.