Identification of factors affecting meropenem pharmacokinetics in critically ill patients: Impact of inflammation on clearance

IntroductionThe purpose of this study was to explore factors influencing meropenem pharmacokinetics (PKs) in critically ill patients by developing a population PK model and to determine the optimal dosing strategy.MethodsThis prospective observational study involved 12 critically ill patients admitted to the intensive care unit and treated with meropenem 1 g infused over 1 h every 8 h. Blood samples were collected on days 1, 2, and 5 immediately prior to dosing, and at 1, 2, 4, and 6 h after the start of infusion. Population PK parameters were estimated using nonlinear mixed-effects model software.ResultsMeropenem PK was adequately described using a two-compartment model. Typical values of total and inter-compartmental clearance were 9.30 L/h and 9.70 L/h, respectively, and the central and peripheral compartment volumes of distribution were 12.61 L and 7.80 L, respectively. C-reactive protein (CRP) was identified as significant covariate affecting total meropenem clearance. The probability of target attainment (PTA) predicted by Monte Carlo simulations varied according to the patients’ CRP. The PTA of 100% time above the minimum inhibitory concentration ≤2 mg/L for bacteria was achieved after a dose of 1 and 2 g infused over 4 h every 8 h in patients with CRP of 30 and 5 mg/dL, respectively.ConclusionThe findings of this study suggest that CRP might be helpful in managing meropenem dosing in critically ill patients. Higher doses and extended infusion may be required to achieve optimal pharmacodynamic targets.     

Pharmacokinetics and Early Tumor Response to Conventional Transarterial Chemoembolization with Sorafenib and Doxorubicin in a VX2 Rabbit Tumor Model

PurposeTo investigate the pharmacokinetics (PK) and early effects of conventional transarterial chemoembolization (TACE) using sorafenib and doxorubicin on tumor necrosis, hypoxia markers, and angiogenesis in a rabbit VX2 liver tumor model.Materials and MethodsVX2 tumor-laden New Zealand White rabbits (N = 16) were divided into 2 groups: 1 group was treated with hepatic arterial administration of ethiodized oil and doxorubicin emulsion (DOX-TACE), and the other group was treated with ethiodized oil, sorafenib, and doxorubicin emulsion (SORA-DOX-TACE). Animals were killed within 3 days of the procedure. Levels of sorafenib and doxorubicin were measured in blood, tumor, and adjacent liver using mass spectrometry. Tumor necrosis was determined by histopathological examination. Intratumoral hypoxia-inducible factor (HIF) 1α, vascular endothelial growth factor (VEGF), and microvessel density (MVD) were determined by immunohistochemistry.ResultsThe median intratumoral concentration of sorafenib in the SORA-DOX-TACE group was 17.7 μg/mL (interquartile range [IQR], 7.42–33.5 μg/mL), and its maximal plasma concentration (C_max) was 0.164 μg/mL (IQR, 0.0798–0.528 μg/mL). The intratumoral concentration and C_max of doxorubicin were similar between the groups: 4.08 μg/mL (IQR, 3.18–4.79 μg/mL) and 0.677 μg/mL (IQR, 0.315–1.23 μg/mL), respectively, in the DOX-TACE group and 1.68 μg/mL (IQR, 0.795–4.08 μg/mL) and 0.298 μg/mL (IQR, 0.241–0.64 μg/mL), respectively, in the SORA-DOX-TACE group. HIF-1α expression was increased in the SORA-DOX-TACE group than in the DOX-TACE group. Tumor volume, tumor necrosis, VEGF expression, and MVD were similar between the 2 groups.ConclusionsThe addition of sorafenib to DOX-TACE delivered to VX2 liver tumors resulted in high intratumoral and low systemic concentrations of sorafenib without altering the PK of doxorubicin.     

Clinical pharmacokinetics of oxaliplatin in a hemodialysis patient with advanced gastric cancer

We administered FOLFOX (oxaliplatin (L-OHP) plus infusional 5-fluorouracil (5-FU) and leucovorin) to an hemodialysis (HD) patient with advanced gastric cancer (AGC), and investigated pharmacokinetics (PKs) and dialyzability of L-OHP. The patient was a 54-year-old Japanese man with a diagnosis of inoperable AGC. FOLFOX was instituted 3?h prior to the start of a 4?h HD period with the L-OHP and 5-FU doses reduced by 50% for the first cycle, and 30% reduced dose was administered for the second cycle. We performed an analysis of the PKs of L-OHP during these two cycles. Volume of distribution and area under the curve of the 30% reduced L-OHP dose were 56.7?L and 30.0?μg·h/mL, respectively. A dose reduction of L-OHP by 30%?50% may be advisable for the initial administration, given the need for careful administration of chemotherapy in HD patients, with particular attention to the development of hematological toxicities and neuropathy.     

Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management

Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English-language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin-warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%–74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3–5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%–67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.     

Tacrolimus overexposure in kidney transplant recipients during the first post‐operative week: caution is required in older patients

In liver transplantation, tacrolimus trough concentrations (Cmin) above 20 ng/mL during the first days led to worse outcome at 1 year but data in the kidney transplant (KT) era are scarce. The aim of this study was to evaluate the impact of tacrolimus overexposure during the first week post‐transplantation on the kidney function (KF) of KT recipients. In this retrospective study, 105 KT recipients were attributed to overexposure group (OG) or normal group according to their Cmin during the first week of treatment. KF was evaluated by comparing the rate of delayed graft function (DGF) and by collecting plasma creatinine from day 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 and at 1 year. Risk factors for developing DGF were also investigated using a multivariate model. DGF was more frequent in OG (43% of patients; P = 0.027) which has higher plasma creatinine on day 7, 14, and 21. OG patients were older with more extended criteria donor's grafts. In the multivariate analysis, only cold ischemia time (CIT) remained associated with DGF (OR = 1.003), while TAC overexposure did not reach significance (P = 0.06; OR = 3.9). In this study, we confirmed the predominant role of CIT as a risk factor for the onset of DGF in kidney transplantation. 43% of KT recipients were overexposed with more DGF, especially older patients.     

Varying the rate of intravenous cocaine infusion influences the temporal dynamics of both drug and dopamine concentrations in the striatum

The faster drugs of abuse reach the brain, the greater is the risk of addiction. Even small differences in the rate of drug delivery can influence outcome. Infusing cocaine intravenously over 5 vs. 90–100 s promotes sensitization to the psychomotor and incentive motivational effects of the drug and preferentially recruits mesocorticolimbic regions. It remains unclear whether these effects are due to differences in how fast and/or how much drug reaches the brain. Here, we predicted that varying the rate of intravenous cocaine infusion between 5 and 90 s produces different rates of rise of brain drug concentrations, while producing similar peak concentrations. Freely moving male Wistar rats received acute intravenous cocaine infusions (2.0 mg/kg/infusion) over 5, 45 and 90 s. We measured cocaine concentrations in the dorsal striatum using rapid‐sampling microdialysis (1 sample/min) and high‐performance liquid chromatography‐tandem mass spectrometry. We also measured extracellular concentrations of dopamine and other neurochemicals. Regardless of infusion rate, acute cocaine did not change concentrations of non‐dopaminergic neurochemicals. Infusion rate did not significantly influence peak concentrations of cocaine or dopamine, but concentrations increased faster following 5‐s infusions. We also assessed psychomotor activity as a function of cocaine infusion rate. Infusion rate did not significantly influence total locomotion, but locomotion increased earlier following 5‐s infusions. Thus, small differences in the rate of cocaine delivery influence both the rate of rise of drug and dopamine concentrations, and psychomotor activity. A faster rate of rise of drug and dopamine concentrations might be an important issue in making rapidly delivered cocaine more addictive.     

Phage therapy: What factors shape phage pharmacokinetics and bioavailability? Systematic and critical review

Bacteriophages are not forgotten viruses anymore: scientists and practitioners seek to understand phage pharmacokinetics in animals and humans, investigating bacteriophages as therapeutics, nanocarriers or microbiome components. This review provides a comprehensive overview of factors that determine phage circulation, penetration, and clearance, and that in consequence determine phage applicability for medicine. It makes use of experimental data collected by the phage community so far (PubMed 1924-2016, including non-English reports), combining elements of critical and systematic review. This study covers phage ability to enter a system by various routes of administration, how (and if) the phage may access various tissues and organs, and finally what mechanisms determine the courses of phage clearance. The systematic review method was applied to analyze (i) phage survival in the gut (gut transit) and (ii) phage ability to enter the mammalian system by many administration routes. Aspects that have not yet been covered by a sufficient number of reports for mathematical analysis, as well as mechanisms underlying trends, are discussed in the form of a critical review. In spite of the extraordinary diversity of bacteriophages and possible phage applications, the analysis revealed that phage morphology, phage specificity, phage dose, presence of sensitive bacteria or the characteristics of treated individuals (age, taxonomy) may affect phage bioavailability in animals and humans. However, once phages successfully enter the body, they reach most organs, including the central nervous system. Bacteriophages are cleared mainly by the immune system: innate immunity removes phages even when no specific response to bacteriophages has yet developed.