Current Issue : April-June Volume : 2025 Issue Number : 2 Articles : 5 Articles
Prosthetic joint infections (PJIs) are a serious complication of orthopedic surgery. Bacteriophage (phage) therapy shows promise as an adjunctive treatment but requires further study, particularly in its pharmacokinetics. Consequently, we performed a pharmacokinetic assessment of phage therapy for PJIs using a Staphylococcus epidermidis Kirschner wire-based prosthesis rat model. We used 52 male Sprague–Dawley rats in four groups: negative controls (no phage, sterile implant), PJI controls (bacteria, no phage), sterile phage (phages given, sterile implant), and PJI (bacteria, phages given). The PJI groups were inoculated with ~106 CFU of S. epidermidis. The groups receiving phage were intra-articularly injected with ~108 PFU of vB_SepM_Alex five days post-implantation. The rats were euthanized between 30 min and 48 h post-injection. The measured phage concentrations between the PJI rats and the sterile controls in periarticular tissues were not significantly different. In a noncompartmental pharmacokinetic analysis, the estimated phage half-lives were under 6 h (combined: 3.73 [IQR, 1.45, 10.07]). The maximum phage concentrations were reached within 2 h after administration (combined: 0.75 [0.50, 1.75]). The estimated phage mean residence time was approximately three hours (combined: 3.04 [1.44, 4.19]). Our study provides a preliminary set of pharmacokinetic parameters that can inform future phage dosing studies and animal models of phage therapy for PJIs....
Background/Objectives: Gabapentin has variable pharmacokinetics (PK), which contributes to difficulty in dosing and increased risk of adverse events. The objective of this study was to leverage gabapentin concentrations from therapeutic drug monitoring (TDM) to develop a population PK (popPK) model and characterize significant covariates that impact gabapentin PK. Methods: Data were retrospectively collected from 82 hospitalized adult patients with TDM gabapentin concentrations. Renal function indicators (i.e., estimated glomerular filtration rate, creatinine clearance, acute kidney injury), body weight parameters (i.e., actual body weight, ideal body weight, adjusted body weight, lean body weight, body mass index, obesity status), fasting plasma glucose levels, and diagnosis of type 2 diabetes were tested as potential covariates. A popPK model was developed in MONOLIX (2020R1, Lixoft, France). Results: A one-compartment model best described gabapentin PK with first-order absorption, dose-dependent bioavailability, first-order elimination, and no lag time. Population parameter estimates for the volume of distribution (Vd), and clearance (Cl) were 44.61 L, and 5.73 L/h, respectively. Serum creatinine was a significant covariate on Cl. Conclusions: The popPK model highlights the importance of renal function in the interindividual variability of gabapentin PK and suggests that diabetes and body weight parameters have no impact on gabapentin PK. Moreover, our study supports the utility of leveraging data obtained from clinical TDM for popPK model development....
Background: Morphine is a commonly prescribed opioid analgesic used to treat chronic pain. Morphine undergoes glucuronidation by UDP-glucuronosyltransferase (UGT) 2B7 to form morphine-3-glucuronide and morphine-6-glucuronide. Morphine is the gold standard for chronic pain management and has a narrow therapeutic index. Reports have shown that chronic pain patients have increasingly used other supplements to treat their chronic pain, including cannabidiol (CBD). Up to 50% of chronic pain patients report that they co-use cannabis with their prescribed opioid for pain management, including morphine. Previous work has shown that cannabidiol is a potent inhibitor of UGT2B7, including morphine-mediated metabolism. Co-use of morphine and CBD may result in unwanted drug–drug interactions (DDIs). Methods: Using available physiochemical and clinical parameters, morphine and CBD physiologically based pharmacokinetic (PBPK) models were developed and validated in both healthy and cirrhotic populations. Models for the two populations were then combined to predict the severity and clinical relevance of the potential DDIs during coadministration of both morphine and CBD in both healthy and hepatic-impaired virtual populations. Results: The predictive DDI model suggests that a ~5% increase in morphine exposure is to be expected in healthy populations. A similar increase in exposure of morphine is predicted in severe hepatic-impaired populations with an increase of ~10. Conclusions: While these predicted increases in morphine exposure are below the Food and Drug Administration’s cutoff (1.25-fold increase), morphine has a narrow therapeutic index and a 5–10% increase in exposure may be clinically relevant. Future clinical studies are needed to fully characterize the clinical relevance of morphine-related DDIs....
Antibiotic resistance in bacteria from companion animals poses significant public health risks. Prudent antibiotic use, particularly through pharmacokinetics/pharmacodynamics modeling, is crucial for minimizing resistance. We investigated the pharmacokinetics/pharmacodynamics of amoxicillin (AMX) against Staphylococcus pseudintermedius. A pharmacokinetic study was conducted on healthy dogs subcutaneously injected with a dose of 15 mg/kg AMX. The antibacterial efficacy of AMX was evaluated against a standard strain from animals (KCTC 3344) and clinical isolates from dogs (B-2, B-7, and B-8), with minimum inhibitory concentrations (MICs) of 0.25, 0.5, 64, and 16 μg/mL, respectively. The half-life of AMX was 7 h, allowing for extended drug efficacy. The time above MIC (%T > MIC) values indicated that the AMX concentrations were maintained above MICs of the two susceptible strains (KCTC 3344 and B-2) for more than 80% of the time when dosed at a one-day interval, suggesting an effective treatment. The area under the curve over 24 h/MIC ratios confirmed the bacteriostatic, bactericidal, and bacterial eradication effects of AMX against S. pseudintermedius strains, except for B-7 (the most resistant strain). These results support improved clinical dosing strategies for AMX against S. pseudintermedius infections in dogs....
Background/Objectives: Spatholobi Caulis (SPC) is a medicinal plant that mainly grows in China and Southeast Asian countries and commonly used in clinics; the pharmacokinetic characteristics in humans need to be determined. This study was to establish the physiologically based pharmacokinetic (PBPK) models of multiple active constituents from SPC in rats, and predict the pharmacokinetic properties of rats with different dosages and extrapolated to humans. Methods: The parameters were collected based on our previous study and by prediction using ADMET Predictor software predict. The PBPK models for 3-methoxydadizein (1), 8-O-methylretusin (2), daidzin (3), and isolariciresinol (4) administered orally to rats were established using GastroPlus software. These models were employed to simulate the pharmacokinetic properties in rats across various dosages, and subsequently extrapolated to humans. The calculated parameters including Cmax, Tmax, and AUC were compared with observed values. The accuracy of the PBPK models was assessed using fold-error (FE) values. Result: The FE values ranged from 1.03 to 1.52, meeting the PBPK model regulations where FE should be less than 2. The sensitivity analysis focusing on the absorption amount and AUC0→t of these four constituents in humans was also conducted. These results confirm the successful establishment of PBPK models of these four constituents from SPC in this study, and these models were applicable to predict pharmacokinetics across various doses and extrapolate across species. Conclusions: The PBPK models of four constituents can be used to predict the pharmacokinetic characteristics in humans after oral administration of SPC and provide useful data for safe and rational medication in clinical practice....
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