European Journal of Drug Metabolism and Pharmacokinetics最新文献

Vadadustat is an innovative drug that inhibits prolyl hydroxylase and has been approved for the treatment of anemia in patients with chronic kidney disease. Its pharmacokinetics are linear, i.e., vadadustat's absorption, distribution, and elimination are predictable. Vadadustat is well absorbed from the gastrointestinal tract, with over 99% of the drug bound to plasma proteins. The majority of the drug is conjugated with glucuronic acid in the liver, and these conjugates are primarily excreted through urine, with a smaller portion eliminated through stool. Only 1% of the unchanged drug is found in the urine, while 9% appears in the stool. In clinical trials, vadadustat demonstrated clear effectiveness compared with placebo, significantly increasing hemoglobin levels in patients with anemia due to chronic kidney disease, with an average increase of 1.43 ± 0.05 g/dL after 6 months of treatment. However, its effectiveness is somewhat lower than that of erythropoietin. The rates and severity of adverse events with vadadustat and erythropoietin are similar. Given that vadadustat is taken orally and has a beneficial efficacy and safety profile, it represents a meaningful addition to the standard treatment for anemia associated with renal failure, working alongside erythropoietin.

Background and objective: Intraperitoneal lidocaine is an emerging strategy for analgesia following abdominal surgery but its pharmacokinetics are poorly quantified. We aimed to develop a pharmacokinetic model for unbound and total lidocaine by intraperitoneal and intravenous routes.

Methods: Unbound and total lidocaine concentrations, and pain scores (visual analogue score 0-10) were from a published randomized control trial of adults (n = 56) undergoing laparoscopic colon resection. Participants received intravenous or intraperitoneal lidocaine (2 mg/kg bolus then 1.5 mg/kg/h infusion) for 72 h postoperatively. Data were pooled with literature-derived alpha-1-acid glycoprotein concentrations (AAG) to support total lidocaine modelling. Unbound kinetics were described using compartmental models with first order absorption between intraperitoneal and plasma compartments. A turnover model described AAG kinetics with constant binding to lidocaine. An inhibitory pharmacodynamic model was explored to link concentration to pain scores.

Results: Maximum lidocaine concentrations after intraperitoneal administration were means (range) of 3.0 (0.4-4.5) mg/L total and 0.6 (0.1-0.9) mg/L unbound. Intraperitoneal absorption was incomplete (bioavailability = 0.66, 95% confidence interval (CI) 0.6-0.76) with a half-time of 0.5 (0.4-0.8) h. A two-compartment model with first order elimination fit best, with unbound clearance 121 (108-136) L/h/70 kg. The binding constant to AAG (K_D) was 2.98 (2.69-3.35) µmol/L. A pharmacodynamic model with C₅₀ of 0.21 mg/L and maximal reduction (E_max) of 6 units captured pain scores and was used to simulate dosing strategies.

Conclusions: A third of the intraperitoneal dose did not reach the central compartment and absorption took ~2 h. Simulations show that 2 mg/kg/h intraperitoneal infusion achieves a 5-point pain score reduction within ~36 min.

Background and objective: Sepsis-induced pathophysiological changes may lead to pharmacokinetic variability which alters antibiotic concentrations at the host infection site. This poses a challenge in clinical practice, as sufficient antibiotic concentrations in tissue are necessary to effectively eradicate bacterial pathogens. In this exploratory study, we aimed to evaluate the potential of routinely used laboratory biomarkers to predict subcutaneous and muscle tissue penetration of moxifloxacin in septic patients.

Methods: We retrospectively analyzed data from 10 septic patients included in a pharmacokinetic study, in which moxifloxacin concentrations in subcutaneous adipose and muscle tissues were measured with microdialysis. We correlated the tissue-to-plasma ratio and protein binding with various clinical biomarkers.

Results: Our results revealed significant correlations for CRP, LDH, BUN, GPT, and total protein with moxifloxacin subcutaneous penetration, and BUN, GOT, and GPT with muscle penetration. Notably, all biomarkers except CRP correlated negatively with tissue penetration. Moreover, we found a positive correlation between moxifloxacin protein binding and total plasma proteins and albumin.

Conclusion: Biomarker tissue correlations suggest that the penetration of moxifloxacin into tissues is a complex process influenced by factors like inflammation, tissue integrity, liver function, protein levels, and renal function. Understanding these interactions might help optimize antibiotic dosing strategies.

Background and objectives: The HIV infection in malnourished conditions raises the concerns with antiretroviral medications, which may worsen the already compromised physiological state. The alteration in the plasma protein binding in malnourished HIV patients exacerbates the unbound fraction of antiretroviral medications, resulting in alterations in the therapeutic effectiveness and toxicity. Thus, the present study investigates the effects of protein deficiency and protein-energy malnutrition on the pharmacokinetics of the antiretroviral efavirenz.

Method: Malnutrition was induced in this study through a modified diet containing only 2% protein. The experiment involved 16 Wistar rats, divided into two groups of 8. The control group was provided with a standard pellet diet (AIN 93G) that contained 19% protein, while the second group was subjected to the low-protein (2%) diet for 90 days. Rats were fed ad libitum with their respective diets during this period. On the 90th day, efavirenz (200 mg/kg, p.o.) was administered, and pharmacokinetic parameters were assessed using HPLC analysis.

Results: The findings indicate that the protein-deficient diet successfully created a model of malnutrition, evidenced by a significant reduction in body weight (26%), hemoglobin levels (33%), total protein (27%), and blood albumin (41%) compared to the control group on a standard diet. The pharmacokinetic analysis of efavirenz in the protein-deficient rats revealed an increase in half-life (T_½) by 51.27%, maximum concentration (C_max) by 31.57%, and area under the curve (AUC 0-∞) by 51.40%, alongside a decrease in total body clearance (45.81%) and volume of distribution (12.1%) relative to the pharmacokinetic profile observed in rats on the standard AIN 93G diet.

Conclusion: These findings indicate that the pharmacokinetic profile of efavirenz is significantly altered under protein-deficient conditions. Therefore, it is recommended that further pharmacokinetic studies be conducted in patients with protein deficiency to determine if standard dosing of efavirenz should be adjusted based on the individual's nutritional status.

Background and objective: Hyperuricemia (HUA) is a metabolic disease closely associated with hypertension. It can induce liver damage, subsequently affecting drug metabolism. However, its specific impacts and underlying mechanisms remain unclear. Therefore, the pharmacokinetics and cytochrome P450 (CYP450) enzyme activities were investigated.

Methods: Twelve healthy Sprague-Dawley rats were randomly assigned into two groups, a control group and an experimental group, with six animals per group. To establish the HUA model, rats in the experimental group received a subcutaneous injection of potassium oxonate (POx) (250 mg/kg), combined with oral administration of a fructose solution (5%, w/v). Serum biochemical parameters were subsequently evaluated, while histopathological examinations of liver and kidney tissues were performed. Plasma amlodipine (ALDP) levels were quantified by employing LC-MS/MS, and pharmacokinetic parameters were analyzed using DAS 3.0 software. Furthermore, activities of six major CYP450 enzyme isoforms were simultaneously determined through the cocktail method.

Results: In the HUA-induced rats, significant elevations in serum uric acid (SUA), blood urea nitrogen (BUN), and creatinine (Cr) were observed, accompanied by distinct pathological lesions within hepatic and renal tissues. Pharmacokinetic analyses demonstrated marked increases in the peak plasma concentration (C_max), terminal elimination half-life (t_½), and time to reach peak concentration (T_max) of ALDP, which were elevated by approximately 2.7-fold, 1.5-fold, and 2.1-fold, respectively. The apparent oral clearance (CL_z/F) significantly decreased by half. Furthermore, the activities of six CYP450 enzymes notably decreased: CYP2E1 by 94%, CYP2C19 by 92%, CYP2C9 by 91%, CYP2D6 by 80%, CYP3A1 by 73%, and CYP1A2 by 7%.

Conclusion: This study successfully established a stable rat model of HUA, and demonstrated that HUA specifically alters drug metabolism by causing liver damage and modulating CYP450 enzyme activities.

Background and objective: Rotigotine, a dopamine agonist, is used to treat Parkinson's disease and restless leg syndrome, with transdermal patches being the primary delivery method in clinical practice. However, quantitative information on the in vivo pharmacokinetics of rotigotine across various dosage regimens via transdermal administration remains limited, and this has been identified as a significant barrier to achieving precision medicine. This study aims to develop a novel physiologically-based systematic pharmacokinetic model tailored to rotigotine transdermal drug delivery. Based on the model, we quantitatively predicted rotigotine distribution patterns in target tissues to assess its in vivo efficacy and safety and to interpret the pharmacokinetic variability in transdermal patches according to covariate reflection.

Methods: The data used to develop the quantitative model included clinical outcomes from single (2-8 mg/24 h) and multiple doses (0.5-8 mg/24 h) of rotigotine transdermal patches administered to healthy adults and patients with idiopathic Parkinson's disease or restless legs syndrome. The model was designed to represent whole-body physiological systems, incorporate liver and kidney clearance mechanisms, and account for the specific physicochemical properties influencing drug permeation and distribution across various tissues.

Results: The model developed in this study effectively quantified the pharmacokinetic profiles of transdermal rotigotine within an acceptable variability. After transdermal application, rotigotine delivery to the target tissue, the brain, occurred rapidly, and the tissue concentrations at steady-state were approximately 10-fold higher than those in plasma. Incorporating weight as a covariate showed that in underweight individuals, tissue exposure to rotigotine increased by 1.61-fold, with a mean half-life extension of 1.50-fold compared to that of the normal weight population.

Conclusion: The quantitative model proposed in this study serves as a foundational tool for advancing precision medicine, reliably characterizing the in vivo pharmacokinetics of rotigotine transdermal delivery across various doses and regimens.

Background and objective: Model-informed precision dosing (MIPD), based on a Bayesian approach and machine learning (ML) algorithms, is a suitable approach to personalize dosage recommendations and to improve the concentration target attainment for each patient. The objective of this study is to compare the predictive performance of two ML approaches, XGBoost and LSTM, with a previously developed Bayesian model of tacrolimus (Tac) in a cohort of Tunisian kidney transplant patients during the early post-transplant period (0-3 months) METHOD: This was a cross-sectional study conducted at the Pharmacology department in Fattouma Bourguiba's hospital in Monastir, Tunisia. We included patients who had undergone kidney transplantation in the Nephrology department of Monastir Hospital and received the Tac immunosuppressant protocol, for whom routine therapeutic drug monitoring (TDM) during the early post-transplant period (0-3 months) had been performed in our department.

Results: A total of 187 Tac predose concentration (C₀) issued from 56 adult renal transplant patients were included in the present study. The whole population was divided into building (n = 39 patients, 119 C₀) and validation groups (n = 17 patients, 68 C₀). In the validation dataset, the RMSE was 0.76, 0.19, and 0.01, and the MAE was 0.55, 0.36, and 0.06, respectively, for the Bayesian approach, XGBoost, and LSTM.

Conclusion: Our study demonstrates that the LSTM approach outperforms XGBoost and Bayesian estimation in predicting tacrolimus concentration in Tunisian kidney transplant patients. Implementing TDM-based LSTM models during the first PT 3 months in clinical practice can significantly enhance patient outcomes and prevent acute kidney rejection in this population.

Background and objective: The pharmacokinetics of drugs can be altered by pathophysiological changes in the body that result from malnutrition. The objective of this study was to evaluate the profiles derived from in vivo studies conducted on non-malnourished (control) and malnourished rats using minimal physiologically based pharmacokinetic (mPBPK) models.

Methods: Single oral doses of atenolol (ATN) and metoprolol (MET) were administered to non-malnourished and malnourished rats. We demonstrate how plasma profiles can be evaluated using mPBPK models with high and low tissue-to-plasma partition coefficients (K_p) and elimination by either kidney or liver. A decrease in blood flow and cardiac output due to beta-blocker administration was assumed. Reference IV profiles from the literature were included to inform the mPBPK model and to help assess the absorption phases of individual oral profiles. Absorption was captured as two or three sequential zero-order processes for both drugs, and IV and oral profiles were assessed by joint fitting. Modeling was performed using both naïve pooling (ADAPT) and population (Monolix) analyses.

Results: The experimental data show increased AUC values of MET and ATN in malnourished rats. Accordingly, an increased bioavailability (from 0.43 to 0.67) for ATN and an increased bioavailability (from 0.42 to 0.84) for MET in the malnourished group were related to higher absorption rates in both absorption phases.

Conclusions: This study demonstrated advantageous use of mPBPK modeling with malnutrition primarily altering drug absorption in this animal model. Also, our analysis offers a blend of known and assumed components assembled mechanistically to suggest a reasonable interpretation of the PK profiles.

Background and objectives: Kratom, a Southeast Asian tree, has been researched for its potential as a therapeutic for substance use disorders. The most abundant alkaloid in kratom, mitragynine, is being investigated individually for opioid use disorder. However, the active metabolite of mitragynine,7-hydroxymitragynine (7-HMG) has raised concerns because of its high binding affinity to μ-opioid receptors and abuse potential. This study examines various pharmacokinetic parameters of 7-HMG in both in vitro and in vivo models.

Methods: In vitro pharmacokinetic properties were investigated using human colorectal adenocarcinoma cell monolayers (Caco-2 cells), rat plasma, rat liver microsomes, and rat hepatocytes to determine the permeability, plasma protein binding, and microsomal and hepatocyte stability of 7-HMG, respectively. Oral and intravenous (IV) pharmacokinetic studies of 7-HMG were performed in male Sprague-Dawley rats.

Results: 7-HMG exhibits high permeability across Caco-2 cells (19.7 ± 1.0 × 10^-6 cm/s), with a relatively low plasma protein binding of 73.1 ± 0.6% to mitragynine. The hepatic extraction ratio was 0.3 and 0.6 in rat liver microsomes and hepatocytes, respectively, indicating that 7-HMG is an intermediate hepatic extraction compound. Oral and IV pharmacokinetic studies were performed in male rats. The volume of distribution was 2.7 ± 0.4 l/kg and the clearance was 4.0 ± 0.3 l/h/kg after IV administration. After oral dosing (5 mg/kg), a C_max of 28.5 ± 5.0 ng/ml and T_max of 0.3 ± 0.1 h were observed. However, the oral bioavailability of 7-HMG was only 2.7 ± 0.3%. The results demonstrate 7-HMG is rapidly absorbed but has low oral bioavailability. Mitragynine pseudoindoxyl (MGPI) is a metabolite of 7-HMG that is a more potent µ-opioid agonist than 7-HMG. The parent-to-metabolite ratio for MGPI following IV 7-HMG administration was 0.5 ± 0.1%, indicating very limited systemic exposure to MGPI.

Conclusions: This study reports the pharmacokinetic parameters of 7-HMG to help with the development of mitragynine, as a therapeutic.

Background and objectives: Cannabis consumption is increasing in both the recreational and medical settings. Tetrahydrocannabinol (THC) is known to produce cardiovascular effects, but the specific roles of THC and its metabolites THC-OH and THC-COOH in cannabinoid-induced cardiovascular effects remain unclear. We hypothesized that THC and THC-OH mediate a cannabinoid-induced increase in heart rate in either an additive or synergistic fashion.

Methods: The present study uses prospectively obtained data to evaluate the effect of THC and its metabolites on heart rate in healthy volunteers through non-linear mixed-effect pharmacokinetic/pharmacodynamic (PK/PD) modeling.

Results: The PK/PD models reveal that THC, THC-OH and a combination of THC and THC-OH, but not THC-COOH, are responsible for THC-induced tachycardia. The EC50 of the THC Emax model was 0.53 µM, 25-fold the EC50 for the THC-OH Emax model. The General Empiric Dynamic Model indicates that THC and THC-OH act synergistically to increase heart rate. Neither sex nor CYP2C9 polymorphism contributes to THC-induced tachycardia.

Conclusion: THC-OH but not THC-COOH contributes to the heart rate effect of THC and THC-OH may be acting in a synergistic manner with THC. This contributes to understanding the cardiovascular effects of THC and cannabis-induced cardiovascular events. Future research including further hemodynamic data will allow a detailed systems pharmacology or response surface model approach.

Trial registration: www.isrctn.com ; registration number ISRCTN53019164.