Clinical Pharmacokinetics最新文献

Background and objective: There is limited information on the pharmacokinetics and optimal dosing of fluconazole in patients undergoing mechanical circulatory support (MCS) device implantation.

Aim: The aim of this study was to describe fluconazole pharmacokinetics and identify dosing regimens that achieve pharmacokinetic/pharmacodynamic targets in this patient cohort.

Methods: In this prospective, single-centre study, adults undergoing MCS device implantation received intravenous fluconazole 200 mg or 400 mg, continued once daily for 5 days. Fluconazole concentrations were measured at four peri-operative time points, on return to the intensive care unit, and on days 3 and 5 following implantation. The area under the concentration-time curve from time zero to 24 h (AUC_0-24) was estimated, with target exposures defined as AUC_0-24/minimum inhibitory concentration (MIC) ≥ 50 for prophylaxis and AUC_0-24/MIC ≥ 100 for therapy. Population pharmacokinetic modelling was performed using non-linear mixed-effects methods and for Monte Carlo dosing simulations.

Results: Sixty-five fluconazole concentrations from 10 male patients (median age 51.5 years; IQR 50.0-57.0) were included. A two-compartment model including an additional renal replacement therapy (RRT)-dependent clearance pathway best described the data. Parameter estimates from the final model included a central volume of distribution of 5.75 L, non-RRT clearance of 0.45 L/h, and RRT clearance of 2.22 L/h. Simulations showed that doses of 800 mg or 12 mg/kg would be required for the highest probability of target attainment for Candida fluconazole MICs up to 4 mg/L (AUC_0-24/MIC ≥ 50) and 2 mg/L (AUC_0-24/MIC ≥ 100).

Conclusion: In patients undergoing MCS device implantation, intravenous fluconazole 200 mg administered pre-operatively and continued daily for 5 days is insufficient for Candida spp. with MICs > 1 mg/L (prophylaxis, AUC_0-24/MIC ≥ 50) and > 0.5 mg/L (treatment, AUC_0-24/MIC ≥ 100).

Gonadotropin-releasing hormone (GnRH) antagonists inhibit estrogen synthesis and secretion, making them promising treatment options for estrogen-dependent diseases, such as endometriosis. This study developed a population pharmacokinetic/pharmacodynamic (PK/PD) model for merigolix, a novel oral GnRH antagonist, to determine its optimal dosing in the treatment of endometriosis. Population PK/PD modeling was performed using NONMEM 7.4, incorporating data from phase I clinical studies involving single and multiple ascending dose (SAD and MAD) trials in healthy premenopausal volunteers. The PK profile was characterized using a two-compartment model incorporating first-order absorption and elimination processes. The temporal delay between merigolix concentration and subsequent estradiol (E2) suppression was described using an indirect response turnover model. The models were evaluated via visual predictive checks, goodness-of-fit plots, and bootstrap analysis. The PK model described merigolix concentrations across various doses (estimated clearance: 549 L/h, central volume of distribution: 1690 L). The PD model demonstrated dose-dependent E2 suppression (estimated maximum inhibitory effect [I_max]: 1, half-maximal inhibitory concentration [IC₅₀]: 0.209 ng/mL). Simulations suggested that, assuming a baseline E2 concentration of 100 pg/mL, daily doses of 120 and 160 mg achieved the clinically meaningful target E2 range of 20-40 pg/mL (partial suppression), while higher doses of 240 and 320 mg resulted in target E2 levels below 20 pg/mL (full suppression), effectively controlling symptoms and minimizing the risk of bone mineral density loss. This PK/PD model provides a quantitative framework for optimizing merigolix dosing and supports the selection of dosing regimens for future clinical trials, potentially offering a novel therapeutic option for endometriosis treatment.

Background and objectives: Diseases such as cystic fibrosis (CF) and non-CF bronchiectasis can cause extensive mucus formation in the lung, which may affect drug distribution and effects. As such, quantitative understanding of drug distribution in mucus may guide treatment optimization. Here, we aimed to develop a modeling framework to evaluate spatial distribution of drugs in mucus with CF as a proof of concept. In a case study, we demonstrated how spatial PK models can be used to predict spatial antimicrobial pharmacodynamics (PD).

Methods: A spatial pharmacokinetic (PK) model in mucus was developed using discretized partial differential equations. Hypothetical drugs with realistic ranges for molecule/particle size (radius, r), mucin binding affinity, and half-lives were used to evaluate the impact of drug-specific factors on spatial distribution in mucus. Mucin concentration and muco-ciliary clearance were evaluated as biological system-specific factors. We then demonstrated how the spatial PK model can be used to predict antimicrobial drug effects of imipenem against the pathogen Pseudomonas aeruginosa in mucus.

Results: Under intravenous PK profiles, molecular/particle size (r) was found to play a dominant role in mucus drug diffusion, while drug-mucin interactions and muco-ciliary clearance showed a minor impact. Small molecule drugs (r <1 nm) could readily penetrate mucus, whereas large molecules or particles (r >20 nm) showed differential spatial drug distribution. Our case study demonstrates that baseline spatial bacterial organization can impact the treatment outcome of imipenem against mucus-associated infections.

Conclusion: The developed spatial PK modeling framework enabled quantitative description of the spatial distribution of drugs in airway mucus and can be of relevance to guide optimization of treatment strategies.

Background: Efsubaglutide alfa is a novel glucagon-like peptide-1 receptor agonist composed of dual GLP-1 molecules fused with the fragment crystallizable (Fc) region of human immunoglobulin G2. It is designed for the treatment of type 2 diabetes mellitus (T2DM) and metabolic diseases.

Objectives: This study aimed to quantitatively describe the exposure-response (E-R) relationship between efsubaglutide alfa exposure and efficacy and safety endpoints in patients with T2DM and to assess the impact of baseline characteristics on the E-R relationship.

Methods: An E-R analysis was conducted using data from 465 drug-naïve participants with T2DM in a phase IIb/III trial (YN011-301), which included a 24-week double-blind period followed by a 28-week open-label period. Participants received once-weekly subcutaneous injections of efsubaglutide alfa 1 mg, 2 mg, or 3 mg or placebo. Regression analysis was performed against the steady-state pharmacokinetic exposure, including steady state peak concentration (C_max,ss), steady state minimum concentration (C_min,ss), steady state average concentration (C_avg,ss), and their logarithms.

Results: The median age was 51.0 years, and the mean baseline glycated hemoglobin (HbA1c) was 8.71%. At weeks 24 and 52, reductions in HbA1c, fasting plasma glucose, area under the concentration-time curve for glucose during the mixed-meal tolerance test, body weight, waist circumference, and body mass index correlated positively with drug exposure. The E-R model indicated that a 10-fold increase in C_min,ss led to a 1.150% decrease in HbA1c at week 24. Baseline HbA1c, age, and neutralizing anti-drug antibody influenced the E-R relationship for HbA1c. Safety analysis showed a positive correlation between drug exposure and the incidence of treatment-related adverse events, particularly nausea and diarrhea, with tolerance developing over time.

Conclusions: Efsubaglutide alfa demonstrates a strong E-R relationship for glycemic control and weight reduction in drug-naïve participants with T2DM. The extended half-life and favorable safety profile of efsubaglutide alfa make it well-suited for once weekly or biweekly monotherapy in patients with newly diagnosed T2DM.

Trial registration: The trial was registered at Clinicaltrials.gov (identifier: NCT04994288).

Background: Despite its common use for analgesia in neonatal intensive care units, the optimal dosing and safety profile of fentanyl, particularly regarding suspected fentanyl-emerged adverse events (FEAEs), such as hypotension, desaturation, and oliguria, are not well-defined.

Objective: This study aimed to develop an optimal therapeutic monitoring and dosing strategy for fentanyl for neonates. A physiologically based pharmacokinetic (PBPK) model for predicting fentanyl pharmacokinetics across various populations, including preterm and term neonates, was developed, and the relationship between predicted fentanyl exposure and FEAE incidence in neonates was assessed.

Methods: A PBPK model was developed and validated against the observed values in the literature. The model's predictive accuracy for fentanyl pharmacokinetics and association with FEAE incidence in an external retrospective cohort of Japanese neonates was evaluated using the predicted concentrations and pharmacokinetic parameters estimated by PBPK simulation.

Results: The PBPK model exhibited reasonable predictive performance for serum fentanyl concentrations in actual neonatal patients (mean error: 9.27% [standard error: 5.06%], root mean squared error: 54.7%). The incidence of any FEAE, particularly oxygen desaturation, was associated with the fentanyl concentration-to-dose ratio, but not with some exposure parameters, such as the area under the curve and maximum concentration. The recommended reduced infusion rate allowed serum fentanyl concentrations to fall within the ranges established by the reported values and our data.

Conclusions: Our PBPK model and proposed dosing strategy may contribute to safer and more effective fentanyl use in neonates.

Background: Depression is common in pregnant women, and selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants during pregnancy. Pregnancy is a period of major physiological changes that impact drug pharmacokinetics (PK). To date, there is limited information about the placental transfer of antidepressants, and differences in fetal exposure between drugs are poorly characterized.

Aims: We aimed to develop physiologically based pharmacokinetic (PBPK) models to assess maternal and fetal exposure to sertraline, escitalopram and paroxetine across pregnancy.

Methods: Transplacental parameters from ex vivo human placenta perfusion experiments were estimated using mixed-effects modeling in Monolix and integrated in pregnancy PBPK models in Simcyp PBPK Simulator. After evaluation of the models by comparison with observed data from literature, maternal PK profiles and fetal exposure at different trimesters of pregnancy were simulated.

Results: The pregnancy PBPK models accurately predicted maternal and fetal concentration time-courses of SSRIs. Simulations showed a decrease in maternal concentrations during pregnancy for all three SSRIs, affecting both total and unbound concentrations. In the third trimester, residual concentrations were predicted to decrease by 56% and 43% for sertraline, 55% and 49% for escitalopram, and 90% and 88% for paroxetine, for total and unbound concentrations respectively. Cord blood-to-maternal plasma area-under-curve (fm AUC) ratios over 24 h were calculated based on model predictions. By late pregnancy, fm AUC ratios were 0.45 for sertraline, 0.91 for escitalopram, and 0.58 for paroxetine.

Conclusions: Quantitative prediction of antidepressants exposure using PBPK modeling integrating ex vivo data will help to better understand the impact of pregnancy-related physiological changes on the PK of these drugs and support evidence-based pharmacotherapy for depression during pregnancy.

Background and objective: The combination of ampicillin (AMP) together with sulbactam (SBC) is a widely used choice for infection prophylaxis in the context of numerous surgical procedures, especially those performed in the field of maxillofacial surgery. Since the pharmacokinetic behavior of these two substances in body tissues is not known in detail owing to sparse tissue data in the literature, the aim of this work was to develop a physiologically based pharmacokinetic (PBPK) model that can predict the concentration versus time courses of AMP and SBC after intravenous administration in plasma, especially bone tissue. Furthermore, the effectiveness of an established prophylaxis regimen based on the developed PBPK model was to be evaluated.

Methods: A PBPK model for middle-aged and elderly populations was created using PK-Sim^® software. A total of nine human clinical studies which included data from plasma, lung, skin, and bone tissue were utilized to verify the model. In addition to the physicochemical properties and ADME (Absorption, Distribution, Metabolism, and Excretion) characteristics of AMP and SBC, the measured drug concentrations from the clinical studies were used for development and validation. The performance of the model was evaluated on the basis of established fold error acceptance criteria for selected pharmacokinetic parameters. Here, the model predictions were compared with the observed values.

Results: The final PBPK model for AMP and SBC could well describe the measured mean concentrations in plasma and in the different body tissues, as these fell within the predicted 5th-95th percentile range for the most part. This applies to 97% of the AMP and 88% of the SBC measurements. Exactly 81% of the fold error values of the pharmacokinetic parameters are within the twofold acceptance criterion. Overall, the average fold errors for the evaluated pharmacokinetic parameters were within the range of 1.01-1.43.

Conclusions: In this work, we present the first PBPK model that simultaneously predicts AMP and SBC in plasma and various tissues. In addition to observed plasma data, the model was also developed and verified with experimentally measured data from the above-mentioned tissues. This allowed a significant limitation of previous PBPK models to be overcome. The effectiveness of established prophylaxis regimes is demonstrated through our model, whereby it must be assumed, owing to measured data for bone tissue, that some individuals do not reach the target values for adequate prophylaxis.

Background and objectives: The use of the 12-dose, once-weekly, rifapentine-based (3HP), short-course tuberculosis preventive treatment (TPT) in children has been limited due to a lack of child-friendly rifapentine formulations. In this study, we compared the relative bioavailability of rifapentine and isoniazid when suspended in water versus whole tablets, using generic adult formulations.

Methods: We assessed the relative bioavailability of non-dispersible rifapentine and isoniazid adult tablets suspended in water compared with whole tablets. Adults with a positive tuberculosis infection test were randomized 1:1:1 to receive two of three rifapentine/isoniazid formulations in separate treatment sequences, including two generic brands of fixed-dose combinations and standalone tablets of rifapentine and isoniazid. Participants received either whole tablets swallowed or tablets suspended in water at a dose of 900 mg for each drug once weekly over 12 weeks with intensive pharmacokinetic sampling up to 48 h post-dose. Nonlinear mixed-effects modelling was used to compare the relative bioavailability of suspended versus whole tablets, with 90% confidence intervals (CI) evaluated against the standard bioequivalence range (80-125%).

Results: In 24 participants, a one-compartment model described rifapentine data well. A two-compartment model with a mixture component for fast/intermediate and slow acetylators best described isoniazid. Rifapentine and isoniazid demonstrated similar bioavailability across all dosing forms, meeting formal bioequivalence criteria. The absorption rates for suspended tablets were faster than those for whole tablets by 22.2% (90% CI 12.4-30.8) for rifapentine and 35% (90% CI 26.1-42.6) for isoniazid.

Conclusion: Both rifapentine and isoniazid, whether in fixed-dose combinations or as standalone, showed similar bioavailability when administered as whole tablets or suspended in water. These findings support dosing in children and other populations without the need to adjust rifapentine or isoniazid doses, thereby supporting broader access to the 3HP regimen.

Pan african clinical trials registry: PACTR202306775627089, registration date June 15, 2023.

Introduction: Olorigliflozin, a selective sodium-glucose cotransporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus (T2DM).

Objective: This trial aimed to assess the pharmacokinetics, pharmacodynamics, and safety of olorigliflozin capsules by comparing results in patients with T2DM with normal renal function and in those with mild and moderate impairment.

Materials and methods: This study administered olorigliflozin 50 mg to 32 Chinese patients with T2DM from a single medical center, of whom 16 showed no renal impairment, eight showed mild impairment, and eight showed moderate impairment. Those with mild impairment were matched to eight without impairment based on sex, age, and body mass index, whereas those with moderate impairment were matched to the remaining eight without impairment.

Results: All 32 participants completed the study. Compared with normal renal function, patients with mild renal impairment had 15.42% higher maximum plasma concentration and 16.22% higher area under the curve from time zero to time t (AUC_0-t), a clinically non-significant difference, with similar geometric mean AUC extrapolated from time zero to infinity (AUC_0-∞). Moderate renal impairment showed 56.71% higher AUC_0-t and 62.27% higher AUC_0-∞ but comparable maximum plasma concentration. Time to maximum plasma concentration was consistent across groups. Both renal impairment groups had decreased renal excretion. At 24 h post-dose, urinary glucose excretion increased: mild renal impairment (14.31-52.31 g) versus matched control (34.32-98.14 g), moderate renal impairment (5.94-38.45 g) versus matched control (9.85-72.83 g), yet absolute levels remained lower in the renal impairment groups. Adverse events (all grade 1-2) had similar rates.

Conclusions: Olorigliflozin capsules (50 mg) may be safe and effective for individuals with T2DM who show no or mild renal impairment, but they may be inappropriate for those who show moderate impairment.