Clinical Pharmacokinetics最新文献

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.

Background and objectives: Efsubaglutide alfa is a long-acting GLP-1 receptor agonist and is designed by fusion of two human GLP-1 molecules with IgG2 Fc via a natural immunoglobulin hinge region. This study evaluates the exposure-response (E-R) relationship of efsubaglutide alfa in patients with type 2 diabetes (T2D) treated with metformin.

Methods: Data were derived from an operational seamless design of randomized, double blind, placebo clinical trial (YN011-302) involving 406 subjects with T2D on stable metformin therapy. Participants received weekly subcutaneous injections of 1 mg or 3 mg efsubaglutide alfa, or placebo. The trial included a 24-week double-blind period and a 28-week open-label period.

Results: Participants had a median age of 55.0 years, mean body weight of 73.7 kg, fasting plasma glucose (FPG) of 9.72 mmol/L, and glycated hemoglobin (HbA1c) of 8.63%. A robust inverse correlation was observed between efsubaglutide alfa exposure and improvements in HbA1c, FPG, glucose area under the curve (AUC) during mixed-meal tolerance test (MMTT), body weight, and body mass index. Efsubaglutide alfa exposure also positively correlated with C-peptide AUC during MMTT, indicating improved beta-cell function. The E-R model indicates that doubling steady-state trough concentrations (C_min,ss) reduced HbA1c by 0.211%, while every 100 ng/mL increase in C_avg,ss led to 0.5 kg reduction in body weight at Week 24. Baseline HbA1c was a predictor of treatment response. Safety analysis revealed a positive correlation between exposure and gastrointestinal adverse events, which decreased over time, suggesting tolerance development.

Conclusions: Efsubaglutide alfa, combined with metformin, significantly improves glycemic control and weight management, with an acceptable safety profile. This E-R model provides insights for dose optimization and trial design, and supports its use as an effective add-on therapy for patients with T2D, as indicated in the drug specification.

Trial registration: The trials were registered at Clinicaltrials.gov (identifier: NCT04998032).

Background and objective: Pyronaridine is a blood schizonticide with a high blood-to-plasma ratio, effective against Plasmodium parasites. As a lipophilic, moderately strong base, it accumulates in low-pH compartments such as lysosomes and parasite food vacuoles, leading to tissue accumulation and differences in drug exposure between healthy individuals and patients with malaria. This study applied physiologically based pharmacokinetic (PBPK) modeling to evaluate the effects of lysosomal sequestration, red blood cell (RBC) accumulation, and parasitemia on pyronaridine pharmacokinetics.

Methods: Data were available from a phase I clinical trial and the PYRAPREG study. PBPK models were developed in PK-Sim® and MoBi®. A standard multicompartment structure was expanded by adding lysosome compartments to relevant organs. To account for malaria infection, Plasmodium parasite compartments were incorporated into RBCs, with volume scaled by parasitemia.

Results: Data from 52 healthy individuals and 25 patients with malaria were used for model optimization. Incorporating lysosomal sequestration was essential for capturing pyronaridine distribution. In patients with malaria, incorporating low hemoglobin (Hb) and drug accumulation in the parasite compartment enabled an adequate description of whole blood pharmacokinetics. Simulations showed that free pyronaridine concentrations in the parasite compartment were over 10-fold higher than that in whole blood. Higher parasitemia was associated with increased area under the curve (AUC)_0-24h and C_max, mainly on day 1, as parasitemia decreased rapidly. However, the subsequent decrease in Hb had the opposite effect, lowering AUC_0-24h and C_max on the following days.

Conclusions: This study demonstrates the value of PBPK modeling in elucidating key pharmacokinetic mechanisms, revealing the critical roles of lysosomal sequestration, Hb level, and parasitemia in pyronaridine disposition.