Clinical Pharmacokinetics[JOURNAL]
Sun
200 papers
Population Pharmacokinetics of a Novel Oral Fosfomycin Prophylactic Scheme in the Plasma and Prostate of Patients Undergoing Endoscopic Surgery for Benign Prostatic Hyperplasia.
Cojutti PG, Berrino PM, Rotaru V … +5 more , Bianchi L, Schiavina R, Brunocilla E, Viale P, Pea F
Clin Pharmacokinet · 2026 Jan · PMID 41182479 · Full text
BACKGROUND AND OBJECTIVE: Fosfomycin trometamol may be a valuable option for antimicrobial prophylaxis before urological surgery for benign prostatic hyperplasia. The objective is to develop a population pharmacokinetic...
BACKGROUND AND OBJECTIVE: Fosfomycin trometamol may be a valuable option for antimicrobial prophylaxis before urological surgery for benign prostatic hyperplasia. The objective is to develop a population pharmacokinetic model of a novel oral fosfomycin prophylactic scheme in the plasma and prostate of patients undergoing endoscopic surgery for benign prostatic hyperplasia. METHODS: One- and two-compartment plasma pharmacokinetic models were fitted to fosfomycin plasma data, and different plasma-prostate linked models were tested by means of non-linear mixed effects modelling. Monte Carlo simulation was used to obtain 1000-subject concentration-time profiles of fosfomycin in the prostate. Probabilities of target attainment ≥ 90% of an area under the plasma concentration-time curve/minimum inhibitory concentration (MIC) > 83.3 and of a 70%t > MIC in the prostate were considered as optimal. Cumulative fractions of response against both wild-type and extended-spectrum beta-lactamase-producing Escherichia coli were calculated. RESULTS: A total of 104 patients, each providing a pair of plasma and prostate concomitant samples were included in the study. A one-compartment pharmacokinetic model was used to describe plasma fosfomycin concentration. Fosfomycin plasma-prostate relationships were adequately described by a direct response model with a power function. Simulations showed that fosfomycin disposition in the prostate was closely related to that in plasma. Optimal probabilities of target attainments were ensured against Enterobacterales having an MIC up to 0.5-1 mg/L in the 12 h vulnerable period after completing the prophylactic scheme. CONCLUSION: A prophylactic regimen of two doses of oral fosfomycin trometamol 3 g 12 h apart before undergoing prostatic surgery may grant effective concentrations in the prostatic tissue of patients for a 12 h vulnerable period.
Low Target Attainment of Intravenous Cefuroxime in Critically Ill Term Neonates and Children: A Pooled Population Pharmacokinetics Study.
Schouwenburg S, Preijers T, Asperen RMW … +6 more , Hartman SJF, de Wildt SN, de Hoog M, Koch BCP, Abdulla A, Wildschut ED
Clin Pharmacokinet · 2026 Jan · PMID 41182478 · Full text
BACKGROUND AND OBJECTIVE: Cefuroxime is a widely prescribed beta-lactam antibiotic, particularly in pediatric cardiac and medical-surgical intensive care units. The aim of this study was to describe intravenous cefuroxim...
BACKGROUND AND OBJECTIVE: Cefuroxime is a widely prescribed beta-lactam antibiotic, particularly in pediatric cardiac and medical-surgical intensive care units. The aim of this study was to describe intravenous cefuroxime disposition in critically ill pediatric patients. Moreover, target attainment of currently applied dosing regimens was evaluated, and suggestions for improving these dosing regimens were provided. METHODS: Two datasets were pooled for population pharmacokinetic (popPK) analysis, using NONMEM version 7.5. To assess the optimal target attainment (> 90% of patients with 100% time [T] > [4×] minimal inhibitory concentration [MIC]), pharmacokinetic (PK) profiles of different dosage regimens (intermittent/continuous) were simulated using the estimated popPK parameters. RESULTS: The cohort consisted of 45 pediatric patients with a median (interquartile range [IQR]) age of 391 days [31-3505] and body weight of 9.0 kg [5.0-29.8]. A two-compartment popPK model with first-order elimination and allometric scaling best described cefuroxime disposition. Intravenous cefuroxime clearance was estimated at 5.29 L/h/70 kg. Postnatal age and creatinine clearance (mL/min/1.73 m) were the best descriptive covariates for the maturation of cefuroxime clearance. Simulations evaluating the current cefuroxime dosing regimens stratified for estimated glomerular filtration rate (eGFR) levels illustrated moderate (< 90%) (eGFR < 30 and 30-80 mL/min/1.73 m) and poor (< 20%) (eGFR 80-120 and > 120 mL/min/1.73 m) cefuroxime target attainment across the entire age range. Alternative dosing regimens, including four times daily schedules and continuous infusion, improved target attainment, particularly in older children and those with augmented renal clearance. CONCLUSIONS: These findings indicate that underexposure due to augmented renal function is possible when applying the current cefuroxime dosing regimens. Future research should focus on individualized dosing strategies to optimize cefuroxime exposure and efficacy in pediatric populations.
Population Pharmacokinetics Analysis of Infliximab in up to 10-Year-Old Patients with Paediatric Inflammatory Bowel Disease: Label-Recommended Dose Fails to Achieve Therapeutic Target Concentration.
Zhao Q, Jongsma MME, Vuijk SA … +15 more , de Winter BCM, Martinez-Vinson C, Kolho KL, Norsa L, Hussey S, Wine E, Cohen S, Shouval DS, Assa A, Lev-Tzion R, de Meij T, Wolters VM, Huynh HQ, Preijers T, de Ridder L
Clin Pharmacokinet · 2026 Jan · PMID 41160254 · Full text
BACKGROUND AND OBJECTIVES: Younger patients with paediatric inflammatory bowel disease (IBD) may require higher infliximab (IFX) doses to attain similar target trough levels compared with older paediatric and adult patie...
BACKGROUND AND OBJECTIVES: Younger patients with paediatric inflammatory bowel disease (IBD) may require higher infliximab (IFX) doses to attain similar target trough levels compared with older paediatric and adult patients with IBD. This study aimed to investigate the population pharmacokinetics (popPK) of infliximab (IFX) in young paediatric patients with inflammatory bowel disease (IBD) (≤ 10 years old), optimize the IFX dosage in this special population and explore whether different IFX assays were comparable. METHODS: IFX therapeutic drug monitoring (TDM) data from young paediatric patients with IBD (≤ 10 years old) were retrospectively collected from 14 European and Canadian centres (2015-2019). External validation of published popPK models was performed by calculating relative mean predictive errors (rMPE) and relative root mean square errors (rRMSE) to assess bias and imprecision. A refined popPK model was then developed using nonlinear mixed-effects modelling in NONMEM version 7.4. PopPK parameters in young paediatric patients with IBD (≤ 10 years old) were compared with those in published paediatric patients (> 10 to < 17 years) and adults. RESULTS: In total, 2150 IFX concentrations from 104 young paediatric patients with IBD (≤ 10 years old) were measured by six different IFX assays. The median (min-max) age and body weight at start of IFX treatment of the population was 8.2 years old (1.2-10.0) and 25 kg (9.5-40.9), respectively. For the external validation, six published popPK models were evaluated. The best-performing model showed values for rMPE and rRMSE at 33.73% and 1189.59%, which rendered all models inadequate for our study population. Subsequently, a refined two-compartmental popPK model was developed. Typical clearance (CL) values (min-max, L/day/65 kg) were 0.615-0.943 for paediatric patients ≤ 10 years, 0.015-0.353 for published paediatric patients (> 10 to < 17 years) and 0.317-0.350 for published adults. Both albumin and C-reactive protein (CRP) could explain the inter-individual variability obtained in CL. Stratifying for IFX assays in the residual error model showed significant differences in relative prediction errors (rPE) between Immundiagnostik and an assay developed by Shomron Ben-Horin (named "in-house" assay) (P < 0.05) and between Caltag and in-house assays (P < 0.05). Post hoc individual CL differed between the Immundiagnostik and Sanquin assays (P = 0.033), while estimated area under the curve for weeks 6-14 (AUC) remained similar (P > 0.05). With label-recommended dosing, IFX concentrations dropped below 5 mg/L for approximately 4 weeks during maintenance. CONCLUSIONS: Paediatric patients ≤ 10 years, demonstrated a higher IFX CL than paediatric patients > 10 to < 17 years and adults, with albumin and CRP explaining the variability of CL. The differences obtained across the IFX assays did not affect overall drug exposure. To maintain trough concentrations above 5 mg/L in paediatric patients ≤ 10 years, a dosing interval of 4 weeks is required.
How is Levetiracetam Monotherapy Currently Monitored in Pregnancy? A Systematic Review.
Rademaker T, Goo Y, Soh MC … +4 more , Pasupathy D, Wong C, Bleasel A, Alffenaar JW
Clin Pharmacokinet · 2026 Jan · PMID 41120802 · Full text
BACKGROUND: Levetiracetam is commonly used as antiepileptic drug during pregnancy and has a well-established safety profile in that setting. Pregnancy-related pharmacokinetic changes may result in decreased levetiracetam...
BACKGROUND: Levetiracetam is commonly used as antiepileptic drug during pregnancy and has a well-established safety profile in that setting. Pregnancy-related pharmacokinetic changes may result in decreased levetiracetam levels and increased seizure frequency during pregnancy. Therapeutic drug monitoring (TDM) of levetiracetam levels may facilitate dose adjustment. Although levetiracetam TDM is widely used in pregnancy, robust guidelines are still lacking, resulting in heterogeneous use of TDM. OBJECTIVES: The aim of this review was to provide insight into levetiracetam TDM strategies utilised during pregnancy. METHODS: A systematic search up to 17 April 2025 was carried out using MEDLINE, Embase, APA PsycINFO, and Cochrane Central Register of Controlled Trials through Ovid. Studies were eligible for inclusion if data on levetiracetam dosing, concentrations, monitoring, efficacy, or safety during pregnancy were available. All articles were assessed for the risk of bias, and relevant data were extracted. RESULTS: The ten studies included revealed significant variability in epilepsy monitoring during pregnancy, TDM strategies, and dose adjustments. An increase in seizure frequency during pregnancy was described. However, data on levetiracetam maternal and foetal safety were limited. CONCLUSIONS: This review highlights the heterogeneity in levetiracetam TDM strategies in pregnancy. The pharmacokinetic changes during pregnancy require dose adjustments to maintain seizure control, but no standardised TDM protocol is available. Future research should focus on standardizing TDM strategies, validating target concentration thresholds, and assessing long-term maternal and foetal safety.
Randomized, Double-Blind, Phase I Pharmacokinetic Study of Subcutaneous Recombinant Human Superoxide Dismutase (rhSOD) in Healthy Volunteers.
Al Jalali V, Bauer M, Jorda A … +8 more , Bergmann F, Wölfl-Duchek M, Partl R, Vcelar B, Katinger D, Bashur R, Schnidar H, Zeitlinger M
Clin Pharmacokinet · 2026 Jan · PMID 41109931 · Full text
BACKGROUND: Excessive production of reactive oxygen species (ROS), particularly superoxide anion ( ), is a key mechanism in diseases such as cancer, inflammatory disorders, neurodegenerative conditions, and metabolic di...
BACKGROUND: Excessive production of reactive oxygen species (ROS), particularly superoxide anion ( ), is a key mechanism in diseases such as cancer, inflammatory disorders, neurodegenerative conditions, and metabolic diseases. Evidence also suggests that microgravity-induced oxidative stress, primarily driven by elevated levels, may contribute to the adverse physiological effects observed in astronauts during extended space missions. Superoxide dismutase (SOD) is critical for mitigating oxidative stress, and exogenous SOD supplementation offers a potential therapeutic strategy. METHODS: This randomized, double-blind, placebo-controlled Phase I study evaluated the safety, tolerability, and pharmacokinetics of recombinant human Cu/Zn-SOD (rhSOD, SOD1) following subcutaneous administration of 40 mg every 12 hours in 16 healthy volunteers. Eight subjects were enrolled each in the single-dose (SD) and multiple-dose (MD) cohorts. Study assessments, including pharmacokinetic sampling, were performed for 72 (SD) or 92 hours (MD). Injection site erythema was objectively assessed using the innovative Standardized Erythema Value (SEV*) method, derived from photographs taken with Scarletred®Vision software (SCARLETRED Holding GmbH). RESULTS: No serious adverse events occurred, and all treatment-related adverse events were mild. Injection site erythema was objectively assessed using the innovative standardized erythema value (SEV*) method, derived from photographs taken with Scarletred Vision software (SCARLETRED Holding GmbH). The Visual Analog Scale scores and SEV* assessments were comparable between the rhSOD and placebo groups. Beyond safety and tolerability, pharmacokinetic analysis revealed that the volume of distribution, clearance, and half-life at presumed steady state were 129 ± 66.3 L, 5.97 ± 1.25 L/h, and 15.0 ± 6.69 h, respectively. Compared with the rapid systemic elimination after intravenous administration of SOD, subcutaneous administration resulted in a favorable plasma concentration-time profile. CONCLUSIONS: These findings suggest that subcutaneous rhSOD may be a promising therapeutic candidate for conditions characterized by excessive exposure or diminished endogenous SOD activity. Further clinical studies are warranted to assess its anti-inflammatory potential in relevant patient populations. EudraCT Number: 2022-000173-11.
Exposure-Response Analysis of Efsubaglutide Alfa in Patients with Type 2 Diabetes Mellitus.
Wang Q, Jiang F, Xu Y … +3 more , Lei Y, Zhang L, Sun X
Clin Pharmacokinet · 2025 Dec · PMID 41107649 · Publisher ↗
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 tr...
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), steady state minimum concentration (C), steady state average concentration (C), 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 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).
Pharmacokinetics, Pharmacodynamics, and Safety of Olorigliflozin in Individuals with Type 2 Diabetes Mellitus with or without Renal Impairment: A Single-Center, Single-Dose, Open-Label Trial.
Chen M, Cao X, An K … +13 more , Wang Y, Yan Q, Men Y, Wang H, He M, Du S, Gu Z, Zhang Y, Wang G, Guo W, Luo L, An Z, Feng P
Clin Pharmacokinet · 2025 Dec · PMID 41105382 · Publisher ↗
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, phar...
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), a clinically non-significant difference, with similar geometric mean AUC extrapolated from time zero to infinity (AUC). Moderate renal impairment showed 56.71% higher AUC and 62.27% higher AUC 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.
Bridging to Paediatric Dosing: Relative Bioavailability of Suspended Rifapentine and Isoniazid in an Open-Label Randomized Trial in Adults on Tuberculosis Preventive Therapy.
Janssen S, Vongjarudech T, Karlsson MO … +9 more , Upton CM, Garcia-Prats AJ, Diacon AH, Wiesner L, Sachs T, van der Laan LE, Salazar-Austin N, Hesseling AC, Svensson EM
Clin Pharmacokinet · 2025 Dec · PMID 41075147 · Full text
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 formu...
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.
Spatial Pharmacokinetic and Pharmacodynamic Modeling in Airway Mucus.
Guo Y, Yin J, Yonucu S … +3 more , Knibbe CAJ, Guo T, van Hasselt JGC
Clin Pharmacokinet · 2025 Dec · PMID 41047457 · Full text
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 understand...
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.
Importance of Lysosomal Trapping and Plasmodium Parasite Infection on the Pharmacokinetics of Pyronaridine: A Physiologically Based Pharmacokinetic Model-Based Study.
Chu WY, Schouten WM, Mavoko HM … +12 more , Tshiongo JK, Yobi DM, Kabasele FA, Kasereka G, Maketa V, Sevene E, Vala A, Shin J, D'Alessandro U, Kayentao K, Huitema ADR, Dorlo TPC
Clin Pharmacokinet · 2025 Dec · PMID 41026410 · Full text
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 su...
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) and C, mainly on day 1, as parasitemia decreased rapidly. However, the subsequent decrease in Hb had the opposite effect, lowering AUC and C 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.
A Physiologically Based Pharmacokinetic Model for the Prediction of Plasma and Bone Tissue Exposure after Prophylactic Administration of Ampicillin/Sulbactam in Patients with Osteonecrosis of the Jaw.
Stapf M, Straub A, Steinacker V … +2 more , Hartmann S, Scherf-Clavel O
Clin Pharmacokinet · 2025 Dec · PMID 41015635 · Full text
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...
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.
Prediction of Maternal and Fetal Exposure to Escitalopram, Sertraline, and Paroxetine by Combining Human Ex Vivo Placenta Perfusion Data and Physiologically Based Pharmacokinetic Modeling.
Préta LH, Bouazza N, Foissac F … +6 more , Froelicher L, Urien S, Buth V, Benaboud S, Tréluyer JM, Lui G
Clin Pharmacokinet · 2025 Dec · PMID 41014441 · Publisher ↗
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...
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.
PEGylated Proteins: How Much Does Molecular Weight Matter?
Fornasari DMM
Clin Pharmacokinet · 2025 Nov · PMID 41006726 · Full text
Polyethylene glycols (PEGs) are inert polymers of repeating ethylene oxide subunits. Attaching PEGs to therapeutic proteins may reduce the protein's immunogenicity and antigenicity, improve solubility and stability, slow...
Polyethylene glycols (PEGs) are inert polymers of repeating ethylene oxide subunits. Attaching PEGs to therapeutic proteins may reduce the protein's immunogenicity and antigenicity, improve solubility and stability, slow protein degradation, and increase the half-life (t). This usually results in less frequent administration, improved quality of life and convenience, and potentially better adherence and lower costs. The advantages and disadvantages of PEGylated proteins differ according to the structure of the PEG moiety, particularly its molecular weight. The larger the PEG molecular weight, the longer the t and time to steady state. PEGs have low toxicity and undergo minimal metabolism. The PEG moiety usually undergoes renal elimination and is excreted in urine, but with greater molecular weights, renal elimination declines and biliary excretion increases. Because PEG molecules are not broken down, there is potential for PEGs to accumulate in the cytoplasm, forming vacuoles, mostly in macrophages, although this does not affect their function. The risk of vacuolation increases with molecular weights > 30 kDa. However, even high molecular weight PEGs are used at doses markedly lower than the European Medicines Agency safety threshold for paediatric use. People can develop antibodies to PEGs, and this may increase the overall clearance of the PEGylated protein if antibody levels are sufficiently high (> 500 ng/mL according to one modelling study). In conclusion, it is important for physicians to understand how PEG molecular weight and architecture can impact stability, immunogenicity, glomerular filtration and cellular uptake, to better understand the overall safety, efficacy and pharmacological profile of PEGylated proteins.
Evaluation of Fentanyl-Emerged Adverse Events and Pharmacokinetics in Neonates: A Physiologically Based Pharmacokinetic Modeling Approach.
Mahdy WYB, Yamamoto K, Joji R … +7 more , Hashimoto M, Nakasone R, Fujioka K, Itohara K, Kitahiro Y, Omura T, Yano I
Clin Pharmacokinet · 2025 Dec · PMID 40999188 · Full text
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 hypo...
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.
Exposure-Response Analysis of Efsubaglutide Alfa in Patients with Type 2 Diabetes Treated with Metformin.
Wang Q, Jiang F, Xu Y … +3 more , Lei Y, Zhang L, Sun X
Clin Pharmacokinet · 2025 Dec · PMID 40991141 · Publisher ↗
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 th...
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) reduced HbA1c by 0.211%, while every 100 ng/mL increase in C 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).
Population Pharmacokinetic Analysis of Balcinrenone in Healthy Participants and Participants with Heart Failure and Chronic Kidney Disease.
Parkinson J, Åstrand M, Melin J … +1 more , Ericsson H
Clin Pharmacokinet · 2025 Nov · PMID 40965596 · Full text
BACKGROUND AND OBJECTIVE: Balcinrenone is a novel mineralocorticoid receptor modulator which, based on preclinical data, maintains cardio-renal benefits without increasing hyperkalemia risk. Balcinrenone is developed in...
BACKGROUND AND OBJECTIVE: Balcinrenone is a novel mineralocorticoid receptor modulator which, based on preclinical data, maintains cardio-renal benefits without increasing hyperkalemia risk. Balcinrenone is developed in combination with dapagliflozin for the treatment of heart failure (HF) with impaired kidney function and chronic kidney disease (CKD). The aim of this work was to apply a population pharmacokinetic (popPK) approach to describe the pharmacokinetics (PK) of balcinrenone, and to quantify the effects of intrinsic and extrinsic factors on balcinrenone PK. METHODS: The assessment was based on data from six clinical studies in healthy participants (NCT03843060, NCT03804645, and NCT04798222), participants with renal impairment (NCT04469907), and participants with HF and CKD (NCT03682497 and NCT04595370) using the immediate-release capsule formulation (chosen for phase 3 studies). RESULTS: Food state (i.e., taking balcinrenone with or without food), renal function (estimated glomerular filtration rate [eGFR], incorporated using power function of eGFR on apparent clearance), and study type (phase 1 studies with mainly healthy participants or phase 1b/2b studies in patients with HF and CKD) were identified as covariates on balcinrenone exposure (area under the curve at steady-state [AUC]). The magnitude of the impact of food state on balcinrenone exposure was minor, with a 1.13-fold (95% confidence interval [CI] 1.06-1.21) increase in AUC when balcinrenone was taken with food compared with in a fasted state. Participants with a lower eGFR were observed to have higher exposure: those with an eGFR of 25 mL/min/1.73 m had a 1.44-fold (95% CI 1.22-1.69) increase in balcinrenone AUC compared with participants with an eGFR of 60 mL/min/1.73 m. Participants from phase 1 studies were estimated to have a 0.49-fold (95% CI 0.41-0.60) lower exposure compared with patients from phase 1b/2b studies. CONCLUSIONS: Participants with HF and CKD were observed to have approximately 50% lower apparent clearance compared with healthy participants and those with renal impairment, after adjusting for differences in eGFR. This may indicate that factors other than renal function may impact the apparent clearance of balcinrenone. The impact of the covariates on balcinrenone exposure (AUC) in the intended patient population was less than 50% relative to a reference participant.
Modeling Whole-Body Dynamic PET Microdosing Data to Predict the Whole-Body Pharmacokinetics of Glyburide in Humans.
Comin L, Marie S, Ursino M … +3 more , Zohar S, Tournier N, Comets E
Clin Pharmacokinet · 2025 Nov · PMID 40960559 · Full text
INTRODUCTION: Whole-body dynamic (WB4D) positron emission tomography (PET) imaging data using radiolabeled analogs of drugs are mostly analyzed using descriptive approaches, with no relationship to traditional pharmacoki...
INTRODUCTION: Whole-body dynamic (WB4D) positron emission tomography (PET) imaging data using radiolabeled analogs of drugs are mostly analyzed using descriptive approaches, with no relationship to traditional pharmacokinetic studies based on blood sampling. Here, we build a pharmacokinetic (PK) model from WB4D PET data obtained using a microdose of radiolabeled glyburide ([C]glyburide) in humans, aiming to describe the biodistribution of this drug and compare estimated pharmacokinetic parameters with the parameters obtained in standard PK studies. METHODS: The present work analyzes data acquired over 40 min after injection of [C]glyburide in 16 healthy subjects using non-linear mixed-effect models (NLMEM). In 10 subjects, a second PET acquisition was performed after rifampicin administration, which may cause a drug-drug interaction and inhibit the liver uptake transport of glyburide. Arterial blood, liver, kidneys, pancreas, and spleen kinetics were modeled using NLMEM. The model-building strategy involved selecting the structural model using baseline [C]glyburide PET data and then selecting the covariate model (rifampicin, age, and gender) and refining the structure of the interindividual variability model using both administration periods. Model selection was based on the corrected Bayesian information criterion and implemented in Monolix software. RESULTS: The final model included seven compartments, with two compartments each for the Liver and kidneys to account for within-tissue exchanges. Rifampicin decreased the Liver distribution by 261%. DISCUSSION: The estimated central volume of distribution (V = 3.6 L) and elimination rate (k = 0.8 h) were consistent with the known pharmacokinetics of glyburide, which is a promising first step in leveraging microdose data to study the WB4D biodistribution. REGISTRATION: EudraCT identifier no. 2017-001703-69.
Population Pharmacokinetic Modeling of Canagliflozin in Advanced Chronic Kidney Disease.
Elenjickal EJ, Mavrakanas TA, Gritsas A … +2 more , Suri RS, Marsot A
Clin Pharmacokinet · 2025 Nov · PMID 40952584 · Publisher ↗
BACKGROUND AND OBJECTIVES: Canagliflozin is an orally active, selective, reversible sodium-glucose cotransport-2 (SGLT-2) inhibitor used in patients with chronic kidney disease (CKD) to prevent cardiovascular (CV) events...
BACKGROUND AND OBJECTIVES: Canagliflozin is an orally active, selective, reversible sodium-glucose cotransport-2 (SGLT-2) inhibitor used in patients with chronic kidney disease (CKD) to prevent cardiovascular (CV) events and CKD progression. Its initiation is currently not recommended in advanced CKD [estimated glomerular filtration rate (eGFR) < 20 mL/min per 1.73 m], end-stage kidney disease, or in those on kidney replacement therapies due to insufficient clinical and safety data. This study aimed to develop a population pharmacokinetic (popPK) model using data from patients with advanced CKD, including those on maintenance hemodialysis (HD), to characterize the steady-state pharmacokinetics (PK) of canagliflozin at 100 mg and 300 mg doses, and to assess the impact of significant covariates on its PK. METHODS: PK data were obtained from a single-center, prospective, single-arm, open-label interventional study conducted in two cohorts. The first cohort was a detailed PK sampling done in 10 patients receiving intermittent HD for at least 3 months and the second cohort included sparse PK sampling in 13 patients with advanced CKD, not yet on dialysis. Canagliflozin PK parameters were modeled using nonlinear mixed-effects modeling (NONMEM version 7.5) with the first-order conditional estimation method with interaction. Model performance was evaluated using goodness of fit plot, bootstrap (n = 1000), and normalized prediction distribution error (NPDE). Model-based simulations were performed using the final model to predict concentration-time profiles at steady state, evaluate the impact of significant covariates on predicted steady-state area under the curve (AUC), and compare PK profiles between patients with non-dialysis CKD and those with hemodialysis. RESULTS: A total of 332 PK observations from 23 patients were analyzed. The mean age of the cohort was 67 ± 15 years with a mean body mass index of 27 ± 5 kg/m. A two-compartment popPK model of canagliflozin with lag-time, sequential zero- and first-order absorption, and first-order elimination was developed. Age was a significant covariate of the absorption rate constant (K), which increased with age. Sex was a significant covariate for the apparent volume of distribution (V/F), which was lower in women (80.7 L in men and 49.1 L in women). Model-based simulations demonstrated that steady-state AUC was 66% higher in women compared with men. Additionally, AUC increased approximately threefold in both sexes when the canagliflozin dose was escalated from 100 mg to 300 mg. Notably, eGFR was not a determinant of steady state exposure. CONCLUSIONS: The developed model demonstrates that steady state canagliflozin exposure is higher in women and with use of higher dose, whereas eGFR does not meaningfully alter drug exposure in patients with advanced CKD. Model-based simulations support the potential use of canagliflozin in HD patients and highlight the need for further evaluation of dose optimization strategies in this high-risk population. TRIAL REGISTRATION: The trials were registered at Clinicaltrials.gov (NCT05309785).
Paracetamol Concentrations and Time-Course of Ductus Arteriosus Diameter in Extremely Preterm Neonates: A Population Pharmacokinetic-Pharmacodynamic Analysis.
Padavia F, Treluyer JM, Cambonie G … +22 more , Flamant C, Rideau A, Tauzin M, Patkai J, Gascoin G, Lumia M, Aikio O, Foissac F, Urien S, Benaboud S, Lui G, Froelicher Bournaud L, Zheng Y, Kemper R, Tortigue M, Baruteau AE, Kallio J, Hallman M, Diallo A, Levoyer L, Roze JC, Bouazza N
Clin Pharmacokinet · 2025 Nov · PMID 40889095 · Publisher ↗
BACKGROUND: Patent ductus arteriosus is a common complication of extreme prematurity. Prophylactic treatment with indomethacin or ibuprofen has shown efficacy on ductus closure but without reducing mortality and morbidit...
BACKGROUND: Patent ductus arteriosus is a common complication of extreme prematurity. Prophylactic treatment with indomethacin or ibuprofen has shown efficacy on ductus closure but without reducing mortality and morbidity. Prophylactic treatment by paracetamol could be a safer alternative. OBJECTIVE: The aim was to build a pharmacokinetic-pharmacodynamic (PKPD) model describing the effect of paracetamol on the time-course of the ductus arteriosus diameter. METHODS: Extremely preterm neonates of 23-26 weeks of gestational age were recruited within 12 h after birth and were treated with prophylactic intravenous paracetamol for 5 days (two dose levels: 20 mg/kg followed by 7.5 mg/kg or 25 mg/kg followed by 10 mg/kg every 6 h). The diameter of ductus arteriosus was determined by echocardiography performed daily until day 7. The PKPD model was built using an I model with effect compartment and exponential disease progression model. Concentrations of paracetamol in the effect compartment were simulated with different doses over time for 500 virtual patients. RESULTS: A total of 29 extremely preterm neonates with median birth weight of 800 g (IQR: 670-860) were included in the study. Between-subject variability was estimated on transfer rate constant between the central compartment and the effect compartment (ke) and maximum drug inhibition (I) parameters. Two subpopulations with different I values were identified: 99% for a first subpopulation of 10 patients and 42% for the second subpopulation of 19 patients. A negative effect of maximum fraction of inspired oxygen (FiO) used during transfer to intensive care unit and a positive effect of intubation and ventilation during treatment were significant on ke. Simulations showed that both dose levels generally enabled patients to reach the concentration needed to achieve 95% of maximal inhibition by the end of treatment. However, the second dose level enabled more than 90% of patients to reach this inhibition threshold as early as day one. CONCLUSION: The relationship between paracetamol and the time-course of ductus arteriosus diameter has been described in extremely preterm neonates. Intravenous paracetamol treatment with a loading dose of 25 mg/kg within 12 h after birth followed by 10 mg/kg every 6 h appears to be effective to accelerate time to ductus closure with limited benefit of a further dose increase.
Hybrid Population Pharmacokinetic-Machine Learning Modeling to Predict Infliximab Pharmacokinetics in Pediatric and Young Adult Patients with Crohn's Disease.
Irie K, Minar P, Reifenberg J … +4 more , Boyle BM, Noe JD, Hyams JS, Mizuno T
Clin Pharmacokinet · 2025 Nov · PMID 40885855 · Full text
BACKGROUND AND OBJECTIVE: Population pharmacokinetic (PK) model-based Bayesian estimation is widely used for dose individualization, particularly when sample availability is limited. However, its predictive accuracy can...
BACKGROUND AND OBJECTIVE: Population pharmacokinetic (PK) model-based Bayesian estimation is widely used for dose individualization, particularly when sample availability is limited. However, its predictive accuracy can be compromised by factors such as misspecified prior information, intra-patient variability, and uncertainties in PK variations. In this study, we developed a hybrid approach that combines machine learning (ML) with population PK-based Bayesian methods to improve the prediction of infliximab concentrations in children with Crohn's disease. METHODS: We calculated prediction errors between Bayesian-estimated and observed infliximab concentrations from 292 measurements across 93 patients. Incorporating clinical patient features, we explored various ML algorithms, including linear regression, random forest, support vector regression, neural networks, and XGBoost to correct the Bayesian-based prediction errors. The predictive performance of these ML models was assessed using root mean square error (RMSE) and mean prediction error (MPE) with 5-fold cross-validation. RESULTS: For Bayesian estimation alone, the RMSE and MPE were 4.8 µg/mL and - 0.67 µg/mL, respectively. Among the ML algorithms, the XGBoost model demonstrated the best performance, achieving an RMSE of 3.78 ± 0.85 µg/mL and an MPE of - 0.03 ± 0.69 µg/mL in 5-fold cross-validation. The ML-corrected Bayesian estimation significantly reduced the absolute prediction error compared with Bayesian estimation alone. CONCLUSION: This hybrid population PK-ML approach provides a promising framework for improving the predictive performance of Bayesian estimation, with the potential for continuous learning from new clinical data to enhance dose individualization.
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