Clinical Pharmacokinetics[JOURNAL]
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200 papers
Population Pharmacokinetics and Pharmacodynamics of Fepixnebart (LY3016859) and Epiregulin in Patients with Chronic Pain.
James DE, Bailey J, van der Walt JS … +2 more , Winkler J, Schoemaker R
Clin Pharmacokinet · 2025 May · PMID 40266472 · Full text
BACKGROUND AND OBJECTIVE: Fepixnebart (LY3016859), a humanized immunoglobulin G4 monoclonal antibody with high binding affinity to epiregulin and tumor growth factor-α, is being developed as a novel analgesic to treat br...
BACKGROUND AND OBJECTIVE: Fepixnebart (LY3016859), a humanized immunoglobulin G4 monoclonal antibody with high binding affinity to epiregulin and tumor growth factor-α, is being developed as a novel analgesic to treat broad-spectrum chronic pain. Early phase clinical studies demonstrated fepixnebart has nonlinear pharmacokinetics in healthy subjects and patients with diabetic nephropathy. This population pharmacokinetic analysis used data from three 26-week, phase 2, proof-of-concept studies in osteoarthritis, diabetic peripheral neuropathic pain (DPNP), and chronic low back pain (CLBP) to characterize the pharmacokinetics of fepixnebart and predict its target engagement by epiregulin. Covariate relationships were also assessed. METHODS: Population analysis was performed using nonlinear mixed-effects modeling software. Covariate relationships were explored graphically by plotting potential covariates versus parameters of interest. Simulated target engagement was predicted using the phase 2 dose regimen for fepixnebart (750 mg intravenous starting dose, followed by 500 mg every 2 weeks). RESULTS: The median simulated target engagement at 2 weeks after the last dose of fepixnebart was predicted to be 92.0%, with 90% of predictions between 86.0 and 96.2% and 68.5% of subjects predicted to exhibit target engagement exceeding 90%. CONCLUSIONS: The phase 2 dose regimen is adequate to test the analgesic effect of fepixnebart in patients with osteoarthritis, DPNP, and CLBP. In the final model, female sex and higher glomerular filtration rate were associated with higher clearance, female sex was associated with larger volume of distribution of the central compartment (V) than male sex, and DPNP was associated with lower V than CLBP. There were no significant effects on the concentration of fepixnebart at which its effect on epiregulin is half-maximal (EC). TRAIL REGISTRY: ClinicalTrials.gov: NCT04529096, NCT04476108, and NCT04456686.
Model-Informed Dose Optimization of Pazopanib in Real-World Patients with Cancer.
Tan Z, Völler S, Yin A … +5 more , Rieborn A, Gelderblom H, van der Hulle T, Knibbe CAJ, Moes DJAR
Clin Pharmacokinet · 2025 May · PMID 40263237 · Full text
BACKGROUND AND OBJECTIVES: Pazopanib is approved for metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma (STS) in a dose of 800 mg once daily (QD) taken under fasted conditions. In clinical practice, approxima...
BACKGROUND AND OBJECTIVES: Pazopanib is approved for metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma (STS) in a dose of 800 mg once daily (QD) taken under fasted conditions. In clinical practice, approximately 60% of patients require dose reductions due to toxicity, with severe liver toxicity necessitating treatment interruptions in over 10% of cases. While a trough concentration (C) target of ≥ 20.5 mg/L has been established for mRCC efficacy, no specific threshold exists for liver toxicity. The objectives of this study were to develop a population pharmacokinetic (POPPK), an exposure-liver toxicity, and an exposure-tumor size dynamics model to optimize pazopanib initial dose in real-world patients. METHODS: In total, 135 patients were included and treated with a median starting dose of 800 mg (interquartile range, IQR: 600-800 mg) QD pazopanib fasted with a median follow-up of 120 (IQR 63-372) days. A population pharmacokinetic model was developed using 460 concentration measurements from 135 patients. Exposure-liver toxicity was evaluated using time-to-event modeling, and exposure-tumor size dynamics was evaluated using tumor growth modelling. RESULTS: The liver toxicity model, with 27 cases of grade ≥ 2 liver toxicity out of 135 patients (20%), identified a C threshold of > 34 mg/L associated with a 3.35-fold increased toxicity risk (P < 0.01). Model simulations showed that an initial dose of 600 mg QD significantly reduced liver toxicity risk (P < 0.001) while maintaining C ≥ 20.5 mg/L for 76% of the simulated individuals. Tumor size dynamics were analyzed using baseline and posttreatment tumor size measurements from 111 patients. The introduction of primary resistance by using a mixture model improved the model fit significantly. Tumor growth and decay rates differed between mRCC and STS but showed no pazopanib exposure dependency across the studied range, suggesting maximal tumor inhibition at current exposure levels. CONCLUSIONS: These findings suggest that an initial pazopanib dose of 600 mg fasted, followed by model-informed precision dosing to maintain C between 20 and 34 mg/L, may improve efficacy-toxicity balance and mitigate treatment interruptions.
Population Pharmacokinetics of Tarlatamab, a Half-Life Extended DLL3-Directed Bispecific T-Cell Engager in Patients with Previously Treated Small Cell Lung Cancer.
Kong S, Minocha M, Chen PW … +5 more , Martinez P, Anderson ES, Parkes A, Houk BE, Lin CW
Clin Pharmacokinet · 2025 May · PMID 40261494 · Publisher ↗
BACKGROUND AND OBJECTIVE: Tarlatamab is a first in class, half-life extended delta-like ligand 3 (DLL3) directed bispecific T-cell engager (BiTE®) immunotherapy that has shown durable efficacy in patients with previously...
BACKGROUND AND OBJECTIVE: Tarlatamab is a first in class, half-life extended delta-like ligand 3 (DLL3) directed bispecific T-cell engager (BiTE®) immunotherapy that has shown durable efficacy in patients with previously treated small cell lung cancer (SCLC). The purpose of this analysis was to develop a population pharmacokinetic (PK) model for tarlatamab. METHODS: This analysis includes data from 420 patients with previously treated small cell lung cancer (8509 samples) pooled across the Phase 1 DeLLphi-300 study (dose range 0.003-100 mg every 2 weeks and 200 mg every 3 weeks) and Phase 2 DeLLphi-301 study (10 mg and 100 mg every 2 weeks). The data were analyzed using a nonlinear-mixed effects modeling approach implemented in NONMEM (v7.5) software and validated using standard statistical approaches. The effects of intrinsic and extrinsic factors on PK parameters and exposures of tarlatamab were evaluated, and the impact of identified covariates were further assessed using simulations. RESULTS: Tarlatamab serum concentration data were best described by a two-compartment model with linear elimination. Tarlatamab clearance (CL) and central volume of distribution (V) were 0.649 L/day and 3.44 L, respectively, for a typical 73-kg individual. The model-estimated median terminal phase elimination half-life was 11.2 days. Tarlatamab pharmacokinetics were not impacted by age, sex, ethnicity, estimates of renal and hepatic function, prior lines of therapy, or baseline disease status. The presence of antidrug antibody (ADA) at any time during the study and bodyweight were found to be statistically significant covariates on CL, and Asian race and bodyweight were found to be statistically significant covariates on V; however, they did not lead to a clinically meaningful impact on exposures. CONCLUSIONS: The pharmacokinetics of tarlatamab was well-described by a two-compartment model with linear elimination. No clinically significant differences were observed on the basis of age, sex, bodyweight, race, ethnicity, estimates of renal and hepatic function, prior lines of therapy, baseline disease status, or emergence of ADA. These results support that no dose adjustment is required on the basis of any of the evaluated covariates.
Population Pharmacokinetic Modelling of Remdesivir and Its Metabolite GS-441524 in Hospitalised Patients with COVID-19.
Roberts DM, Liu X, Parker SL … +16 more , Burke A, Peek J, Carland JE, Murnion B, Seah V, Wallis SC, Sumi CD, Pandey S, Buscher H, Byrne A, Sandaradura I, Bowen D, Holz S, Stewart AG, Hajkowicz KM, Roberts JA
Clin Pharmacokinet · 2025 May · PMID 40261493 · Full text
BACKGROUND AND OBJECTIVES: There are limited data testing whether the licensed dose of remdesivir and its active metabolite GS-441524 achieve target concentrations in hospitalised patients with confirmed severe acute res...
BACKGROUND AND OBJECTIVES: There are limited data testing whether the licensed dose of remdesivir and its active metabolite GS-441524 achieve target concentrations in hospitalised patients with confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of coronavirus disease-2019 (COVID-19). The objectives of this study were to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalised patients treated for COVID-19 and develop a model to inform dose optimisation in clinical use. METHODS: This was a prospective, open-labelled, multi-centre, observational study in four Australian hospitals in adults with confirmed SARS-CoV-2 infection. Patients were administered the licensed remdesivir dose. Remdesivir and GS-441524 concentrations were quantified in multiple plasma samples at different times in the dosing interval by ultra-high-performance liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Patients were divided into two groups: pharmacokinetic model building and external validation. A population pharmacokinetic analysis was built using non-linear mixed-effects modelling. Monte Carlo simulations were performed to describe the impact of age, kidney function and dosing regimen on drug concentrations. RESULTS: In total, 33 patients were enrolled (median age 70 years, estimated glomerular filtration rate (eGFR) 80 mL/min/1.73 m). The pharmacokinetics for both compounds were adequately described by a two-compartment model (one compartment for each compound) with first-order elimination. Key covariates included in the final model were age and eGFR. GS-441524 plasma concentrations exceeded the lowest reported half-maximal effective concentration (EC) with the recommended dosage, and higher dosages exceeded the lowest reported 90%-effective concentration (EC). CONCLUSIONS: The licensed remdesivir dose may achieve target concentrations of GS-441524, but higher dosages may optimise outcomes. Dose adjustments are guided primarily by kidney function.
Anti-infectives in Pediatric Patients with Cystic Fibrosis: A Comprehensive Review of Population Pharmacokinetic Analyses.
Yaliniz A, El Hassani M, Blanchard AC … +1 more , Marsot A
Clin Pharmacokinet · 2025 May · PMID 40254714 · Publisher ↗
Pulmonary complications are the leading cause of morbidity and mortality in pediatric patients with cystic fibrosis. Altered pharmacokinetic parameters in this population, as well as high inter- and intra-individual vari...
Pulmonary complications are the leading cause of morbidity and mortality in pediatric patients with cystic fibrosis. Altered pharmacokinetic parameters in this population, as well as high inter- and intra-individual variability, complicate the optimization of anti-infective treatments. In this review, we aim to summarize and describe all anti-infective population pharmacokinetic (popPK) models applied to pediatric populations with cystic fibrosis. Our objectives were to identify the most-reported structural models and retained covariates and to compare the dosing regimens used in clinical routine with those recommended in literature and guidelines. A literature search was done through the PubMed database from inception to August 2024. Studies were retained only if they complied with the inclusion and exclusion criteria. The review included 21 popPK models covering the pharmacokinetic profiles of eight different molecules. Among these, five are recommended antibiotics for treating pulmonary infections in patients with cystic fibrosis. All models incorporated body composition and/or renal function measures as covariates in their pharmacokinetic parameter equations. Standard dosing regimens in the studies were consistent with guidelines and literature recommendations. This is the first review summarizing and describing all anti-infective popPK models in pediatric patients with cystic fibrosis. Improved estimation of pharmacokinetic parameters and a clearer understanding of variability sources will enhance the optimization of antibiotic treatment in clinical practice. Finally, the impact of new targeted therapies on the management of this population will have to be closely monitored in the years ahead.
Pharmacokinetics and Pharmacodynamics of Prusogliptin (DBPR108), a Once-Daily Dipeptidyl Peptidase-4 Inhibitor, in Patients with Type 2 Diabetes.
Liu W, Yang K, Lin Y … +11 more , Lu C, Liu J, Zhou H, Wang J, Zhang T, Yao L, Qi H, Zhang X, Jia R, Li X, Jing S
Clin Pharmacokinet · 2025 May · PMID 40252162 · Full text
BACKGROUND AND OBJECTIVE: DBPR108 (prusogliptin) is a novel, orally bioavailable dipeptidyl peptidase-4 (DPP-4) inhibitor. This study investigated the pharmacokinetics and pharmacodynamic characteristics of DBPR108 table...
BACKGROUND AND OBJECTIVE: DBPR108 (prusogliptin) is a novel, orally bioavailable dipeptidyl peptidase-4 (DPP-4) inhibitor. This study investigated the pharmacokinetics and pharmacodynamic characteristics of DBPR108 tablets in patients with type 2 diabetes. METHODS: In this randomized, parallel-group, open-label, phase I study, Chinese adults with type 2 diabetes, glycated hemoglobin of 7.0-9.5%, and body mass index of 19-35 kg/m were randomized 1:1:1 to once-daily DBPR108 50-, 100-, or 200-mg tablet groups. The primary endpoints included pharmacokinetic and pharmacodynamic characteristics after a single dose and multiple doses of DBPR108. RESULTS: In total, 30 patients were randomized with 10 patients in each group. DBPR108 was quickly absorbed with median time to reach the maximum plasma concentration of 1.5-4 h at steady state. Exposure to DBPR108 at steady-state increased dose proportionally with mean maximum steady-state plasma DBPR108 concentration during dosage intervals of 119, 256, and 567 ng/mL in the 50-, 100-, and 200-mg groups, respectively. Accumulation ratio of DBPR108 ranged from 0.85 to 1.3, and steady state was reached after four continuous daily doses. After multiple doses of DBPR108, maximum inhibitory efficacy of DPP-4 increased with higher dose levels ranging from 62.1 to 89.4%. Active glucagon-like peptide-1 levels increased after DBPR108 administration. In addition, six patients experienced treatment-emergent adverse events without leading to treatment interruption or discontinuation. CONCLUSIONS: DBPR108 was well tolerated in Chinese patients with type 2 diabetes, and both the pharmacokinetic and pharmacodynamic profiles support once-daily dosage regimens of DBPR108 in future studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05146869); registered 23 November 2021.
A Systematic Review of Pharmacokinetic Studies of Colistin and Polymyxin B in Adult Populations.
Zamri PJ, Lim SMS, Sime FB … +2 more , Roberts JA, Abdul-Aziz MH
Clin Pharmacokinet · 2025 May · PMID 40246790 · Full text
BACKGROUND AND OBJECTIVE: The pharmacokinetics of polymyxins are highly variable and conventional dosing regimens may likely lead to sub-optimal exposures and outcomes, particularly in critically ill patients with multi-...
BACKGROUND AND OBJECTIVE: The pharmacokinetics of polymyxins are highly variable and conventional dosing regimens may likely lead to sub-optimal exposures and outcomes, particularly in critically ill patients with multi-drug-resistant infections. The aim of this systematic review is to describe the published pharmacokinetic data and to investigate variables that have been shown to affect the pharmacokinetics of colistimethate sodium, colistin, and polymyxin B in adult populations. METHODS: Sixty studies were identified. A total of 27 and 33 studies described the pharmacokinetics of colistin and polymyxin B, respectively. RESULTS: The most common dosing regimen for colistimethate sodium was a loading dose of 9 MIU, followed by 9 MIU/day in two to three divided doses, while for polymyxin B, a loading dose of 100-200 mg, followed by 50-100 mg every 12 h was given. Studies that used colistin sulfate instead of colistimethate sodium reported lower inter-individual variability, which may be attributed to the formulation of colistin sulfate being an active drug. The volume of distribution for colistin is typically lower in healthy individuals than in critically ill patients, owing to variations in physiological and pathological conditions. The clearance of colistimethate sodium in critically ill patients not undergoing dialysis was higher, around 13 L/h, compared with those receiving continuous renal replacement therapy, where clearance ranged from 2.31 to 8.23 L/h. In patients receiving continuous renal replacement therapy, clearance of colistin was higher compared with colistimethate sodium (2.06-6.63 L/h and 1.57-3.85 L/h, respectively). Colistin protein binding in critically ill patients ranged from 51% to 79%. The volume of distribution of polymyxin B was similar between critically ill and acutely ill patients, with range of 6.3-33.1 L and 6.22-38.6 L, respectively. Clearance of polymyxin B was also almost similar between critically ill and acutely ill patients (range of 1.27-2.32 L/h). There were two studies that reported free drug concentrations instead of the total drug concentrations of polymyxin B. In critically ill patients, protein binding ranged from 48.8% to 92.4% for polymyxin B. Creatinine clearance was the most common patient characteristic associated with altered clearance of colistimethate sodium and/or colistin, and polymyxin B. CONCLUSIONS: Critically ill patients exhibit complex pharmacokinetics for colistin and polymyxin B, influenced by renal function, body weight, and clinical factors such as acute kidney injury, augmented renal clearance, serum albumin, and liver function. These factors necessitate individualized dosing adjustments to avoid toxicity and achieve therapeutic efficacy. Model-informed precision dosing provides a promising approach to optimize their use by integrating population pharmacokinetic parameters, patient-specific variables, and therapeutic drug monitoring, ensuring a balance between efficacy, safety, and resistance prevention.
Impact of Hypothermic Temperature Control on Plasma and Soft Tissue Pharmacokinetics of Penicillin/Beta-Lactamase Inhibitor Combinations in Patients Resuscitated After Cardiac Arrest.
Stommel AM, Matzneller P, Al Jalali V … +6 more , Wulkersdorfer B, Lackner E, Mueller M, Dorn C, Holzer M, Zeitlinger M
Clin Pharmacokinet · 2025 May · PMID 40208479 · Full text
BACKGROUND AND OBJECTIVES: Penicillin/beta-lactamase inhibitors are often used to treat aspiration pneumonia in patients resuscitated after cardiac arrest (CA). The impact of hypothermic temperature control on the pharma...
BACKGROUND AND OBJECTIVES: Penicillin/beta-lactamase inhibitors are often used to treat aspiration pneumonia in patients resuscitated after cardiac arrest (CA). The impact of hypothermic temperature control on the pharmacokinetics of amoxicillin/clavulanate (AMO/CLAV) and ampicillin/sulbactam (AMP/SULB) has not been studied. Our objective was to evaluate the effects of hypothermic temperature control on the plasma and soft tissue pharmacokinetics of AMO/CLAV and AMP/SULB, including pulmonary concentrations of AMP/SULB, in patients resuscitated after CA. METHODS: This prospective clinical study involved ten adult patients after CA receiving either AMO/CLAV 2 g/0.2 g or AMP/SULB 2 g/1 g intravenously every 8 h. Patients underwent hypothermic temperature control (33 ± 1 °C) for 24 h, followed by normothermia. Plasma, urine, muscle, and subcutaneous pharmacokinetics were measured and plasma protein-binding assessed for each subject. Microdialysis determined unbound drug concentrations in soft tissues. The pulmonary concentration of AMP/SULB was analyzed in the epithelial lining fluid. RESULTS: No significant differences in plasma pharmacokinetics or renal excretion of AMO/CLAV and AMP/SULB were observed between the two temperature conditions. Soft tissue concentrations showed no consistent trend. Pharmacokinetic/pharmacodynamic targets (time that the unbound plasma concentrations were above the minimal inhibitory concentration [MIC] for MIC up to 8 mg/L) were met but not for 16 mg/L. Pulmonary concentrations of AMP/SULB in the epithelial lining fluid showed no clear trend. CONCLUSION: This study indicates that hypothermic temperature control does not significantly affect plasma concentrations, soft tissue concentrations, or renal excretion of AMO/CLAV and AMP/SULB in patients resuscitated after CA. However, pulmonary concentrations of AMP/SULB exhibited interindividual variability.
Pharmacokinetics and Safety of Levofloxacin for Treatment of Rifampicin-Resistant Tuberculosis During Pregnancy and the Postpartum Period: Results from IMPAACT P1026s.
Hughes JA, Pinilla M, Brooks KM … +17 more , Eke AC, Stek A, Best BM, Mirochnick M, Browning R, Wiesner L, George K, Knowles K, De Koker P, Ngocho JS, Fairlie L, Chakhtoura N, Hesseling AC, Decloedt E, Shapiro DE, van Schalkwyk M, IMPAACT P1026s Protocol Team
Clin Pharmacokinet · 2025 Apr · PMID 40155501 · Full text
BACKGROUND AND OBJECTIVE: Treatment of rifampicin-resistant tuberculosis (RR-TB) often includes fluoroquinolones, but data on long-term exposure during and after pregnancy are limited. We examined the pharmacokinetics an...
BACKGROUND AND OBJECTIVE: Treatment of rifampicin-resistant tuberculosis (RR-TB) often includes fluoroquinolones, but data on long-term exposure during and after pregnancy are limited. We examined the pharmacokinetics and safety of levofloxacin in an observational cohort of pregnant and postpartum women receiving treatment for RR-TB. METHODS: Participants were enrolled in their second or third trimester and underwent intensive pharmacokinetic sampling to quantify levofloxacin plasma concentrations at 20-26 weeks' and 30-38 weeks' gestation and at 2-8 weeks postpartum. The levofloxacin plasma concentration target was 7 µg/mL. Pharmacokinetic parameters over 12 and 24 h were described using non-compartmental analysis and within-participant comparison during pregnancy versus postpartum. Adverse events were extracted from medical records. Infants were enrolled in utero and followed on study for 4-6 months after birth. RESULTS: A total of 11 pregnant women, with a median age of 31 years, received RR-TB treatment including levofloxacin; 6 (55%) were living with HIV. In the second trimester, third trimester, and postpartum, median maximum plasma drug concentration values were 10.3, 10.6, and 10.6 µg/mL, and area under the concentration time curve over 12 h (AUC) were 69.0, 77.6, and 80.2 µg·h/mL, respectively. Compared with postpartum, median AUCs were lower and clearance was higher in the second but not the third trimester. Eight (72%) women and seven (64%) infants experienced severe or life-threatening adverse events or outcomes that were unlikely to be related to levofloxacin. CONCLUSIONS: Levofloxacin AUC was lower in the second trimester than the third trimester of pregnancy and the postpartum period, but exposures overall were within target ranges. Further research is warranted to explore the clinical significance of these findings.
Pharmacokinetics and Safety of Navitoclax in Hepatic Impairment.
Patel M, Potluri J, Marbury T … +9 more , Lawitz E, Rondon JC, Hoffman DM, Siddani SR, Marsh KC, Kim EJ, Uddin ME, Menon RM, Polepally AR
Clin Pharmacokinet · 2025 Apr · PMID 40146460 · Publisher ↗
BACKGROUND AND OBJECTIVE: Navitoclax, an orally bioavailable B-cell lymphoma-2 (Bcl-2) family protein inhibitor, inhibits antiapoptotic Bcl-2 family proteins (with high affinity to Bcl-XL, Bcl-2, and Bcl-W). Navitoclax i...
BACKGROUND AND OBJECTIVE: Navitoclax, an orally bioavailable B-cell lymphoma-2 (Bcl-2) family protein inhibitor, inhibits antiapoptotic Bcl-2 family proteins (with high affinity to Bcl-XL, Bcl-2, and Bcl-W). Navitoclax in combination with ruxolitinib has been investigated to treat patients with myelofibrosis (MF). METHODS: Since navitoclax undergoes hepatic metabolism, we evaluated the pharmacokinetics (PK) and safety of single-dose navitoclax 50 mg in a phase 1 study in participants with mild (N = 6), moderate (N = 6), or severe (N = 1) hepatic impairment and matched participants with normal hepatic function (N = 7). All participants in this study were enrolled per Child-Pugh classification, with demographics matched per age, weight, and race. RESULTS: Navitoclax maximum plasma concentration (C), area under the plasma concentration-time curve for time zero to infinity (AUC), and terminal elimination half-life (t) in participants with mild or moderate hepatic impairment were comparable to participants with normal hepatic function. The change in C and AUC values in participants with mild and moderate hepatic impairment were within 25% of normal hepatic function. Overall, 2/20 (10%) participants receiving a 50 mg single dose reported grade 1 treatment-emergent adverse events of nausea (N = 1) and diarrhea (N = 1). CONCLUSIONS: In summary, no new safety issues were identified. On the basis of the pharmacokinetic results, no dose adjustment is required for patients with MF with mild or moderate hepatic impairment.
Volume Kinetics of Gelofusine 4% During Vascular Surgery.
Balan C, Boros C, Bubenek-Turconi SI … +1 more , Hahn RG
Clin Pharmacokinet · 2025 Apr · PMID 40121598 · Full text
OBJECTIVES: The volume kinetics of a commercially available colloid fluid, Gelofusine, have not been studied previously. METHODS: Intravenous Gelofusine 10 mL/kg was infused over 30 min in 15 patients undergoing vascular...
OBJECTIVES: The volume kinetics of a commercially available colloid fluid, Gelofusine, have not been studied previously. METHODS: Intravenous Gelofusine 10 mL/kg was infused over 30 min in 15 patients undergoing vascular surgery. Of the 15 patients, 14 were classified as American Society of Anesthesiologists (ASA) class III status. The distribution and elimination of the infused volume was calculated with mixed-model kinetics based on 280 measurements of the hemoglobin-derived plasma dilution (19 per patient) collected over 180 min. RESULTS: The expanded central fluid space volume (V, the plasma) amounted to 2.16 L (95% confidence interval [CI] 1.06-2.35) at baseline. The maximum volume expansion of V was 706 mL (95% CI 599-812) after infusing Gelofusine 800 mL. Elimination occurred with a half-life of 115 min (95% CI 110-124). Noradrenaline was infused in eight of the 15 patients, leading to a dose-dependent reduction in elimination half-life. For example, an infusion rate of 3 µg/min decreased the half-life to 60 min (- 48%). Distribution of the infused volume to the extravascular space was small (15%), and redistribution to the plasma was accelerated by noradrenaline. Mean arterial pressure and urinary creatinine were not statistically significant covariates, and the model was not strengthened by considering the urine output. Infusion protocols aiming to achieve steady state plasma volume expansion during surgery can begin with a fast infusion over 20 min, then decreasing the rate by 80%. CONCLUSION: The kinetics of Gelofusine was predictable in patients of American Society of Anesthesiologists class III status undergoing vascular surgery, with the fluid expanding the vascular space and the half-life shortened by noradrenaline. TRIAL REGISTRATION: Retrospectively registered with ClinicalTrials.gov NCT06474052, June 24, 2024.
Leveraging Clinical Data to Enhance the Performance Evaluation of Ceftriaxone Population Pharmacokinetic Models in Children.
Schouwenburg S, Preijers T, Abdulla A … +3 more , Wildschut ED, Koch BCP, de Hoog M
Clin Pharmacokinet · 2025 Apr · PMID 40102293 · Full text
INTRODUCTION: Sepsis affects approximately 8% of pediatric intensive care unit (PICU) admissions in high-income countries. Ceftriaxone, a broad-spectrum beta-lactam antibiotic, is widely used for treating severe infectio...
INTRODUCTION: Sepsis affects approximately 8% of pediatric intensive care unit (PICU) admissions in high-income countries. Ceftriaxone, a broad-spectrum beta-lactam antibiotic, is widely used for treating severe infections and bacterial meningitis in children. Despite its frequent use, limited studies address the population pharmacokinetic (popPK) of ceftriaxone in pediatrics. External validation of popPK models is essential to confirm their suitability for individualized dosing in PICU patients, enabling selection of the model best suited to this population. METHODS: This study used data from the EXPAT Kids study, a prospective pharmacokinetics /pharmacodynamics (PK/PD) study. The included popPK models were implemented in NONMEM, with diagnostic goodness-of-fit and visual predictive check analyses performed to assess model accuracy. Predictive performance was evaluated using the relative prediction error, relative root mean square error, and mean (absolute) percentage error. RESULTS: The predictive performance of the evaluated models varied widely. The included models showed only modest performance and generally seemed to overpredict ceftriaxone concentrations. Unbound ceftriaxone popPK models did not perform adequately. None of the models met all the predefined thresholds for accuracy and precision. CONCLUSIONS: Our external dataset comprised high ceftriaxone trough concentrations, indicating re-evaluation of current ceftriaxone dosing regimens to minimize the risk of overdosing and prevent toxicity. Future research should focus on the fine dosing balance for ceftriaxone, especially in patients with meningitis, by considering adequate exposure while preventing high trough concentrations. Model-informed precision dosing may enhance the use of the optimal individual dosage for critically ill children. However, our findings highlight the importance of externally evaluating ceftriaxone popPK models in the PICU population.
Correction: Influence of Ageing on the Pharmacodynamics and Pharmacokinetics of Chronically Administered Medicines in Geriatric Patients: A Review.
Ngcobo NN
Clin Pharmacokinet · 2025 Mar · PMID 40088398 · Full text
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Pharmacokinetics and Target Attainment of Teicoplanin: A Systematic Review.
Mouton JWA, De Clercq A, De Paepe P … +6 more , Petrovic M, Desmet T, Brüggemann RJ, Schouten JA, Jager NGL, De Cock PA
Clin Pharmacokinet · 2025 Apr · PMID 40064832 · Publisher ↗
BACKGROUND AND OBJECTIVE: Teicoplanin is a glycopeptide antibiotic used to treat severe Gram-positive infections. This systematic review provides a comprehensive overview of the current knowledge on the pharmacokinetics...
BACKGROUND AND OBJECTIVE: Teicoplanin is a glycopeptide antibiotic used to treat severe Gram-positive infections. This systematic review provides a comprehensive overview of the current knowledge on the pharmacokinetics of teicoplanin across the entire population, with the aim to identify gaps in the existing literature, prioritise pharmacokinetic research, and support optimal dosing strategies. METHODS: A systematic literature search of the MEDLINE, Embase, Web of Science, and Scopus databases was conducted. Articles published until 1 October 2024 were identified as eligible when they included a pharmacokinetic analysis of teicoplanin. Relevant pharmacokinetic data were extracted from all included articles. Allometric scaling was carried out for reported values of clearance (CL) and volume of distribution (Vd) to an individual of 70 kg. Articles were categorised into eight subgroups. A qualitative assessment of the included studies was conducted using the clinical pharmacokinetic statement checklist. RESULTS: In total, 85 articles were included in this review. Pharmacokinetic data for 186 healthy volunteers, 130 neonates, 788 children, 1434 adult patients, 48 older adults (≥ 65 years), 674 critically ill patients, 33 patients with impaired renal function, and 159 patients with extracorporeal elimination techniques were extracted for a total of 3452 subjects. Unbound concentrations were assessed in 7.1% of the articles. The Vd ranged from 1.5 to 583 L/70 kg. The CL ranged from 0.0073 to 6.38 L/h/70 kg. Covariates on drug disposition were identified in 55.3% of studies, 65.6% of which identified a relationship between renal function and CL. Target attainment was described in 42.4% of articles. Dosing recommendations were provided in 61.2% of all studies. Studies had an average quality score of 69.9% ± standard deviation 15.7. CONCLUSION: Individual dosing strategies based on renal function need to be developed, particularly in patients with immature or impaired renal function, using state-of-the art pharmacokinetic/pharmacodynamic modelling approaches. Since teicoplanin is highly plasma protein bound and it is suggested that total concentrations cannot be easily translated to unbound concentrations, future research should also include the measurement of unbound concentrations for pharmacokinetic and target attainment evaluation. TRIAL REGISTRATION: Prospectively registered in PROSPERO. TRIAL REGISTRATION NUMBER: CRD42023483334. Registration date: 03/12/2023.
Evaluation of Safety and Pharmacokinetics of DDCI-01, a Phosphodiesterase Type 5 Inhibitor, in Healthy Participants.
Li Q, Huang SS, Zhang DC … +4 more , Zhang WY, Mao YM, Chen R, Jing ZC
Clin Pharmacokinet · 2025 Apr · PMID 40048121 · Publisher ↗
AIM: The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of single escalating oral doses of DDCI-01 (a novel, highly selective, long-acting phosphodiesterase type 5 inhibitor) administere...
AIM: The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of single escalating oral doses of DDCI-01 (a novel, highly selective, long-acting phosphodiesterase type 5 inhibitor) administered via capsules to healthy volunteers. METHODS: This randomized, double-blind, placebo-controlled, single ascending dosing, Phase Ia clinical study involved 52 healthy volunteers who were randomized (3:1 ratio) to receive a single oral dose of DDCI-01 (1.25, 2.5, 5, 10, 20, 40, or 60 mg) or a placebo. Adverse events and pharmacokinetic parameters were evaluated after 14 days post-administration. RESULTS: Within the studied dose range, DDCI-01 was safe and tolerable. Mild adverse events incidence was > 10% in all 39 volunteers receiving DDCI-01: myalgia (eight cases, 20.51%) and spontaneous penile erection (four cases, 10.26%). Drug exposure (C, AUC, and AUC) increased with increasing dosage; however, no linear correlation was observed between drug exposure and dosage. The drug exposure increase was less than the expected dose-proportional increase. Terminal half-life of DDCI-01 ranged between 35.5 and 40.6 hours, whereas the values of apparent clearance (CL/F) and apparent volume (V/F) were in the range of 1.1-3.0 L/h and 59-175 L, respectively. Both CL/F and V/F increased with increasing doses of DDCI-01. CONCLUSIONS: DDCI-01 demonstrated favorable safety and pharmacokinetic profiles within the dose range. The findings of this first-in-human study support further research for the indications of DDCI-01, such as pulmonary arterial hypertension and erectile dysfunction. REGISTRATION: Chinese Center for Drug Evaluation (CDE) registry number CTR20201564. The date of registration: August 3, 2020.
Opportunities for Precision Dosing of Cytotoxic Drugs in Non-Small Cell Lung Cancer: Bridging the Gap in Precision Medicine.
Kicken MP, Deenen MJ, van der Wekken AJ … +3 more , van den Borne BEEM, van den Heuvel MM, Ter Heine R
Clin Pharmacokinet · 2025 Apr · PMID 40045151 · Full text
Precision dosing of classical cytotoxic drugs in oncology remains underdeveloped, especially in treating non-small cell lung cancer (NSCLC). Despite advancements in targeted therapy and immunotherapy, classical cytotoxic...
Precision dosing of classical cytotoxic drugs in oncology remains underdeveloped, especially in treating non-small cell lung cancer (NSCLC). Despite advancements in targeted therapy and immunotherapy, classical cytotoxic agents continue to play a critical role in NSCLC treatment. However, the current body surface area (BSA)-based dosing of these agents fails to adequately address interindividual variability in pharmacokinetics. By better considering patient characteristics, treatment outcomes can be improved, reducing risks of under-exposure and over-exposure. This narrative review explores opportunities for precision dosing for key cytotoxic agents used in NSCLC treatment: cisplatin, carboplatin, pemetrexed, docetaxel, (nab-)paclitaxel, gemcitabine, and vinorelbine. A comprehensive review of regulatory reports and an extensive literature search were conducted to evaluate current dosing practices, pharmacokinetics, pharmacodynamics, and exposure-response relationships. Our findings highlight promising developments in precision dosing, although the number of directly implementable strategies remains limited. The most compelling evidence supports using the biomarker cystatin C for more precise carboplatin dosing and adopting weekly dosing schedules for docetaxel, paclitaxel, and nab-paclitaxel. Additionally, we recommend direct implementation of therapeutic drug monitoring (TDM)-guided dosing for paclitaxel. This review stresses the urgent need to reassess conventional dosing paradigms for classical cytotoxic agents to better align with the principles of the precision dosing framework. Our recommendations show the potential of precision dosing to improve NSCLC treatment, addressing gaps in the current dosing of classical cytotoxic drugs. Given the large NSCLC patient population, optimising the dosing of these agents could significantly improve treatment outcomes and reduce toxicity for many patients.
Ticagrelor is Associated with Increased Rosuvastatin Blood Concentrations in Patients who have had a Myocardial Infarction.
Dermota T, Jug B, Trontelj J … +1 more , Božič Mijovski M
Clin Pharmacokinet · 2025 Apr · PMID 40029501 · Full text
AIMS: The primary objective of this study was to determine whether concomitant therapy with ticagrelor and rosuvastatin affects rosuvastatin plasma concentrations in patients receiving rosuvastatin 40 mg/day after myocar...
AIMS: The primary objective of this study was to determine whether concomitant therapy with ticagrelor and rosuvastatin affects rosuvastatin plasma concentrations in patients receiving rosuvastatin 40 mg/day after myocardial infarction. METHODS: We included 93 patients who had experienced a myocardial infarction and were receiving high-dose rosuvastatin 40 mg/day and a P2Y12 receptor antagonist, either ticagrelor, prasugrel or clopidogrel. We used liquid chromatography with tandem mass spectrometry to measure rosuvastatin plasma concentrations after liquid-liquid extraction. RESULTS: Rosuvastatin plasma concentrations (9.7 ng/mL) were approximately twice as high in patients receiving ticagrelor therapy as in those receiving prasugrel (5.1 ng/mL, p < 0.001) or clopidogrel (5.0 ng/mL, p = 0.009), and ticagrelor was an independent factor influencing rosuvastatin concentrations. In addition, creatinine levels were associated with increased rosuvastatin concentrations (p = 0.039). CONCLUSION: Our results suggest an important pharmacokinetic interaction between ticagrelor and rosuvastatin, leading to approximately two-fold higher rosuvastatin plasma concentrations in those receiving concomitant ticagrelor than in those receiving prasugrel or clopidogrel. The association is significant and independent of other potential factors influencing rosuvastatin levels, indicating its potential clinical relevance.
Pharmacokinetics of Opioid Infusions in the Adult Intensive Care Unit Setting-A Systematic Review.
Beaucage-Charron J, Rinfret J, Trottier G … +4 more , Sévigny MM, Burry L, Marsot A, Williamson D
Clin Pharmacokinet · 2025 Mar · PMID 40025366 · Publisher ↗
INTRODUCTION: Pharmacokinetics (PKs) of drugs are often altered in the intensive care unit (ICU). Opioids are often used in the ICU, particularly as continuous infusions, and their characteristics lead them to undergo PK...
INTRODUCTION: Pharmacokinetics (PKs) of drugs are often altered in the intensive care unit (ICU). Opioids are often used in the ICU, particularly as continuous infusions, and their characteristics lead them to undergo PK alterations. We conducted a systematic review to assess the PK of opioid infusions in the ICU. METHODS: Embase, MEDLINE, PubMed, CINAHL, and Evidence-Based Medicine Reviews (EBMR) were searched from inception to March 2024. Studies were included if they evaluated PKs of opioid infusions in adult patients in the ICU. Two reviewers independently selected and extracted data. RESULTS: Out of the 1040 records screened, 17 studies were included. Five studies were conducted on fentanyl, seven on morphine, one on hydromorphone, two on remifentanil, two on alfentanil, and one on sufentanil. Most studies where observational studies or case series. The mean age was 56 years old. Duration of the infusion varied between 3 h and 20 days. PKs of fentanyl, sufentanil, and hydromorphone were significantly impaired, whereas the PKs of morphine, alfentanil, and remifentanil were impaired to a lesser degree. The PK parameter that was most affected by critical illness was the half-life (T½). CONCLUSIONS: To counter these PK alterations, new therapeutic avenues must be further explored in the ICU to individualize opioid infusions.
Population Pharmacokinetics of Cefepime in Critically Ill Children and Young Adults: Model Development and External Validation for Monte Carlo Simulations and Model-Informed Precision Dosing.
Morales Junior R, Hambrick HR, Mizuno T … +12 more , Pavia KE, Paice KM, Tang P, Schuler E, Krallman KA, Johnson L, Collins M, Gibson A, Curry C, Kaplan J, Goldstein S, Tang Girdwood S
Clin Pharmacokinet · 2025 Apr · PMID 39988706 · Full text
BACKGROUND AND OBJECTIVE: This study aimed to develop a population pharmacokinetic model for cefepime in critically ill pediatric and young adult patients to inform dosing recommendations and to evaluate the model's pred...
BACKGROUND AND OBJECTIVE: This study aimed to develop a population pharmacokinetic model for cefepime in critically ill pediatric and young adult patients to inform dosing recommendations and to evaluate the model's predictive performance for model-informed precision dosing. METHODS: Patients in the pediatric intensive care unit receiving cefepime were prospectively enrolled for clinical data collection and opportunistic plasma sampling for cefepime concentrations. Nonlinear mixed effects modeling was conducted using NONMEM. Allometric body weight scaling was included as a covariate with fixed exponents. Monte Carlo simulations determined optimal initial dosing regimens against susceptible pathogens. The model's predictions were evaluated with an external dataset. RESULTS: Data from 510 samples across 100 patients were best fit with a two-compartment model with first-order elimination. Estimated glomerular filtration rate and cumulative percentage of fluid balance were identified as significant covariates on clearance and central volume of distribution, respectively. Internal validation showed no model misspecification. External validation confirmed that bias and precision for both population and individual predictions were within commonly accepted ranges. Monte Carlo simulations suggested that the usual dose of 50 mg/kg may require a 3-h infusion or a 6-h dosing interval to keep concentrations above the Pseudomonas aeruginosa minimum inhibitory concentration (≤ 8 mg/L) throughout the dosing interval for patients with normal or augmented renal clearance. CONCLUSION: A cefepime population pharmacokinetic model for critically ill pediatric patients was successfully developed, accounting for patient renal function, fluid status, and body size, using real-world data. The model was internally and externally validated for use in optimal dosing simulations and model-informed precision dosing.
Correction: Clinical Pharmacokinetics of Psilocin After Psilocybin Administration: A Systematic Review and Post‑Hoc Analysis.
Otto ME, van der Heijden KV, Schoones JW … +4 more , van Esdonk MJ, Borghans LGJM, Jacobs GE, van Hasselt JGC
Clin Pharmacokinet · 2025 Mar · PMID 39982684 · Full text
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