Clinical Pharmacokinetics[JOURNAL]
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200 papers
Utilization of Apixaban Pharmacokinetics for Dose Optimization in High-Risk Elderly Patients.
Goldstein R, Sandouka K, Zighan L … +3 more , Ya'ari S, Bialer M, Muszkat M
Clin Pharmacokinet · 2026 Apr · PMID 41689732 · Full text
BACKGROUND AND OBJECTIVE: Direct oral anticoagulants have largely replaced vitamin K antagonists, for example, warfarin, because of their favorable safety profile and predictable pharmacokinetics, with apixaban being the...
BACKGROUND AND OBJECTIVE: Direct oral anticoagulants have largely replaced vitamin K antagonists, for example, warfarin, because of their favorable safety profile and predictable pharmacokinetics, with apixaban being the most widely used direct oral anticoagulant. Although routine therapeutic drug monitoring is not required, measuring apixaban plasma concentrations may be useful in high-risk clinical scenarios. This aim of this study was to evaluate the impact of a repeat apixaban concentration measurement combined with a pharmacokinetic analysis and dose adjustment on drug concentrations and clinical outcomes. METHODS: We conducted a retrospective observational cohort study at Hadassah Mount Scopus Hospital, including elderly patients hospitalized between January 2020 and September 2024 with prescriptions for apixaban. Patients with two appropriately timed, maximum apixaban plasma concentrations within 90 days were analyzed. RESULTS: A total of 127 patients were included (median age 79 years, maximum age 97 years; 51% female). At baseline, 16% had subtherapeutic apixaban plasma concentrations and 20% had supratherapeutic concentrations. Female sex was associated with subtherapeutic concentrations while a standard dose (10 mg/day) of apixaban was associated with supratherapeutic plasma concentrations. Dose adjustment was more common in patients with standard dose therapy and in patients with an out-of-range baseline apixaban measurement with adjusted odds ratio of 6.1 and 95% confidence interval of 2.2-16.9 and 4.9 (95% confidence interval 1.9-12.7), respectively. In patients who had undergone repeated apixaban maximum plasma concentration measurements, we found 24 bleeding events and six thrombotic or embolic events within a 1-year follow-up from the second maximum plasma concentration measurement. Bleeding events were more common in patients whose maximum plasma concentration was out of the therapeutic range (28% vs 15%), CONCLUSIONS: Dose adjustment based on apixaban plasma concentration monitoring increased the proportion of patients who have apixaban concentrations within the therapeutic range. In high-risk elderly patients, an apixaban concentration measurement coupled with active intervention (e.g., dose adjustment) is likely to be clinically beneficial in avoiding bleeding and thromboembolic events.
Leveraging Model-Informed Drug Development to Predict Asciminib Efficacy in Second-Line Treatment of Chronic Myeloid Leukemia in Chronic Phase.
Sy SKB, Yoon DY, Yang Y … +7 more , Darstein C, Dasgupta K, Kapoor S, Wu S, Kawakita Y, Hoch M, Grosch K
Clin Pharmacokinet · 2026 Apr · PMID 41670862 · Publisher ↗
BACKGROUND AND OBJECTIVES: The efficacy of asciminib was proven in newly diagnosed (first-line, 1L) patients with Philadelphia-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) and in patients treated with...
BACKGROUND AND OBJECTIVES: The efficacy of asciminib was proven in newly diagnosed (first-line, 1L) patients with Philadelphia-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) and in patients treated with at least two prior tyrosine kinase inhibitors (third-line, 3L+). Given that no randomized controlled trial has been conducted for second-line (2L) patients with CML, this analysis aims to infer the efficacy of asciminib in the 2L setting using the 80 mg once-daily dosing regimen and to support the use of asciminib in patients with CML-CP irrespective of line of therapy. METHODS: Data (n = 430) were used from three studies, including first-in-human and ASCEMBL in 3L+ and ASC4FIRST in 1L trials, to evaluate the effect of line of therapy on efficacy on the basis of the time-course of BCR::ABL1 mRNA transcripts. Previously adapted to characterize the effect of nilotinib as a 1L and 2L therapy on a CML surrogate marker, the model has three compartments representing quiescent leukemic stem cells and proliferating drug-susceptible and resistant bone marrow cells, wherein the effect of asciminib was modeled as an enhancement of the elimination of susceptible cells. RESULTS: Asciminib efficacy in 2L was inferred from 1L by borrowing information from nilotinib data. A credibility assessment showed robust prediction accuracy and precision of the model with external 2L data from the ASC2ESCALATE study (n = 36). Major molecular response (MMR) rates in 2L were predicted to be 61-67% at week 48 and 70-76% at week 96, with the 80 mg total daily dose. CONCLUSIONS: A model-informed drug development (MIDD) approach was applied to predict 2L efficacy and supported global regulatory approval of asciminib across treatment lines, despite limited clinical data in 2L.
Single Saliva Sample Model-Informed Precision Dosing of Levofloxacin for Multidrug-Resistant Tuberculosis.
Nguyen TA, Nguyen TP, Nguyen AT … +8 more , Dinh LV, Nguyen HB, Vu HD, Nguyen TNB, Vu D, Fox GJ, Alffenaar JC, Stocker SL
Clin Pharmacokinet · 2026 Apr · PMID 41665863 · Full text
BACKGROUND AND OBJECTIVES: Levofloxacin is an essential drug in multidrug-resistant tuberculosis (MDR-TB) treatment, but high pharmacokinetic variability necessitates therapeutic drug monitoring (TDM) to optimise exposur...
BACKGROUND AND OBJECTIVES: Levofloxacin is an essential drug in multidrug-resistant tuberculosis (MDR-TB) treatment, but high pharmacokinetic variability necessitates therapeutic drug monitoring (TDM) to optimise exposure and improve outcomes. Traditional TDM requires invasive blood sampling, limiting feasibility. Saliva sampling, a non-invasive matrix may simplify implementation. We aimed to develop a levofloxacin population pharmacokinetic (popPK) model integrating plasma and saliva data, and to evaluate saliva-based limited sampling strategies to support model-informed TDM for levofloxacin in practice. METHODS: Adults receiving oral levofloxacin for ≥ 7 days had plasma and saliva samples collected at 0, 2, and 5 h post-dose. A plasma-and-saliva popPK model was developed using NONMEM, including covariate evaluation. Predictive performance of saliva-based limited sampling strategies for estimating plasma AUC was assessed using Bayesian estimation and Monte Carlo simulations. RESULTS: A total of 57 patients with 342 paired plasma-saliva samples were evaluated. One-compartment model incorporating saliva bio-compartment with first-order absorption (with a lag time) and elimination best described the data. No significant covariates were identified. Simulations showed that the three-point saliva strategy (0, 2, 5 h) predicted plasma AUC within clinically acceptable limit (< 15% prediction error). A single 2-h sample yielded comparable accuracy. Two- and three-sample saliva strategies up to 16 h post-dose also showed clinically acceptable accuracy. CONCLUSIONS: The developed popPK model enables reliable estimation of levofloxacin exposure from limited saliva samples. A single 2-h post-dose saliva concentration may support model-informed levofloxacin TDM in routine MDR-TB care. This approach may be beneficial in settings where plasma-based TDM is logistically or ethically challenging.
Systemic Pharmacokinetic Principles of Therapeutic Peptides.
Nordell P, Jansson-Löfmark R, Gennemark P
Clin Pharmacokinet · 2026 Apr · PMID 41661442 · Full text
INTRODUCTION: Peptide-based therapeutics represent a rapidly expanding class of drugs. Endogenous peptides typically exhibit short elimination half-lives due to proteolytic cleavage and renal filtration. However, modific...
INTRODUCTION: Peptide-based therapeutics represent a rapidly expanding class of drugs. Endogenous peptides typically exhibit short elimination half-lives due to proteolytic cleavage and renal filtration. However, modifications such as amino acid substitutions and fatty-acid conjugation can significantly prolong their half-lives, enabling, for example, once weekly dosing. This study revisits the systemic pharmacokinetics of peptide drugs using classical pharmacokinetic principles and elucidates the scaling of peptide pharmacokinetics across species. METHODS: Preclinical and clinical pharmacokinetic data were collected from published literature and AstraZeneca internal sources, covering four unconjugated peptides (teduglutide, apraglutide, pramlintide, and exenatide) and five fatty-acid conjugated peptides (tirzepatide, cotadutide, liraglutide, semaglutide and pemvidutide). Algebraic equations for clearance, volume of distribution, and plasma half-life were derived. RESULTS: Theoretical predictions from these models were broadly consistent with collected data; however, there was a tendency to overpredict the volume of distribution. Furthermore, for each peptide drug, these pharmacokinetic parameters were well described by inter-species allometric relationships. The allometric exponents for apparent clearance ranged from 0.58 to 0.88 (geometric mean: 0.72; n = 9; R ≥ 0.93), while those for apparent volume of distribution ranged from 0.89 to 1.1 (geometric mean: 0.98; n = 8; R ≥ 0.88). Notably, there were no differences in scaling exponents between unconjugated and fatty-acid conjugated peptides. CONCLUSION: In summary, our results underscore that the systemic pharmacokinetics of peptide drugs generally follow size-related physiological scaling patterns and provide quantitative tools to facilitate translational assessments in the drug discovery process.
Nomograms for Therapeutic Drug Monitoring of High-Dose Amikacin in Critically Ill Patients: Insights from a Population Pharmacokinetic Analysis and Dosing Simulation.
Nguyen TC, Le DV, Nguyen HA … +12 more , Nam Tien NT, Nguyen THN, Vu DH, Nguyen HA, Pham HN, Nguyen CT, Nguyen DMV, Pham TT, Do NS, Dang QT, Dao XC, Alffenaar JC
Clin Pharmacokinet · 2026 Apr · PMID 41661441 · Publisher ↗
BACKGROUND AND OBJECTIVE: This study evaluated the probability of pharmacokinetic/pharmacodynamic efficacy target attainment and developed a dosing interval identification nomogram to minimize toxicity risks of high-dose...
BACKGROUND AND OBJECTIVE: This study evaluated the probability of pharmacokinetic/pharmacodynamic efficacy target attainment and developed a dosing interval identification nomogram to minimize toxicity risks of high-dose amikacin. METHODS: Therapeutic drug monitoring was performed in critically ill patients receiving high-dose (30 mg/kg) amikacin intravenously. Population pharmacokinetic modeling and Monte Carlo simulation were performed in NONMEM 7.5.1. The probability of target attainment and the cumulative fraction of response for the local Klebsiella pneumoniae population were assessed using maximum concentration/minimum inhibitory concentration ≥ 8 as the efficacy target. Nomograms stratified by the renal function group were established to guide dosing intervals to avoid exceeding the toxicity minimum concentration threshold of 2.5 mg/L. RESULTS: A total of 251 patients with 488 amikacin concentrations were included. The amikacin pharmacokinetics was best described by a two-compartment model. The creatinine clearance and adjusted body weight were significant covariates for clearance and the central volume of distribution, respectively. Amikacin 30 mg/kg achieved a probability of target attainment > 90% for minimum inhibitory concentrations < 8 mg/L and around 80% for minimum inhibitory concentrations of 8 mg/L. This regimen showed a cumulative fraction of response of 63.5% for K. pneumoniae, while attaining a cumulative fraction of response of 96.8% for susceptible isolates. The 30-mg/kg nomograms in patients with creatinine clearance < 60 and ≥ 60 mL/min showed accurate dosing intervals with around 90% of virtual patients for the post-infusion period from 20 to 32 h and from 6 to 32 h, respectively. CONCLUSIONS: Nomogram-aided dosing interval adjustment of high-dose amikacin (30 mg/kg) maximized the efficacy and safety target attainment for critically ill patients with infections caused by susceptible K. pneumoniae.
Pharmacokinetics, Pharmacodynamics and Safety of Fultagliptin Benzoate Tablets, a DPP-4 Inhibitor, in Patients With Varying Degrees of Renal Insufficiency and Matched Healthy Volunteers: A Phase I Clinical Trial.
Chen Y, Hu C, Cao X … +7 more , Men Y, Wang Y, Zhang R, Guan H, Shi L, Liu F, Miao J
Clin Pharmacokinet · 2026 Apr · PMID 41661440 · Publisher ↗
BACKGROUND: DPP-4 inhibitors are a class of oral hypoglycemic drugs commonly used in the treatment of type 2 diabetes mellitus (T2DM). Fultagliptin benzoate is a novel and high-selective DPP-4 inhibitor. The renal excret...
BACKGROUND: DPP-4 inhibitors are a class of oral hypoglycemic drugs commonly used in the treatment of type 2 diabetes mellitus (T2DM). Fultagliptin benzoate is a novel and high-selective DPP-4 inhibitor. The renal excretion of many medications, including DPP-4 inhibitors, can be altered in patients with renal impairment. This study investigates the pharmacokinetics, pharmacodynamics, and safety of fultagliptin benzoate tablets in mild and moderate renal impairment (RI) compared with normal renal function to ensure safety and efficacy across these groups. METHODS: A single-dose, non-randomized, open-label, and parallel-control phase I study was performed. Pharmacokinetics, pharmacodynamics, and safety of fultagliptin benzoate tablets were evaluated. RESULTS: A total of 18 participants were enrolled and completed the study. After oral administration of a single dose of fultagliptin benzoate tablets 12 mg under fasted conditions, fultagliptin was absorbed with median time to reach peak concentration (T) of 4.50, 3.00, and 5.50 hours in healthy participants, patients with mild RI, and patients with moderate RI, respectively, and eliminated with mean elimination half-life (t) of 32.27, 40.22, and 46.38 h, respectively. Compared with healthy participants, patients with mild RI had similar peak concentration (C), while area under the concentration-time curve from time zero to the last measured concentration (AUC) and AUC from time zero to infinity (AUC) increased by 24.7% and 25.0%, respectively. In patients with moderate RI, C, AUC, and AUC increased by 27.5%, 86.4%, and 87.9%, respectively. Comparing the renal clearance rate (CL) with that of the healthy participants (8.96 ± 2.24 L/h), the CL values (mean ± SD) of patients with mild RI and patients with moderate RI were 6.615 ± 1.34 L/h and 4.54 ± 1.20 L/h, respectively, which were approximately 73.8% and 50.6% of that of the healthy participants. For pharmacodynamic biomarkers, the DPP-4 inhibition rate (E) in all groups of participants was > 90%. The duration of DPP-4 inhibition rate over 80% in the three groups showed an increasing trend. Fultagliptin benzoate tablets were well tolerated in all participants during the study. CONCLUSION: In patients with mild RI, the small increase in exposure to fultagliptin was not considered clinically relevant. Although a significant increase in exposure was observed in patients with moderate RI without eliciting issues related to efficacy and safety, a half-dose reduction may be considered for the protection of participants. TRIAL REGISTRATION: ClinicalTrials.gov (NCT06883656); registered 12 March 2025 (retrospectively registered).
Evaluation and Improvement of Specialized Vancomycin Pharmacokinetic Models for Pediatric Cardiovascular Intensive Care Unit and Pediatric Oncology Patients.
McCarthy MG, Keizer RJ, Hughes JH
Clin Pharmacokinet · 2026 Apr · PMID 41656454 · Full text
BACKGROUND AND OBJECTIVE: Dose optimization of vancomycin in distinct pediatric subpopulations is inherently complex due to altered vancomycin pharmacokinetics associated with certain conditions or circumstances, such as...
BACKGROUND AND OBJECTIVE: Dose optimization of vancomycin in distinct pediatric subpopulations is inherently complex due to altered vancomycin pharmacokinetics associated with certain conditions or circumstances, such as cancer or postoperative cardiac surgery. Numerous population pharmacokinetic models have been developed that aim to capture these alterations; however, it is currently unclear whether these specialized models are necessary, or if covariates in a well-specified general model can adequately capture pharmacokinetic variation between special subpopulations. Here, we conduct an external evaluation comparing the predictive performance of published general and specialized population pharmacokinetic models in pediatric oncology and pediatric cardiovascular intensive care unit (CVICU) patients in order to address this question, and guide model selection decisions for model-informed precision dosing of vancomycin in these subpopulations. METHODS: The predictive error, bias, and accuracy of two general, six oncology-supporting, and three CVICU-supporting pharmacokinetic models were compared in two multi-site data sets of pediatric oncology (N = 371, 1392 drug levels, 20 sites) and pediatric CVICU (N = 219, 1136 drug levels, 11 sites) patients, respectively. The best performing model(s) in each subpopulation were refit to evaluate whether predictive performance could be further improved over the published models. RESULTS: We find that although specialized models performed better than general population models for pediatric CVICU patients, a general model (Colin 2019) performed better than all specialized models for pediatric oncology patients. We additionally report a refit version of the Shimamoto 2024 model for pediatric CVICU patients, which performed better than all published CVICU-supporting models in our data set. CONCLUSION: Population pharmacokinetic models developed on distinct pediatric subpopulations are not necessarily more fit-for-purpose than models developed on a general population. Both well-specified general models and specialized models may be capable of achieving suitable clinical performance in these subpopulations, and this assessment of model fit-for-purpose must be made on a case-by-case basis.
Methodologies for Population Pharmacokinetic Modeling of Target-Site Drug Exposure: A Narrative Review of Current Strategies.
Mehciz M, Rietveld PCS, Koch BCP … +1 more , Preijers T
Clin Pharmacokinet · 2026 Apr · PMID 41656453 · Full text
Model-informed precision dosing (MIPD) is increasingly used to guide drug dosing based on population pharmacokinetic (popPK) models developed mainly using plasma concentration data. However, plasma levels may not always...
Model-informed precision dosing (MIPD) is increasingly used to guide drug dosing based on population pharmacokinetic (popPK) models developed mainly using plasma concentration data. However, plasma levels may not always correlate well with drug concentrations at the site of action, potentially leading to under- or overestimation of target-site exposure. It is, therefore, important to evaluate which popPK modeling approaches effectively describe drug concentrations at target sites other than plasma to support the selection and implementation of appropriate modeling techniques. This review outlines four general modeling strategies described in literature characterizing the relationship between plasma and target-site drug concentrations. The first approach includes rate constants describing inflow and outflow, which is especially useful for unidirectional transport or large flow rate differences. Second, intercompartmental clearance models capture bidirectional transport with a single parameter that is directly comparable with elimination clearance or blood flow. Third, effect compartment models are used to describe delayed tissue distribution. Lastly, the target site can be modeled as part of either the central or the peripheral compartment. Although therapeutic drug monitoring (TDM) based on target-site concentrations has been suggested, implementation is limited by invasive sampling procedures, limited sample volumes, and the lack of established pharmacokinetic/pharmacodynamic targets. Nevertheless, even small differences in target-site exposure can result in clinical implications, and the applicability of drug monitoring using target-site concentrations has been shown in critically ill patients. In conclusion, target-site concentrations have been successfully predicted using different modeling methodologies and have demonstrated potential to optimize therapy in select clinical cases.
β-Lactam Antibiotics in Obese Adults: A Review of Population Pharmacokinetic Analyses.
Annane G, Crevier B, Ouyahia A … +1 more , Marsot A
Clin Pharmacokinet · 2026 Mar · PMID 41649772 · Publisher ↗
Obesity is becoming more prevalent, and it significantly alters drug pharmacokinetics (PK), potentially impacting the efficacy and safety of β-lactam antibiotics. Population pharmacokinetic (popPK) modeling plays a cruci...
Obesity is becoming more prevalent, and it significantly alters drug pharmacokinetics (PK), potentially impacting the efficacy and safety of β-lactam antibiotics. Population pharmacokinetic (popPK) modeling plays a crucial role in optimizing dosing strategies, yet there is variability in how these models account for obesity-related physiological changes. This review aims to synthesize published popPK studies on β-lactams in obese populations, highlighting key findings and modeling approaches. A literature review was conducted to identify popPK studies evaluating β-lactam antibiotics in obese individuals. Relevant databases were searched for studies reporting PK parameters, covariates, and dosing recommendations. A total of 24 studies met the predefined selection criteria. The majority employed two-compartment models with creatinine clearance (CL) and total body weight (TBW) as the most common covariates for clearance (CL) and volume of distribution (V). Estimated PK parameters differed within the same β-lactam, which indicates that obesity influences the PK of β-lactams, though the extent of its impact differs based on the specific drug, patient characteristics, and selected covariates. This review highlights the key aspects of popPK models in obese populations treated with β-lactams. Despite the growing prevalence of obesity, its influence on β-lactam antibiotics remains uncertain.
A Mycophenolate Pharmacokinetic Study with New Insights into Enterohepatic Recirculation in Kidney Transplant Recipients.
Mohamed ME, Saqr A, Onyeaghala G … +11 more , Remmel RP, Staley C, Dorr CR, Teigen L, Guan W, Vo D, El-Rifai R, Oetting WS, Matas AJ, Israni AK, Jacobson PA
Clin Pharmacokinet · 2026 Mar · PMID 41649771 · Full text
BACKGROUND: Mycophenolic acid (MPA) has complex pharmacokinetics in part due to enterohepatic recirculation (EHR). A deeper understanding of MPA pharmacokinetics and specifically how EHR and patterns of EHR affect exposu...
BACKGROUND: Mycophenolic acid (MPA) has complex pharmacokinetics in part due to enterohepatic recirculation (EHR). A deeper understanding of MPA pharmacokinetics and specifically how EHR and patterns of EHR affect exposure will improve immunosuppression outcomes. This study provides a contemporary and comprehensive assessment of MPA and metabolites in the blood and urine with a focus on EHR characteristics. METHODS: Kidney transplant recipients (n = 84) receiving mycophenolate mofetil (MMF) and tacrolimus underwent an intensive MPA pharmacokinetic assessment. Pharmacokinetics of MPA and its metabolites, EHR%, and number of secondary peaks were determined. The associations between EHR, the number of secondary peaks, and achievement of MPA therapeutic range were studied. MMF dose proportionality with MPA exposure was evaluated. RESULTS: MPA exhibited high pharmacokinetic variability, with 5.5-fold differences in AUC, 18.4-fold differences in trough concentrations, and a 3.4-fold difference in EHR%. Median MPA EHR% was 40.5%. There were no significant associations between EHR% and MPA AUC or trough. MPA AUC and trough were significantly associated with the number of MPA secondary peaks (0, 1, or ≥ 2 peaks). Participants without secondary peaks showed the highest percentage of subtherapeutic MPA AUC and troughs, while participants with ≥ 2 peaks were more likely to be supratherapeutic. CONCLUSIONS: There was no association between the EHR% and MPA AUC or trough. We identified three distinct patterns of MPA secondary peaks (0, 1, or ≥ 2 peaks), which were significantly associated with MPA AUC and trough. Studies to evaluate the relationship of MPA EHR measures and clinical outcomes are needed. TRIAL REGISTRY: Clinical Trial Notation: clinicaltrials.gov, NCT04953715.
Use of a Cystatin C-Based GFR Equation in a Population Pharmacokinetic Model of Methotrexate Clearance in Adult Patients with Lymphoma.
Taylor ZL, Barreto EF, Cole KC … +7 more , Rule AD, Kashani KB, Leung N, Thompson CA, Witzig TE, Ramsey LB, Barreto JN
Clin Pharmacokinet · 2026 Mar · PMID 41606413 · Full text
BACKGROUND: High-dose methotrexate (HDMTX) is a key treatment for lymphoma with central nervous system involvement. Whether incorporating cystatin C into glomerular filtration rate estimation improves methotrexate (MTX)...
BACKGROUND: High-dose methotrexate (HDMTX) is a key treatment for lymphoma with central nervous system involvement. Whether incorporating cystatin C into glomerular filtration rate estimation improves methotrexate (MTX) clearance prediction remains unclear. OBJECTIVES: We aimed to evaluate whether cystatin C-inclusive glomerular filtration rate equations improve MTX clearance prediction and to explore the relationship between MTX exposure and acute kidney injury (AKI) in adult patients with lymphoma receiving HDMTX. METHODS: This was a prospective single-center study performed on 80 adult patients with lymphoma receiving HDMTX (1.5-8 g/m) over a 4-h infusion. A population pharmacokinetic model was constructed using data from 80 administrations of HDMTX and 427 serum MTX concentrations. The population pharmacokinetic model estimated MTX concentrations were included in a logistic regression to assess the relationship between MTX exposure and AKI. RESULTS: A two-compartment model best described the pharmacokinetic data, with baseline albumin and CKD-EPI creatinine-cystatin C (eGFRCr-CysC) as significant covariates on clearance. Seventeen patients (21%) developed any-stage AKI. Among those receiving ≤ 3.5 g/m, model-estimated 4-h MTX concentrations were associated with AKI (odds ratio: 1.02 per µmol/L; p = 0.0038), with an optimal threshold of 160 µmol/L (area under the concentration-time curve: 0.818). Patients above this threshold were 22 times more likely to experience AKI (p = 0.0005). This association was not observed in patients treated with 8 g/m. Despite a lower dose and exposure, patients receiving ≤ 3.5 g/m demonstrated a stronger concentration-toxicity relationship. CONCLUSIONS: Our results support the use of cystatin C-inclusive glomerular filtration rate estimates in MTX pharmacokinetic modeling and suggest early MTX concentration sampling may identify AKI risk, enabling proactive, AKI-mitigating clinical interventions during HDMTX therapy.
Accurate Estimation of Glomerular Filtration Rate in Critically Ill Infants and Children Using a Iohexol Population Pharmacokinetic Modeling Approach.
Dhont E, Destere A, Gerard A … +6 more , Bouveyron C, Snauwaert E, Vanhaesebrouck S, De Paepe P, Woillard JB, De Cock P
Clin Pharmacokinet · 2026 Mar · PMID 41591642 · Publisher ↗
BACKGROUND AND OBJECTIVE: Accurate assessment of the glomerular filtration rate (GFR) is crucial in critically ill children, yet standard estimation formulas (eGFR) perform poorly, especially in the youngest. Iohexol pla...
BACKGROUND AND OBJECTIVE: Accurate assessment of the glomerular filtration rate (GFR) is crucial in critically ill children, yet standard estimation formulas (eGFR) perform poorly, especially in the youngest. Iohexol plasma clearance is the reference standard for measured GFR; however, its routine use is limited by logistical constraints. This study aims to develop and internally validate a population pharmacokinetic model of iohexol in critically ill children, to derive a practical model-based GFR estimation formula (eGFR), and to compare its predictive performance against established eGFR formulas (eGFR, eGFR). METHODS: After administration of iohexol, up to six blood samples were drawn from 107 patients over a 6-hour interval. Data from 93 patients were used for model building, and from 31 patients for internal validation. Reference clearances were obtained using the post hoc Bayesian clearance estimates. Predictive performances of eGFR, eGFR and eGFR were compared with reference clearances using bias, imprecision, Total Deviation Index, concordance correlation coefficient, and the percentage of predictions within 10 and 30% error (P10, P30) around reference clearances. RESULTS: The final model identified body surface area, serum creatinine, cystatin C, postoperative status, and clonidine treatment as significant predictors of iohexol clearance. eGFR demonstrated minimal bias (-0.8%) and imprecision (21%) and high accuracy (P30 = 87%), particularly in patients under 2 years of age (P30 = 90 vs 40% for eGFR). Furthermore, eGFR also demonstrated superiority over eGFR, which exhibited moderate bias (-5.4%) and reduced accuracy (P30 = 68%). CONCLUSIONS: A model-derived GFR estimation formula based on iohexol population pharmacokinetic modeling might allow for an accurate bedside assessment of kidney function in critically ill children, outperforming the Schwartz and Smeets/Pierce formulas, particularly in infants. External validation in larger pediatric intensive care unit populations, across the full age and GFR range, is warranted to confirm the generalizability of this equation and its potential for broader clinical application. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT05179564, registered retrospectively on 5 January, 2022.
Pharmacokinetics and Safety of a Single Dose of Brensocatib in Participants with Hepatic Impairment and Matched Participants with Normal Hepatic Functions.
Usansky H, Au Yeung S, Li S … +4 more , Marbury T, Lawitz E, Kayali Z, Stein DS
Clin Pharmacokinet · 2026 Mar · PMID 41586857 · Full text
AIM: Brensocatib is an oral, competitive, and reversible dipeptidyl peptidase 1 (DPP1) inhibitor in development for the treatment of neutrophil-mediated diseases. Brensocatib is a substrate of CYP3A, P-glycoprotein, and...
AIM: Brensocatib is an oral, competitive, and reversible dipeptidyl peptidase 1 (DPP1) inhibitor in development for the treatment of neutrophil-mediated diseases. Brensocatib is a substrate of CYP3A, P-glycoprotein, and breast cancer resistance protein (BCRP). Its absorption, distribution, metabolism, and elimination could be potentially affected by a decrease in hepatic function. This study evaluated the pharmacokinetics (PK), safety, and tolerability of brensocatib in participants with varying degrees of hepatic impairment and matched participants with normal hepatic function. METHODS: In this phase 1, multicenter, open-label study, 27 participants with normal hepatic function or mild, moderate, and severe hepatic impairment, based on numerical Child-Pugh classifications, received a single, oral 25-mg dose of brensocatib. Blood and urine samples were collected to evaluate brensocatib PK, urinary excretion, and plasma protein binding. RESULTS: Demographic and baseline characteristics were generally similar across hepatic impairment groups and matched healthy participants. The systemic exposure (area under the curve, AUC) and renal clearance (CL) of brensocatib were generally comparable across all groups (≤ 20% difference in AUC compared with healthy participants and CL 1.34-1.84 L/h versus 1.66 L/h in healthy participants). The mean elimination half-life was also similar across all hepatic function groups (27.9-31.4 h). Regression analyses indicated no significant relationships between brensocatib systemic exposure and Child-Pugh scores. Unbound brensocatib in plasma slightly increased by the severity of hepatic impairment. The fraction of unbound brensocatib (F) was correlated with serum albumin, suggesting that brensocatib is mainly bound to albumin in plasma. Treatment-emergent adverse events (TEAEs) occurred in 14.8% (4/27) of participants; most TEAEs were mild, and two TEAEs occurring in one participant were considered severe. No new safety findings were observed. CONCLUSIONS: No new safety signals were identified in participants with or without hepatic impairment treated with a single dose of 25 mg brensocatib. The oral absorption and elimination of brensocatib were not significantly altered in participants with mild, moderate, or severe hepatic impairment, suggesting that dose adjustment for brensocatib treatment in patients with hepatic impairment is not necessary. TRIAL REGISTRY: Clinical Trial Registration Number: NCT05517525.
Therapeutic Drug Monitoring for Improving Tuberculosis Treatment Outcomes: A Scoping Review of Clinical Studies.
Noeriman AR, Sumarheni S, Hasanah AN … +5 more , Apriani L, Santoso P, Alffenaar JC, Gafar F, Ruslami R
Clin Pharmacokinet · 2026 Feb · PMID 41566098 · Publisher ↗
BACKGROUND: Therapeutic drug monitoring (TDM) is a tool used for dose optimization to achieve therapeutic concentrations associated with improved outcomes. However, evidence supporting its benefits for tuberculosis (TB)...
BACKGROUND: Therapeutic drug monitoring (TDM) is a tool used for dose optimization to achieve therapeutic concentrations associated with improved outcomes. However, evidence supporting its benefits for tuberculosis (TB) treatment remains limited. This scoping review evaluated clinical studies on TDM and its impact on TB treatment outcomes. METHODS: A scoping review was performed using a systematic search in PubMed, Embase, Web of Science, ClinicalTrials.gov, and the World Health Organization (WHO) Clinical Trials Registry for interventional and observational studies published until 3 May 2025. We included studies evaluating TDM in adults or children treated for drug-susceptible or drug-resistant TB at any setting worldwide, which reported treatment outcomes, adverse events, or clinical/microbiological surrogate markers. The PRISMA guidelines for scoping reviews were followed to report the findings. RESULTS: Of the 5820 studies screened by title and abstract, 31 studies from 10 countries were eligible for inclusion in this review. No published clinical trials on the implementation of TDM were identified, although two are currently ongoing. Overall, compared with the non-TDM group, TDM was associated with faster culture conversion (mean 34 versus 49 days), shorter treatment duration (mean 32 versus 36 weeks) and fewer adverse events. Although all included studies reported high treatment success rates (ranging from 67% to 100%), no statistically significant differences were observed in end-of-treatment outcomes between TDM and non-TDM groups. Dose adjustments guided by TDM were recommended by all included studies, despite variability in results. CONCLUSIONS: Observational data suggest that TDM in TB treatment was associated with improved effectiveness and fewer adverse events. However, further investigation through well-controlled studies is needed to minimize potential bias and justify its routine use.
The Effect of Taking Cabozantinib with a Light Breakfast: A Randomized Crossover Pharmacokinetic Study (SKIPPY 1).
Rieborn A, Guchelaar NAD, van Gelder T … +8 more , Gelderblom H, Luelmo SAC, Kerssemakers N, Hamberg PAP, Koolen SLW, Mathijssen RHJ, Moes DJAR, van der Hulle T
Clin Pharmacokinet · 2026 Mar · PMID 41555108 · Full text
BACKGROUND AND OBJECTIVE: Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma. The current patient-unfriendly advice to ingest cabozantinib in a fasted state is based...
BACKGROUND AND OBJECTIVE: Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma. The current patient-unfriendly advice to ingest cabozantinib in a fasted state is based on an increase of 57% in the area under the concentration-time curve after ingestion with a high-fat meal. Taking cabozantinib with a meal that is suitable for daily practice to increase bioavailability could aid in developing alternative dosing strategies. In this study, we aim to investigate the impact of taking cabozantinib with a light breakfast on exposure and toxicity. METHODS: An open-label, randomized, cross-over, pharmacokinetic evaluation study was performed. In the standard regimen, patients took cabozantinib in a fasted state. In the experimental regimen, patients took cabozantinib with a light breakfast. After 4 weeks, pharmacokinetic samples were obtained for area under the concentration-time curve from 0 to 24 h estimation and patients thereafter switched to the other regimen. Patients were monitored for serious adverse events. RESULTS: Twelve patients completed study procedures. The area under the concentration-time curve for taking cabozantinib in a fasted state and with a light breakfast showed a mean difference of + 8.3% (geometric mean ratio, 90% confidence interval 101-117). Similar results were obtained for trough concentration (mean difference 2.5%, geometric mean ratio, 90% confidence interval 90.7-116.0) and maximum concentration (mean difference 14%, geometric mean ratio, 90% confidence interval 103.7-127.6). No differences in serious adverse events were observed. CONCLUSIONS: Taking cabozantinib with a light breakfast leads to a small increase in exposure. Patients for whom taking cabozantinib in a fasted state is unpleasant are now able to take it with a light breakfast, without an increased risk for exposure-related toxicity. CLINICAL TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov under the number NCT05263245.
Model-Based Alternative Dosing Strategies for Subcutaneous Nivolumab to Improve Cost Effectiveness.
Wang Y, Bukkems LH, Ter Heine R … +13 more , van Hasselt JGC, Koolen SLW, Hendrikx JJMA, Van der Hulle T, Kapiteijn E, Zwaveling J, Becker A, van den Heuvel MM, Theelen WSME, Oude Munnink TH, Smit EF, Guchelaar HJ, Moes DJAR
Clin Pharmacokinet · 2026 Apr · PMID 41524895 · Full text
BACKGROUND: The increasing use of the immune checkpoint inhibitor nivolumab places a significant financial burden on healthcare systems, contributes to environmental concerns, and strains hospital capacities. The nivolum...
BACKGROUND: The increasing use of the immune checkpoint inhibitor nivolumab places a significant financial burden on healthcare systems, contributes to environmental concerns, and strains hospital capacities. The nivolumab average exposure and exposure variation of a fixed subcutaneous (SC) dosing regimen (1200 mg every 4 weeks) is significantly higher compared with 3-mg/kg every 2 weeks intravenous dosing. OBJECTIVES: We aimed to develop alternative dosing regimens for SC nivolumab to reduce drug expenses and lower the treatment burden for patients while ensuring effective exposure. METHODS: Population pharmacokinetic simulation was conducted using a population pharmacokinetic model developed by the license holder to explore alternative SC regimens. In this process, patients were divided into three weight groups: less than 60 kg, 60-90 kg, and more than 90 kg. Furthermore, two experimental progressive alternative dosing regimens were developed, one based on a minimum effective concentration-driven approach. The second progressive alternative regimen was based on using the 1200-mg SC formulation as an intravenous infusion. RESULTS: We developed an alternative bodyweight-based regimen consisting of SC 1200 mg every 7 weeks (<60 kg), 1200 mg every 6 weeks (60-90 kg), and 1200 mg every 5 weeks (>90 kg). This new alternative dosing regimen would save an average of €24,345 (35%) per patient per year compared with SC 1200 mg every 4 weeks. The results for the first experimental, progressive, extended-interval dosing regimen for patients with melanoma indicate that 95% of patients exceed a steady-state trough concentration of 2.5 mg/L when administered SC 1200 mg every 10 weeks. This dosing regimen would decrease the yearly cost from €68,870 to €27,548 (60% less) per patient per year. The second experimental progressive regimen using SC 1200 mg as an intravenous administration every 7 weeks leads to a potential saving of €29,516, which is a 43% decrease compared with the SC 1200-mg approved regimen. CONCLUSIONS: The developed dosing regimen with a bodyweight-dependent interval offers a cost-effective and patient-friendly method to optimize SC nivolumab use while ensuring adequate exposure, which can be directly implemented in clinical practice. Moreover, the two experimental progressive proposed regimens provide a rationale for a clinical non-inferiority study in which alternative dose regimens are compared to standard dosing according to the drug label.
Correction: Population Pharmacokinetic Modeling of Oxcarbazepine and Its Active Metabolite 10‑Monohydroxy Derivative to Inform Dosing in Children with Obesity.
Sinha J, Zimmerman K, Balevic SJ … +12 more , Hornik C, Muller WJ, Rathore M, Meyer M, Finkelstein Y, Al-Uzri A, Lakhotia A, Goldstein S, Chen JY, Anand R, Gonzalez D, Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee
Clin Pharmacokinet · 2026 Feb · PMID 41493701 · Full text
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Population Pharmacokinetic and Pharmacodynamic Modeling to Support Molar Dose Ratio Determination of Long-Acting Insulin Analogs.
Tang D, Gao X, Zhu M … +8 more , Shu C, Dong Y, Yu X, Chen H, Li X, Zhang X, Cai D, Feng S
Clin Pharmacokinet · 2026 Mar · PMID 41489799 · Publisher ↗
BACKGROUND AND OBJECTIVE: INS068 is a new soluble, long-acting insulin analog intended to cover basal insulin requirements in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). The purpose...
BACKGROUND AND OBJECTIVE: INS068 is a new soluble, long-acting insulin analog intended to cover basal insulin requirements in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). The purpose of this study was to determine the molar dose ratio of INS068 to insulin degludec (IDeg) by comparing the clinical pharmacokinetic (PK) and pharmacodynamic (PD) profiles of INS068 and IDeg. The PD endpoints include glucose infusion rate (GIR) and glycated hemoglobin (HbA1c). METHOD: Population pharmacokinetic and pharmacodynamic (PopPK/PD) analysis was performed to characterize INS068 and IDeg PK and PD profiles. Data from 307 subjects across three Phase I studies and one Phase II study were used to establish the population pharmacokinetic (PopPK) model, of which two euglycemic clamp (Phase I) studies were used to establish PopPK-GIR model, and one Phase II study was used to establish PopPK-HbA1c model. Nonlinear mixed-effects modeling was used to investigate the PK and PD relationships of INS068 and IDeg. Model-based simulations were performed to determine the molar dose ratio of INS068 to IDeg. RESULTS: The PopPK model of INS068 and IDeg was described by a one-compartment model with linear absorption with a lag time and elimination. Significant covariate effects of body weight, population, and treatment (INS068 vs IDeg) were identified for PK parameters of INS068 and IDeg. However, except for body weight and T2DM patients, the other significant covariates (treatment and T1DM patients) had no clinically relevant effects on PK exposures. The relationship between GIR and insulin concentrations in effect compartment was described by a direct response model with sigmoidal E drug effect. The relationship between insulin concentration and HbA1c was well described by an indirect response model. The covariate analysis of the PopPK-GIR and PopPK-HbA1c models showed that treatment (INS068 vs IDeg) had no significant impact on the PD parameters. The results of model-based simulation demonstrated that the PK and PD of INS068 and IDeg were comparable. CONCLUSION: This analysis supported molar dose ratio of INS068 to IDeg as 1. INS068 had similar potency compared to IDeg, with one unit of INS068 composed of 6 nmol of active ingredient (1 U = 6 nmol).
Population Pharmacokinetics of Intravenous Cefuroxime in Plasma and Bone of Patients with Prosthetic Joint Infection: Is There Room for Dose Optimization?
de Waard GC, Zhao Q, Veltman ES … +6 more , van Oldenrijk J, Bos PK, Bahmany S, Muller A, Preijers T, Koch BCP
Clin Pharmacokinet · 2026 Mar · PMID 41484345 · Publisher ↗
BACKGROUND AND OBJECTIVE: Prosthetic joint infections are serious infections that require perioperative antibiotic prophylaxis. Cefuroxime may be used as prophylaxis, and this study aims to evaluate the current dosing re...
BACKGROUND AND OBJECTIVE: Prosthetic joint infections are serious infections that require perioperative antibiotic prophylaxis. Cefuroxime may be used as prophylaxis, and this study aims to evaluate the current dosing regimen to prevent infection during the perioperative period by performing population pharmacokinetic (PK) analysis of plasma and bone in patients with prosthetic joint infection (PJI). METHODS: Both plasma and bone samples were taken perioperatively and analyzed using NONMEM. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) in both plasma and bone of various dosing regimens. RESULTS: A total of 44 plasma and 38 bone samples from 25 patients were included. The median bone concentration at 30-60 min after administration was 18.2 (9.9-25.3) mg/L and the bone-to-plasma ratio was 0.269 (interquartile range [IQR] 0.179-0.269), while the median bone concentration at 90-120 min after administration was 12.6 (5.9-18.6) mg/L and the bone-to-plasma ratio was 0.125 (IQR 0.073-0.160). A two-compartment model with allometric scaling and proportional errors best described plasma and bone concentrations. Only estimated glomerular filtration rate could partly explain the inter-individual variability (IIV) of clearance (CL). A single dose of 1500 mg cefuroxime failed to maintain bone concentrations above target concentrations for Staphylococcus aureus beyond 3.83 h post administration. CONCLUSION: A population PK model was developed to characterize the disposition of cefuroxime in both plasma and bone compartments. Although adequate cefuroxime bone penetration within 1 h was observed in patients with PJI with rapid clearance, simulations predicted less optimal levels of cefuroxime after 3.5 h. The clinical implications need to be researched and confirmed.
A Pharmacokinetic Analysis of Intravenous Fluconazole in Adult Patients Undergoing Mechanical Circulatory Support Device Implantation.
Cairns KA, Hernandez-Mitre MP, Peel TN … +12 more , Abbott IJ, Kaye DM, Marasco S, Daly D, Warner V, Coldham A, Pope JD, Schneider HG, Dooley MJ, Liu X, Roberts JA, Udy AA
Clin Pharmacokinet · 2026 Mar · PMID 41430005 · Publisher ↗
BACKGROUND AND OBJECTIVE: There is limited information on the pharmacokinetics and optimal dosing of fluconazole in patients undergoing mechanical circulatory support (MCS) device implantation. AIM: The aim of this study...
BACKGROUND AND OBJECTIVE: There is limited information on the pharmacokinetics and optimal dosing of fluconazole in patients undergoing mechanical circulatory support (MCS) device implantation. AIM: The aim of this study was to describe fluconazole pharmacokinetics and identify dosing regimens that achieve pharmacokinetic/pharmacodynamic targets in this patient cohort. METHODS: In this prospective, single-centre study, adults undergoing MCS device implantation received intravenous fluconazole 200 mg or 400 mg, continued once daily for 5 days. Fluconazole concentrations were measured at four peri-operative time points, on return to the intensive care unit, and on days 3 and 5 following implantation. The area under the concentration-time curve from time zero to 24 h (AUC) was estimated, with target exposures defined as AUC/minimum inhibitory concentration (MIC) ≥ 50 for prophylaxis and AUC/MIC ≥ 100 for therapy. Population pharmacokinetic modelling was performed using non-linear mixed-effects methods and for Monte Carlo dosing simulations. RESULTS: Sixty-five fluconazole concentrations from 10 male patients (median age 51.5 years; IQR 50.0-57.0) were included. A two-compartment model including an additional renal replacement therapy (RRT)-dependent clearance pathway best described the data. Parameter estimates from the final model included a central volume of distribution of 5.75 L, non-RRT clearance of 0.45 L/h, and RRT clearance of 2.22 L/h. Simulations showed that doses of 800 mg or 12 mg/kg would be required for the highest probability of target attainment for Candida fluconazole MICs up to 4 mg/L (AUC/MIC ≥ 50) and 2 mg/L (AUC/MIC ≥ 100). CONCLUSION: In patients undergoing MCS device implantation, intravenous fluconazole 200 mg administered pre-operatively and continued daily for 5 days is insufficient for Candida spp. with MICs > 1 mg/L (prophylaxis, AUC/MIC ≥ 50) and > 0.5 mg/L (treatment, AUC/MIC ≥ 100).
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