Clinical Pharmacokinetics[JOURNAL]
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200 papers
Rifampicin Exposure in Tuberculosis Patients with Comorbidities in Sub-Saharan Africa: Prioritising Populations for Treatment-A Systematic Review and Meta-analysis.
Said B, Pétermann Y, Howlett P … +8 more , Guidi M, Thoma Y, Kajogoo VD, Sariko M, Heysell SK, Alffenaar JW, Mpolya E, Mpagama S
Clin Pharmacokinet · 2025 Aug · PMID 40608197 · Full text
BACKGROUND AND OBJECTIVES: Emerging evidence suggests that comorbidities like human immunodeficiency virus (HIV) infection, diabetes mellitus (DM), and malnutrition in tuberculosis (TB) patients can alter drug concentrat...
BACKGROUND AND OBJECTIVES: Emerging evidence suggests that comorbidities like human immunodeficiency virus (HIV) infection, diabetes mellitus (DM), and malnutrition in tuberculosis (TB) patients can alter drug concentrations, thereby affecting the treatment outcomes. For these populations, personalised strategies such as therapeutic drug monitoring (TDM) may be essential. We investigated the variations of drug levels within comorbid populations and analysed the differences in patterns observed between sub-Saharan Africa (SSA) and non-SSA regions. METHODS: We performed a systematic review and meta-analysis of rifampicin drug pharmacokinetics (PK) through searches of major databases from 1980 to December 2023. A random-effects meta-analysis model using R-studio version 4.3.2 was conducted to estimate pooled serum rifampicin exposure (area under the concentration-time curve [AUC], and peak maximum concentration [C]) between patients with TB-HIV infection, and TB-DM. RESULTS: From 3300 articles screened, 24 studies met inclusion criteria, contributing 33 comorbidity subgroups for meta-analysis. In SSA, 14 subgroups assessed rifampicin PK in TB-HIV, 1 in TB-DM, and none in TB-malnutrition. The pooled mean C was below the recommended range (8-24 mg/L) for all subgroups. For TB-HIV, the pooled C was 5.59 mg/L, 95% CI (4.59-6.59), I = 97% for SSA populations and 5.59 mg/L, 95% CI (3.65; 6.59) for non-SSA populations. The C for TB-DM in SSA (9.60 ± 4.4 mg/L) exceeded non-SSA (4.27 mg/L, 95% CI [2.77-5.76]). The lowest AUC was in TB-HIV (SSA, 29.09 mg/L h, 95% CI [21.06; 37.13, I = 91%]). High variability and heterogeneity (I >90%) were observed, with most studies (20/23) showing low bias. CONCLUSION: Our results emphasise the need for individualised dosing and targeted TDM implementation among TB-HIV and TB-DM populations on rifampicin in SSA. Although all populations exhibited low C levels, TB-HIV populations may be prioritised as AUC levels were lowest. In clinical settings in SSA, C-based TDM is more practical, but AUC can be used in treatment where feasible.
Population Pharmacokinetic and Pharmacodynamic Modelling and Simulation for Nedosiran Clinical Development and Dose Guidance in Pediatric Patients with Primary Hyperoxaluria Type 1.
Zhang S, Gamallo P, Rawson V
Clin Pharmacokinet · 2025 Sep · PMID 40601241 · Full text
BACKGROUND AND OBJECTIVES: Nedosiran (Rivfloza) is an RNA interference (RNAi) therapy approved for individuals aged ≥ 2 years with primary hyperoxaluria type 1 (PH1), a rare autosomal-recessive disorder causing renal fai...
BACKGROUND AND OBJECTIVES: Nedosiran (Rivfloza) is an RNA interference (RNAi) therapy approved for individuals aged ≥ 2 years with primary hyperoxaluria type 1 (PH1), a rare autosomal-recessive disorder causing renal failure and systemic oxalosis. Nedosiran silences lactate dehydrogenase (LDH) mRNA in hepatocytes, reducing oxalate levels. This study evaluated the model-informed clinical development of nedosiran to support proposed doses in children aged 2 to < 12 years with PH1. METHODS: A population pharmacokinetic/pharmacodynamic (Pop-PK/PD) model characterizing the plasma concentration-time profile of nedosiran and its effect on the spot urine oxalate-to-creatinine ratio (Uox/Cr) was developed using data from six trials. Simulations assessed spot Uox/Cr reduction in children aged 2 to < 12 years for the proposed dosing regimen versus those aged ≥ 12 years weighing ≥ 50 kg with similar renal function. RESULTS: The datasets included 2087 PK (N = 148) and 668 spot Uox/Cr (N = 41, with PH1) observations. Body weight, estimated glomerular filtration rate (eGFR), and PH type were covariates in the PK model, with body weight in low and high percentiles affecting nedosiran exposures. Moderate renal impairment (eGFR 30-59 mL/min/1.73 m) increased exposure, while only age was significant for baseline Uox/Cr in the PD model. Simulations showed similar Uox/Cr reduction and times to maximum effect in children aged 2 to < 12 years, treated once-monthly (Q1M) with 3.5 mg/kg, compared to those aged ≥ 12 years treated Q1M with 170 mg. CONCLUSIONS: Simulations based on the final Pop-PK/PD model support the 3.5 mg/kg Q1M dosing regimen in children aged 2 to < 12 years with PH1 and relatively intact kidney function (eGFR ≥30 mL/min/1.73 m). TRIAL REGISTRATION: Trials are registered at ClinicalTrials.gov with study numbers NCT03392896 (PHYOX1), NCT03847909 (PHYOX2), NCT04042402 (PHYOX3), and NCT05001269 (PHYOX8) and at EudraCT with study numbers 2018-003098-91 (PHYOX2) and 2018-003099-10 (PHYOX3).
A Population Pharmacokinetic Model and Dosing Algorithm to Guide the Tacrolimus Starting and Follow-Up Dose in Living and Deceased Donor Kidney Transplant Recipients.
Francke MI, Sassen SDT, Lloberas N … +8 more , Colom H, Elens L, Moudio S, de Vries APJ, Moes DJAR, van Schaik RHN, Hesselink DA, de Winter BCM
Clin Pharmacokinet · 2025 Sep · PMID 40588615 · Full text
INTRODUCTION: Tacrolimus treatment is complicated by its narrow therapeutic range and large inter- and intra-patient variability. This study aimed to develop a population pharmacokinetic model and dosing algorithm to pre...
INTRODUCTION: Tacrolimus treatment is complicated by its narrow therapeutic range and large inter- and intra-patient variability. This study aimed to develop a population pharmacokinetic model and dosing algorithm to predict an individual's dose requirement following living and deceased donor kidney transplantation. METHODS: In this international, multicenter, retrospective study, data was collected from patients who had received a living or a deceased donor kidney and received tacrolimus twice daily. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). RESULTS: This study included 13,427 tacrolimus concentrations from 1180 kidney transplant recipients. A two-compartment model with first-order absorption best described the data. The mean absorption rate was 6.59/h, apparent clearance 20.7 L/h, central volume of distribution 705 L, and peripheral volume of distribution 7670 L. Higher age, creatinine, and hematocrit, as well as lower height, were associated with lower tacrolimus clearance. Tacrolimus clearance was higher for cytochrome P450 (CYP) 3A5*1 carriers compared with CYP3A5*3/*3 individuals, and lower for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients. Together, these covariates explained 19.3% of the inter-individual variability in clearance. From the full model, a starting dose algorithm was developed with age, height, and the CYP3A4 and CYP3A5 genotypes as covariates. Both the full model and the starting dose algorithm were successfully internally validated. CONCLUSIONS: In this international, multicenter study, age, CYP3A4 and CYP3A5 genotype, creatinine, height, and hematocrit were identified as significant covariates associated with tacrolimus pharmacokinetics, and can be used to predict the optimal individual's dose requirement for both living and deceased donor kidney transplant recipients.
Population Pharmacokinetics and Pharmacodynamics Modeling for the Use of Recaticimab in Healthy Volunteers and Patients with Hypercholesterolemia.
Shu C, Wang Y, Feng S … +2 more , Yang S, Shen K
Clin Pharmacokinet · 2025 Sep · PMID 40587053 · Publisher ↗
INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein secreted by the liver that binds to low-density lipoprotein (LDL) receptors, which leads to a decreased ability of the liver to clear LDL-C...
INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein secreted by the liver that binds to low-density lipoprotein (LDL) receptors, which leads to a decreased ability of the liver to clear LDL-C from circulation. By inhibiting PCSK9, it is possible to provide early intervention to achieve clinical benefits. METHODS: The database was built using data derived from seven clinical studies, population pharmacokinetic/pharmacodynamic (PopPK/PD) and PK/PD analyses were conducted via nonlinear mixed effects analysis with NONMEM software. The parameter estimation of the model was performed using the first-order conditional estimation with interaction (FOCE-I) method. The stepwise covariate method (SCM) was used to develop and evaluate the final model. RESULTS: A target-mediated drug disposition model (TMDD) model and an indirect response model were developed to illustrated the PopPK profile and PK/PD profile of recaticimab. The PopPK final model was described as a one-compartment TMDD model with a combined residual error model. The PopPK/PD final model was described as an indirect response model with an additive residual error model. Body weight, body mass index, age, statin therapy, and sex were introduced on the model as significant covariates. DISCUSSION: No adjustment of clinical dosage is required based on the PopPK and PopPK/PD covariates. Estimated glomerular filtration rate and anti-drug antibodies are not significant covariates for any PopPK parameter. After achieving a steady state, switching the dosing regimen and prolonging the dosing interval should not cause concerns about drug efficacy. TRIAL REGISTRATION: NCT03634436, NCT03944109, NCT05370950, NCT04455581, NCT04849000, NCT04885218, NCT04844125.
A Novel Approach to Evaluating the Design of Pediatric Pharmacokinetic Studies Focused on Accurate Dose Selection.
Zou Y, Nedelman J, Karlsson MO … +1 more , Svensson EM
Clin Pharmacokinet · 2025 Sep · PMID 40587052 · Full text
BACKGROUND AND OBJECTIVE: In pediatric trial design, it is particularly essential to maximize data utilization and ensure robust designs while minimizing sample collection. A common criterion to justify pediatric pharmac...
BACKGROUND AND OBJECTIVE: In pediatric trial design, it is particularly essential to maximize data utilization and ensure robust designs while minimizing sample collection. A common criterion to justify pediatric pharmacokinetic study designs is based on parameter precision (PP) evaluation, recommended by the US Food and Drug Administration. Here, we propose an alternative approach to design evaluation based on accuracy for dose selection (ADS). METHODS: This work was conducted using a simulation-and-reestimation framework, based on a real-case scenario of designing the single-dose pharmacokinetic study of the anti-tuberculosis (TB) drug pretomanid, with the aim of selecting doses for the next multidose long-term study. The study powers were computed using the ADS approach under scenarios with (1) real-case conditions, (2) high variabilities, (3) available options of tablet doses for selections. The study power using a PP approach was computed to compare with the ADS approach. RESULTS: The ADS approach suggested that the design selected accurate doses with study power >80% in almost all dosing weight groups, whereas the PP approach found the design underpowered for clearance. The ADS-based power was decreased to ~65% in the smallest weight groups given high variability. Varying the options of dose levels affected the ADS-based power non-monotonically, although fewer levels generally yielded higher power. CONCLUSION: The ADS approach practically evaluates the precision in dose selection, providing a directly relevant decision criterion for designing pediatric pharmacokinetic studies and could be an alternative for power evaluation when the study is focused on determining doses using discrete tablet sizes.
Effect of Efsubaglutide Alfa on the Pharmacokinetics of Metformin and Digoxin in Healthy Participants.
Wu X, He J, Wu J … +5 more , Liu W, Xu Y, Li Y, Zhang J, Wang Q
Clin Pharmacokinet · 2025 Sep · PMID 40587051 · Publisher ↗
BACKGROUND: Efsubaglutide alfa, as a novel glucagon-like peptide-1 receptor agonist, was developed for the treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medica...
BACKGROUND: Efsubaglutide alfa, as a novel glucagon-like peptide-1 receptor agonist, was developed for the treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (digoxin and metformin) was evaluated in healthy participants. METHODS: We conducted a single-center, open-label, fixed-sequence clinical trial involving 32 healthy participants who were assigned to either digoxin (N = 16) or metformin (N = 16) groups. The participants received oral doses of digoxin (0.25 mg, single dose) or metformin (1000 mg at first dose, 500 mg twice daily for 2 days) before and after subcutaneous injections of 3 mg efsubaglutide alfa at steady state. Pharmacokinetic parameters of digoxin and metformin before and after the administration of efsubaglutide alfa injections were measured, and safety assessments were conducted throughout the study. RESULTS: Efsubaglutide alfa slightly delayed the time to reach peak plasma concentration (T) of digoxin but had no substantial effect on its elimination. While the maximum concentration (C) of digoxin decreased by approximately 24% (from 1.75 ± 0.673 to 1.37 ± 0.545 ng/mL), and AUC increased by about 15% (from 20.2 ± 3.53 to 23.2 ± 4.04 ng/h/mL). In the metformin group, efsubaglutide alfa did not noticeably affect T, C, or the overall pharmacokinetics, as demonstrated by a consistent AUC (from 7557 ± 2155 to 8737 ± 2852 ng/h/mL). Adverse events with efsubaglutide alfa and co-administered medication were comparable to those reported during treatment with efsubaglutide alfa alone and were mostly gastrointestinal-related. CONCLUSIONS: No clinically significant pharmacokinetic change of digoxin and metformin was identified, and no new safety issues were observed with the co-administration of efsubaglutide alfa injection. These findings suggest that no dose adjustments are required for digoxin and metformin when co-administration with efsubaglutide alfa. GOV IDENTIFIER: NCT05694221.
Pharmacokinetics of Sufentanil After Epidural Administration During the Course of Extensive Abdominal Surgery.
Bienert A, Moor AB, Okuńska P … +9 more , Ber J, Siluk D, Waszczuk M, Kusza K, Bartkowiak T, Szrama J, Kluzik A, Koszel T, Wiczling P
Clin Pharmacokinet · 2025 Sep · PMID 40581890 · Full text
BACKGROUND AND OBJECTIVE: Epidural sufentanil is widely used for intraoperative analgesia and is recognized as a safe and effective route of administration when carefully monitored and administered at the lowest effectiv...
BACKGROUND AND OBJECTIVE: Epidural sufentanil is widely used for intraoperative analgesia and is recognized as a safe and effective route of administration when carefully monitored and administered at the lowest effective doses. Optimizing drug dosing requires a precise understanding of its pharmacokinetics. While it is known that sufentanil concentrations in the blood decline more slowly after epidural administration compared with intravenous administration, and the flip-flop phenomenon has been observed in this context, a pharmacokinetic model accounting for this phenomenon has not yet been described. METHODS: This study aimed to develop a pharmacokinetic model of sufentanil following epidural administration, with a focus on its absorption from the epidural space. The study was performed in 23 patients, aged 30-83 years with an American Society of Anesthesiologists (ASA) classification of 2-3, undergoing major abdominal (oncologic and non-oncologic) surgery under general anesthesia and epidural analgesia. Blood samples were collected, and sufentanil concentrations were measured at time points ensuring coverage of the absorption phase. Population analysis was performed using a full Bayesian approach implemented in Stan/Torsten programs with the "cmdstanr" and "bbr.bayes" packages in RStudio. RESULTS: The Bayesian approach helped incorporate prior information about sufentanil disposition. A two-compartment disposition model with two-compartmental absorption best described the data, featuring a fast absorption rate constant into plasma and the peripheral compartment, and a slow redistribution process from the epidural fat compartment. CONCLUSIONS: This study mechanistically describes the flip-flop pharmacokinetics of sufentanil and allows for more precise dosing of epidural sufentanil (NCT06069219).
Population Pharmacokinetics Model of Thioguanine in Patients with Inflammatory Bowel Disease.
Bayoumy AB, de Boer NKH, Keizer RJ … +1 more , Derijks LJJ
Clin Pharmacokinet · 2025 Aug · PMID 40581725 · Full text
BACKGROUND: Thioguanine (TG) has recently been rediscovered as an immunosuppressive agent in the treatment of inflammatory bowel disease (IBD). This prodrug is directly converted into its active metabolites, 6-thioguanin...
BACKGROUND: Thioguanine (TG) has recently been rediscovered as an immunosuppressive agent in the treatment of inflammatory bowel disease (IBD). This prodrug is directly converted into its active metabolites, 6-thioguanine nucleotides (6-TGNs), targeting the inhibition of RAC1 GTPase in inflammatory conditions, disrupting key cellular signaling pathways necessary for T-cell activation and survival, thereby contributing to its immunosuppressive action. In IBD, TG is used fixed dose and may benefit from model-informed precision dosing (MIPD) to optimize treatment efficacy and minimize toxicity. However, a population pharmacokinetic (PopPK) model to do so is lacking. OBJECTIVE: To develop a PopPK model for TG in IBD patients, enhancing the understanding of TG's pharmacokinetics and supporting the implementation of model-informed precision dosing (MIPD). METHODS: We employed a dataset comprising 131 6-TGN trough concentrations from 28 IBD patients treated with TG. The data were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate pharmacokinetic parameters and explore the influence of covariates such as weight and 5-ASA use on drug disposition. Model fit-for-purpose was evaluated through computation of the model's forecasting performance. RESULTS: The developed PopPK model was a one-compartment model with first-order absorption. A one-compartment TG model was stable, and able to estimate pharmacokinetic parameters with good precision (relative standard error [RSE] 15%) with weight and aminosalicylic acid (5-ASA) use significantly affected TG clearance. Forecasting performance was also adequate with a relative root mean squared error (rRMSE) of 24.1% and practically no systematic bias (mean percentage error [MPE] 0.2%). CONCLUSION: This study presents the first PopPK model of thioguanine for IBD, offering a novel tool for MIPD in clinical settings. Future studies should explore additional covariates such as TPMT genotype and drug interactions to further refine dosing recommendations for diverse patient populations.
SHR-1918, A Monoclonal Antibody Against Angiopoietin-Like 3, in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Study.
Qin R, Ye L, Duan L … +9 more , Li M, He W, Mei X, Li D, Jin R, Lv C, Zhu M, Wang S, Xie Z
Clin Pharmacokinet · 2025 Aug · PMID 40576753 · Publisher ↗
BACKGROUND AND OBJECTIVE: Angiopoietin-like 3 (ANGPTL3) increases serum low-density lipoprotein cholesterol and triglyceride by reducing their clearance. SHR-1918 is a monoclonal antibody against ANGPTL3. This study asse...
BACKGROUND AND OBJECTIVE: Angiopoietin-like 3 (ANGPTL3) increases serum low-density lipoprotein cholesterol and triglyceride by reducing their clearance. SHR-1918 is a monoclonal antibody against ANGPTL3. This study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of SHR-1918 in healthy subjects. METHODS: Six dose cohorts (100, 300, 450, 750, 900, and 1200 mg) were planned, each containing 12 healthy subjects randomized (9:3) to receive a single dose of subcutaneous SHR-1918 or placebo. Subjects were followed up to day 148 for the 100-mg cohort and day 190 for the other cohorts. RESULTS: A total of 72 subjects were enrolled (SHR-1918, n = 54; placebo, n = 18). SHR-1918 was well tolerated at 100-1200 mg. Treatment-emergent adverse events were comparable between the SHR-1918 (90.7%) and placebo (94.4%) groups. All treatment-emergent adverse events were mild or moderate in severity, with no serious adverse events or treatment-emergent adverse events leading to death. Maximum serum concentration was reached 7.98-10.0 days after injection, and mean half-life was 29.4-53.5 days across the dose range. Serum low-density lipoprotein cholesterol and triglyceride markedly and rapidly decreased upon SHR-1918 administration, whereas those in the placebo group were above baseline at most follow-up visits. The largest median percentage decline in serum low-density lipoprotein cholesterol and triglyceride ranged from - 28.7 to - 49.1% and from - 46.6 to - 82.8%, respectively. For dose levels 300 mg or higher, the low-density lipoprotein cholesterol reduction remained over 30% for 64 days and triglyceride reduction remained over 50% for 85 days. CONCLUSIONS: SHR-1918 was well tolerated and showed promising efficacy in lipid reduction among healthy subjects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT05432544 (24 June, 2022).
Model-Informed Precision Dosing of Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria.
Ter Avest M, Langemeijer SMC, van den Heuvel LPWJ … +3 more , Baas LM, van de Kar NCAJ, Ter Heine R
Clin Pharmacokinet · 2025 Aug · PMID 40560515 · Full text
BACKGROUND AND OBJECTIVE: Eculizumab is an expensive therapeutic monoclonal antibody inhibiting complement C5 and approved for various indications, including the rare disease paroxysmal nocturnal hemoglobinuria. Eculizum...
BACKGROUND AND OBJECTIVE: Eculizumab is an expensive therapeutic monoclonal antibody inhibiting complement C5 and approved for various indications, including the rare disease paroxysmal nocturnal hemoglobinuria. Eculizumab is administered in a "one-dose-fits-all" dosing paradigm in adults, which is inflexible and suboptimal in some patients. Therefore, the aim of this study was to develop alternative dosing regimens that may improve patient friendliness or improve cost effectiveness. METHODS: A prospective observational pharmacokinetic study was conducted in 27 patients with paroxysmal nocturnal hemoglobinuria. The dataset was enriched with pharmacokinetic and pharmacodynamic data of a previous study of patients with atypical hemolytic uremic syndrome. A population pharmacokinetic/pharmacodynamic model was developed and this model was used to explore alternative and individualized dosing regimens. RESULTS: A two-compartment model with parallel linear and non-linear elimination best described the data. No intra-individual variability in clearance could be observed for patients with paroxysmal nocturnal hemoglobinuria in contrast to patients with atypical hemolytic uremic syndrome. An inhibitory Emax model described the relationship between plasma concentrations and complement activity. We predicted that only 52.0% of patients with paroxysmal nocturnal hemoglobinuria have adequate complement inhibition on day 7 with the standard loading dose, compared with 99.9% of the patients with an alternative weight-based loading dose, without an increase in treatment costs. A 4-weekly dosing regimen was developed and therapeutic drug monitoring will enable interval prolongation to 4 weeks without relevant increases in cumulative drug use compared to the approved dose. CONCLUSIONS: The pharmacokinetics of eculizumab are similar in patients with atypical hemolytic uremic syndrome and patients with paroxysmal nocturnal hemoglobinuria, yet less variable in patients with paroxysmal nocturnal hemoglobinuria. Alternative dosing regimens can improve treatment in terms of efficacy and patient friendliness. CLINICAL TRIAL REGISTRATION: ClincialTrials.gov identifier: NCT04079257.
Population Pharmacokinetics and Exposure-Response Analysis of Benralizumab in Chinese Adults, Adolescents, and Pediatric Participants with Severe Eosinophilic Asthma.
Jin Y, Guiastrennec B, Stuke M … +7 more , Yao Y, Zhang Y, Barker P, Jison M, Penland RC, Ding J, Lukka PB
Clin Pharmacokinet · 2025 Aug · PMID 40551003 · Full text
INTRODUCTION: Benralizumab is approved as add-on subcutaneous therapy in patients aged ≥ 12 years with severe eosinophilic asthma in > 80 countries, including mainland China. OBJECTIVE: The study objective was to update...
INTRODUCTION: Benralizumab is approved as add-on subcutaneous therapy in patients aged ≥ 12 years with severe eosinophilic asthma in > 80 countries, including mainland China. OBJECTIVE: The study objective was to update benralizumab population pharmacokinetic (popPK) and exposure-response (ER) models in Chinese, Asian (including Chinese), and non-Asian participants. METHODS: Benralizumab popPK/ER models for asthma exacerbation rate and pre-bronchodilator forced expiratory volume in 1 second (FEV) were updated for three benralizumab trials involving Chinese, Asian (including Chinese), and non-Asian participants. The ER analysis examined correlations between pharmacokinetic quartiles and annual asthma exacerbation rate (AAER) ratios with simulations comparing predicted clinical outcomes. RESULTS: Updated data included 17,465 benralizumab concentrations (n = 2855). The updated model predicted a slight, and not clinically relevant, increase (< 14%) in benralizumab exposure for Chinese versus non-Asian adults. Median exposure increased in Chinese adolescents versus adults owing to body weight differences, but no dose adjustment was needed. Chinese children weighing < 35 kg receiving a 10 mg dose had similar exposure to those weighing ≥ 35 kg receiving a 30 mg dose. In Chinese versus non-Chinese participants, there was no trend concerning AAER ratios across different trough concentration quartiles; the maximal treatment effect significantly increased (+127%; p < 0.001), and there was no statistically significant effect on pre-bronchodilator FEV. Steady-state simulations showed lower predicted AAER ratios in Chinese (0.38; 95% confidence interval [CI] 0.32-0.45) than in non-Chinese adults (0.64; 95% CI 0.60-0.71), and no relevant differences between Chinese adults (0.46; 95% CI 0.38-0.54) and adolescents (0.46; 95% CI 0.37-0.55). CONCLUSION: The benralizumab popPK/ER models showed good predictive performance across Chinese demographics. TRIAL REGISTRATION NUMBER: NCT03186209. TRIAL REGISTRATION DATE: 6 July 2017.
Pharmacokinetics of Binimetinib in Participants with Hepatic Impairment.
Piscitelli J, Hahn E, Wollenberg L … +3 more , Chavira R, Del Frari L, Reddy MB
Clin Pharmacokinet · 2025 Aug · PMID 40549341 · Full text
BACKGROUND AND OBJECTIVE: Binimetinib is approved for multiple indications at a therapeutic dose of 45 mg twice a day (BID), in combination with encorafenib. A clinical hepatic impairment (HI) study was designed to evalu...
BACKGROUND AND OBJECTIVE: Binimetinib is approved for multiple indications at a therapeutic dose of 45 mg twice a day (BID), in combination with encorafenib. A clinical hepatic impairment (HI) study was designed to evaluate the pharmacokinetics (PK), safety, and tolerability of a single oral dose of binimetinib in participants with mild, moderate, and severe HI compared with demographically matched healthy participants with respect to age, gender, and body weight. METHODS: Participants were enrolled according to National Cancer Institute (NCI) classification criteria for hepatic function based on their total bilirubin and aspartate aminotransferase levels at screening. Participants enrolled into Group 1 (normal hepatic function) were matched to participants enrolled into Groups 2, 3, and 4 (mild, moderate, and severe HI, respectively) with respect to age, gender, and body weight. Dose-normalized PK parameters were evaluated because of a difference in doses for the severe HI group compared to the other groups, with the dose reduction due to the increased exposures observed in the moderate HI group. RESULTS: Among 27 PK evaluable participants, changes in binimetinib dose-normalized PK parameters C/D and AUC/D were minimal in participants with mild HI compared to the normal hepatic function group. Both the moderate and severe HI groups had significant changes as AUC/D increased by 81% and 111%, respectively, compared to the normal hepatic function group. Unbound AUC/D for the moderate and severe HI groups increased by 280% and 248% compared to the normal hepatic function group, respectively. CONCLUSION: Based on these findings on total and unbound exposures, dose reductions are recommended for binimetinib in cancer patients with moderate and severe HI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02050815, registered 29 January 2014.
Determining the Optimal Dosing of Methyldopa in Pregnancy-Induced Hypertension Using PBPK-PD Modeling.
Liu X, Wang W, Zhu J … +4 more , Chen J, Wang X, Chen D, Ouyang D
Clin Pharmacokinet · 2025 Aug · PMID 40516012 · Publisher ↗
BACKGROUND: Pregnancy-induced hypertension is a significant risk factor for adverse maternal and fetal outcomes, with methyldopa being a commonly prescribed antihypertensive for its safety profile. However, the physiolog...
BACKGROUND: Pregnancy-induced hypertension is a significant risk factor for adverse maternal and fetal outcomes, with methyldopa being a commonly prescribed antihypertensive for its safety profile. However, the physiological changes during pregnancy may alter the pharmacokinetics (PK) and pharmacodynamics (PD) of methyldopa, complicating the establishment of optimal dosing regimens. OBJECTIVE: This study aims to develop and validate a pregnancy-specific physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model for methyldopa to optimize dosing strategies and support individualized treatment plans for managing pregnancy-induced hypertension effectively. METHODS: The PBPK-PD model for methyldopa was developed using PK-Sim, MoBi, and MATLAB software, incorporating pregnancy-specific physiological parameters from the literature. The development process involved: (a) constructing and validating a PBPK model for non-pregnant individuals based on intravenous and oral administration, including renal clearance, serum clearance, and enzyme clearance; (b) extending the model to a pregnant PBPK model and validating it for oral administration; (c) constructing a PK/PD model using the maximum effect model; and (d) integrating the PBPK and PK/PD models to form a unified PBPK-PD model. This model was then used to simulate mean arterial pressure (MAP) responses across different stages of pregnancy. Finally, the optimal dosing regimen was calculated. RESULTS: The model verification results show a good fit, indicating that the parameters are appropriate. The pregnancy model indicated no significant change in phenol sulfotransferase (PST) activity during pregnancy. The physiologically based pharmacokinetic-pharmacodynamic simulations across different stages of pregnancy show fluctuations in both PK and PD; however, these variations are not particularly significant. Ultimately, the results indicate that 500 mg is the optimal dosing regimen for patients with MAP ≤ 130 mmHg. For MAP > 130 mmHg, additional antihypertensive medications are recommended. Due to its delayed onset, methyldopa should be combined with other antihypertensives during the first 48 hours. CONCLUSION: The PBPK-PD model developed in this study provides a valuable tool for optimizing methyldopa therapy, supporting personalized treatment strategies, and improving blood pressure management and maternal and fetal health outcomes in pregnancy-induced hypertension.
Effect of Amiodarone on Apixaban Exposure in Patients after Cardiac Surgery-A Population Pharmacokinetic Study.
Morath B, Foerster KI, Chiriac U … +8 more , Zaradzki M, Hoppe-Tichy T, Schrey D, Burhenne J, Czock D, Karck M, Haefeli WE, Wicha SG
Clin Pharmacokinet · 2025 Aug · PMID 40474043 · Full text
AIM: To investigate the effect of amiodarone on apixaban pharmacokinetics in cardiac surgery patients with postoperative atrial fibrillation. METHODS: Apixaban concentrations of postoperative cardiac surgery patients wit...
AIM: To investigate the effect of amiodarone on apixaban pharmacokinetics in cardiac surgery patients with postoperative atrial fibrillation. METHODS: Apixaban concentrations of postoperative cardiac surgery patients with or without amiodarone therapy were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in clinical routine. A population pharmacokinetic model was built using nonlinear mixed effects modeling in NONMEM 7.5 using first-order conditional estimation with interaction. The impact of amiodarone and creatinine clearance (CrCL) on apixaban exposure under various dosing regimens was analyzed using Simulx (Lixoft). RESULTS: A total of 33 patients with 76 apixaban concentrations were included. A one-compartment model best described the pharmacokinetics of apixaban with a clearance (CL/F) of 3.05 L/h, apparent volume of distribution (V/F) of 23.7 L, and an absorption rate constant (k) of 0.652/h. Interindividual variability (IIV) was observed in CL/F but not in V/F and k. The covariates amiodarone and CrCL were independently associated with apixaban CL/F. Under concomitant amiodarone therapy, simulations predicted an increase of 44-49% in apixaban area under the concentration-time curve (AUC), and AUC nearly doubled at CrCL 35 mL/min. A dose of 2.5 mg apixaban twice daily (b.i.d.) was identified as a potential dosing option in the CrCL range of 15-50 mL/min under amiodarone comedication. CONCLUSIONS: Concomitant amiodarone therapy reduced apixaban CL/F and increased the risk of high exposure in patients with impaired renal function. A dose of 2.5 mg apixaban b.i.d. for a CrCL range of 30-50 mL/min under concomitant amiodarone therapy was identified as a new dosing option.
Effect of Obesity on Pharmacokinetics of Lidocaine and its Active Metabolites in Chinese Patients Undergoing Laparoscopic Bariatric Surgery: A Prospective Clinical Study.
Zhang M, Jin Y, Yuan X … +4 more , He C, Han M, Tu F, Wang Z
Clin Pharmacokinet · 2025 Aug · PMID 40464869 · Publisher ↗
BACKGROUND AND OBJECTIVE: Obesity can alter the physiological profile of individuals, potentially impacting the pharmacokinetics of anesthetic agents. This study compared the pharmacokinetic profiles of lidocaine and its...
BACKGROUND AND OBJECTIVE: Obesity can alter the physiological profile of individuals, potentially impacting the pharmacokinetics of anesthetic agents. This study compared the pharmacokinetic profiles of lidocaine and its metabolites between obese patients and normal-weight patients following a single intravenous bolus during surgical operation, to inform dosing strategies for the obese Chinese population. METHODS: Twenty-nine obese patients scheduled for laparoscopic sleeve gastrectomy and 29 normal-weight patients for laparoscopic cholecystectomy were enrolled. Lidocaine (2%, 1.5 mg/kg) was administered intravenously to obese patients and normal-weight patients on the basis of adjusted body weight (ABW) and total body weight, respectively. Plasma samples were collected to analyze the pharmacokinetic profiles of lidocaine and its metabolites. Adverse events (AEs) were recorded throughout the study. RESULTS: Obese patients had a significantly longer half-life for lidocaine (2.27 ± 0.69 h vs 0.94 ± 0.16 h, p < 0.0001), a higher volume of distribution (105 ± 27.3 L vs 54.9 ± 14.0 L, p < 0.0001), and a lower clearance (33.6 ± 9.08 L/h vs 40.5 ± 8.67 L/h, p = 0.008) compared to normal-weight patients. Although exposure to lidocaine was similar between groups within 2 hours, obese patients had lower metabolite concentrations due to decreased metabolic capacity. The plasma concentrations in all patients remained below the toxic concentration of 5 μg/mL, and no serious lidocaine-related AEs were reported. CONCLUSIONS: Obesity significantly affects the pharmacokinetics of lidocaine and its active metabolites, and administering lidocaine intravenously via ABW is safe and reasonable for obese patients. CLINICAL TRIAL REGISTRATION: ChiCTR2200064980, 25 October 2022.
Population Cellular Kinetics of Idecabtagene Vicleucel in Patients with Triple-Class-Exposed Relapsed/Refractory Multiple Myeloma.
Wu F, Zhou J, Zheng X … +6 more , Masilamani M, Cheng Y, Caia A, Cook M, Piasecki J, Lamba M
Clin Pharmacokinet · 2025 Jul · PMID 40461939 · Full text
BACKGROUND: Idecabtagene vicleucel (ide-cel, ABECMA) is an autologous, B-cell maturation antigen (BCMA)-directed, chimeric antigen receptor (CAR) T-cell therapy. The current modeling analyses aim to characterize the cell...
BACKGROUND: Idecabtagene vicleucel (ide-cel, ABECMA) is an autologous, B-cell maturation antigen (BCMA)-directed, chimeric antigen receptor (CAR) T-cell therapy. The current modeling analyses aim to characterize the cellular kinetics (CK) of ide-cel and to assess the covariate effects impacting ide-cel cellular kinetics in patients with relapsed/refractory multiple myeloma. METHODS: A modified piecewise model was developed to characterize ide-cel CK through the nonlinear mixed effects method. The model parameterization was conducted using the ide-cel whole-blood transgene data in CK-evaluable subjects (N = 225) from the ide-cel arm of the study KarMMa-3 (NCT03651128). The structural model consists of an initial lag phase and then saturable cell expansion, followed by conversion from effector cells to memory cells and their elimination. Model simulations were performed to evaluate covariate effects on ide-cel exposure parameters. RESULTS: The piecewise CK model with saturable expansion sufficiently captured the clinically observed ide-cel transgene data. The simulations using the final population CK model suggested that the magnitude of covariate effects on ide-cel exposure parameters was considerably smaller than the intersubject variability in the population. Additional analyses revealed a negative effect of treatment-emergent immunogenicity on the ide-cel persistence. Apparent associations were identified between cellular kinetic parameters and clinical responses. CONCLUSIONS: The cellular kinetics of ide-cel can be adequately described by the modified piecewise model. No clinically meaningful covariate effects on cellular kinetics were identified from this modeling study. The population CK model suggests that higher cell expansion rate and lower elimination rates of effector and memory cells were observed in patients with longer progression-free survival.
Population Pharmacokinetic Analysis of Enalapril and Enalaprilat in Newly Treated Children with Heart Failure: Implications for Safe Dosing of Enalapril (LENA Studies).
Steichert M, Cawello W, Laeer S … +1 more , LENA Consortium
Clin Pharmacokinet · 2025 Jul · PMID 40461938 · Full text
BACKGROUND: Enalapril orodispersible minitablets (ODMT) have been authorised by the European Medicines Agency for the treatment of heart failure in children from birth to 17 years of age in 2023. Consequently, the use of...
BACKGROUND: Enalapril orodispersible minitablets (ODMT) have been authorised by the European Medicines Agency for the treatment of heart failure in children from birth to 17 years of age in 2023. Consequently, the use of enalapril in very young and angiotensin-converting enzyme inhibitor (ACEi) naïve patients is expected to increase. OBJECTIVES: Simultaneous characterisation of the pharmacokinetics (PK) of enalapril and the active metabolite enalaprilat in ACEi naïve children with heart failure using a combined population pharmacokinetic (PopPK) model and identification of clinically relevant covariates for the dosing of enalapril in this population. METHODS: Data of ACEi naïve subjects from the European project 'Labeling of Enalapril from Neonates up to Adolescents' (LENA) were analysed using nonlinear mixed effects modelling. In the prospective, open-label, multicentre phase II/III PK bridging studies, children with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) received enalapril ODMT according to an age- and weight-dependent dosing regimen. Allometric scaling was implemented for the disposition parameters of enalapril and enalaprilat. Stepwise covariate modelling was used to test the covariates age, sex, serum creatinine and Ross score. The final model was validated using nonparametric bootstrap analysis. Simulations were performed to assess the impact of the covariates after the first dose and at steady state. RESULTS: The analysed dataset comprised 173 enalapril and 268 enalaprilat serum concentrations from 34 subjects aged 25 days to 2.1 years (median age = 0.3 years). A combined model consisting of a one-compartment model for enalapril coupled with a one-compartment model for enalaprilat with absorption lag was selected as the structural model. Covariate analysis revealed that the weight-adjusted apparent clearance of enalaprilat increases with increasing age and decreases with increasing serum creatinine. In addition, the weight-adjusted apparent volume of distribution of enalaprilat decreases with increasing Ross score. The simulations indicated that serum creatinine levels above the normal reference range, age and weight were clinically relevant covariates for both the first dose and the steady state dose of enalapril. Furthermore, the simulations indicated that the Ross score is a clinically relevant covariate for the first dose of enalapril. CONCLUSIONS: The results of the PopPK analysis and simulations indicated that, in addition to the currently considered parameters of weight and renal function, the parameters of age and severity of heart failure should also be considered when dosing enalapril in children with heart failure. TRIAL REGISTRATION: Trial registration number (date of registration): EudraCT 2015-002335-17 (30 November 2015), EudraCT 2015-002396-18 (30 November 2015). The trials were registered on the EU Clinical Trials Register ( https://www.clinicaltrialsregister.eu ).
A Population Pharmacokinetic Analysis for Piperacillin/Tazobactam in Patients with End-Stage Kidney Disease Undergoing Intermittent Haemodialysis: Extension of a General-Purpose Model.
Kong D, Koomen JV, Vanommeslaeghe F … +4 more , Delanghe S, Van Biesen W, Colin PJ, Eloot S
Clin Pharmacokinet · 2025 Aug · PMID 40459722 · Full text
BACKGROUND AND OBJECTIVE: End-stage kidney disease (ESKD) patients undergoing haemodialysis (HD) require a dosing regimen that balances the low endogenous clearance with the additional dialyser clearance. This study aime...
BACKGROUND AND OBJECTIVE: End-stage kidney disease (ESKD) patients undergoing haemodialysis (HD) require a dosing regimen that balances the low endogenous clearance with the additional dialyser clearance. This study aimed to expand a previously proposed general-purpose pharmacokinetic model for piperacillin/tazobactam with a new population of ESKD patients undergoing intermittent high-flux haemodialysis. METHODS: Inter- and intradialytic blood samples were collected in ESKD patients undergoing intermittent high-flux haemodialysis, in HD or haemodiafiltration (HDF) mode, who received piperacillin/tazobactam during routine care. The previous general-purpose model was expanded to reflect changes in the pharmacokinetics in the new patient population. A covariate search was performed focussing on factors that explained variability between patients in endogenous and dialysis clearance. Simulations were performed to determine the probability of target attainment with current dosing recommendations in this specific population. RESULTS: In 20 ESKD patients, 195 piperacillin/tazobactam concentrations were determined. The general-purpose model was successfully expanded, wherein endogenous piperacillin/tazobactam clearance in patients with/without residual diuresis was 63% (95% confidence interval [CI] 49.5-73.0%) and 78.6% (95% CI 66.3-86.4%) lower compared with the general population, respectively. Extraction ratios of piperacillin and tazobactam ranged from 64 to 80%. Differences in probability of target attainment (PTA) for piperacillin were observed between patients with normal kidney function and ESKD patients undergoing haemodialysis with current dosing recommendations. CONCLUSION: We successfully expanded a general-purpose model to reflect the piperacillin/tazobactam pharmacokinetics in ESKD patients undergoing intermittent haemodialysis using high-flux dialysers. The current dosing recommendations provide inconsistent probability of target attainment in ESKD patients compared with the general population.
Utilizing Opportunistic Computed Tomography Imaging to Refine Lean Body Weight Estimates in Patients with Obesity.
Alikhani R, Horbal S, Rothberg AE … +1 more , Pai MP
Clin Pharmacokinet · 2025 Jul · PMID 40450646 · Full text
INTRODUCTION: While dual-energy X-ray absorptiometry (DEXA) is the gold standard for measuring lean body weight (LBW), computed tomography (CT) provides muscle composition and distribution metrics that can refine LBW for...
INTRODUCTION: While dual-energy X-ray absorptiometry (DEXA) is the gold standard for measuring lean body weight (LBW), computed tomography (CT) provides muscle composition and distribution metrics that can refine LBW for better weight-based dosing. We explored how existing computed tomography (CT) images could be utilized to better estimate LBW. METHODS: Sixty-three adult patients (71.4% female) with a median age of 53.4 years and mean BMI of 36.84 having both DEXA and CT scans were retrospectively analyzed to assess the relationship between CT-based skeletal muscle variables and DEXA-derived LBW. RESULTS: Linear regression results revealed significant correlations. CT-derived skeletal muscle area (SMA) strongly predicted DEXA-derived LBW (p value < 0.05 and R between 0.67 and 0.80) at four different vertebra levels. DEXA-derived LBW showed a strong correlation with a height, weight, and sex-based estimate of LBW using an equation developed in 2005 (LBW). A final model incorporating SMA with the LBW equation improved the coefficient of determination at all four vertebra levels (R 0.82-0.86). DISCUSSIONS/CONCLUSION: This study demonstrates opportunistic CT scan data may improve an existing equation for LBW that has been predictive of select drug pharmacokinetic parameters. Improving LBW estimation may enable improved personalized drug dosing strategies in patients with obesity and other populations that benefit from using LBW over total body weight.
Population Pharmacokinetics for Belantamab Mafodotin Monotherapy and Combination Therapies in Patients with Relapsed/Refractory Multiple Myeloma.
Papathanasiou T, Kaullen J, Polireddy K … +6 more , Chen X, Ho YL, Taylor A, Struemper H, Carreño F, Ferron-Brady G
Clin Pharmacokinet · 2025 Jun · PMID 40447948 · Full text
BACKGROUND AND OBJECTIVE: Belantamab mafodotin is an antibody-drug conjugate (ADC) comprising a monoclonal antibody targeting B-cell maturation antigen (BCMA) conjugated to the microtubule inhibitor monomethyl auristatin...
BACKGROUND AND OBJECTIVE: Belantamab mafodotin is an antibody-drug conjugate (ADC) comprising a monoclonal antibody targeting B-cell maturation antigen (BCMA) conjugated to the microtubule inhibitor monomethyl auristatin F via a protease-resistant maleimidocaproyl linker (cysteine maleimidocaproyl monomethyl auristatin F [cys-mcMMAF]). Belantamab mafodotin monotherapy population pharmacokinetics (PopPK) were previously described in relapsed/refractory multiple myeloma (RRMM). This analysis aimed to further characterize the PopPK of belantamab mafodotin ADC and cys-mcMMAF when administered intravenously in patients with RRMM using data from monotherapy and combination therapy studies. METHODS: Data from belantamab mafodotin monotherapy trials (DREAMM-2 [NCT03525678], DREAMM-3 [NCT04162210], DREAMM-12 [NCT04398745], DREAMM-14 [NCT05064358]) and combination trials with lenalidomide/dexamethasone (DREAMM-6 [NCT03544281]) or bortezomib/dexamethasone (DREAMM-6, DREAMM-7 [NCT04246047]) were used to develop PopPK models using non-linear mixed-effect modeling. The models described ADC pharmacokinetics using a linear, two-compartment model with decreasing clearance (CL) over time described by a sigmoidal time function, and cys-mcMMAF pharmacokinetics using a linear two-compartment model with cys-mcMMAF input rate governed by proteolytic ADC degradation that was modulated by a drug-to-antibody ratio that declined exponentially after each dose. Models were externally validated using DREAMM-8 (NCT04484623) study data (belantamab mafodotin plus pomalidomide/dexamethasone). RESULTS: The analyses included 977 patients, with 8880 measurable ADC and 6354 measurable cys-mcMMAF concentrations. Final ADC model covariates included soluble BCMA (sBCMA), albumin, serum immunoglobulin G, body weight, and body mass index (BMI) all at baseline as well as race and combination therapy. The final cys-mcMMAF model included covariates of baseline sBCMA, serum immunoglobulin G, albumin, body weight, BMI, and race. Typical ADC parameter estimates were 0.926 L/day for initial CL, 10.8 L for steady-state volume of distribution, and 13.0 days for initial elimination half-life. Following monotherapy, CL was reduced by 33.2% to 0.619 L/day over time, resulting in an elimination half-life of 16.8 days. Following combination treatment, CL was reduced by 44.0% to 0.518 L/day, resulting in an elimination half-life of 19.1 days. Cys-mcMMAF had typical values of 642 L/day for CL and 12.3 L for the central volume of distribution. The models adequately described ADC/cys-mcMMAF pharmacokinetics as confirmed during external validation. Alternate models with β2 microglobulin in place of baseline sBCMA also described the pharmacokinetics well. Simulated cycle 1 ADC exposures were most affected by disease-related characteristics: greater disease burden resulted in lower exposure. Predicted cycle 1 ADC and cys-mcMMAF exposures were not meaningfully different between combinations and monotherapy. Mild-to-severe renal impairment, mild-to-moderate hepatic impairment according to National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification, age, ethnicity, region, prior treatments, and prior anti-CD38 therapy did not affect ADC or cys-mcMMAF pharmacokinetics or exposures. CONCLUSIONS: The updated PopPK models adequately described ADC and cys-mcMMAF pharmacokinetics. Mild-to-severe renal impairment, mild-to-moderate hepatic impairment (NCI-ODWG), age, ethnicity, region, prior treatments, and prior anti-CD38 therapy did not significantly impact ADC or cys-mcMMAF pharmacokinetics, and combinations showed no meaningful difference in cycle 1 exposure compared with monotherapy.
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