Clinical Pharmacokinetics[JOURNAL]
Sun
200 papers
Development and Clinical Application of a Real-World Population Pharmacokinetic Model of Rivaroxaban in Asian Patients with Atrial Fibrillation.
Lai NS, Lin CJ, Kuo CH … +5 more , Peng YF, Tang SC, Huang CF, Lin SY, Lin SW
Clin Pharmacokinet · 2026 Jun · PMID 42143668 · Full text
BACKGROUND: Rivaroxaban, a factor Xa inhibitor, is used to prevent stroke in patients of atrial fibrillation (AF). This study aimed to establish a population pharmacokinetic (PPK) model for rivaroxaban using real-world d...
BACKGROUND: Rivaroxaban, a factor Xa inhibitor, is used to prevent stroke in patients of atrial fibrillation (AF). This study aimed to establish a population pharmacokinetic (PPK) model for rivaroxaban using real-world data, apply it to concentration prediction, and investigate the association between drug exposure and clinical outcomes. METHODS: Patients with AF receiving rivaroxaban were enrolled from an observational cohort (2016-2023) to measure plasma concentrations. An independent cohort was randomly selected to validate the PPK model. Clinical outcomes of interest included stroke or systemic thromboembolism, and major bleeding. RESULTS: A total of 226 patients contributed to 452 rivaroxaban concentration measurements. Rivaroxaban pharmacokinetics were adequately described using a one-compartment model with first-order elimination. The estimated apparent clearance (CL/F) and the volume of distribution (V/F) were 6.13 L/h and 45.57 L, respectively. CL/F was significantly influenced by creatinine clearance and concomitant use of cytochrome 3A4 or P-glycoprotein inhibitors, whereas V/F was associated with lean body weight. External validation demonstrated a good predictive performance at the individual level. Patients with low trough concentrations tended to have an increased risk of systemic thromboembolism, whereas those with high trough concentrations tended to have a higher risk of major bleeding. CONCLUSIONS: In an Asian population, rivaroxaban pharmacokinetics are influenced by renal function, lean body weight, and drug interactions. The developed PPK model facilitates the estimation of rivaroxaban concentrations at standardized timepoints from random samples. This provides a practical tool for standardized exposure assessment and the identification of patients at risk for adverse clinical outcomes. REGISTRATION: ClinicalTrials.gov identifier no. NCT05333666.
Population Pharmacokinetic/Pharmacodynamic Modeling of Therapeutic Enzymes in Lysosomal Storage Diseases.
Barzel I, van der Ploeg AT, Pijnappel WWMP … +3 more , van der Kuy PHM, van den Hout JMP, Preijers T
Clin Pharmacokinet · 2026 May · PMID 42101576 · Full text
BACKGROUND: Lysosomal storage diseases (LSDs) are rare genetic disorders treated with enzyme replacement therapy (ERT). However, treatment outcomes are highly variable, reflecting the complexities of therapeutic enzyme p...
BACKGROUND: Lysosomal storage diseases (LSDs) are rare genetic disorders treated with enzyme replacement therapy (ERT). However, treatment outcomes are highly variable, reflecting the complexities of therapeutic enzyme pharmacology, patient heterogeneity and therapy response. Population pharmacokinetic/pharmacodynamic (popPK/PD) modeling can help characterize this variability, identify covariates, and optimize dosing strategies. OBJECTIVES: This review aimed to provide a comprehensive overview of published popPK and popPD models of therapeutic enzymes in LSDs, summarize modeling strategies and study characteristics, and evaluate the quality of the available models. METHODS: A systematic search of Medline, Embase, and Web of Science (inception-March 2025) identified studies reporting popPK and/or popPD models of therapeutic enzymes in patients with LSDs. Data on study characteristics, structural and statistical model choices, covariate analyses, and evaluation methods were extracted and compared. RESULTS: This review included studies describing 6 popPK models and 3 popPD models of therapeutic enzymes in LSD. All models were developed using the nonlinear mixed-effects (NLME) modeling approach. The PK characteristics were adequately described using a two-compartment model in three studies, a three-compartment model in two studies, and a one-compartment model in one study. Three studies additionally assessed PK parameters in monocytes, leukocytes, and cerebrospinal fluid (CSF). Among all tested covariates, total body weight (TBW) was identified as a significant predictor for clearance (CL) and volume of distribution in the central compartment (V) in three studies. In one study evaluating PK parameters in CFS, age-based scaling was applied instead of weight-based allometric scaling to improve model fit. PopPD models were limited, with exposure-response relationships described either by an inhibitory maximal effect (I) model or by a longitudinal logistic regression model with a first-order Markov element. CONCLUSIONS: PopPK modeling of therapeutic enzymes in LSDs is relatively well established. However, progress in popPD modeling remains limited. Existing models support the use of indirect response and maximum effect (E) models to describe the delayed and saturable effects of ERT, and innovative approaches such as intracellular PK assessment and Markov modeling illustrate the potential of advanced pharmacometric methods. Nevertheless, there remains a need to further clarify the role of drug concentration measurements in target cells, to characterize CNS distribution in LSDs affecting the brain following intrathecal administration of ERTs and intravenous administration of a novel fusion protein, and to identify robust PD biomarkers in defining exposure-response relationships of therapeutic enzymes in LSDs.
Precision Dosing of Vancomycin: A Systematic Review of Population Pharmacokinetics Models and Comparative Evaluation of Software Tools.
Dia N, Hoffert Y, Edwina AE … +3 more , Tournoy J, Spriet I, Dreesen E
Clin Pharmacokinet · 2026 Jun · PMID 42082885 · Publisher ↗
BACKGROUND AND OBJECTIVES: Vancomycin is a widely used antibiotic with a narrow therapeutic window and considerable pharmacokinetic variability, necessitating accurate and precise dosing. Population pharmacokinetics (pop...
BACKGROUND AND OBJECTIVES: Vancomycin is a widely used antibiotic with a narrow therapeutic window and considerable pharmacokinetic variability, necessitating accurate and precise dosing. Population pharmacokinetics (popPK) models have become essential for facilitating model-informed precision dosing (MIPD) of vancomycin. We aimed to summarise and compare popPK models of vancomycin and evaluate MIPD software modules incorporating these models. METHODS: We systematically searched PubMed, EMBASE, and reference lists of relevant articles from inception through 01 January 2026 to identify articles describing the development of compartmental, one-stage parametric popPK models based on data from adult patients (aged ≥ 18 years) receiving intravenous vancomycin. We extracted and summarised key information on study design, patients, vancomycin dosing regimens, sampling strategies, quantification methods, modelling techniques, and covariates. We contacted providers of MIPD software tools and invited them to complete an online questionnaire assessing the features and clinical integration of their vancomycin module. We evaluated the incorporated models and their clinical applicability. RESULTS: We identified 99 adult-applicable vancomycin popPK models across 97 articles: 48 (48.5%) were one-compartment, 47 (47.5%) two-compartment models, and 4 (4.0%) three-compartment models. Kidney function estimators and body weight metrics were the most commonly retained covariates on clearance and volume of distribution, respectively. Of 18 identified MIPD software tool providers, 13 (72.2%) completed the questionnaire, confirming the inclusion of vancomycin modules. These tools incorporated a total of 101 vancomycin models, of which 48 were intended for adults. Three tools had been evaluated in prospective non-interventional studies, and two in a prospective interventional trial. Five tools were certified as conforming to European Union (EU) regulatory standards under the Medical Devices Directive and were in the process of obtaining EU conformity under the Medical Device Regulation. Mapping published models to tool implementations revealed partial overlap, limited transparency on model selection and lack of model‑level external validation, underscoring the need for structured evaluation before routine clinical adoption. CONCLUSION: This review presents a comprehensive overview of vancomycin popPK models and MIPD software modules for adult patients. Our findings highlight the diversity among popPK models and the need for standardised reporting, transparent model selection, and prospective evaluation to support clinical implementation of MIPD.
Effect of Enzalutamide on Morphine Exposure in Patients with Prostate Cancer.
Op 't Hoog CJP, Mehra N, van der Weij B … +6 more , Olofsen E, Somford DM, van Oort IM, Hamberg P, van Erp NP, Boerrigter E
Clin Pharmacokinet · 2026 May · PMID 42081083 · Full text
BACKGROUND AND OBJECTIVE: Pain management in patients with prostate cancer receiving enzalutamide is challenging owing to its high potential for drug-drug interactions. Morphine is generally preferred because of its favo...
BACKGROUND AND OBJECTIVE: Pain management in patients with prostate cancer receiving enzalutamide is challenging owing to its high potential for drug-drug interactions. Morphine is generally preferred because of its favorable metabolic profile, but the effect of enzalutamide on the pharmacokinetics of morphine is unclear. The objective of this study was to assess whether a drug-drug interaction exists between enzalutamide and morphine in patients with prostate cancer. METHODS: In a multicenter two-arm parallel study, 24 men with prostate cancer received morphine with enzalutamide (n = 12) and without enzalutamide (n = 12). Plasma concentrations of morphine and its active metabolite morphine-6-glucuronide were measured. Pharmacokinetic parameters were calculated using a non-compartmental analysis. Geometric mean ratios (GMR) of the area under the plasma concentration-time curves were calculated. No clinically relevant interaction was defined if 90% of the confidence interval (CI) of the GMR of morphine was within the range of 0.5-2.0. RESULTS: Morphine exposure was similar between both groups, with the 90% CI falling within the range of 0.5-2.0 (GMR 1.01; 90% CI 0.77-1.31). The exposure of morphine-6-glucuronide was increased with enzalutamide (GMR 1.77; 90% CI 1.43-2.17). CONCLUSIONS: The exposure of morphine was unaffected by enzalutamide, while morphine-6-glucuronide exposure was increased. Because of the inconclusive potency of morphine-6-glucuronide and its uncertain ability to cross the blood-brain barrier, the increase is likely of modest clinical significance. Therefore, morphine and enzalutamide can be safely combined when starting at a low dose and titrated based on efficacy and tolerability. CLINICAL TRIAL REGISTRATION: NCT05339672.
Evaluating Bayesian Vancomycin Dosage Adjustment in Neonates: A Simulation-Based Virtual TDM Study.
Ravix A, Thoma Y, Cathignol A … +7 more , Thoueille P, Marzolini C, Giannoni E, Buclin T, Csajka C, Dao K, Guidi M
Clin Pharmacokinet · 2026 Jun · PMID 42068514 · Publisher ↗
BACKGROUND AND OBJECTIVES: Therapeutic drug monitoring (TDM) of vancomycin, ideally based on the ratio of the daily area under the curve to the minimal inhibitory concentration at steady state (AUC/MIC), is hindered by s...
BACKGROUND AND OBJECTIVES: Therapeutic drug monitoring (TDM) of vancomycin, ideally based on the ratio of the daily area under the curve to the minimal inhibitory concentration at steady state (AUC/MIC), is hindered by sampling limitations in neonates, so trough concentration (C) is often used as a surrogate. This virtual TDM study aimed to evaluate the performance of Bayesian model-informed precision dosing (MIPD) for vancomycin in neonates. METHODS: Reference pharmacokinetic (PK) parameters and drug concentrations were simulated in NONMEM for 1000 virtual neonates using a published population PK model. Four TDM strategies were compared based on the percentage of patients achieving an AUC/MIC between 360 and 540 h. Strategy 1 maintained the initial regimen unchanged; strategy 2 adjusted doses using a standard rule of three to target a C of 10-15 mg/L; strategies 3 and 4 used the MIPD software Tucuxi with a steady-state C and two concentrations after the first dose, respectively, for Bayesian dosage optimization. Individual dosages were adjusted following each strategy, recalculating AUC to determine the percentage of target attainment. Iterative adjustments were performed by resampling C. A sub-study evaluated optimal sampling time by comparing Tucuxi-estimated AUC with the reference value. RESULTS: Less than 49% of patients reached the target with strategy 1, leading to frequent vancomycin overexposure. Strategy 2 enabled over 75% of patients to achieve AUC/MIC between 360 and 540 h with every-8-h regimens, but only 31% with longer dosing intervals. Strategies 3 and 4 allowed over 74% of patients to reach the target after one TDM cycle and 100% after four cycles, regardless of the initial dosing regimen. A single sample sufficed for accurate AUC prediction. CONCLUSION: This virtual TDM study indicates that Bayesian MIPD optimizes vancomycin exposure in neonates, while simplifying the sampling strategy. This approach deserves to be integrated and validated in routine neonatal care.
Impacts of Uremic Toxins on the Population Pharmacokinetics of Total Mycophenolic Acid and its Glucuronide Metabolite in Adult Kidney Transplant Recipients.
Al-Dajani AR, Rong Y, Adhiya J … +5 more , Dhungana P, Mayo P, Colbourne P, Gourishankar S, Kiang TKL
Clin Pharmacokinet · 2026 Jun · PMID 42065853 · Publisher ↗
BACKGROUND AND OBJECTIVE: Mycophenolic acid (MPA) exhibits considerable inter-individual variability in drug exposure, which can result in acute graft rejection as well as hematological or infectious adverse effects. Evi...
BACKGROUND AND OBJECTIVE: Mycophenolic acid (MPA) exhibits considerable inter-individual variability in drug exposure, which can result in acute graft rejection as well as hematological or infectious adverse effects. Evidence from our group and others indicates that certain uremic toxins may contribute to this variability through pharmacokinetic (PK) interactions. This study aimed to develop a novel population PK (popPK) model to investigate how conjugated metabolites of p-cresol and indole (i.e., toxicokinetically important uremic toxins) affect total MPA PK, and to conduct model-based simulations to identify potentially relevant dosing recommendations. METHODS: A prospective observational study enrolled adult kidney transplant recipients on steady-state oral mycophenolate mofetil (MMF; prodrug of MPA) with tacrolimus (±prednisone). Total plasma concentrations of p-cresol sulfate (pCS), p-cresol glucuronide (pCG), indoxyl sulfate (IxS), indoxyl glucuronide (IxG), MPA, and its major glucuronide metabolite (MPAG) were quantified with our validated liquid chromatography tandem-mass spectrometry assays. PopPK modelling was conducted with stochastic approximation expectation-maximization, and Monte-Carlo simulation was used to assess the potential impacts of significant covariates on MPA exposure. RESULTS: Forty-one participants contributed 283 samples across three early post-transplant periods (~1, ~3, and ~6 months). The final popPK model was described by first-order absorption (K = 0.672 [0.47-0.99] h, estimate [95% confidence interval]) with lag time (T = 0.403 [0.39-0.42] h), two compartments for MPA (central volume, V = 1.09 [0.75-1.53] L; peripheral volume, V = 113.9 [76.33-197.33] L; intercompartmental clearance, Q = 15.9 [10.11-25.61] L/h; and clearance = fixed at 1.4 L/h), and a single compartment for MPAG (clearance, CL = 0.296 [0.23-0.35] L/h; MPA-to-MPAG metabolic conversion, K = 3.21 [2.46-4.18] h). A proportional error model with inter-individual and inter-occasional variability best described the random effects. Potentially significant covariates were "pCS exposure" on MPA T, K, and Q (covariate coefficients, β = - 0.226 [-0.53 to 0.079], -0.133 [-0.25 to -0.033], and -0.162 [-0.39 to 0.13], respectively); "IxS exposure" and "estimated glomerular filtration rate (eGFR)" on CL (β = -0.181 [-0.28 to -0.035] and 0.407 [0.085-0.73], respectively); and "IxG exposure" on MPA T (β = 0.295 [-0.0057 to 0.59]). The model was validated by goodness-of-fit plots, residual plots, visual-predictive checks, and non-parametric bootstrapping. Model simulations identified pCS as a covariate positively influencing total MPA exposure; that pCS and eGFR had negative effects on MPAG exposure, potentially opposing the effects of IxS; whereas IxG had no effect on either MPA or MPAG. CONCLUSION: To our knowledge, this is the first popPK model to mechanistically characterize PK interactions between uremic toxins and total MPA in kidney transplant recipients. Our findings indicate that each toxin has distinct interaction effects, with pCS emerging as potentially relevant. Additional investigations are required to elucidate the clinical impacts of the identified toxin-MPA PK interactions in this population.
Population Pharmacokinetics of Sacubitril/Valsartan in Patients with Heart Failure and End-Stage Renal Disease Undergoing Peritoneal Dialysis.
Jin Y, Xu N, Yang W … +7 more , Liu B, Liu R, Shi Y, Zhang M, Xiang X, Wang Z, Zhu X
Clin Pharmacokinet · 2026 Jun · PMID 42053769 · Publisher ↗
BACKGROUND AND OBJECTIVE: Cardiovascular risk is markedly increased in end-stage renal disease. Although sacubitril/valsartan provides cardiovascular benefits in heart failure, evidence supporting its use in end-stage re...
BACKGROUND AND OBJECTIVE: Cardiovascular risk is markedly increased in end-stage renal disease. Although sacubitril/valsartan provides cardiovascular benefits in heart failure, evidence supporting its use in end-stage renal disease, particularly in patients undergoing peritoneal dialysis, remains limited. This study aimed to characterize the pharmacokinetics of sacubitril/valsartan in patients with heart failure and end-stage renal disease undergoing peritoneal dialysis and to determine whether dose adjustment is warranted. METHODS: In this prospective study, plasma, urine, and peritoneal dialysate samples were collected from 40 patients with heart failure and end-stage renal disease undergoing peritoneal dialysis, and population pharmacokinetic models were developed to simultaneously characterize valsartan and LBQ657 pharmacokinetic profiles across the three matrices. Covariates' effects were quantitatively evaluated using a forest plot. Renal and peritoneal dialysate excretion fractions of valsartan and LBQ657 were estimated based on population pharmacokinetic models. RESULTS: A one-compartment model with first-order absorption and elimination, incorporating urinary excretion and bidirectional exchange with peritoneal dialysate, was developed to characterize the pharmacokinetics of valsartan and LBQ657 in patients with end-stage renal disease. Fat-free mass was a key determinant of non-renal clearance and exposure for both analytes. A covariate analysis showed that, relative to the median fat-free mass (42.2 kg), a fat-free mass of 58.95 kg was associated with a 54% lower valsartan area under the concentration-time curve during steady state and a 26% lower LBQ657 area under the concentration-time curve during steady state. Urinary and peritoneal dialysate eliminations of valsartan and LBQ657 were minimal, not exceeding 1% and 7%, respectively. CONCLUSIONS: The population pharmacokinetic models for valsartan and LBQ657 adequately characterized profiles in plasma, urine, and peritoneal dialysate in patients with heart failure and end-stage renal disease undergoing peritoneal dialysis. In this special population, the impact of peritoneal dialysis was minimal, and no dose adjustment is required based on peritoneal dialysis status. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier no. ChiCTR2200055924.
Clinical Validation of Venetoclax Volumetric Microsampling in Patients with Leukemia with Assessment of Whole-Blood-to-Plasma Conversion Strategies and Self-Microsampling Feasibility.
Levens AD, Rijstenbil J, Metscher E … +4 more , von dem Borne P, Albersen A, Swen JJ, Moes DJAR
Clin Pharmacokinet · 2026 Jun · PMID 42020921 · Full text
BACKGROUND AND OBJECTIVE: Venetoclax shows substantial pharmacokinetic (PK) variability and frequent toxicity, making it an archetypal candidate for PK monitoring. Capillary microsampling may facilitate decentralized PK...
BACKGROUND AND OBJECTIVE: Venetoclax shows substantial pharmacokinetic (PK) variability and frequent toxicity, making it an archetypal candidate for PK monitoring. Capillary microsampling may facilitate decentralized PK monitoring of venetoclax. However, clinical validation is lacking. This study aimed to clinically validate capillary microsampling for venetoclax and to assess the feasibility of home-based self-microsampling. METHODS: Adult patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) receiving oral venetoclax therapy provided paired venous plasma and capillary samples using dried blood spot (DBS) and volumetric absorptive microsampling (VAMS) devices. We evaluated individualized hematocrit-based microsample-to-plasma correction models and previously published whole-blood-to-plasma conversion strategies. Agreement and predictive performance were assessed according to international microsampling validation criteria. The feasibility of home-based self-microsampling was evaluated by examining patients' ability to collect samples independently, the proportion of usable returned samples, and device usability. RESULTS: A total of 25 patients contributed 64 sets of paired venous plasma, DBS, and VAMS samples. Uncorrected DBS and VAMS venetoclax concentrations underestimated plasma concentrations (mean bias - 21% and - 14%, respectively) and showed clear hematocrit dependence. Individualized hematocrit-plasma/microsample ratio models showed excellent performance, with 95% of DBS and 91% of VAMS concentrations within ± 20% of plasma and low bias and imprecision across all validation metrics. Literature-based correction strategies showed lower acceptance rates and wider limits of agreement. Among patients attempting self-microsampling, 18 of 21 sampled independently, 76% of returned DBS/VAMS samples were suitable for analysis, and usability ratings were higher for VAMS than DBS. CONCLUSIONS: Capillary microsampling enables accurate venetoclax quantification in patients with AML and CLL when individualized hematocrit-based microsample-to-plasma conversion is applied. Both DBS and VAMS met international validation criteria, and home-based self-microsampling proved feasible. Venetoclax home-based self-microsampling warrants further study as a tool for decentralized PK monitoring.
Population Pharmacokinetics for Pediatric Extrapolation of GenSci006: A 3.75-mg Triptorelin Acetate Microsphere Formulation for Central Precocious Puberty.
Wang K, Sun Z, Xu F … +6 more , Liu L, Luo T, Gao W, Zhao T, Ma G, Zhu X
Clin Pharmacokinet · 2026 Jun · PMID 41957338 · Publisher ↗
BACKGROUND AND OBJECTIVES: Triptorelin acetate microspheres are long-acting gonadotropin-releasing hormone (GnRH) agonist used for treating central precocious puberty (CPP). GenSci006 is a newly developed 3.75-mg formula...
BACKGROUND AND OBJECTIVES: Triptorelin acetate microspheres are long-acting gonadotropin-releasing hormone (GnRH) agonist used for treating central precocious puberty (CPP). GenSci006 is a newly developed 3.75-mg formulation intended as a local alternative to Diphereline. This study aimed to characterize the pharmacokinetics (PK) of GenSci006 using population pharmacokinetic (PopPK) modeling with pediatric extrapolation, to evaluate pharmacodynamic (PD) comparability, and to support a fixed-dose regimen for CPP. METHODS: This study comprised two components: (1) PopPK modeling and model-based simulation to characterize exposure and support pediatric extrapolation; and (2) a comparative pharmacodynamic assessment based on serum luteinizing hormone (LH) responses. RESULTS: The final PopPK model employed a three-compartment structure with mixed sequential absorption phases (two first-order and a zero-order absorption), capturing triptorelin's multiphasic release. Covariates, including weight, age, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), serum creatinine, total bilirubin, and creatinine clearance, showed no significant effect on PK. Allometric scaling (exponents 0.75 for clearance [CL] and 1 for central volume distribution [V]) was applied to simulate pediatric exposure. Simulations indicated that at a fixed 3.75-mg dose, exposure decreased with increasing weight, with an approximately 1.7-fold difference between the 20-30 kg and 40-50 kg groups. In the comparative PD analysis, serum LH exposure profiles were comparable between GenSci006 and the reference product over the 0-672-h assessment period. CONCLUSION: Model-based simulations predicted approximately two-fold higher exposure in lighter children (20-30 kg) compared with adults. This difference was not clinically meaningful given the plateau PD effect and wide therapeutic range of triptorelin.
Why the Assay Matters in Model-Informed Precision Dosing: An Example of Ustekinumab in Crohn's Disease.
Zhang W, Wang Z, Dervieux T … +5 more , Geukens N, Verstockt B, Ferrante M, Vermeire S, Dreesen E
Clin Pharmacokinet · 2026 Jun · PMID 41951930 · Publisher ↗
BACKGROUND AND OBJECTIVE: Systematic bias between therapeutic drug monitoring assays may lead to inappropriate treatment decisions in clinical practice. While such bias is well recognized, its impact on model-informed pr...
BACKGROUND AND OBJECTIVE: Systematic bias between therapeutic drug monitoring assays may lead to inappropriate treatment decisions in clinical practice. While such bias is well recognized, its impact on model-informed precision dosing remains unexplored. In this study, we evaluate how assay bias affects the predictive performance of population pharmacokinetic models, using ustekinumab in patients with Crohn's disease as an example. METHODS: We repurposed data from 83 patients with Crohn's disease. Ustekinumab concentrations were measured using both an homogeneous mobility shift assay and enzyme-linked immunosorbent assay. Two corresponding population pharmacokinetic models were developed. Bayesian forecasting was performed under matched and mismatched combinations of assay data and population pharmacokinetic models. Predictive accuracy and precision were assessed using relative bias and relative root mean square error, with predefined thresholds for clinical acceptability. Agreement between assays and clearance estimates was evaluated using Bland-Altman plots, Deming regression, and concordance correlation coefficients. Model prior flattening strategies were explored to mitigate mismatches between model priors and therapeutic drug monitoring data. RESULTS: Ustekinumab concentrations measured by the homogenous mobility shift assay were overall 8.1 mg/L higher than those measured by an enzyme-linked immunosorbent assay (95% confidence interval -23.6, 39.7). Clearance estimates from the homogenous mobility shift assay-based population pharmacokinetic model were systematically lower (0.107 L/day; relative standard error, 7.6%) compared with those from the enzyme-linked immunosorbent assay-based population pharmacokinetic model (0.235 L/day; relative standard error, 5.4%). When assay data and population pharmacokinetic models were matched, Bayesian forecasting yielded clinically acceptable predictions across all scenarios (relative bias <20%, 95% confidence interval including zero). Mismatched combinations led to reduced accuracy. Precision was highest using the homogenous mobility shift assay data, irrespective of the population pharmacokinetic model. Flattening strategies improved predictive performances in some mismatched scenarios but did not fully recover bias. CONCLUSIONS: Assay bias has a clinically relevant impact on the predictive performance of model-informed precision dosing. Our findings underscore the importance of aligning the therapeutic drug monitoring assay format with the assay format used to build the population pharmacokinetic model to ensure accurate and clinically acceptable dosing predictions.
Exposure-Response Relationships of Antibody Drug Conjugates in Solid Tumours.
Lucassen MJJ, Buitelaar PLM, Jacobs BAW … +3 more , Schutte T, Steeghs N, Huitema ADR
Clin Pharmacokinet · 2026 May · PMID 41920510 · Full text
Over the last decade, there has been an increase in development of antibody drug conjugates (ADCs), a drug class designed to bring chemotherapeutic agents to tumour sites. The pharmacokinetics of ADCs are complex, due to...
Over the last decade, there has been an increase in development of antibody drug conjugates (ADCs), a drug class designed to bring chemotherapeutic agents to tumour sites. The pharmacokinetics of ADCs are complex, due to their multifaceted structure consisting of an antibody linked to a (chemotherapeutic) payload. This review provides an overview of the pharmacokinetics of approved ADCs for patients with solid tumours in relation to toxicity and/or efficacy outcomes. Due to the complex nature and in vivo modifications of an ADC, the pharmacokinetic exposure is measured partially or with surrogate entities. These entities include the calculated drug-to-antibody ratio (DAR)-corrected ADC, measured conjugated antibody, total antibody and/or free payload concentration. A clear exposure-efficacy and exposure-toxicity relation was evident for the majority of ADCs. A higher exposure of almost all ADCs approved for patients with solid tumours, specifically the conjugated antibody entity, was related to higher objective response rates. A higher exposure of the free circulating cytotoxic payload and of the surrogate entities of ADC exposure, of ADCs with cleavable linkers, was related to toxicity. This is unsurprising as a higher circulating payload may induce toxicities associated with the related chemotherapeutic compound. Non-cleavable linkers increase the plasma stability compared to cleavable linkers, resulting in the absence of an (systemic) exposure-toxicity relation. The exposure-response relations for efficacy and toxicity seem apparent based on current literature, but quantification of all ADC components should be considered to fully elucidate the exposure-response relations. This is a crucial next step for dose optimisation and development of a new generation of this important new therapeutic class.
Pharmacokinetic Comparability Assessment of Tixagevimab and Cilgavimab Developed for COVID-19 Prevention and Treatment Using Standard Exposure Metrics and Partial Area Under the Curve.
Zhang H, Tang W, Sadow S … +9 more , Baronio R, Tullio AN, Hirao L, Dzutseva V, Chen CC, Kiazand A, Chang LJ, Cohen TS, Gibbs M
Clin Pharmacokinet · 2026 May · PMID 41917376 · Full text
BACKGROUND AND OBJECTIVE: AZD7442 is a combination of extended half-life monoclonal antibodies (mAbs; tixagevimab and cilgavimab), developed to neutralize SARS-CoV-2. This open-label Phase 1 study compared pharmacokineti...
BACKGROUND AND OBJECTIVE: AZD7442 is a combination of extended half-life monoclonal antibodies (mAbs; tixagevimab and cilgavimab), developed to neutralize SARS-CoV-2. This open-label Phase 1 study compared pharmacokinetics (PK) of three AZD7442 formulations in which component mAbs were (1) co-formulated versus separately formulated and (2) derived from clonal cell line or cell pool material when separately formulated. METHODS: Healthy adults were randomized 1:1:1 to receive intramuscular (IM) AZD7442 300 mg (150 mg each of tixagevimab and cilgavimab) via one injection of co-formulated tixagevimab and cilgavimab from clonal cell line material (treatment A), or two sequential injections of tixagevimab and cilgavimab formulated separately either from clonal cell line (treatment B) or cell pool material (treatment C). Serial blood samples were collected up to 360 days post-dose to evaluate serum concentrations and anti-drug antibody responses. Standard exposure metrics (C, AUC and AUC) were used for PK comparability assessment between treatments (A vs B, B vs C and A vs C). A post hoc analysis using partial area under the curve (pAUC) was also conducted. RESULTS: In total, 224 participants were randomized and dosed. Serum concentration-time profiles overlapped post dosing across treatments. Median time to reach peak concentration occurred within 2 weeks with mean terminal half-life 74-84 days. Pharmacokinetic comparability for tixagevimab, cilgavimab and AZD7442 was demonstrated between treatments, with geometric mean ratios (GMR) and 90% CI within 0.8000-1.2500 using traditional exposure metrics (C, AUC and AUC) and partial AUCs (pAUCs; AUC, AUC, AUC, or AUC), except for comparison of treatment A versus B for tixagevimab, where the lower 90% CI bound for AUC GMR (0.7933) was slightly below the pre-defined threshold of 0.8000. Low immunogenicity and acceptable safety profiles were observed across treatments. CONCLUSIONS: Pharmacokinetic comparability of tixagevimab, cilgavimab and AZD7442 was demonstrated between the different treatments based on analyses using traditional bioequivalence metrics or pAUCs. Partial AUC could serve as an exposure metric when evaluating PK comparability for extended half-life mAbs. TRIAL REGISTRY: Clinical trials registration number: ClinicalTrials.gov NCT05166421.
Optimising Paediatric Medication Adherence Through Innovative Drug Formulations and Delivery Systems.
Ngcobo NN
Clin Pharmacokinet · 2026 Apr · PMID 41879949 · Full text
Medication adherence remains a significant challenge in healthcare, particularly in paediatric populations, where non-adherence has a substantial impact on therapeutic outcomes and contributes to increased healthcare cos...
Medication adherence remains a significant challenge in healthcare, particularly in paediatric populations, where non-adherence has a substantial impact on therapeutic outcomes and contributes to increased healthcare costs. This manuscript emphasises the central role of drug formulations and delivery systems in shaping adherence behaviours in children. Given the unique pharmacokinetic characteristics of paediatric patients, formulation design has a critical impact on medication efficacy, safety and acceptability. By integrating pharmacological considerations with innovative formulation strategies and tailored care approaches, this work provides practical and evidence-informed pathways to enhance medication adherence and improve clinical outcomes in paediatric care.
Population Pharmacokinetic Modelling of Unbound Mycophenolic Acid and its Glucuronide in Adult Kidney Transplant Recipients in Early Post-Transplant.
Rong Y, Al-Dajani A, Adhiya J … +5 more , Dhungana P, Mayo P, Colbourne P, Gourishankar S, Kiang TKL
Clin Pharmacokinet · 2026 May · PMID 41874950 · Publisher ↗
BACKGROUND AND OBJECTIVE: The first-line immunosuppressant mycophenolic acid (MPA) is characterised by complex, variable pharmacokinetics (PK) with high protein binding, where the relationship between total and unbound d...
BACKGROUND AND OBJECTIVE: The first-line immunosuppressant mycophenolic acid (MPA) is characterised by complex, variable pharmacokinetics (PK) with high protein binding, where the relationship between total and unbound drug can be difficult to predict early post-transplant. We developed a novel population pharmacokinetic (popPK) model for unbound MPA and its major glucuronide (MPAG) in adult kidney transplant recipients to characterise the pharmacologically relevant unbound drug. METHODS: This prospective, observational study included de novo adult kidney transplant recipients on steady-state oral mycophenolate mofetil with tacrolimus (±prednisone). The PopPK modelling was performed using stochastic approximation expectation-maximisation, and simulations evaluated the impact of significant covariates on unbound MPA area-under the concentration-time curves (AUC). RESULTS: Forty-one participants (aged 48.3±12.1 years, mean±SD) from 63 occasions representing three study visits (~1, ~3, and ~6 months post-transplant) were enrolled. A structural model based on first-order absorption (k=4 h, fixed) with lag time (T=0.38 [0.11-0.56] h; estimate [95% confidence interval]), two-compartments for unbound MPA (volume V=4213.41 [2675.47-8337.53] L; V=23321.08 [4334.80-54459.85] L; clearance=4.87 L h, fixed), one-compartment for unbound MPAG (transfer rate=0.18 [0.15-0.21] h; V=18.23 [12.40-32.77] L; clearance=5.64 [4.14-10.70] L h), and constant error with between-subject and between-occasion effects best described the data. Of 19 covariates, "age" and "alkaline phosphatase" influenced unbound MPA V (β=3.62 [-0.61-8.13]) and unbound MPAG clearance (β=-0.98 [-1.51-(-)0.21]), respectively. Simulations showed age-dependent reductions in unbound MPA AUC and age/dose-dependent shifts in the proportions of patients within the theoretical unbound MPA target range. CONCLUSIONS: A popPK model simultaneously characterising unbound MPA and MPAG was developed and evaluated. Simulations indicated that age-dependent MPA dosing may be warranted to optimise unbound therapeutic exposures.
Pharmacokinetics of Asciminib 200 mg in the Presence of a Strong CYP3A4 Inducer, Phenytoin, in Healthy Participants.
Hoch M, Taylor AJ, Huth F … +8 more , Jamalapuram S, Loisios-Konstantinidis I, Quinlan M, Kranidi A, Coleman D, Espurz N, Bellibas SE, Pierre AS
Clin Pharmacokinet · 2026 May · PMID 41845155 · Full text
BACKGROUND AND OBJECTIVES: Asciminib is indicated for the treatment of adult patients with newly diagnosed or previously treated Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) at...
BACKGROUND AND OBJECTIVES: Asciminib is indicated for the treatment of adult patients with newly diagnosed or previously treated Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) at a total daily dose of 80 mg, as well as adult patients with Ph+ CML with the T315I mutation at 200 mg twice daily. In patients with the T315I mutation, responses have been observed at doses of ≥150 mg twice daily and dose reduction to 160 mg twice daily is permitted for management of adverse reactions. The objective of this study was to assess the effect of strong CYP3A4 induction, through phenytoin, on the pharmacokinetics (PK) of single dose asciminib 200 mg. Coproporphyrin-1 (CP-1) was also measured to evaluate the effect of asciminib 200 mg on organic anion transporting polypeptide 1B (OATP1B). METHODS: This Phase 1 open-label fixed-sequence study evaluated the PK of a single oral dose of asciminib in healthy participants when administered alone and in combination with phenytoin. A single dose of 200 mg asciminib was administered on Day 1, followed by the administration of phenytoin 100 mg three times daily from Day 6 to Day 23, taken 8 h apart to ensure full induction. On Day 20, the morning doses of phenytoin and asciminib were co-administered. Serial blood samples were collected for the assessment of asciminib PK and CP-1 plasma concentrations. RESULTS: All 15 participants who enrolled were male and 14 received study treatment per protocol. Following co-administration with phenytoin, asciminib-adjusted geometric mean maximum plasma concentration (C), area under the curve to the last plasma concentration (AUC) and AUC to infinity (AUC) were reduced by 22%, 34%, and 34%, with test/reference ratios of 0.780 (90% CI: 0.718-0.847), 0.662 (90% CI: 0.624-0.703), and 0.664 (90% CI: 0.626-0.705), respectively. A single oral dose of asciminib 200 mg did not have a relevant effect on CP-1 plasma exposure. CONCLUSIONS: These data support that, considering its large therapeutic window, asciminib 200 mg twice daily can be used without any dose adjustment when co-administered with a strong CYP3A4 inducer drug. Furthermore, asciminib is not an OATP1B inhibitor up to this dose.
Single Saliva Sample Linezolid Dosing for Multidrug-Resistant Tuberculosis: A Population Pharmacokinetic Modelling of Plasma and Saliva.
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 May · PMID 41845154 · Full text
BACKGROUND AND OBJECTIVE: Therapeutic drug monitoring (TDM) of linezolid for treating multidrug-resistant tuberculosis (MDR-TB) is recommended but is hindered by the invasive and logistical challenges of plasma sampling....
BACKGROUND AND OBJECTIVE: Therapeutic drug monitoring (TDM) of linezolid for treating multidrug-resistant tuberculosis (MDR-TB) is recommended but is hindered by the invasive and logistical challenges of plasma sampling. Saliva is a promising alternative, but a saliva pharmacokinetic model to inform dosing is lacking. This study aimed to develop a saliva-based population pharmacokinetic (popPK) model and evaluate limited sampling strategies for linezolid in MDR-TB. METHODS: Plasma and saliva samples were collected at pre-dose, 2-, and 5-h post-dose from adults treated with linezolid for ≥ 7 days. A saliva-plasma popPK model was developed in NONMEM with covariate analysis. Bayesian estimation and Monte Carlo simulations were used to evaluate the predictive performance of saliva limited sampling strategies for predicting plasma AUC. A ±20% bias versus reference was considered acceptable. RESULTS: One-compartment plasma model incorporating a saliva hypothetical effect compartment with first-order absorption and elimination best described the data (102 paired saliva-plasma samples, 17 patients). Body weight influenced volume of distribution with an exponent of 1.1 (95% CI 1.01-1.18). The three-sample (pre-dose, 2-, and 5-h) saliva strategy adequately predicted plasma AUC with < 5% median bias. A single saliva sample at pre-dose or 2 h post-dose provided accurate plasma AUC predictions (< 5% median bias). CONCLUSIONS: The validated model enables reliable estimation of plasma AUC using limited saliva samples. A single saliva sample (pre-dose or 2 h post-dose) can accurately predict plasma AUC, supporting saliva-based TDM as a practical alternative to plasma-based monitoring of linezolid in MDR-TB.
Correction: 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 41817902 · Full text
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Population Pharmacokinetic Modeling of Encorafenib in Healthy Participants and Patients with BRAF V600-Mutant Solid Tumors: A Semi-mechanistic Autoinduction Model.
Yang DZ, Hahn EM, Piscitelli J … +2 more , Pithavala YK, Hibma JE
Clin Pharmacokinet · 2026 May · PMID 41817901 · Full text
BACKGROUND AND OBJECTIVE: Encorafenib is a potent and selective adenosine triphosphate-competitive BRAF V600-mutant kinase inhibitor. Encorafenib is approved for multiple indications in combination with binimetinib or ce...
BACKGROUND AND OBJECTIVE: Encorafenib is a potent and selective adenosine triphosphate-competitive BRAF V600-mutant kinase inhibitor. Encorafenib is approved for multiple indications in combination with binimetinib or cetuximab. This analysis aimed to develop a global population pharmacokinetics (popPK) model characterizing encorafenib disposition across tumor types. METHODS: The popPK analysis was based on nine phase 1 to 3 studies in participants with melanoma, colorectal cancer (CRC), non-small cell lung cancer, or other solid tumors, and healthy participants. A total of 1310 participants who received encorafenib as monotherapy or in combination were included. Nonlinear mixed effects modeling was performed using NONMEM v7.5.0. A semi-mechanistic enzyme turnover model was assessed to quantify the autoinduction effect. Stepwise covariate modeling using Perl-speaks-NONMEM (version 5.3.0) evaluated a broad range of covariates. RESULTS: A two-compartment model with first-order absorption and concentration-dependent autoinduction successfully characterized the concentration-time profile of encorafenib. Encorafenib apparent clearance (CL/F) was estimated to be 12.2 L/h after the first dose in a typical adult and increased by 186% to 35 L/h at steady state. This model indicates that maximum autoinduction is expected within 14 days of daily dosing (autoinduction half-life 64 h). Age and tumor type (melanoma, metastatic CRC, other [healthy, lung tumors, other solid tumors]) on CL/F and body weight on volume of distribution were significant covariates; these effects were not determined to be clinically significant. CONCLUSIONS: This model successfully described the PK of encorafenib over time and across tumor types. No dose modifications are suggested on the basis of intrinsic or extrinsic factors evaluated.
Model-Informed Precision Dosing of Protein Kinase Inhibitors: Evaluation of Model-Averaging and Flattened Priors Methods.
Le Louedec F, Morvan L, Mourey L … +12 more , Maillard M, Vachoux C, Yakoubi M, Tosi D, Gravis G, Roubaud G, Thuillier F, Boyle H, Thomas F, White-Koning M, Puisset F, Chatelut É
Clin Pharmacokinet · 2026 May · PMID 41801644 · Full text
BACKGROUND AND OBJECTIVES: Therapeutic drug monitoring of protein kinase inhibitors (PKIs) usually relies on the measure of a single trough concentration at steady-state (C). When the sampling time differs from the troug...
BACKGROUND AND OBJECTIVES: Therapeutic drug monitoring of protein kinase inhibitors (PKIs) usually relies on the measure of a single trough concentration at steady-state (C). When the sampling time differs from the trough, it is theoretically possible to predict C from maximum a posteriori (MAP) Bayesian estimates of PK parameters. However, several questions remain with regards to model-informed precision dosing (MIPD) of PKIs, such as choosing which model to use when several are available in the literature. Alternative techniques, such as flattened priors and model averaging may outperform standard analyses. The aim of this work is to report a comprehensive fit-for-purpose validation of MIPD for sunitinib and pazopanib. METHODS: Concentration data from 41 renal cancer patients included in the SUP-R trial (NCT02555748) measured 2 and 6 hours after an intake were analyzed (MAP-Bayesian estimation of PK parameters) in order to predict C at the current cycle and at the next cycle. Different models from the literature were tested, as well as the model-averaging and flattened priors features available in the R package 'mapbayr'. RESULTS: The quality of C predictions depended on the model used. Flattening priors rarely improved or worsened the predictions. Model averaging was robust across the different scenarios tested and should be preferred to using a single model. Overall, a precision of 20% to 25% was achieved, with a minimal bias (< 5%). CONCLUSION: The benefit of the model-averaging method for the model-informed precision dosing of sunitinib and pazopanib is likely applicable to other protein kinase inhibitors. Thanks to 'mapbayr', this framework was implemented as a standalone shiny application to be used in clinical settings.
Predicting Cumulative Neonatal Sodium Benzoate Exposures During Breastfeeding with Physiologically Based Pharmacokinetic Modelling.
Wang S, Hamadeh A, Mian P … +1 more , Edginton AN
Clin Pharmacokinet · 2026 May · PMID 41758461 · Publisher ↗
BACKGROUND AND OBJECTIVE: Sodium benzoate (SB) is used as a second-line therapy to treat rare urea cycle disorders (UCDs) in paediatric and adult patients. However, lactation data for SB do not exist, leading to uncertai...
BACKGROUND AND OBJECTIVE: Sodium benzoate (SB) is used as a second-line therapy to treat rare urea cycle disorders (UCDs) in paediatric and adult patients. However, lactation data for SB do not exist, leading to uncertainties regarding the extent of infant drug exposure due to breastfeeding while taking this medication. These uncertainties may lead to cessation of breastfeeding, unnecessarily depriving both mother and infant of its numerous benefits. Thus, this study aims to develop and apply a paediatric physiologically based pharmacokinetic (PBPK) model to predict the compounded neonatal SB exposure from both in utero and from breastfeeding. METHODS: An adult whole-body PBPK model for SB was first developed and validated with literature-based plasma concentrations after oral or intravenous doses. To account for age-related changes in SB pharmacokinetics, the adult model was scaled to paediatric populations using age-dependent algorithms to capture physiological and anatomical changes, while ontogeny functions were developed to capture maturation of enzymes and transporters where possible. A published cord-coupled PBPK modelling workflow was followed to simulate the cumulative pre- and post-natal drug exposure levels in breastfed infants, accounting for variability in milk ingestion volumes and assuming a conservative milk-to-plasma ratio of 1:1. The upper area under the curve (AUC) ratio (UAR) was used for risk assessment, taking the ratio between the AUC for the highest risk (95 percentile simulated AUC) infants and the median maternal AUC following a therapeutic SB dose and multiplying by 100% to report as a percentage. RESULTS: The paediatric PBPK model captured observed SB plasma concentrations in both neonates and children with acceptable bias and precision, supported by the average-fold error (AFE: 1.17) and the absolute AFE (AAFE: 1.24) evaluation metrics, respectively. Neonatal SB exposure levels were the highest on the first day of life (UAR: 14.2%) due to the presence of residual prenatal drug levels. Subsequent UAR values were low (1.5-3.3%) on postnatal days 1-31, suggesting rapid neonatal clearance and negligible contribution of prenatal exposure relative to breastfeeding exposure for the infant's total drug burden. CONCLUSION: This study is the first to report a paediatric PBPK model of SB pharmaceutical use, incorporating prenatal and lactational exposure to assess the cumulative risk of exposure for the breastfed infant. Model predictions suggest that SB exposure through breastfeeding is minimal and unlikely to cause adverse outcomes when compared with clinical studies. These findings may support clinical decision making in the absence of clinical lactation data; however, empirical studies are needed to validate the predictions given the limited information on milk transfer, enzyme ontogeny, and neonatal concentrations.
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