Clinical Pharmacokinetics[JOURNAL]
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200 papers
Evaluation of Preliminary Bronchodilation Effect on Aerosol Delivery from a Dry Powder Inhaler for Patients with Chronic Obstructive Pulmonary Disease with Suboptimal Peak Inspiratory Flow Rate.
Hassan MI, Laz NI, Madney YM … +2 more , Abdelrahim MEA, Harb HS
Clin Pharmacokinet · 2025 Nov · PMID 40880053 · Full text
BACKGROUND: Suboptimal peak inspiratory flow rates (PIFR) are common in patients with chronic obstructive pulmonary disease (COPD), hindering effective medication dispersion and aerosol delivery. This study aimed to asse...
BACKGROUND: Suboptimal peak inspiratory flow rates (PIFR) are common in patients with chronic obstructive pulmonary disease (COPD), hindering effective medication dispersion and aerosol delivery. This study aimed to assess whether administering a preliminary bronchodilator dose via a pressurized metered-dose inhaler (pMDI) improves aerosol drug delivery via dry powder inhaler (DPI) in patients with COPD with suboptimal PIFR (< 60 L/min), compared with those with optimal PIFR (≥ 60 L/min). METHODS: Overall, 24 patients with COPD were evaluated. PIFR was measured using the In-Check Dial G16, dividing patients into optimal and suboptimal groups. All patients received a 200 µg dose of salbutamol via Diskus DPI. Patients with COPD with suboptimal PIFR received two puffs (100 µg each) preceded by a preliminary salbutamol dose administered via pMDI. Urine salbutamol levels (USAL30) and salbutamol that was eluted from filters (SALF) were measured after 30 min to assess lung deposition through high-performance liquid chromatography (HPLC). RESULTS: Patients with COPD with suboptimal PIFR without a preliminary dose had significantly lower USAL30 than the optimal group (4.99% versus 6.18%, p = 0.013). A preliminary dose improved USAL30 in the suboptimal group but did not reach statistical significance (5.45% versus 4.99%, p = 0.071). CONCLUSIONS: A significant difference in aerosol drug delivery was observed between optimal and suboptimal groups without a preliminary dose, suggesting that inhaler selection in patients with COPD may need to be individualized on the basis of inspiratory flow capability. Administering a preliminary dose of pMDI before using a DPI minimally affects the suboptimal inhalation through DPI.
Correction: Effect of Hepatic Impairment or Renal Impairment on the Pharmacokinetics of Aficamten.
Xu D, Lutz JD, Divanji P … +6 more , Li J, Benattia Y, Griffith A, Heitner SB, Kupfer S, German P
Clin Pharmacokinet · 2025 Sep · PMID 40848106 · Full text
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Challenging Traditional ADME Assumptions for Physiologically Based Pharmacokinetic Models for Intravenous Administration of Iron-Carbohydrate Nanomedicines: Potential Utility of Gold Nanoparticle Models as a Roadmap.
Alston AB, Lin Z, Gustafson HH … +4 more , Flühmann B, Digigow R, Ayala-Nunez V, Schmidt S
Clin Pharmacokinet · 2025 Oct · PMID 40815410 · Full text
Intravenous iron-carbohydrate complexes are a class of nanomedicines that are widely used globally to treat iron deficiency and iron deficiency anemia associated with a wide spectrum of disease states. Despite being wide...
Intravenous iron-carbohydrate complexes are a class of nanomedicines that are widely used globally to treat iron deficiency and iron deficiency anemia associated with a wide spectrum of disease states. Despite being widely used in clinical practice for more than seven decades, the understanding of their in vivo disposition including tissue biodistribution and kinetics of the nanoparticle degradation at the cellular level is not well-understood. Moreover, the critical quality attributes that influence in vivo pharmacokinetics have not been fully defined. In particular, the carbohydrate moiety plays an influential role in how the nanoparticulate iron-carbohydrate complex interacts with the biological system. Developing a physiologically based pharmacokinetic (PBPK) model would facilitate a deeper understating of the key nanomedicine attributes that predict in vivo performance. Because endogenous iron metabolism complicates pharmacokinetic modeling for this complex class of drugs, models of gold nanoparticles may provide a substantive roadmap to begin to build a viable PBPK model for iron-carbohydrate nanomedicines. In the future, PBPK models that integrate recent mechanistic data regarding tissue biodistribution and intracellular iron kinetics for parameterization have the potential to improve manufacturing quality and clinical use of these complex drugs.
Immunoglobulin G Receptors (FcγR), in Addition to Target-Antigen and Neonatal Fc Receptor (FcRn), Influence Rituximab Pharmacokinetics.
Ternant D, Le Tilly O, Cartron G … +6 more , Desvignes C, Bensalem A, Mulleman D, Bejan-Angoulvant T, Gouilleux-Gruart V, Paintaud G
Clin Pharmacokinet · 2025 Nov · PMID 40810921 · Full text
INTRODUCTION: Rituximab, an anti-cluster of differentiation (CD)-20 monoclonal antibody, is used in the treatment of non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia, and rheumatoid arthritis. The pharmacokinetic...
INTRODUCTION: Rituximab, an anti-cluster of differentiation (CD)-20 monoclonal antibody, is used in the treatment of non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia, and rheumatoid arthritis. The pharmacokinetics of rituximab have been reported to be target mediated, but this alone may not fully explain the nonlinear decay of its concentrations over time. OBJECTIVE: This study aimed to explore the potential role of immunoglobulin (Fc gamma receptor; FcγR) and neonatal Fc receptor (FcRn) in the disposition of rituximab. METHODS: Concentration-time data from 108 patients with NHL, 118 with chronic lymphocytic leukemia, and 90 with rheumatoid arthritis were collected to refine a two-compartment population pharmacokinetic model with target-mediated drug disposition and irreversible binding approximation. Non-specific rituximab elimination was described using an intercompartment FcRn-mediated disposition model. Additionally, rituximab was assumed to bind to FcγR-expressing cells in both central and peripheral compartments; its disposition resulting from these mechanisms was described using quasi-steady-state interaction models. RESULTS: The FcRn-mediated disposition model provided a satisfactory description of the data and was further improved by incorporating central and peripheral FcγR quasi-steady-state interaction models with steady-state dissociation constants estimated at 586 and 418 nM, respectively. CD19 cell count was related to target-mediated elimination rate constant (p = 1.7 × 10) and inversely related to non-specific elimination (assessed by estimated FcRn amount, p = 2.1 × 10). In patients with NHL, FcγR levels in central and peripheral compartments increased with baseline metabolic tumor volume (p = 7.0 × 10 and p = 5.0 × 10, respectively). CONCLUSION: The pharmacokinetics of rituximab are mediated both by Fab (target) interactions and by FcγR and FcRn interactions.
Methodological Techniques Used in Machine Learning to Support Individualized Drug Dosing Regimens Based on Pharmacokinetic Data: A Scoping Review.
Methaneethorn J, Duangchaemkarn K, Reisfeld B … +1 more , Habiballah S
Clin Pharmacokinet · 2025 Sep · PMID 40810920 · Publisher ↗
BACKGROUND AND OBJECTIVE: Individualized drug dosing is a highly effective strategy for optimizing therapeutic outcomes, especially for drugs with high inter-individual variability. Population pharmacokinetic modeling is...
BACKGROUND AND OBJECTIVE: Individualized drug dosing is a highly effective strategy for optimizing therapeutic outcomes, especially for drugs with high inter-individual variability. Population pharmacokinetic modeling is a widely used approach to characterize inter-individual variability in therapeutic drug monitoring. However, the development of population pharmacokinetic models is labor intensive and requires significant technical expertise. Machine learning (ML) represents a promising alternative for personalized drug dosing strategies. Despite numerous studies applying ML in this context, no previous work has comprehensively reviewed and compared their methodologies and predictive performance. This scoping review addresses this gap in the existing literature with the aim to examine the methodological approaches used in ML-based pharmacokinetic modeling for dose optimization. METHODS: Five databases were systematically searched from their inception to May 2025. Studies comparing predictions of drug concentrations or pharmacokinetic parameters between ML and population pharmacokinetic models were included. Studies published in non-English language, reviews, protocols, or studies that did not employ ML models for individualized dose regimens or treatment plans were excluded. RESULTS: Fifty-eight studies were included. We found that boosting-based models, tree-based models, instance-based, and regression-based models were the most commonly used ML approaches. Approximately 31% of the studies integrated ML with population pharmacokinetic models, while the remainder developed stand-alone ML models. Inconsistencies in reporting were evident, as only 60% of the studies detailed their feature selection methods. Model evaluation approaches also varied: 47% of ML models used internal test sets, while the remainder employed external datasets or mixed approaches. In terms of predictive accuracy, ML models performed comparably to or better than population pharmacokinetic models, especially for drugs with significant pharmacokinetic variability. CONCLUSIONS: This review identifies substantial heterogeneity in ML modeling approaches, feature selection, and model evaluation. To enhance the reproducibility and clinical applicability of ML models in individualized drug dosing, standardization in reporting and methodological practices is essential.
Clinical Pharmacology Profile of the Claudin 18.2 Antibody Zolbetuximab.
Yang J, Yamada A, Shitara K … +10 more , Xu RH, Ilson D, Lonardi S, Klempner SJ, Ueno Y, Takeuchi M, Pavese J, Wojtkowski T, Matsangou M, Poondru S
Clin Pharmacokinet · 2025 Oct · PMID 40804604 · Full text
Zolbetuximab is a first-in-class chimeric (mouse/human) monoclonal antibody targeted to the tight junction protein claudin 18.2 (CLDN18.2), an emerging biomarker in gastric/gastroesophageal junction (G/GEJ) cancer. This...
Zolbetuximab is a first-in-class chimeric (mouse/human) monoclonal antibody targeted to the tight junction protein claudin 18.2 (CLDN18.2), an emerging biomarker in gastric/gastroesophageal junction (G/GEJ) cancer. This review summarizes the clinical pharmacology of zolbetuximab on the basis of available clinical trial data. Population pharmacokinetics (PK) were evaluated using data from eight clinical studies (n = 714). Zolbetuximab PK following intravenous administration was described by a two-compartment model with linear and time-dependent clearance components. On the basis of simulations using the 800/600 mg/m every 3 weeks (Q3W) dosing regimen from phase 3 trials, gastrectomy (versus no gastrectomy) was predicted to increase zolbetuximab C by ≥ 50%, but without apparent effects on the benefit-risk profile of zolbetuximab. No dose adjustments are necessary for individuals with mild/moderate renal impairment or mild hepatic impairment. Zolbetuximab PK was not different among the ethnicities evaluated (White, Asian, Chinese, Japanese, Korean). There were no apparent safety or PK ramifications of zolbetuximab coadministration with oxaliplatin or 5-fluorouracil. The incidence of antidrug antibodies to zolbetuximab was low, with no apparent clinical consequence. Exposure-response analysis suggested that higher zolbetuximab exposures may prolong survival outcomes but may also increase the probability of experiencing gastrointestinal events and infusion-related reactions. A proposed alternative 800/400 mg/m every 2 weeks (Q2W) regimen for use in combination with Q2W chemotherapy was shown to have comparable safety and efficacy to the 800/600 mg/m Q3W regimen. Zolbetuximab, the first and only approved therapy targeted to CLDN18.2, is a valuable new treatment option for patients with CLDN18.2-positive, locally advanced unresectable or metastatic G/GEJ cancer.
Double Peaking Phenomena in Pharmacokinetic Disposition Revisited.
Yousef M, Brocks DR, Löbenberg R … +1 more , Davies NM
Clin Pharmacokinet · 2025 Oct · PMID 40802044 · Publisher ↗
Multiple peaking in pharmacokinetics refers to the occurrence of two or more peaks of drug plasma concentrations following a single dose administration. It complicates interpretation of pharmacokinetics parameters and in...
Multiple peaking in pharmacokinetics refers to the occurrence of two or more peaks of drug plasma concentrations following a single dose administration. It complicates interpretation of pharmacokinetics parameters and influences clinical decision-making regarding drug efficacy and bioequivalence. This review re-examines and extends an earlier seminal review on the physicochemical and formulation-related causes and physiological mechanisms of multiple peaking. In addition to the previously discussed mechanisms, factors such as lymphatic drug uptake, enterogastric recycling, hepatoenteric recycling, dual absorption pathways, overdose scenarios, and pharmacobezoar formation have also been identified as contributors to the multiple peaking phenomenon. Furthermore, the role of specialized formulations, particularly pulsatile drug delivery systems (PDDS), has been explored in relation to their impact on this complex pharmacokinetics behavior. Moreover, this review highlights advanced modeling tools, namely physiologically based pharmacokinetic modeling (PBPK), illustrating how they can be applied to decipher complex absorption profiles, and highlights bioequivalence considerations for products exhibiting multiple peaks, such as partial area under the curve (pAUC). Improved identification and modeling of this phenomenon is critical to optimizing drug development, therapeutic monitoring, precision dosing, and regulatory decision-making.
Malnutrition and Its Effect on Drug Pharmacokinetics: A Clinical Perspective.
Ngcobo NN
Clin Pharmacokinet · 2025 Sep · PMID 40797120 · Full text
Malnutrition significantly alters the pharmacokinetics of medications, particularly in vulnerable populations such as children, pregnant women, elderly individuals, and individuals in low- and middle-income countries. Th...
Malnutrition significantly alters the pharmacokinetics of medications, particularly in vulnerable populations such as children, pregnant women, elderly individuals, and individuals in low- and middle-income countries. These populations are often more vulnerable to the effects of malnutrition because of physiological, metabolic and socioeconomic factors. Changes in body composition, organ function and plasma protein levels associated with malnutrition can impact drug absorption, distribution, metabolism and excretion. In malnourished individuals, decreased serum albumin levels may increase the free (unbound) fraction of highly protein-bound acidic drugs, potentially elevating the risk of toxicity. However, this relationship is not universally straightforward, as it depends on the drug's protein-binding characteristics, hepatic and renal function, volume of distribution and compensatory changes in drug clearance. In addition, malnutrition's effects on liver enzymes, such as cytochrome P450 isoforms, and kidney function can result in unpredictable drug clearance, particularly for narrow-therapeutic-index medications. Emerging evidence also highlights the interplay between malnutrition and pharmacogenomics, with genetic variations further modulating drug metabolism and response. Addressing these complexities requires the development of tailored dosing regimens and adaptive therapeutic strategies to optimise treatment outcomes in these at-risk groups. This review accentuates the critical need for more robust research to inform clinical guidelines and improve health equity in managing malnourished populations globally.
A Tacrolimus Population Pharmacokinetic Model for Adult Allogeneic Hematopoietic Cell Transplant Recipients Provides Clinical Opportunities for Precision Dosing.
Dunlap TC, Zhu J, Weiner DL … +21 more , Kemper RM, DeVane SC, Ma F, Nguyen V, Coghill JM, Dang V, Grgic T, Jamieson K, Miller J, Myers J, Patel T, Riches M, Serody JS, Trepte M, Vincent BG, Wood WA, Ptachcinski JR, Shaw JR, Weimer E, Armistead PM, Crona DJ
Clin Pharmacokinet · 2025 Nov · PMID 40794300 · Full text
BACKGROUND: Tacrolimus is a cornerstone of acute graft-versus-host disease (aGVHD) prophylaxis in allogeneic hematopoietic cell transplant (allo-HCT) recipients. However, a narrow therapeutic index and high interindividu...
BACKGROUND: Tacrolimus is a cornerstone of acute graft-versus-host disease (aGVHD) prophylaxis in allogeneic hematopoietic cell transplant (allo-HCT) recipients. However, a narrow therapeutic index and high interindividual variability in pharmacokinetics (PK) make starting dose selection a major challenge in clinical practice. METHODS: Data from two PK studies conducted at the University of North Carolina Medical Center (UNCMC) were used to develop an oral tacrolimus population pharmacokinetic (popPK) model specific to adult allo-HCT recipients. Monte Carlo simulations were performed to compare the likelihood of achieving the UNCMC institutional target trough concentration range (ITR) (5-10 ng/mL) on the day of transplant (D0) under the current institutional dosing protocol, dosing recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC), and model-derived dosing recommendations. RESULTS: In total, 290 allo-HCT recipients contributed a total of 906 PK samples to the final analysis. A two-compartment popPK model adequately described the PK data. Population typical values of apparent clearance (TVCL/F) for 70 kg individuals receiving reduced intensity conditioning were 0.33 L/h/kg for CYP3A5 poor metabolizers (PMs) and 0.70 L/h/kg for intermediate and normal metabolizers (IMs and NMs). The probability of the population-level average D0 trough concentration being within the UNCMC ITR under the current UNCMC weight-based dosing protocol, CPIC-based, and model-derived dosing strategies were estimated to be 37%, 45%, and 76%, respectively. CYP3A5 IMs and NMs were predicted to require a 100% dose increase relative to CYP3A5 PMs. CONCLUSIONS: We propose a new oral tacrolimus dosing strategy for adult allo-HCT recipients, which suggests the current weight-based dosing paradigm is insufficient. This new strategy includes CYP3A5 metabolizer phenotypes and conditioning regimen intensity, and could increase the percentage of allo-HCT recipients achieving target concentrations on D0. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT04645667.
Drug-Drug Interactions Between Direct Oral Anticoagulants and Other Medications in Patients with Pulmonary Embolism: Results from the Lungenembolie Augsburg (LEA).
Schmelzer KP, Freuer D, Fischer S … +3 more , Berghaus TM, Linseisen J, Meisinger C
Clin Pharmacokinet · 2025 Oct · PMID 40782145 · Publisher ↗
BACKGROUND AND AIM: Direct oral anticoagulants (DOACs) are now a well-established class of medication for blood clot prevention and treatment. So far, literature evaluating real-world data on the drug-drug interactions (...
BACKGROUND AND AIM: Direct oral anticoagulants (DOACs) are now a well-established class of medication for blood clot prevention and treatment. So far, literature evaluating real-world data on the drug-drug interactions (DDIs) between DOACs and other medications in patients with pulmonary embolism (PE) is limited. This study aims to investigate these interactions in patients with PE to address this and improve patient care. MATERIALS AND METHODS: In a retrospective study, patients' medications were recorded upon hospital discharge and reviewed again 3 months later. A clinical decision support system (AiDKlinik Release 3.5) was initially used to screen for DDIs and drug-related problems. Subsequently, medications were entered into Lexicomp, a comprehensive drug interaction database, to gain detailed scientific explanations and references for the identified interactions and their mechanisms. Binary logistic random intercept models were used to identify potential risk factors of drug-anticoagulation interactions. RESULTS: The 477 included PE patients had a median intake of five drugs. Drug-anticoagulation interactions depended strongly on the number of medications taken (P value < 0.001). However, the association was non-linear, resulting in a saturation effect for a higher number of drugs. The odds ratio for having at least one drug-anticoagulation interaction was 0.40 (95% confidence interval 0.17-0.96; P value = 0.040) in patients with hypertension. CONCLUSIONS: The potential for DDIs with DOACs represents a significant concern. By being aware of the most common interactions, risk factors and avoidance strategies, the safety and efficacy of therapy can be optimized.
A Phase IIa, Single-Blind, Placebo-Controlled, Parallel-Group Study to Assess Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Brensocatib in Adults with Cystic Fibrosis.
Konstan MW, Tolle JJ, DiMango E … +8 more , Flume PA, Usansky H, Teper A, Ramirez CN, Flarakos J, Basso J, Li S, Vergara M
Clin Pharmacokinet · 2025 Oct · PMID 40753522 · Full text
BACKGROUND AND OBJECTIVES: Brensocatib, an oral, competitive, and reversible inhibitor of dipeptidyl peptidase 1 (DPP1), reduces exacerbations and lung function decline in non-cystic fibrosis bronchiectasis (NCFBE). This...
BACKGROUND AND OBJECTIVES: Brensocatib, an oral, competitive, and reversible inhibitor of dipeptidyl peptidase 1 (DPP1), reduces exacerbations and lung function decline in non-cystic fibrosis bronchiectasis (NCFBE). This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of brensocatib in adults with cystic fibrosis (CF), comparing these findings with data from previous trials in healthy adults and in those with NCFBE to inform dose selection for future clinical trials. METHODS: A phase IIa, single-blind, randomized, placebo-controlled trial was conducted to assess the PK, PD, safety, and tolerability of brensocatib in adults with CF. Participants were randomly assigned to receive once-daily brensocatib (10 mg, 25 mg, or 40 mg) or placebo for 28 days. The study planned enrollment of up to 34 adults, stratified on the basis of their CF transmembrane conductance regulator (CFTR) modulator use, to evaluate the PK profile of brensocatib and its safety compared with placebo. Primary PK parameters, including maximum plasma concentration (C), time to maximum concentration (T), area under the concentration-time curve from 0 to 24 h (AUC), and half-life (t), were determined on day 1 and day 28. Dose-dependency of brensocatib exposure was analyzed, and safety and tolerability were assessed through treatment-emergent adverse events. Data from participants were compared with previous data from healthy adults and from those with NCFBE. RESULTS: A total of 29 participants were randomized to treatment, with 21 stratified to the CFTR modulator group. Baseline characteristics were similar among cohorts. Mean age was 37.9 (standard deviation (SD) 14.6) years, and most participants exhibited mild-to-moderate lung disease. PK analysis showed dose-dependent and predictable brensocatib exposure, with comparable profiles between participants with and without use of CFTR modulators. In addition, PK profiles in participants were comparable to those of healthy adults and of those with NCFBE. Pharmacodynamic analysis revealed dose-dependent reduction in neutrophil serine protease (NSP) activity, reaching saturation around the 25-mg dose, particularly in blood. Brensocatib at all doses was well tolerated with no new identified safety signals. CONCLUSIONS: Brensocatib demonstrated consistent PK profiles independent of CFTR therapy and comparable to those of healthy and NCFBE adults. Brensocatib reduced blood and sputum NSP levels. The safety profile was comparable to previous studies, with no new safety concerns identified, supporting the use of similar dosing for adults with CF as for other populations. These findings advocate for further investigation of brensocatib in CF. CLINICAL TRIAL REGISTRATION: NCT05090904.
Comment on "Understanding Voriconazole Metabolism: A Middle-Out Physiologically-Based Pharmacokinetic Modelling Framework Integrating In Vitro and Clinical Insights".
Helsby NA, Hannam JA
Clin Pharmacokinet · 2025 Sep · PMID 40750726 · Publisher ↗
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Author's Reply to Helsby and Hannam: 'Understanding Voriconazole Metabolism: A Middle-Out Physiologically-Based Pharmacokinetic Modelling Framework Integrating In Vitro and Clinical Insights'.
Saleh A, Schulz J, Schlender JF … +7 more , Aulin LBS, Konrad AP, Kluwe F, Mikus G, Huisinga W, Kloft C, Michelet R
Clin Pharmacokinet · 2025 Sep · PMID 40750725 · Full text
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Role of Antidrug Antibodies in Oncolytic Viral Therapy: A Dynamic Modelling Approach in Cancer Patients Treated with V937 Alone or in Combination.
Parra-Guillen ZP, Trocóniz IF, Freshwater T
Clin Pharmacokinet · 2025 Oct · PMID 40750724 · Full text
BACKGROUND AND OBJECTIVE: Oncolytic viruses (OVs) are a growing immuno-oncology therapeutic class that rely on their capability to activate the dormant endogenous anti-tumor immune response in order to control or eradica...
BACKGROUND AND OBJECTIVE: Oncolytic viruses (OVs) are a growing immuno-oncology therapeutic class that rely on their capability to activate the dormant endogenous anti-tumor immune response in order to control or eradicate tumor cells. Given their intrinsic mechanisms of action and their biological nature, development of antidrug antibodies (ADA) represents an important aspect to consider during clinical evaluation. ADAs can potentially affect viral kinetics and/or dynamics, ultimately resulting in reductions or even loss of drug efficacy. Here, we present a semi-mechanistic pharmacokinetic/pharmacodynamic model characterizing the interplay between V937 and neutralizing ADA in cancer patients receiving the V937 oncolytic virus. METHODS: The quantitative framework has been developed integrating viral load and ADA titers from 208 cancer patients who received V937 following intratumoral or intravascular administration, in monotherapy or in combination with pembrolizumab. RESULTS: The model successfully captured both V937 time course and the dynamics of ADAs under the different settings, showing no meaningful impact of ADAs on viral kinetics. Moreover, tumor response was neither affected by the preexistence or development of ADAs, which can be explained by the primary role of the immune system in the response. CONCLUSIONS: This quantitative and (semi-) mechanistic framework can be expanded to other oncolytic viruses and used to explore under which scenarios a relevant impact could be observed, thus supporting the development of novel oncolytic viral therapies.
Population Modeling of Factor IX Activity Following Administration of Fidanacogene Elaparvovec Gene Therapy in Participants with Hemophilia B.
Wojciechowski J, Gaitonde P, Hughes JH … +1 more , Ravva P
Clin Pharmacokinet · 2025 Oct · PMID 40750723 · Full text
BACKGROUND AND OBJECTIVE: Fidanacogene elaparvovec (BEQVEZ™), an adeno-associated virus-based gene therapy approved for the treatment of hemophilia B, enables endogenous production of factor IX (FIX), preventing bleeding...
BACKGROUND AND OBJECTIVE: Fidanacogene elaparvovec (BEQVEZ™), an adeno-associated virus-based gene therapy approved for the treatment of hemophilia B, enables endogenous production of factor IX (FIX), preventing bleeding and reducing the need for FIX replacement. Nonlinear mixed-effects models are routinely used for population pharmacokinetic analyses of FIX replacement therapies but have not previously been applied to FIX activity observations from gene therapy trials. A nonlinear mixed-effects modeling approach was used to characterize FIX activity following fidanacogene elaparvovec and/or FIX replacement, identify covariates affecting FIX activity, and estimate the longer-term durability of FIX activity after a single dose of fidanacogene elaparvovec. METHODS: Population modeling using NONMEM was performed with FIX activity data pooled from 11 clinical trials in participants with hemophilia B (three fidanacogene elaparvovec studies [n = 63]; eight nonacog alfa studies [n = 274]). FIX activity was assessed by one-stage clotting assays. RESULTS: FIX activity was described by a compartmental model for gene and protein expression and a three-compartment model for FIX disposition. Covariates included age and body weight on gene-therapy-related parameters. Following fidanacogene elaparvovec administration, model-predicted FIX activity reached a median (90% prediction interval) peak of 13.5 (3.12-41.3) IU/dL and remained within 50% of the peak for a median of 8.67 (0.411-15.0) years. At 15 years post-infusion, median predicted FIX activity was 4.11 (1.15-17.6) IU/dL. CONCLUSIONS: Model-based estimates showed that a single dose of fidanacogene elaparvovec elicited long-lasting elevations in FIX activity, suggesting most individuals would not require prophylactic FIX replacement for at least 15 years post-infusion. GOV IDENTIFIER: NCT00364182, NCT01335061, NCT00037557, NCT00093171, NCT00093210, NCT03861273, NCT03307980, NCT02484092.
The Influence of Patient Factors on the Population Pharmacokinetics of Colchicine: Implications for Safe and Effective Dosing.
Wright DFB, Hishe HZ, Dalbeth N … +4 more , Horne A, Drake J, Haslett J, Stamp LK
Clin Pharmacokinet · 2025 Oct · PMID 40719983 · Full text
BACKGROUND AND OBJECTIVES: The factors that predict colchicine plasma concentrations and the impact on safety and efficacy are under-researched. We aimed to determine the probability of achieving steady-state plasma conc...
BACKGROUND AND OBJECTIVES: The factors that predict colchicine plasma concentrations and the impact on safety and efficacy are under-researched. We aimed to determine the probability of achieving steady-state plasma concentrations within the nominal therapeutic range of 0.5-3 ng/mL. METHODS: Colchicine plasma concentrations from 78 people with gout were analysed using non-linear mixed effects. Body size, kidney function, concomitant drugs, ethnicity, sex, age and adherence were tested as covariates in the model. Simulations were conducted to determine the probability of achieving steady-state minimum, maximum and average concentrations within the therapeutic range of 0.5-3 ng/mL under different doses and for different patient characteristics. We considered colchicine doses that produced > 80% of steady-state average concentrations < 3 ng/mL and > 0.5 ng/mL to have a reasonable probability of safety and efficacy. RESULTS: A two-compartment pharmacokinetic model with zero-order absorption was the best fit. Body weight, sex and statin use were significant predictors of colchicine pharmacokinetics, reducing the between-subject variance on clearance by about 40%. The model predicted that colchicine dosages of ≤ 1.5 mg daily carry a low risk of toxicity based on the criteria defined here. Efficacious concentrations were achieved for all dosages tested except 0.5 mg daily, where concentrations below the proposed therapeutic range may occur in those with a body weight > 80 kg. Higher colchicine dosages of > 1.5 mg daily may exceed the proposed upper limit of safety in many individuals, particularly those with low body weight who are taking statins. CONCLUSION: A model for the pharmacokinetics of colchicine was developed and evaluated. Low-dose regimes (≤ 1.5 mg daily) are not predicted to achieve concentrations above the proposed safety threshold of 3 ng/mL in most people, although concentrations below the lower limit of the therapeutic range may occur in those taking 0.5-mg doses who are > 80 kg in body weight. Higher colchicine dosages of > 1.5 mg daily may exceed the proposed upper limit of safety in individuals with low body weight who are taking statins.
TDM-Based Tailored Dosing of Durvalumab in Lung Cancer Patients: A Comprehensive Population Pharmacokinetic-Pharmacoeconomic Evaluation.
de Vries F, Franssen EJF, Smit AAJ … +9 more , Moes DJAR, van der Wekken AJ, Munnink TO, Hendrikx JJMA, Dumoulin DW, Koolen SLW, Kievit W, van den Heuvel MM, Ter Heine R
Clin Pharmacokinet · 2025 Oct · PMID 40711703 · Full text
BACKGROUND: The increasing use of immune checkpoint inhibitors, such as durvalumab, places a significant financial burden on healthcare systems, strains hospital capacities, and contributes to environmental concerns. OBJ...
BACKGROUND: The increasing use of immune checkpoint inhibitors, such as durvalumab, places a significant financial burden on healthcare systems, strains hospital capacities, and contributes to environmental concerns. OBJECTIVE: We aimed to develop alternative dosing strategies to optimize durvalumab administration, reduce unnecessary drug use, and ensure sustainable cancer care without sacrificing efficacy. METHODS: Using the population pharmacokinetic model developed by the licensing holder, we designed two alternative dosing strategies for non-small cell lung cancer based on therapeutic drug monitoring. Adjustments were made to the dose or administration interval, following regulatory standards for in silico dose optimization. A pharmacoeconomic evaluation was conducted to estimate potential cost savings from a medical perspective. RESULTS: Both alternative strategies achieved high exposure levels, with 98.1-99.0% of patients exceeding a predefined efficacy target, surpassing the 95.4% predicted by the license holder for the approved 10 mg/kg 2-weekly regimen. They also reduced overall drug exposure by 7-24% and eliminated drug wastage, resulting in an average annual cost reduction of €25,163 (22.9%) per patient. CONCLUSION: Therapeutic drug monitoring-guided adjustments for durvalumab offer a potentially cost-saving way to optimize drug use, reduce healthcare burdens, and lessen environmental impact while ensuring adequate patient exposure. Our proposal's evidence provides a solid basis for a non-inferiority study.
Clinical Pharmacokinetics and Pharmacodynamics of Remimazolam.
de Jong BT, Eleveld DJ, Mason KP … +1 more , Struys MMRF
Clin Pharmacokinet · 2025 Sep · PMID 40690147 · Full text
Remimazolam is a benzodiazepine with a high affinity for the γ-aminobutyric acid type A-receptor thereby inducing sedation and amnesia. It is a short-acting drug, has a fast onset, short duration of action, and a predict...
Remimazolam is a benzodiazepine with a high affinity for the γ-aminobutyric acid type A-receptor thereby inducing sedation and amnesia. It is a short-acting drug, has a fast onset, short duration of action, and a predictable recovery profile. Remimazolam is metabolized mainly into CNS7054. In recent years, numerous population pharmacokinetic and combined pharmacokinetic/pharmacodynamic studies have been published. This narrative review aims to give an overview of and insight into pharmacokinetic/pharmacodynamic models and related clinical effects. Body weight, age and American Society of Anesthesiologists classification, sex, hepatic function, and extracorporeal circulation have been shown to significantly impact remimazolam pharmacokinetics. Body mass index, race, concomitant opioid administration, and a CNS7054-induced tolerance effect may be covariates. The labeling of remimazolam is not consistent worldwide as it has been approved for general anesthesia and/or sedation in different countries. To date, remimazolam is only approved by the intravenous route. Remimazolam has been approved for general anesthesia and/or sedation. The incidence of postoperative nausea and vomiting seems higher compared with propofol, yet pain on injection is less common. One study has published population pharmacokinetics in children. Reports on alternative methods to intravenous administration have been sparse.
Pharmacokinetics, Pharmacodynamics, and Urinary Recovery of Oral Mescaline Hydrochloride in Healthy Participants.
Mueller L, Klaiber A, Ley L … +5 more , Becker AM, Thomann J, Luethi D, Schmid Y, Liechti ME
Clin Pharmacokinet · 2025 Oct · PMID 40658345 · Full text
BACKGROUND AND OBJECTIVE: Mescaline is a classic serotonergic psychedelic with a long history of human use. The present study analyzed the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship, and urinary recov...
BACKGROUND AND OBJECTIVE: Mescaline is a classic serotonergic psychedelic with a long history of human use. The present study analyzed the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship, and urinary recovery of oral mescaline hydrochloride. METHODS: Data from 105 single-dose administrations (100-800 mg) in 49 participants from two phase I trials were analyzed with compartmental pharmacokinetics and pharmacokinetic-pharmacodynamic modeling. A one-compartment model with first-order absorption, elimination, and a lag time was used to describe mescaline plasma concentrations. Acute subjective effects, assessed by visual analog scales (range 0-100%), were modeled using a sigmoid E model linked to plasma concentrations via a first-order rate constant (k). RESULTS: Mescaline showed dose-proportional increases in total exposure and maximal concentrations, with a peak concentration reached within 2.0 h (geometric mean) and a half-life of 3.5 h across all doses. Mean model-predicted onset of "any drug effect" occurred around 1 hour post-dose. Maximum predicted effect intensity and duration increased with dose, from 13% and 2.8 h at 100 mg to 89% and 15 h at 800 mg. Over all conditions, 53% of the dose was excreted into urine unchanged, and 31% was excreted as the main metabolite 3,4,5-trimethoxyphenylacetic acid over 24-30 h. CONCLUSIONS: These findings provide the first detailed pharmacokinetic-pharmacodynamic characterization of mescaline in humans and indicate an oral bioavailability of at least 53%, limited by first-pass metabolism to 3,4,5-trimethoxyphenylacetic acid, followed by predominant renal elimination of both analytes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04227756 and NCT04849013.
Revisiting Acyclovir Dosing for Adult Viral Encephalitis Using a Full Bayesian LeiCNS PBPK Modeling Approach.
Sun M, Manson ML, Märtson AG … +3 more , Bodilsen J, de Lange ECM, Guo T
Clin Pharmacokinet · 2025 Sep · PMID 40652445 · Full text
BACKGROUND AND OBJECTIVE: Acyclovir is a primary treatment for central nervous system (CNS) infections caused by herpes simplex virus (HSV) and varicella-zoster virus (VZV). However, patient outcomes remain suboptimal, d...
BACKGROUND AND OBJECTIVE: Acyclovir is a primary treatment for central nervous system (CNS) infections caused by herpes simplex virus (HSV) and varicella-zoster virus (VZV). However, patient outcomes remain suboptimal, despite acyclovir treatment. Given the lack of alternative therapies, there is a pressing clinical need to revisit acyclovir dosing for viral encephalitis. This study aimed to evaluate current and alternative acyclovir dosing regimens using a Bayesian CNS physiologically based pharmacokinetic (PBPK) modeling approach. METHOD: A full Bayesian analysis was performed using LeiCNS3.0 model to describe acyclovir's CNS distribution. Simulations were performed for standard dosing (10 mg/kg TID) and various alternative dosing regimens. Drug efficacy was evaluated using 50%fT > IC (50% of the dosing interval with drug concentration above IC) and C > IC (minimum concentration of the drug exceeding IC). A toxicity threshold of 25 mg/L for plasma peak concentration was applied. RESULTS: The standard regimen (10 mg/kg TID) achieved the 50%fT > IC target but failed to consistently meet the C > IC target, particularly for VZV. Alternative regimens of increasing the dosing frequency to QID or extending infusion durations to 1.5 h or 2 h improved efficacy while maintaining safety. Prolonged infusion durations reduced peak plasma concentration thus lowered toxicity risks CONCLUSIONS: The Bayesian CNS PBPK modeling approach demonstrated robust predictive capacity for CNS PK. Current acyclovir dosing regimens may be inadequate for treating HSV and VZV encephalitis. Alternative dosing strategies involving increased frequency or extended infusion durations appear more effective and safer. Future efforts should focus on refining the PK/pharmacodynamic (PD) relationship between acyclovir exposure and antiviral efficacy to improve therapeutic outcomes.
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