Clinical Pharmacokinetics[JOURNAL]
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200 papers
Clinical Pharmacology of Loop Diuretics in Critical Care.
Ferrari F, Zanza C, Tesauro M … +6 more , Longhitano Y, Planinsic R, Voza A, Fumagalli J, Scaravilli V, Grasselli G
Clin Pharmacokinet · 2025 Jul · PMID 40445471 · Full text
Loop diuretics are a cornerstone in the management of fluid overload in critically ill patients; however, their use is often complicated by variable pharmacokinetics and the phenomenon of diuretic resistance. This narrat...
Loop diuretics are a cornerstone in the management of fluid overload in critically ill patients; however, their use is often complicated by variable pharmacokinetics and the phenomenon of diuretic resistance. This narrative review comprehensively examines the pharmacokinetic properties of loop diuretics and discusses the implications of altered pharmacokinetics due to factors such as organ dysfunction, fluid shifts, and concomitant medications, highlighting the challenges in achieving therapeutic targets. Furthermore, we explore the adverse events associated with loop diuretic administration, including electrolyte imbalances and ototoxicity. The review delves into the concept of diuretic resistance, exploring its multifactorial origins, including altered pharmacodynamics and increased compensatory mechanisms. Various strategies to overcome diuretic resistance are presented, including combination therapy with other diuretics, optimizing dosing regimens, and utilizing novel pharmacological agents. Given the complexity of loop diuretic therapy in critically ill patients, a tailored approach is crucial for optimizing fluid management and mitigating adverse effects. This review aims to inform clinicians about the nuances of loop diuretic use in critical care settings, providing insights into pharmacological strategies and clinical considerations essential for enhancing patient outcomes.
Clinical Pharmacokinetics of Inhaled Drugs for Pulmonary Hypertension.
Lin Y, Su Y, Cheng Z … +2 more , Zhu B, Pei Q
Clin Pharmacokinet · 2025 Jul · PMID 40437342 · Publisher ↗
Pulmonary hypertension (PH) is a serious condition characterized by elevated blood pressure in the pulmonary arteries. Current treatment approaches mainly focus on using vasodilator agents to reduce pulmonary blood press...
Pulmonary hypertension (PH) is a serious condition characterized by elevated blood pressure in the pulmonary arteries. Current treatment approaches mainly focus on using vasodilator agents to reduce pulmonary blood pressure and improve blood flow. Inhalation treatments offer targeted delivery to the lungs, improving efficacy and reducing systemic side effects. Understanding the pharmacokinetics (PK) of the molecules used in the inhalation treatment is crucial for dose optimization and drug product development. This review examines the clinical PK characteristics of key inhaled PH drugs (approved and investigational agents), including epoprostenol, iloprost, treprostinil, vardenafil, imatinib, seralutinib, MK-5475, milrinone, and sodium nitrite. We provide detailed analyses of their PK parameters and explore how disease conditions, inter-subject variability, and inhaled formulations and devices impact clinical PK characteristics. Future research would focus on how disease-specific factors affect drug behavior and the prediction of pulmonary drug concentrations. This will support more precise drug delivery and personalized treatment strategies for PH.
Population Pharmacokinetic Analysis of an Octreotide Depot (CAM2029) in the Treatment of Acromegaly.
Glatard A, Friberg-Hietala S, Keutzer L … +3 more , Hansson A, Johnsson M, Tiberg F
Clin Pharmacokinet · 2025 Jul · PMID 40418492 · Full text
INTRODUCTION: Octreotide is a first-generation somatostatin receptor ligand (SRL) approved for acromegaly treatment. CAM2029 is a sustained-release subcutaneous octreotide injection designed to improve treatment convenie...
INTRODUCTION: Octreotide is a first-generation somatostatin receptor ligand (SRL) approved for acromegaly treatment. CAM2029 is a sustained-release subcutaneous octreotide injection designed to improve treatment convenience for patients and bioavailability over alternative SRL treatments. The aim of this analysis was to characterise the pharmacokinetic (PK) properties of CAM2029. METHODS: Using nonlinear mixed-effects modelling, 4098 observations from three trials, including 216 healthy participants and participants with acromegaly, were used to develop a population PK model of octreotide after administration of CAM2029 or immediate-release (IR) octreotide. Simulated octreotide plasma concentration profiles after administration of clinically justified dosing regimens of CAM2029 and octreotide IR were compared. RESULTS: Octreotide disposition was best described by a two-compartmental distribution with a first-order elimination model. The rapid initial and slow subsequent drug release of CAM2029 was best characterised by two simultaneous first-order absorption processes, whereas octreotide IR absorption was described by a single first-order pathway. The model was qualified to describe octreotide concentrations and supported the robustness of dosing CAM2029 every 4 weeks (Q4W) ± 1 week. Simulations indicated that the average concentration during a dosing interval at steady state for 20 mg CAM2029 Q4W was similar to 0.25 mg octreotide IR every 8 h, but with reduced daily fluctuation. CONCLUSIONS: This population PK model supports the use of CAM2029 as a potential alternative treatment option to both octreotide IR and long-acting repeatable (LAR) for acromegaly treatment. The octreotide bioavailability for CAM2029 was similar to octreotide IR and approximately 5 to 6 fold higher than octreotide LAR, with a more rapid onset. TRIAL REGISTRATIONS: 2020-002643-35 (EudraCT), NCT04076462 (date of registration: 3rd September 2019), NCT04125836 (date of registration: 14th October 2019).
Optimizing Nortriptyline Dosing: A Comparison between Pharmacogenetics-Based, Phenotype-Based, and Standard Dosing.
Vos CF, Coenen MJH, Ter Hark SE … +4 more , Schellekens AFA, Aarnoutse RE, Janzing JGE, Ter Heine R
Clin Pharmacokinet · 2025 Jul · PMID 40413686 · Full text
BACKGROUND AND OBJECTIVE: Nortriptyline, a tricyclic antidepressant, has an important role in the pharmacotherapy of major depressive disorder (MDD). Individualized dosing approaches, such as pharmacogenetics-based and p...
BACKGROUND AND OBJECTIVE: Nortriptyline, a tricyclic antidepressant, has an important role in the pharmacotherapy of major depressive disorder (MDD). Individualized dosing approaches, such as pharmacogenetics-based and phenotype-based dosing, may enhance early achievement of therapeutic plasma concentrations, but their comparative accuracy has not been investigated. Our objective was to compare the accuracy of three nortriptyline dosing strategies: pharmacogenetics-based, phenotype-based, and standard dosing. METHODS: Using pharmacokinetic modeling based on data from a randomized controlled trial, we assessed and compared the following dosing strategies: pharmacogenetics-based dosing depending on the cytochrome P-450 (CYP) 2D6 genotype, phenotype-based dosing determined by the plasma concentration measured after a single nortriptyline administration, and standard dosing (125 mg/day). A population pharmacokinetic model was developed to assess phenotype-based dosing recommendations. We evaluated the dosing strategies by comparing the number of participants with predicted therapeutic, subtherapeutic, and supratherapeutic plasma concentrations using Chi-squared (χ) tests. Variability in plasma concentrations was assessed using F-tests. RESULTS: Both pharmacogenetics-based (χ (1) = 8.0, p = 0.01) and phenotype-based dosing (χ (1) = 5.3, p = 0.02) significantly increased the likelihood of achieving therapeutic plasma concentrations compared with standard dosing while reducing plasma concentration variability. No significant difference was found in the prediction of therapeutic concentrations between the two individualized dosing strategies (χ (1) = 0.33, p = 0.56). CONCLUSIONS: Pharmacogenetics-based and phenotype-based dosing demonstrate greater accuracy in predicting therapeutic nortriptyline plasma concentrations than standard dosing. Further research is warranted to explore the clinical application of model-informed precision dosing for nortriptyline and other psychotropic medications.
Pharmacokinetic/Pharmacodynamic Modelling and Monte Carlo Simulations to Predict Cytomegalovirus Viral Load in Pediatric Transplant Recipients Treated with (val)Ganciclovir.
Koloskoff K, Franck B, Benito S … +6 more , Welzel J, Autmizguine J, Theoret Y, Briand A, Ovetchkine P, Woillard JB
Clin Pharmacokinet · 2025 Jul · PMID 40411698 · Full text
BACKGROUND AND OBJECTIVES: Cytomegalovirus (CMV) infection poses significant challenges in pediatric transplant recipients. Ganciclovir and its prodrug valganciclovir are primary treatments because of their potent antivi...
BACKGROUND AND OBJECTIVES: Cytomegalovirus (CMV) infection poses significant challenges in pediatric transplant recipients. Ganciclovir and its prodrug valganciclovir are primary treatments because of their potent antiviral effects. Balancing efficacy and toxicity is particularly critical in children. This study aimed to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for (val)ganciclovir and assess the relationship between area under the concentration-time curve (AUC) and CMV viral loads via Monte Carlo simulations. METHODS: We conducted a retrospective analysis including 184 viral load samples from 36 transplanted children treated with ganciclovir/valganciclovir. We developed a population pharmacodynamic model using Monolix and performed Monte Carlo simulations to assess viral load decline with varying AUCs. Internal validation was performed using goodness-of-fit plots and bootstraps. RESULTS: We used a viral turnover model with stimulated degradation to model the pharmacodynamic data. Model validation showed no bias or misspecification. Simulations indicated that maintaining an AUC ≥ 40 mg·h/L achieved an 85.4% probability of undetectable viral load after 28 days of therapy. An AUC > 30 mg·h/L provided 80.9% probability of reducing viral loads by - 1 log after 2 weeks. AUC values > 60 mg·h/L offered minimal incremental benefits. CONCLUSION: The pharmacodynamic model accurately predicted observed data. Simulations indicated that maintaining a ganciclovir plasma AUC around 40-60 mg·h/L maximized antiviral efficacy. An AUC > 60 mg·h/L might increase the risk of adverse events without providing additional efficacy.
Comment on "Ticagrelor is Associated with Increased Rosuvastatin Blood Concentrations in Patients Who Have Had a Myocardial Infarction".
Wang Z, Chan KH, Chan ECY
Clin Pharmacokinet · 2025 Jul · PMID 40408049 · Publisher ↗
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Author's Reply to Chan et al.: "Ticagrelor is Associated with Increased Rosuvastatin Blood Concentrations in Patients Who Have Had a Myocardial Infarction".
Dermota T, Jug B, Trontelj J … +1 more , Božič Mijovski M
Clin Pharmacokinet · 2025 Jul · PMID 40408048 · Publisher ↗
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Integrated Two-Analyte Population Pharmacokinetics Model of Patritumab Deruxtecan (HER3-DXd) Monotherapy in Patients with Solid Tumors.
Xu Y, Lee M, Joshi R … +8 more , Wang X, Husband H, Byrne R, Waterhouse T, Abutarif M, Vaddady P, Garimella T, Li L
Clin Pharmacokinet · 2025 Jun · PMID 40408047 · Publisher ↗
BACKGROUND AND OBJECTIVE: Patritumab deruxtecan (HER3-DXd, also known as MK-1022) is an antibody-drug conjugate comprising a fully human monoclonal antibody against human epidermal growth factor receptor 3 (HER3) attache...
BACKGROUND AND OBJECTIVE: Patritumab deruxtecan (HER3-DXd, also known as MK-1022) is an antibody-drug conjugate comprising a fully human monoclonal antibody against human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload, deruxtecan (DXd), via a tetrapeptide-based cleavable linker. We developed a population pharmacokinetic (PK) model for anti-HER3-ac-DXd (anti-HER3 antibody conjugated DXd) and DXd to characterize their PKs and investigate the impact of preselected covariates. METHODS: Data were pooled from four phase I/II studies including patients with breast, lung, and colorectal cancer (N = 733) treated with HER3-DXd monotherapy (1.6-8.0 mg/kg intravenously every 3 weeks). An integrated population PK model, established using stepwise methodology, simultaneously described both anti-HER3-ac-DXd and DXd disposition. RESULTS: Anti-HER3-ac-DXd PK was described by a two-compartment model with three elimination pathways: linear transient clearance, nonspecific time-dependent clearance, and nonlinear Michaelis-Menten clearance. DXd PK was described by a one-compartment model with two clearance pathways: linear and nonlinear Michaelis-Menten clearance. The formation of DXd was rate limited by all three clearance pathways of anti-HER3-ac-DXd. Moderate hepatic impairment was a significant covariate on DXd but not anti-HER3-ac-DXd exposure. Other prespecified covariates did not have a clinically important impact on exposure to anti-HER3-ac-DXd or DXd. CONCLUSIONS: The final integrated population PK model characterized the PK of both anti-HER3-ac-DXd and DXd in patients with solid tumors treated with HER3-DXd and supported the selected 5.6 mg/kg Q3W dosing regimen. Consistent with current data, dose adjustment based on the covariates investigated is not warranted.
Population Pharmacokinetics of Elexacaftor, Tezacaftor and Ivacaftor in a Real-World Cohort of Adults with Cystic Fibrosis.
Magnas P, Bouazza N, Foissac F … +11 more , Froelicher Bournaud L, Lui G, Carlier N, Da Silva J, Fesenbeckh J, Kanaan R, Honoré I, Martin C, Treluyer JM, Burgel PR, Benaboud S
Clin Pharmacokinet · 2025 Jun · PMID 40405059 · Publisher ↗
BACKGROUND AND OBJECTIVES: Elexacaftor-tezacaftor-ivacaftor (ETI), a combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, has become the therapeutic standard of care for most people with...
BACKGROUND AND OBJECTIVES: Elexacaftor-tezacaftor-ivacaftor (ETI), a combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, has become the therapeutic standard of care for most people with cystic fibrosis (pwCF). People with cystic fibrosis exhibit differences in CFTR genotypes and have important differences in phenotypic characteristics including age, body weight, pancreatic status, disease severity, and comorbidities. While these differences predict large interindividual variability (IIV) in ETI exposure, there is a unique dose regimen recommended for adults. This raises questions around the "one-dose fits all" strategy. OBJECTIVES: The aims of this study were to describe real-world population pharmacokinetics (Pop-PK) of ETI in adults with CF and identify factors associated with IIV. METHOD: As part of the ongoing French national observational cohort study the Pop-PK analysis included 552 plasma concentrations drawn routinely from 325 adults with CF. RESULTS: A one-compartment model with first order absorption and elimination best represented all three compounds, and an additional lag-time for elexacaftor PK data. Large IIV was observed in ETI, with an area under the curve (AUC for elexacaftor and tezacaftor, and AUC for ivacaftor) ranging respectively, from 58.7-422.9 mg⋅h/L; 38.0-207.7 mg⋅h/L and 4.9-64.9 mg⋅h/L. The main sources of IIV identified in the final ETI Pop-PK models were body weight, age, exocrine pancreatic insufficiency and CFTR genotype. CONCLUSION: This study established the first ETI Pop-PK analysis in adults with CF and identified several covariates that explain IIV. Therapeutic drug monitoring may be beneficial for patients with a small body weight, older ages, carrying one ETI-responsive CFTR variant or those with no exocrine pancreatic insufficiency and especially for patients who combine these characteristics. Therapeutic drug monitoring may also prove to be useful in individuals experiencing adverse events, in those with reduced effectiveness, or to help manage non-adherence issues.
Pharmacokinetics and Lung Deposition After Administration of Inhaled Mosliciguat (BAY 1237592): Results from Randomized Phase I Studies in Healthy Men.
Saleh S, Mundry T, Nagelschmitz J … +3 more , Buetehorn U, Holzschuh S, Nikkho SM
Clin Pharmacokinet · 2025 Jun · PMID 40402373 · Full text
BACKGROUND AND OBJECTIVE: Mosliciguat is the first soluble guanylate cyclase activator designed for dry powder inhalation. It is currently under development for the treatment of pulmonary hypertension; the inhaled route...
BACKGROUND AND OBJECTIVE: Mosliciguat is the first soluble guanylate cyclase activator designed for dry powder inhalation. It is currently under development for the treatment of pulmonary hypertension; the inhaled route of administration delivers the drug to the pulmonary vasculature with the aim of improving pulmonary hemodynamics. We conducted three phase I trials in healthy male volunteers to characterize the pharmacokinetic profile of mosliciguat, focusing on lung deposition after inhalation with a low-resistance device in a lactose carrier-based dry powder formulation. METHODS: Study 1 was a randomized, open-label, four-way crossover study (Part 2) comparing the pharmacokinetics of mosliciguat by inhalation (1000 μg), inhalation (1000 μg) with charcoal block, in oral solution (1000 μg), and intravenously (100 μg). (The oral and intravenous doses were selected in Part 1 of the study.) Study 2 was an 8-day, randomized, single-blind, placebo-controlled, multiple-dose escalation study of once-daily inhaled mosliciguat (480, 1000, and 2000 μg). Study 3 was a 2-week, multiple-dose, randomized, placebo-controlled, single-blind study of once-daily inhaled mosliciguat 1000 μg. RESULTS: In Study 1 (Part 2) the absolute bioavailability of inhaled mosliciguat was 18.8% without charcoal block and 16.3% with charcoal block. The absolute bioavailability of oral mosliciguat was 23.1%. Pharmacokinetic parameters showed low-to-moderate inter-subject variability. Time to maximum plasma concentration (t) was 2.0 h after inhalation and 1.0 h after oral administration; half-life was 15.1 and 4.4 h, respectively. Based on accumulation ratios in Study 2, the area under the concentration-time curve (AUC) and maximum plasma concentration (C) increased by 45-51% and 15-21%, respectively, across doses at day 8. In Study 2 the half-life of inhaled mosliciguat with multiple dosing was 57.4 and 42.3 h at doses of 1000 and 2000 µg, respectively. Data showed moderate variability in AUC and C (geometric coefficients of variation, 26.6% and 24.7%, respectively, in study 3 on day 1). Trough levels showed accumulation ratios of 1.7-2.1 in Study 2 (day 8) and 2.5 in Study 3 (day 14). In all three studies, mosliciguat was well tolerated, without major systemic effects on heart rate or blood pressure. CONCLUSIONS: Inhaled mosliciguat had a longer t and half-life than oral mosliciguat. Accumulation data suggest formation of a mosliciguat depot in the lungs and continuous transfer to the systemic circulation, with an indication of an increase in accumulation ratio with longer duration of treatment.
Pharmacokinetics of Ivacaftor, Tezacaftor, Elexacaftor, and Lumacaftor in Special Cystic Fibrosis Populations: A Systematic Review.
Elzinga FA, Malik PRV, Akkerman OW … +5 more , Rottier BL, van der Vaart H, Touw DJ, Koppelman GH, Mian P
Clin Pharmacokinet · 2025 Jul · PMID 40399734 · Full text
BACKGROUND AND OBJECTIVE: Following the development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (ivacaftor, tezacaftor, elexacaftor, and lumacaftor), the prognosis for people diagnosed with c...
BACKGROUND AND OBJECTIVE: Following the development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (ivacaftor, tezacaftor, elexacaftor, and lumacaftor), the prognosis for people diagnosed with cystic fibrosis (pwCF) has improved. Understanding the pharmacokinetics (PK) of CFTR modulators is crucial to provide optimal care, particularly in special cystic fibrosis (CF) populations such as pwCF with hepatic impairment, pancreatic insufficiency, those who are pregnant or lactating, or who are children. We aim to provide an overview of the PK of CFTR modulators in these populations. METHODS: A systematic literature search was carried out in PubMed and Embase on 20 June 2024. Studies were considered relevant when information on PK or exposure of CFTR-modulating drugs was available. RESULTS: PwCF with mild/moderate hepatic impairment do not exhibit substantially higher exposure to CFTR modulators compared with those without liver involvement or healthy individuals. Similarly, exocrine pancreatic insufficiency has no effect on the PK of CFTR modulators in adult pwCF. In contrast, pediatric pwCF are exposed to higher levels of CFTR modulators relative to adults, as children receive higher weight-based doses (mg/kg) to ensure equivalent therapeutic efficacy. CONCLUSIONS: The PK of CFTR modulators have been more extensively studied in adults, pwCF with mild/moderate hepatic impairment, and children. However, ensuring adequate dosing remains challenging. Knowledge gaps persist for adults with severe hepatic impairment (Child-Pugh Class C), children with CF-induced hepatic impairment, and pregnant or lactating pwCF. Future research addressing these gaps, through incorporating routine clinical data, is crucial for improving clinical guidelines and optimizing dosing regimens, thereby advancing towards evidence-based utilization of CFTR modulators.
Exploring the Influence of Obesity and CYP2 C19 Genotype on Lansoprazole Pharmacokinetics in Pediatric Patients: A Population Modeling Approach.
Helfer VE, Gonzalez D, Kyler KE … +11 more , Dunlap TC, Williams V, Radford J, Selvarangan R, Sasidharan A, Chan S, Artz N, Retke B, Toren P, Gibson K, Shakhnovich V
Clin Pharmacokinet · 2025 Jul · PMID 40379961 · Full text
BACKGROUND AND OBJECTIVE: Pediatric pharmacokinetics pose unique challenges, particularly concerning drug dosing in the presence of obesity and genetic variability in drug-metabolizing enzymes such as cytochrome P450 (CY...
BACKGROUND AND OBJECTIVE: Pediatric pharmacokinetics pose unique challenges, particularly concerning drug dosing in the presence of obesity and genetic variability in drug-metabolizing enzymes such as cytochrome P450 (CYP) 2C19. This study aimed to develop a lansoprazole pediatric population pharmacokinetic (popPK) model considering obesity, obesity-associated changes in inflammatory cytokines and the liver, and CYP2C19 genotype, and to assess implications for dosing strategies. METHODS: Pediatric subjects with and without obesity (6-21 years, n = 47) received one oral dose of 1.2 mg/kg fat-free mass (FFM), not exceeding 60 mg. Plasma concentrations were measured at multiple time points, and a popPK analysis using NONMEM with stepwise covariate modeling was performed. Simulations compared exposures between children without and with obesity (BMI percentile ≥ 95th) after two dosing strategies: U.S. Food and Drug Administration (FDA)-approved total body weight-tiered and FFM-based dosing. RESULTS: A total of 537 lansoprazole concentrations were modeled using a two-compartment model with Weibull absorption and linear elimination. Parameters were allometrically scaled to FFM with fixed exponents of 0.75 for clearances and 1 for volumes. CYP2C19 was identified as a significant covariate for CL/F. No significant differences in lansoprazole exposure were observed between children with and without obesity, with both dosing approaches. Higher exposure was noted in poor/intermediate metabolizers of CYP2C19. FFM-based dosing led to similar levels of exposure between children (aged 6-11 years) and adolescents (aged 12-17 years). CONCLUSIONS: Obesity was not associated with differences in lansoprazole pharmacokinetics in children. A FFM-based dosing approach could result in comparable exposure between children and adolescents. Dose adjustments are supported for poor/intermediate metabolizers of CYP2C19.
An Adult Population Pharmacokinetic Model to Simulate Subcutaneous Administration of a Fixed Dose of Furosemide in Adolescents with Heart Failure and Volume Overload.
Hornik CP, Foote HP, Kendig E … +1 more , Mohr J
Clin Pharmacokinet · 2025 Jun · PMID 40360952 · Full text
BACKGROUND: Subcutaneous furosemide administered with the On-Body Infusor could be useful in children with heart failure (HF) and congestion due to volume overload, but the appropriate dosing regimen is unknown. OBJECTIV...
BACKGROUND: Subcutaneous furosemide administered with the On-Body Infusor could be useful in children with heart failure (HF) and congestion due to volume overload, but the appropriate dosing regimen is unknown. OBJECTIVE: This study aimed to develop a population pharmacokinetic (popPK) model to determine the subcutaneous furosemide dosing regimen in children with HF who are appropriate for On-Body Infusor use. METHODS: Samples collected from 15 adults with HF who received subcutaneous or intravenous furosemide in a randomized phase II/III study (NCT02329834) were used to develop the popPK model with covariates identified by forward inclusion and backward elimination; validation was by bootstrapping. The model was allometrically scaled from a 70-kg adult body weight to simulate furosemide pharmacokinetics in virtual adolescents aged 12-17 years by weight category (42.5-50.0, > 50-60, and > 60-70 kg) for subcutaneous furosemide 80 mg (30 mg over 1 h then 12.5 mg/h for 4 h). RESULTS: Furosemide pharmacokinetics were best characterized using a two-compartment model with first-order absorption and elimination. After scaling to adolescents in subcutaneous dosing simulations, estimated furosemide clearance was 1.55 mL/min/kg. Estimated exposure (mean area under the plasma concentration-time curve at 24 h) was 16,800 µg⋅h/L in adolescents weighing 42.5-50.0 kg, 14,700 µg⋅h/L in adolescents weighing > 50-60 kg, and 13,000 µg⋅h/L in adolescents weighing > 60-70 kg versus 12,400 µg⋅h/L in adults. CONCLUSIONS: Simulated furosemide exposure was consistent with published values, supporting an 80-mg dose of subcutaneous furosemide (30 mg over the first hour, then 12.5 mg/h for 4 h) for adolescents aged 12-17 years with body weight ≥ 42.5 kg.
A Systematic Review and Classification of the Effects of P-glycoprotein Inhibitors and Inducers in Humans, Using Digoxin, Fexofenadine, and Dabigatran as Probe Drugs.
Coumau C, Csajka C
Clin Pharmacokinet · 2025 Jun · PMID 40349292 · Full text
P-glycoprotein is a critical efflux transporter that may significantly affect the pharmacokinetics of various drugs by influencing their absorption, distribution and elimination. While European and American regulatory gu...
P-glycoprotein is a critical efflux transporter that may significantly affect the pharmacokinetics of various drugs by influencing their absorption, distribution and elimination. While European and American regulatory guidelines provide lists of P-glycoprotein modulators, they lack specificity concerning in vivo studies and clear guidance on inducers, creating uncertainty in their clinical relevance. A systematic search on in vivo clinical studies involving healthy volunteers using fexofenadine, dabigatran and digoxin as P-glycoprotein substrates has been performed in accordance with the PRISMA guidelines. A total of 151 studies assessing the impact of P-glycoprotein modulators on the concentration-time profile of P-glycoprotein substrates were retrieved. Additionally, data on the P-glycoprotein modulators' effect on cytochrome P450 3A4 induction or inhibition were also collected. P-gp modulators were classified as potent, moderate, weak or non-interactors for P-glycoprotein, with or without cytochrome P450 3A4 impact, on the basis of the area under the concentration-time curve ratio. This classification was adapted from the Food and Drug Administration criteria for cytochrome interactions. This systematic review identified 49 area under the plasma concentration-time curve ratio values corresponding to P-glycoprotein inhibitors, 23 to P-glycoprotein inducers and 131 to non-interactors. Of these, only 32.5% and 41.1% were classified as weak to potent, respectively. Only 0.7% of inhibitors and no inducers were classified as potent. This suggests that most P-glycoprotein modulators have a limited impact on drug exposure. The potential for interaction increases when P-glycoprotein modulators also affect cytochrome P450 3A4, which is the case for 59.9% of P-glycoprotein modulators. However, some moderate P-glycoprotein modulators may have clinically significant effects depending on the therapeutic margin of the substrate and the clinical context.
The Impact of Dietary Interventions on the Pharmacokinetics of Antifungal Drugs: A Systematic Review with Meta-analyses.
Wiesner-Kiełczewska A, Zagrodzki P, Paśko P
Clin Pharmacokinet · 2025 Jun · PMID 40347349 · Publisher ↗
BACKGROUND AND OBJECTIVE: Managing food-drug interactions may help to optimize the efficacy and safety of antifungal therapy. This systematic review followed Preferred Reporting Items for Systematic reviews and Meta-Anal...
BACKGROUND AND OBJECTIVE: Managing food-drug interactions may help to optimize the efficacy and safety of antifungal therapy. This systematic review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to evaluate how food, beverages, antacids, and mineral supplements influence the pharmacokinetic (PK) parameters or pharmacokinetic/pharmacodynamic (PK/PD) indices of 14 orally administered antifungal drugs. METHODS: We considered all studies evaluating the effects of food, beverages, antacids, and mineral supplements on PK parameters and PK/PD indices of oral antifungal drugs for inclusion. We excluded in vitro, in silico, animal studies, reviews, and alcohol-related investigations. Searches were conducted in Medline (via PubMed), Embase, and Cochrane Library from database inception to June 2024. We evaluated the risk of bias using the National Institutes of Health (NIH) tool for before-after studies and the Cochrane tool for parallel and cross-over trials. We performed meta-analyses when two or more studies with comparable designs were available; otherwise, results were summarized qualitatively. RESULTS: The review included 73 studies from 68 reports. Only studies investigating the effect of dietary interactions on PK parameters were found. Meta-analyses were conducted for seven antifungal drugs, while qualitative synthesis covered the remaining drugs. Open-label, cross-over studies accounted for 58% of trials, aligning with Food and Drug Administration (FDA) recommendations. A high risk of bias appeared in 33% of studies, while only 7% showed low risk. Among 11 antifungals with food-effect data, seven (64%) exhibited clinically important interactions. High positive food effects (area under the concentration-time curve (AUC) or peak serum concentration (C) increased by > 45%) were seen for griseofulvin, itraconazole capsules and tablets (except rice-based meals), and posaconazole immediate-release tablets and suspension. A moderate positive impact of high-fat meals (AUC or C increased in the range of 35-45%) occurred for ibrexafungerp and oteseconazole. A high negative food effect was observed on the absorption of voriconazole and itraconazole oral suspension or super bioavailable (SUBA) capsules (AUC or C decreased by > 40%). Antacids strongly reduced itraconazole and ketoconazole absorption, while nutritional supplements improved posaconazole bioavailability. Acidic beverages such as Coca Cola substantially enhanced the absorption of itraconazole, ketoconazole, and posaconazole, whereas orange juice significantly reduced itraconazole bioavailability. CONCLUSION: Interactions were influenced by such factors as drug physicochemical properties, type of dietary intervention, drug formulation, and patient characteristics. Although the review largely filled the existing gaps in recommendations, we judged the overall quality of evidence as low owing to outdated studies, methodological inconsistencies, and uneven data availability. Further research involving PK/PD indices is needed to link the postprandial changes in the bioavailability of antifungal drugs with their clinical efficacy. OTHER: The protocol of the systematic review was registered in March 2024 in the Open Science Framework (OSF) Registries ( https://doi.org/10.17605/OSF.IO/HAVK9 ).
Maternal-Fetal Physiologically Based Population Pharmacokinetics Model Development of Lopinavir/Ritonavir in HIV/HBV Co-infected Pregnant Women to Quantitatively Describe the Gestational PK Characteristics and Predict the Potential Disease-Drug-Drug Interaction (DDDI).
Song L, Guo X, Yang W … +2 more , Song J, Liu D
Clin Pharmacokinet · 2025 Jun · PMID 40323543 · Publisher ↗
BACKGROUND AND OBJECTIVE: Lopinavir/ritonavir (LPV/r) has been widely used in HIV/HBV co-infected pregnant-women. We aim to characterize the maternal-fetal (m-f) pharmacokinetic (PK) of LPV/r and support the dose optimiz...
BACKGROUND AND OBJECTIVE: Lopinavir/ritonavir (LPV/r) has been widely used in HIV/HBV co-infected pregnant-women. We aim to characterize the maternal-fetal (m-f) pharmacokinetic (PK) of LPV/r and support the dose optimization and potential drug-drug interaction (DDI) evaluation in this population. METHODS: Lopinavir PK characteristics in human immunodeficiency virus/hepatitis B virus (HIV/HBV) co-infected pregnant women (n = 35) and fetus were calculated using non-compartmental analysis followed by quantification of maternal PK characteristics using population PK (PopPK) analysis. A maternal-fetal lopinavir physiologically based pharmacokinetic (PBPK) model was developed by incorporating trans-placental transfer, disease- and pregnancy-related physiological changes. This final population PBPK model was applied to simulate different dose regimens of LPV/r and potential DDI risks under different drug combination scenarios. RESULTS: (AUC) of lopinavir in co-infected pregnancy was first reported to be 34.1 and 31.0 mg/L/h for the 2nd and 3rd trimesters. The PBPK-simulated PK parameters were within 0.75 to ~ 1.16-fold of the observations at different stages of pregnancy. The m-f PBPK model-simulated umbilical vein:maternal plasma (UV:MP) ratio of lopinavir was around 0.16 at late trimester, which is consistent with the PopPK model-simulated individual value of 0.116. Simulated results indicated that a standard dose of LPV/r (400/100 mg Q12 h) might not target the effective therapeutic concentration. Model-simulated DDI results suggested that lopinavir increased dose or shortened dosing interval when co-administered with rifampicin in HIV/HBV co-infected pregnancy. CONCLUSIONS: This work successfully applied model-informed approaches to quantitatively assess lopinavir m-f PK and also provided a novel strategy for DDI risk evaluation and dosing optimization for other P-gp substrates in HIV/HBV co-infected pregnant women.
Prediction of Interspecies Translation for Targeting Delivery Coefficients of GalNAc-siRNA Silencing Apolipoprotein C-III Using a Mechanistic Minimal Physiologically Based Pharmacokinetic/Pharmacodynamic Model.
Tian Z, Luo H, Chu Y … +5 more , Liu Y, Gao S, Song L, Yang Z, Liu D
Clin Pharmacokinet · 2025 Jun · PMID 40317426 · Publisher ↗
BACKGROUND AND OBJECTIVE: The emerging N-acetylgalactosamine-small interfering RNA (GalNAc-siRNA) conjugates lead the way for liver-targeting delivery to exert gene-silencing therapeutic effects. To facilitate the drug d...
BACKGROUND AND OBJECTIVE: The emerging N-acetylgalactosamine-small interfering RNA (GalNAc-siRNA) conjugates lead the way for liver-targeting delivery to exert gene-silencing therapeutic effects. To facilitate the drug development of GalNAc-siRNA, further detailed understanding of the key modality-specific mechanisms underlying the temporal discordance between pharmacokinetics and pharmacodynamics and how these processes can be extrapolated from animals to humans is needed. METHODS: A mechanistic minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK-PD) model for an investigational new apolipoprotein C-III (APOC3)-silencing GalNAc-siRNA (RBD5044) was developed using available pharmacokinetic/pharmacodynamic (PK/PD) data. The aim was to explore hepatic-targeting delivery processes, the PK/PD relationship, and interspecies translation. RESULTS: First, multiple PK/PD datasets from mice were satisfactorily fitted using the mPBPK-PD model. Second, we translated the mice model to the monkey model, validated it, and then extrapolated from mice and monkeys to humans to simulate the PK/PD characteristics. We then mechanistically summarized and proposed the essential in vivo delivery processes of GalNAc-siRNA after subcutaneous administration (termed "ADUEB": Absorption [into system circulation], Disposition [distribution to liver target and elimination], Uptake [into hepatocytes], Escape [from endosome and lysosome compartments], and Binding [with argonaute2 to form RNA-induced silencing complex]). The targeting delivery coefficients of these processes achieved with the model using RBD5044 and the published data of another GalNAc-siRNA (fitusiran) quantitatively reflected the delivery efficiency and rate-limiting factors in targeted hepatocytes. CONCLUSION: This study successfully constructed the mPBPK-PD model and conducted interspecies extrapolation for a GalNAc-siRNA targeting APOC3. Promising quantitative insights into a hepatic-targeted GalNAc-siRNA delivery system are provided to characterize the unique temporal disconnection of PK/PD properties and evaluate the key in vivo delivery processes. It will promote model-informed strategies and quantitative mechanistic understanding to support efficient drug development, evaluation, and clinical application of this modality in the future.
Scoping Review of Paediatric Population Pharmacokinetic Models of Morphine.
Stokes MA, Kamel NA, Festa MS … +2 more , Sandaradura I, Stocker SL
Clin Pharmacokinet · 2025 Jun · PMID 40310579 · Full text
OBJECTIVE AND PURPOSE: This scoping review aimed to summarise all available population pharmacokinetic models of morphine and its metabolites (morphine-3-glucoronide [M3G], morphine-6-glucoronide [M6G]) in children and d...
OBJECTIVE AND PURPOSE: This scoping review aimed to summarise all available population pharmacokinetic models of morphine and its metabolites (morphine-3-glucoronide [M3G], morphine-6-glucoronide [M6G]) in children and describe how morphine exposure varies across paediatric age groups and settings. Identifying the factors that contribute to pharmacokinetic variability may improve our understanding of a patient's pharmacodynamic response to morphine. METHODS: We searched Embase and MEDLINE databases from inception to 8 March 2024 for paediatric population pharmacokinetic models of morphine and its metabolites. Two reviewers independently screened abstracts and full texts and extracted the data. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. RESULTS: In total, 21 paediatric population pharmacokinetic models of morphine were identified; 12 studies also included morphine metabolites (M3G and/or M6G). Neonates and young children (< 6 years) were the most studied age groups (18/21; 86%), whereas older children (> 6 years) and adolescents (> 10 years) were included in only 6 of the 21 (29%) models. Morphine pharmacokinetics were most commonly described with two-compartment (52%) and one-compartment (38%) structure with first-order elimination. Several model covariates were identified: bodyweight, post-natal age for neonates, body temperature, therapeutic cooling, duration of mechanical ventilation, and genetic variation in drug transporters that mediate the uptake of morphine (e.g. OCT1). CONCLUSION: Several population pharmacokinetic models of morphine and its metabolites in paediatrics have been published across diverse patient groups. Bodyweight and age-related covariates emerged as the most common factors affecting clearance and distribution; other covariates, including mechanical ventilation, therapeutic cooling, and genetic variation, also impacted morphine pharmacokinetics. Further research should focus on validating the predictive accuracy of paediatric morphine models in different patient populations and the combined effect of covariates, such as those related to critical illness and genetic variation, on morphine pharmacokinetics.
Pharmacometabolomics Detects Various Unreported Metoprolol Metabolites in Urine of (Potential) Living Kidney Donors and Kidney Transplant Recipients.
Heddema WA, Hof MAJ, Sosnowski P … +4 more , Bakker SJL, Hopfgartner G, Klont F, TransplantLines Investigators
Clin Pharmacokinet · 2025 May · PMID 40285825 · Full text
BACKGROUND AND OBJECTIVE: Metoprolol is primarily metabolized via the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme, which underlies interindividual variation in conversion rates and may benefit from pharmacogenetics-d...
BACKGROUND AND OBJECTIVE: Metoprolol is primarily metabolized via the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme, which underlies interindividual variation in conversion rates and may benefit from pharmacogenetics-driven therapy personalization. However, the field relies heavily on knowledge of a drug's metabolism, often originating from early-phase clinical trials with single-dose administration in small samples of healthy volunteers. Pharmacogenetics could thus benefit from real-world drug metabolism studies. METHODS: We conducted a real-world drug metabolism study for metoprolol in 18 (potential) living kidney donors and 374 kidney transplant recipients from the Transplant Lines Food and Nutrition Biobank and Cohort Study (NCT02811835) using existing liquid chromatography-high resolution mass spectrometry pharmacometabolomic data. RESULTS: In both groups, we confirmed the presence of seven expected metabolites, including the high-abundance substances metoprolol acid and hydroxymetoprolol. We were unable to detect deisopropylmetoprolol and a metabolite known as "H 119/68". However, we did find putative further oxidized forms, namely the expected variant of deisopropylmetoprolol in which the primary amine is removed and the leftover methyl group is oxidized into a carboxylic acid ("H 104/83") and an unknown/unreported metoprolol metabolite that we refer to as "metoprolol benzoic acid". Moreover, we found nine other previously unknown/unreported metabolites, putatively reflecting N-glucuronidated metoprolol, four glucuronidated versions of hydroxymetoprolol, and a formylated, a glucuronidated, and two hydroxylated versions of metoprolol acid. Interestingly, the same metabolites were detected in potential living kidney donors and kidney transplant recipients, and metabolite profiles did not differ between both groups in principal component analysis. CONCLUSION: We found more metoprolol metabolites than previously reported, calling for replication studies and evaluation of pharmacogenetic testing approaches to realize safer, more effective metoprolol therapy.
Variability in Meropenem Distribution and Clearance in Children with Sepsis: Population-Based Pharmacokinetics with Assessment of Renal Biomarkers.
Le J, Huynh J, Vo B … +10 more , Mai A, Mak RH, Momper JD, Capparelli EV, Harvey H, Avedissian S, Bradley E, Sitapati A, Singh K, Bradley JS
Clin Pharmacokinet · 2025 May · PMID 40272699 · Full text
BACKGROUND AND OBJECTIVE: Meropenem dosing to achieve therapeutic exposure in critically ill children with sepsis is challenging due to a spectrum of renal function, from augmented renal clearance (ARC) to acute kidney i...
BACKGROUND AND OBJECTIVE: Meropenem dosing to achieve therapeutic exposure in critically ill children with sepsis is challenging due to a spectrum of renal function, from augmented renal clearance (ARC) to acute kidney injury (AKI). The objective of this study was to define meropenem plasma concentrations and pharmacodynamic exposure metrics in children with septic shock during the first 3 days of PICU hospitalization. METHODS: We prospectively evaluated meropenem clearance (CL) and volume of distribution (V), innovatively assessing renal biomarkers (serum creatinine [SCr], serum cystatin C [SCys], and neutrophil gelatinase-associated lipocalin [SNgal]), in infants aged ≥ 4 weeks and children on intravenous (IV) meropenem 20 mg/kg every 8 h from 2019 to 2023. Cases with sepsis were matched to controls without sepsis. RESULTS: Analysis included 27 participants (19 cases and 8 controls) with 309 meropenem serum concentrations. Median age was 11.8 (range 0.6-19.6) years, weight 36.3 (7.2-98.0) kg, SCr 0.33 (0.09-2.57) mg/dL, SCys 451.1 (178.3-1824.1) ng/mL, and SNgal 180.7 (23.2-1403.0) ng/mL. A 2-compartment, population pharmacokinetic (PK) model via NONMEM best described data, with weight on V and allometric scaling on CL. Using the final model with SCys in V and estimated glomerular filtration rate (eGFR)-MS in CL, the median V was 0.23 (range 0.07-0.57) L/kg and CL 0.15 (0.05-0.49) L/h/kg, with eGFR-MS 139 (23-365) mL/min/1.73 m from AKI to ARC. Meropenem clearance, V and eGFR-MS were significantly decreased in cases versus controls, with higher variability of eGFR-MS in cases. CONCLUSION: Wide variation in meropenem concentrations in children with sepsis as compared to those without sepsis prompt close monitoring of GFR and drug concentrations in this population.
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