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- Effect of Amiodarone on Apixaban Exposure in Patients after Cardiac
Surgery—A Population Pharmacokinetic Study-
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Abstract: To investigate the effect of amiodarone on apixaban pharmacokinetics in cardiac surgery patients with postoperative atrial fibrillation.
PubDate: 2025-06-05
- Effect of Obesity on Pharmacokinetics of Lidocaine and its Active
Metabolites in Chinese Patients Undergoing Laparoscopic Bariatric Surgery:
A Prospective Clinical Study-
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Abstract: Background and Objective Obesity can alter the physiological profile of individuals, potentially impacting the pharmacokinetics of anesthetic agents. This study compared the pharmacokinetic profiles of lidocaine and its metabolites between obese patients and normal-weight patients following a single intravenous bolus during surgical operation, to inform dosing strategies for the obese Chinese population. Methods Twenty-nine obese patients scheduled for laparoscopic sleeve gastrectomy and 29 normal-weight patients for laparoscopic cholecystectomy were enrolled. Lidocaine (2%, 1.5 mg/kg) was administered intravenously to obese patients and normal-weight patients on the basis of adjusted body weight (ABW) and total body weight, respectively. Plasma samples were collected to analyze the pharmacokinetic profiles of lidocaine and its metabolites. Adverse events (AEs) were recorded throughout the study. Results Obese patients had a significantly longer half-life for lidocaine (2.27 ± 0.69 h vs 0.94 ± 0.16 h, p < 0.0001), a higher volume of distribution (105 ± 27.3 L vs 54.9 ± 14.0 L, p < 0.0001), and a lower clearance (33.6 ± 9.08 L/h vs 40.5 ± 8.67 L/h, p = 0.008) compared to normal-weight patients. Although exposure to lidocaine was similar between groups within 2 hours, obese patients had lower metabolite concentrations due to decreased metabolic capacity. The plasma concentrations in all patients remained below the toxic concentration of 5 μg/mL, and no serious lidocaine-related AEs were reported. Conclusions Obesity significantly affects the pharmacokinetics of lidocaine and its active metabolites, and administering lidocaine intravenously via ABW is safe and reasonable for obese patients. Clinical Trial Registration ChiCTR2200064980, 25 October 2022.
PubDate: 2025-06-04
- A Population Pharmacokinetic Analysis for Piperacillin/Tazobactam in
Patients with End-Stage Kidney Disease Undergoing Intermittent
Haemodialysis: Extension of a General-Purpose Model-
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Abstract: Background and Objective End-stage kidney disease (ESKD) patients undergoing haemodialysis (HD) require a dosing regimen that balances the low endogenous clearance with the additional dialyser clearance. This study aimed to expand a previously proposed general-purpose pharmacokinetic model for piperacillin/tazobactam with a new population of ESKD patients undergoing intermittent high-flux haemodialysis. Methods Inter- and intradialytic blood samples were collected in ESKD patients undergoing intermittent high-flux haemodialysis, in HD or haemodiafiltration (HDF) mode, who received piperacillin/tazobactam during routine care. The previous general-purpose model was expanded to reflect changes in the pharmacokinetics in the new patient population. A covariate search was performed focussing on factors that explained variability between patients in endogenous and dialysis clearance. Simulations were performed to determine the probability of target attainment with current dosing recommendations in this specific population. Results In 20 ESKD patients, 195 piperacillin/tazobactam concentrations were determined. The general-purpose model was successfully expanded, wherein endogenous piperacillin/tazobactam clearance in patients with/without residual diuresis was 63% (95% confidence interval [CI] 49.5–73.0%) and 78.6% (95% CI 66.3–86.4%) lower compared with the general population, respectively. Extraction ratios of piperacillin and tazobactam ranged from 64 to 80%. Differences in probability of target attainment (PTA) for piperacillin were observed between patients with normal kidney function and ESKD patients undergoing haemodialysis with current dosing recommendations. Conclusion We successfully expanded a general-purpose model to reflect the piperacillin/tazobactam pharmacokinetics in ESKD patients undergoing intermittent haemodialysis using high-flux dialysers. The current dosing recommendations provide inconsistent probability of target attainment in ESKD patients compared with the general population.
PubDate: 2025-06-03
- Population Cellular Kinetics of Idecabtagene Vicleucel in Patients with
Triple-Class–Exposed Relapsed/Refractory Multiple Myeloma-
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Abstract: Background Idecabtagene vicleucel (ide-cel, ABECMA) is an autologous, B-cell maturation antigen (BCMA)-directed, chimeric antigen receptor (CAR) T-cell therapy. The current modeling analyses aim to characterize the cellular kinetics (CK) of ide-cel and to assess the covariate effects impacting ide-cel cellular kinetics in patients with relapsed/refractory multiple myeloma. Methods A modified piecewise model was developed to characterize ide-cel CK through the nonlinear mixed effects method. The model parameterization was conducted using the ide-cel whole-blood transgene data in CK-evaluable subjects (N = 225) from the ide-cel arm of the study KarMMa-3 (NCT03651128). The structural model consists of an initial lag phase and then saturable cell expansion, followed by conversion from effector cells to memory cells and their elimination. Model simulations were performed to evaluate covariate effects on ide-cel exposure parameters. Results The piecewise CK model with saturable expansion sufficiently captured the clinically observed ide-cel transgene data. The simulations using the final population CK model suggested that the magnitude of covariate effects on ide-cel exposure parameters was considerably smaller than the intersubject variability in the population. Additional analyses revealed a negative effect of treatment-emergent immunogenicity on the ide-cel persistence. Apparent associations were identified between cellular kinetic parameters and clinical responses. Conclusions The cellular kinetics of ide-cel can be adequately described by the modified piecewise model. No clinically meaningful covariate effects on cellular kinetics were identified from this modeling study. The population CK model suggests that higher cell expansion rate and lower elimination rates of effector and memory cells were observed in patients with longer progression-free survival.
PubDate: 2025-06-03
- Population Pharmacokinetic Analysis of Enalapril and Enalaprilat in Newly
Treated Children with Heart Failure: Implications for Safe Dosing of
Enalapril (LENA Studies)-
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Abstract: Background Enalapril orodispersible minitablets (ODMT) have been authorised by the European Medicines Agency for the treatment of heart failure in children from birth to 17 years of age in 2023. Consequently, the use of enalapril in very young and angiotensin-converting enzyme inhibitor (ACEi) naïve patients is expected to increase. Objectives Simultaneous characterisation of the pharmacokinetics (PK) of enalapril and the active metabolite enalaprilat in ACEi naïve children with heart failure using a combined population pharmacokinetic (PopPK) model and identification of clinically relevant covariates for the dosing of enalapril in this population. Methods Data of ACEi naïve subjects from the European project ‘Labeling of Enalapril from Neonates up to Adolescents’ (LENA) were analysed using nonlinear mixed effects modelling. In the prospective, open-label, multicentre phase II/III PK bridging studies, children with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) received enalapril ODMT according to an age- and weight-dependent dosing regimen. Allometric scaling was implemented for the disposition parameters of enalapril and enalaprilat. Stepwise covariate modelling was used to test the covariates age, sex, serum creatinine and Ross score. The final model was validated using nonparametric bootstrap analysis. Simulations were performed to assess the impact of the covariates after the first dose and at steady state. Results The analysed dataset comprised 173 enalapril and 268 enalaprilat serum concentrations from 34 subjects aged 25 days to 2.1 years (median age = 0.3 years). A combined model consisting of a one-compartment model for enalapril coupled with a one-compartment model for enalaprilat with absorption lag was selected as the structural model. Covariate analysis revealed that the weight-adjusted apparent clearance of enalaprilat increases with increasing age and decreases with increasing serum creatinine. In addition, the weight-adjusted apparent volume of distribution of enalaprilat decreases with increasing Ross score. The simulations indicated that serum creatinine levels above the normal reference range, age and weight were clinically relevant covariates for both the first dose and the steady state dose of enalapril. Furthermore, the simulations indicated that the Ross score is a clinically relevant covariate for the first dose of enalapril. Conclusions The results of the PopPK analysis and simulations indicated that, in addition to the currently considered parameters of weight and renal function, the parameters of age and severity of heart failure should also be considered when dosing enalapril in children with heart failure. Trial Registration Trial registration number (date of registration): EudraCT 2015-002335-17 (30 November 2015), EudraCT 2015-002396-18 (30 November 2015). The trials were registered on the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu).
PubDate: 2025-06-03
- Utilizing Opportunistic Computed Tomography Imaging to Refine Lean Body
Weight Estimates in Patients with Obesity-
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Abstract: Introduction While dual-energy X-ray absorptiometry (DEXA) is the gold standard for measuring lean body weight (LBW), computed tomography (CT) provides muscle composition and distribution metrics that can refine LBW for better weight-based dosing. We explored how existing computed tomography (CT) images could be utilized to better estimate LBW. Methods Sixty-three adult patients (71.4% female) with a median age of 53.4 years and mean BMI of 36.84 having both DEXA and CT scans were retrospectively analyzed to assess the relationship between CT-based skeletal muscle variables and DEXA-derived LBW. Results Linear regression results revealed significant correlations. CT-derived skeletal muscle area (SMA) strongly predicted DEXA-derived LBW (p value
PubDate: 2025-06-01
- Clinical Pharmacology of Loop Diuretics in Critical Care
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Abstract: 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.
PubDate: 2025-05-30
- Population Pharmacokinetics for Belantamab Mafodotin Monotherapy and
Combination Therapies in Patients with Relapsed/Refractory Multiple
Myeloma-
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Abstract: Background and Objective Belantamab mafodotin is an antibody-drug conjugate (ADC) comprising a monoclonal antibody targeting B-cell maturation antigen (BCMA) conjugated to the microtubule inhibitor monomethyl auristatin F via a protease-resistant maleimidocaproyl linker (cysteine maleimidocaproyl monomethyl auristatin F [cys-mcMMAF]). Belantamab mafodotin monotherapy population pharmacokinetics (PopPK) were previously described in relapsed/refractory multiple myeloma (RRMM). This analysis aimed to further characterize the PopPK of belantamab mafodotin ADC and cys-mcMMAF when administered intravenously in patients with RRMM using data from monotherapy and combination therapy studies. Methods Data from belantamab mafodotin monotherapy trials (DREAMM-2 [NCT03525678], DREAMM-3 [NCT04162210], DREAMM-12 [NCT04398745], DREAMM-14 [NCT05064358]) and combination trials with lenalidomide/dexamethasone (DREAMM-6 [NCT03544281]) or bortezomib/dexamethasone (DREAMM-6, DREAMM-7 [NCT04246047]) were used to develop PopPK models using non-linear mixed-effect modeling. The models described ADC pharmacokinetics using a linear, two-compartment model with decreasing clearance (CL) over time described by a sigmoidal time function, and cys-mcMMAF pharmacokinetics using a linear two-compartment model with cys-mcMMAF input rate governed by proteolytic ADC degradation that was modulated by a drug-to-antibody ratio that declined exponentially after each dose. Models were externally validated using DREAMM-8 (NCT04484623) study data (belantamab mafodotin plus pomalidomide/dexamethasone). Results The analyses included 977 patients, with 8880 measurable ADC and 6354 measurable cys-mcMMAF concentrations. Final ADC model covariates included soluble BCMA (sBCMA), albumin, serum immunoglobulin G, body weight, and body mass index (BMI) all at baseline as well as race and combination therapy. The final cys-mcMMAF model included covariates of baseline sBCMA, serum immunoglobulin G, albumin, body weight, BMI, and race. Typical ADC parameter estimates were 0.926 L/day for initial CL, 10.8 L for steady-state volume of distribution, and 13.0 days for initial elimination half-life. Following monotherapy, CL was reduced by 33.2% to 0.619 L/day over time, resulting in an elimination half-life of 16.8 days. Following combination treatment, CL was reduced by 44.0% to 0.518 L/day, resulting in an elimination half-life of 19.1 days. Cys-mcMMAF had typical values of 642 L/day for CL and 12.3 L for the central volume of distribution. The models adequately described ADC/cys-mcMMAF pharmacokinetics as confirmed during external validation. Alternate models with β2 microglobulin in place of baseline sBCMA also described the pharmacokinetics well. Simulated cycle 1 ADC exposures were most affected by disease-related characteristics: greater disease burden resulted in lower exposure. Predicted cycle 1 ADC and cys-mcMMAF exposures were not meaningfully different between combinations and monotherapy. Mild-to-severe renal impairment, mild-to-moderate hepatic impairment according to National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification, age, ethnicity, region, prior treatments, and prior anti-CD38 therapy did not affect ADC or cys-mcMMAF pharmacokinetics or exposures. Conclusions The updated PopPK models adequately described ADC and cys-mcMMAF pharmacokinetics. Mild-to-severe renal impairment, mild-to-moderate hepatic impairment (NCI-ODWG), age, ethnicity, region, prior treatments, and prior anti-CD38 therapy did not significantly impact ADC or cys-mcMMAF pharmacokinetics, and combinations showed no meaningful difference in cycle 1 exposure compared with monotherapy.
PubDate: 2025-05-30
- Clinical Pharmacokinetics of Inhaled Drugs for Pulmonary Hypertension
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Abstract: 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.
PubDate: 2025-05-28
- Population Pharmacokinetic Analysis of an Octreotide Depot (CAM2029) in
the Treatment of Acromegaly-
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Abstract: 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).
PubDate: 2025-05-26
- Optimizing Nortriptyline Dosing: A Comparison between
Pharmacogenetics-Based, Phenotype-Based, and Standard Dosing-
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Abstract: 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 (χ2) tests. Variability in plasma concentrations was assessed using F-tests. Results Both pharmacogenetics-based (χ2 (1) = 8.0, p = 0.01) and phenotype-based dosing (χ2 (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 (χ2 (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.
PubDate: 2025-05-25
- Pharmacokinetic/Pharmacodynamic Modelling and Monte Carlo Simulations to
Predict Cytomegalovirus Viral Load in Pediatric Transplant Recipients
Treated with (val)Ganciclovir-
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Abstract: 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 AUC0-24 ≥ 40 mg·h/L achieved an 85.4% probability of undetectable viral load after 28 days of therapy. An AUC0-24> 30 mg·h/L provided 80.9% probability of reducing viral loads by − 1 log after 2 weeks. AUC0-24 values> 60 mg·h/L offered minimal incremental benefits. Conclusion The pharmacodynamic model accurately predicted observed data. Simulations indicated that maintaining a ganciclovir plasma AUC0-24 around 40–60 mg·h/L maximized antiviral efficacy. An AUC0-24> 60 mg·h/L might increase the risk of adverse events without providing additional efficacy.
PubDate: 2025-05-24
- Integrated Two-Analyte Population Pharmacokinetics Model of Patritumab
Deruxtecan (HER3-DXd) Monotherapy in Patients with Solid Tumors-
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Abstract: 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.
PubDate: 2025-05-23
- Comment on “Ticagrelor is Associated with Increased Rosuvastatin Blood
Concentrations in Patients Who Have Had a Myocardial Infarction”-
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PubDate: 2025-05-23
- Author’s Reply to Chan et al.: “Ticagrelor is Associated with
Increased Rosuvastatin Blood Concentrations in Patients Who Have Had a
Myocardial Infarction”-
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PubDate: 2025-05-23
- Pharmacokinetics and Lung Deposition After Administration of Inhaled
Mosliciguat (BAY 1237592): Results from Randomized Phase I Studies in
Healthy Men-
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Abstract: 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 (tmax) 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 (Cmax) 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 Cmax (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 tmax 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.
PubDate: 2025-05-22
- Population Pharmacokinetics of Elexacaftor, Tezacaftor and Ivacaftor in a
Real-World Cohort of Adults with Cystic Fibrosis-
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Abstract: 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 (AUC0–24h for elexacaftor and tezacaftor, and AUC0–12h 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.
PubDate: 2025-05-22
- Pharmacokinetics of Ivacaftor, Tezacaftor, Elexacaftor, and Lumacaftor in
Special Cystic Fibrosis Populations: A Systematic Review-
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Abstract: 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.
PubDate: 2025-05-21
- Exploring the Influence of Obesity and CYP2 C19 Genotype on Lansoprazole
Pharmacokinetics in Pediatric Patients: A Population Modeling Approach-
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Abstract: 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.
PubDate: 2025-05-16
- An Adult Population Pharmacokinetic Model to Simulate Subcutaneous
Administration of a Fixed Dose of Furosemide in Adolescents with Heart
Failure and Volume Overload-
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Abstract: 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.
PubDate: 2025-05-13
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