Clinical Pharmacokinetics最新文献

Background and objective: This study aimed to develop a population pharmacokinetic model for cefepime in critically ill pediatric and young adult patients to inform dosing recommendations and to evaluate the model's predictive performance for model-informed precision dosing.

Methods: Patients in the pediatric intensive care unit receiving cefepime were prospectively enrolled for clinical data collection and opportunistic plasma sampling for cefepime concentrations. Nonlinear mixed effects modeling was conducted using NONMEM. Allometric body weight scaling was included as a covariate with fixed exponents. Monte Carlo simulations determined optimal initial dosing regimens against susceptible pathogens. The model's predictions were evaluated with an external dataset.

Results: Data from 510 samples across 100 patients were best fit with a two-compartment model with first-order elimination. Estimated glomerular filtration rate and cumulative percentage of fluid balance were identified as significant covariates on clearance and central volume of distribution, respectively. Internal validation showed no model misspecification. External validation confirmed that bias and precision for both population and individual predictions were within commonly accepted ranges. Monte Carlo simulations suggested that the usual dose of 50 mg/kg may require a 3-h infusion or a 6-h dosing interval to keep concentrations above the Pseudomonas aeruginosa minimum inhibitory concentration (≤ 8 mg/L) throughout the dosing interval for patients with normal or augmented renal clearance.

Conclusion: A cefepime population pharmacokinetic model for critically ill pediatric patients was successfully developed, accounting for patient renal function, fluid status, and body size, using real-world data. The model was internally and externally validated for use in optimal dosing simulations and model-informed precision dosing.

Background: Atrial fibrillation (AF) has multiple cardio-metabolic comorbidities, including obesity. The use of direct oral anticoagulants (DOACs) in patients with AF and obesity is still uncertain owing to the concern of possible ineffective DOAC plasma concentration. We evaluated the peak and trough plasma concentrations of DOACs in AF patients with different degrees of obesity.

Methods: Observational single-center study including patients with obesity and AF, between April 2022 and April 2024. Obesity was defined as body mass index (BMI) ≥ 30.0 kg/m². The 2-hour peak and trough DOAC plasma concentrations were assessed. Intake of DOAC was verified on site. Multivariable logistic regression analysis was used to assess the odds ratio (OR) and 95% confidence interval (95% CI) of factors associated with below-range trough concentration (BRTC) and below-range peak concentration (BRPC).

Results: In total, 160 patients (33.8% women) with a mean age of 73.2 ± 9.1 years were included. The median BMI was 32.3 kg/m². DOACs prescribed were apixaban (46.8%), rivaroxaban (21.8%), dabigatran (16.4%), and edoxaban (15.0%); 18.1% and 14.4% had BRTC and BRPC concentrations, respectively. Patients with BRTC were more frequently treated with edoxaban and dabigatran and had a higher BMI. On multivariable logistic regression analysis, dabigatran [hazard ratio (HR) 3.039, 95% CI 1.155-7.999, p = 0.024) and BMI ≥ II class (OR 2.625, 95% CI 1.087-6.335, p = 0.032] were associated with BRTC. Dabigatran (OR 4.296, 95% CI 1.523-12.120, p = 0.006) and apixaban (OR 0.277, 95% CI 0.096-0.802, p = 0.018) were directly and inversely associated with BRPC, respectively.

Conclusions: A nonnegligible proportion of patients with obesity and AF have below-range plasma concentrations of DOACs. Assessment of DOAC plasma concentration in obesity class ≥ II may be useful in these patients.

Background and objectives: This study investigates the pharmacokinetics (PK) of entrectinib and its metabolite M5 (CYP3A4 substrates) in patients with hepatic impairment (HI) and applies physiologically based pharmacokinetic (PBPK) modelling to understand the observed changes mechanistically.

Method: After a single oral administration of entrectinib at 100 mg, measured plasma concentrations for entrectinib and M5 in control subjects and HI patients were compared to predictions made with Simcyp^®. Model sensitivity analyses explored the possible reasons for mismatches to observed data. Reduced oral absorption due to lower bile salt (BS) levels in the intestinal lumen in hepatic impairment was examined.

Results: Physiologically based pharmacokinetic model simulations overestimated the 80% increase in entrectinib area under the plasma concentration curve between 0h to infinity (AUC_inf) observed in patients with severe HI, predicting a > 2-fold rise. Observed maximal plasma concentration (C_max) increased by 25% from controls to mild HI but decreased by 61% from mild to severe HI. Although the model predicted C_max within a 2-fold range, there was a trend to greater over-prediction with increasing HI severity. For M5, PBPK modelling did not capture the observed trends well. The C_max and AUC_inf were overestimated in HI patients and the trend to reduction of C_max with minimal change in AUC_inf with increasing severity of HI was not well captured. Decreasing Simcyp^® default luminal BS concentrations by 2-, 6-, and 8.7-fold for mild, moderate, and severe HI improved the predictions for both entrectinib and M5.

Conclusion: Physiologically based pharmacokinetic model simulations tended to overestimate the observed moderate changes in entrectinib exposures due to HI. For improved prediction of poorly soluble lipophilic drugs like entrectinib there is a need for PBPK models of HI to account for additional pathophysiological changes such as reduced intestinal BS levels.

Trial registration: NCT number: NCT04226833.

Background and objective: Aficamten, a small-molecule, selective cardiac myosin inhibitor, is under development for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Aficamten is primarily eliminated by hepatic metabolism with renal excretion playing a minor role. The objective of this investigation was to evaluate the pharmacokinetics (PK) of aficamten in moderate hepatic impairment or mild to moderate renal impairment to inform dosing recommendations in HCM patients with mild or moderate hepatic impairment or mild to moderate renal impairment.

Methods: The impact of hepatic impairment on the PK of single-dose aficamten 20 mg was evaluated in a phase 1 single-dose, open-label, parallel-group study, in healthy participants with moderate (n = 8) hepatic impairment (Child-Pugh B classification) versus participants with normal hepatic function (n = 8). Safety was monitored throughout. The effect of renal impairment on aficamten PK was assessed using population PK (PopPK) modelling of phase 2/3 clinical data in patients with oHCM.

Results: Aficamten PK was similar in participants with moderate hepatic impairment and those with normal hepatic function. No serious or severe treatment-emergent adverse events or clinically significant laboratory abnormalities were reported. There were no clinical meaningful differences in aficamten exposure in patients with oHCM with mild or moderate renal impairment and those with normal renal function.

Conclusions: No clinically relevant changes in aficamten PK were observed in participants with moderate hepatic impairment. Population PK analysis indicated mild or moderate renal impairment and had no statistically or clinically significant impact on aficamten PK in patients with oHCM. Aficamten dose adjustment may not be necessary in patients with mild or moderate hepatic or renal impairment.

Objectives: Pharmacokinetic (PK) boosting is the intentional use of strong inhibitors of metabolic enzymes or transporters to boost the systemic exposure of a therapeutic drug. PK boosting is expanding to therapeutic areas outside human immunodeficiency virus (HIV) therapy. Data on the PK of the booster cobicistat and its effect on CYP3A-substrates outside of HIV therapy are lacking. This study aimed to describe the PK of once- and twice-daily cobicistat regimens in healthy volunteers and patients with rheumatoid arthritis, cancer, or HIV infection and to investigate the interplay between cobicistat and the anticancer drug olaparib.

Methods: Cobicistat levels from 683 samples from 66 subjects in four clinical trials were included in the analysis. For olaparib, 261 samples from 12 subjects from one trial were included. Population PK analysis was performed by nonlinear mixed-effects modelling.

Results: Both cobicistat and olaparib PK were adequately described by a well-stirred liver model with one central compartment and Erlang type absorption. Cobicistat PK was similar across patient populations and dosing regimens. Cobicistat increased olaparib prehepatic bioavailability 1.65-fold (RSE 6%) and decreased intrinsic clearance 0.34-fold (RSE 6.5%). A correlation between olaparib PK and cobicistat exposure could not be identified. The interindividual variability in olaparib clearance was lower with cobicistat than without cobicistat.

Conclusions: The developed pharmacokinetic models adequately described cobicistat and olaparib plasma concentrations. PK boosting with cobicistat at 150 mg twice daily led to an increase in olaparib bioavailability and decrease in clearance. This effect was not correlated with cobicistat exposure, which may reflect saturation of the boosting effect of cobicistat at this dose.

Trial registration numbers (date of registration): NCT02565888 (30-09-2015), NCT00825929 (19-01-2009), Netherlands Trial Register NL7766 (18-12-2018), NCT05078671 (22-09-2021).

Introduction and objective: Physiologically based pharmacokinetic (PBPK) models are increasingly used to predict food effect (FE) but model parameterization is challenged by in vitro-in vivo (IVIV) disconnect and/or parameter nonidentifiability. To overcome these issues, we propose a simplified PBPK model, in which all solubility-driven processes are lumped into a single parameter, solubility, which is optimized against observed concentration-time data.

Methods: A set of commercially available biopharmaceutical classification system (BCS) II/IV compounds was selected to measure the solubility in a fasted state simulated intestinal fluid (FaSSIF) medium. The compounds were ranked from the lowest to the highest dose-adjusted FaSSIF solubility (FaSSIF/D) value and subdivided into three areas based on an upper and a lower limit: drugs with FaSSIF/D > upper limit having no FE, drugs with FaSSIF/D < lower limit having FE, and drugs between the limits said to be in the sensitivity range (SR), for which we tested the hypothesis that solubility-limited absorption (SLA) identified by simplified PBPK model can reliably predict positive FE if their exposures are not impacted by gut efflux or gut metabolism.

Results: We demonstrate, using a subset of drugs within SR for which PBPK models were available, that drugs with SLA exhibited a positive FE, while those with no SLA did not show FE.

Conclusions: This proposal allows for a reliable binary prediction of FE to enable timely decisions on the need for pilot FE studies as well as the timing of pivotal FE studies.