Estimation Of Clearance Research Articles

Population Pharmacokinetics of Casirivimab and Imdevimab in Pediatric and Adult Non-Infected Individuals, Pediatric and Adult Ambulatory or Hospitalized Patients or Household Contacts of Patients Infected with SARS-COV-2

IntroductionCasirivimab (CAS) and imdevimab (IMD) are two fully human monoclonal antibodies that bind different epitopes on the receptor binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and block host receptor interactions. CAS + IMD and was developed for the treatment and prevention of SARS-CoV-2 infections.MethodsA population pharmacokinetic (PopPK) analysis was conducted using pooled data from 7598 individuals from seven clinical studies to simultaneously fit concentration–time data of CAS and IMD and investigate selected covariates as sources of variability in PK parameters. The dataset comprised CAS + IMD-treated pediatric and adult non-infected individuals, ambulatory or hospitalized patients infected with SARS-CoV-2, or household contacts of patients infected with SARS-CoV-2.ResultsCAS and IMD concentration–time data were both appropriately described simultaneously by a two-compartment model with first-order absorption following subcutaneous dose administration and first-order elimination. Clearance estimates of CAS and IMD were 0.193 and 0.236 L/day, respectively. Central volume of distribution estimates were 3.92 and 3.82 L, respectively. Among the covariates identified as significant, body weight and serum albumin had the largest impact (20–34%, and ~ 7–31% change in exposures at extremes, respectively), while all other covariates resulted in small differences in exposures. Application of the PopPK model included simulations to support dose recommendations in pediatrics based on comparable exposures of CAS and IMD between different weight groups in pediatrics and adults following weight-based dosing regimens.ConclusionsThis analysis provided important insights to characterize CAS and IMD PK simultaneously in a diverse patient population and informed pediatric dose selection.

Feasibility of safe outpatient treatment in pediatric patients following intraventricular radioimmunotherapy with 131I-omburtamab for leptomeningeal disease

BackgroundRadiolabeled antibody 131I-omburtamab was administered intraventricularly in patients with leptomeningeal disease under an institutionally approved study (#NCT03275402). Radiation safety precautions were tailored for individual patients, enabling outpatient treatment based on in-depth, evidence-based recommendations for such precautions. The imperative advancement of streamlined therapeutic administration procedures, eliminating the necessity for inpatient isolation and resource-intensive measures, holds pivotal significance. This development bears broader implications for analogous therapies within the pediatric patient demographic.MethodsIntraventricular radioimmunotherapy (RIT) with 925–1850 MBq (25–50 mCi) of 131I-omburtamab was administered via the Ommaya reservoir, in designated rooms within the pediatric ambulatory care center. Dosimeters were provided to staff involved in patient care to evaluate exposure during injection and post-administration. Post-administration exposure rate readings from the patient on contact, at 0.3 m, and at 1 m were taken within the first 30 min, and the room was surveyed after patient discharge. Duration of radiation exposure was calculated using standard U.S. Nuclear Regulatory Commission (US NRC) regulatory guidance recommendations combined with mean exposure rates and whole-body clearance estimates. Exposure rate measurements and clearance data provided patient-specific precautions for four cohorts by age: < 3 y/o, 3–10 y/o, 10–18 y/o, and 18+.ResultsPost-administration exposure rates for patients ranged from 0.16 to 0.46 µSv/hr/MBq at 0.3 m and 0.03–0.08 µSv/hr/MBq at 1 m. Radiation exposure precautions ranged from 1 to 10 days after release for the four evaluated cohorts. Based on the highest measured exposure rates and slowest whole-body clearance, the longest precautions were approximately 78% lower than the regulatory guidance recommendations. Radiation exposure to staff associated with 131I-omburtamab per administration was substantially below the annual regulatory threshold for individual exposure monitoring.Conclusion131I-omburtamab can be administered on an outpatient basis, using appropriate patient-based radiation safety precautions that employ patient-specific exposure rate and biological clearance parameters. This trial is registered with the National Library of Medicine’s ClinicalTrials.gov. The registration number is NCT03275402, and it was registered on 7 September 2017. The web link is included here. https://clinicaltrials.gov/study/NCT03275402.

Population toxicokinetics of carbamazepine and its metabolite carbamazepine-10,11-epoxide in adults

ABSTRACT Background Carbamazepine is one of the most commonly used antiseizure medications. Although carbamazepine pharmacokinetics in epileptic patients is well described, much less is known about these processes in the patients who experienced self-poisoning episode by this drug. Therefore, the aim of our investigation was to perform population toxicokinetics of carbamazepine and its metabolite carbamazepine-10,11-epoxide in adults. Research design and methods Software program NONMEM and the ADVAN2 TRANS2 subroutine were used for establishing a population toxicokinetic model for the estimation of clearance and volume of distribution based on of the sum values of carbamazepine and carbamazepine-10,11-epoxide concentrations. Results Our results indicated that the adult patients’ ability to eliminate carbamazepine and carbamazepine-10,11-epoxide following acute carbamazepine self-poisoning was strongly associated with the high levels of CRP and ASP, as well as by the treatment with sedation. Conclusions Our study should provide better understanding of the toxicokinetics of carbamazepine taken in overdose and better management of patient population admitted to hospital.

Pharmacokinetics of Human Plasma-Derived Antithrombin in Pediatric Patients Supported on Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) support of critically ill pediatric patients is associated with increased risk of thromboembolic events, and unfractionated heparin is used commonly for anticoagulation. Given reports of acquired antithrombin (AT) deficiency in this patient population and associated concern for heparin resistance, AT activity measurement and off-label AT replacement have become common in pediatric ECMO centers despite limited optimal dosing regimens. We conducted a retrospective cohort study of pediatric ECMO patients (0 to <18 years) at a single academic center to characterize the pharmacokinetics (PK) of human plasma-derived AT. We demonstrated that a two-compartment turnover model appropriately described the PK of AT, and the parameter estimates for clearance, central volume, intercompartmental clearance, peripheral volume, and basal AT input under non-ECMO conditions were 0.338 dL/h/70 kg, 38.5 dL/70 kg, 1.16 dL/h/70 kg, 40.0 dL/70 kg, and 30.4 units/h/70 kg, respectively. Also, ECMO could reduce bioavailable AT by 50% resulting in 2-fold increase of clearance and volume of distribution. To prevent AT activity from falling below predetermined thresholds of 50% activity in neonates and 80% activity in older infants and children, we proposed potential replacement regimens for each age group, accompanied by therapeutic drug monitoring.

Dosimetry of [64Cu]FBP8: a fibrin-binding PET probe.

This study presents the biodistribution, clearance and dosimetry estimates of [64Cu]Fibrin Binding Probe #8 ([64Cu]FBP8) in healthy subjects. This prospective study included 8 healthy subjects to evaluate biodistribution, safety and dosimetry estimates of [64Cu]FBP8, a fibrin-binding positron emission tomography (PET) probe. All subjects underwent up to 3 sessions of PET/Magnetic Resonance Imaging (PET/MRI) 0-2 hours, 4h and 24h post injection. Dosimetry estimates were obtained using OLINDA 2.2 software. Subjects were injected with ~400 MBq of [64Cu]FBP8. Subjects did not experience adverse effects due to the injection of the probe. [64Cu]FBP8 PET images demonstrated fast blood clearance (half-life = 67 min) and renal excretion of the probe, showing low background signal across the body. The organs with the higher doses were: the urinary bladder (0.075 vs. 0.091 mGy/MBq for males and females, respectively); the kidneys (0.050 vs. 0.056 mGy/MBq respectively); and the liver (0.027 vs. 0.035 mGy/MBq respectively). The combined mean effective dose for males and females was 0.016 ± 0.0029 mSv/MBq, lower than the widely used [18F]fluorodeoxyglucose ([18F]FDG, 0.020mSv/MBq). This study demonstrates the following properties of the [64Cu]FBP8 probe: low dosimetry estimates; fast blood clearance and renal excretion; low background signal; and whole-body acquisition within 20 minutes in a single session. These properties provide the basis for [64Cu]FBP8 to be an excellent candidate for whole-body non-invasive imaging of fibrin, an important driver/feature in many cardiovascular, oncological and neurological conditions.

Estimation of minimum foot clearance using a single foot-mounted inertial sensor and personalized foot geometry scan

The real-world measurement of minimum foot clearance (mFC) during the swing phase of gait is critical in efforts to understand and reduce the risk of trip-and-fall incidents in populations with gait impairments. Past research has focused on measuring clearance of a single point on a person’s foot, typically the toe—however, this may overestimate mFC and may even be the wrong region of the foot in cases of gait impairments or interventions. In this work, we present a novel method to reconstruct the swing-phase trajectory of an arbitrary number of points on a person’s shoe and estimate the instantaneous height and location of whole-foot mFC. This is achieved using a single foot-mounted inertial sensor and personalized shoe geometry scan, assuming a rigid-body IMU-shoe system. This combination allows collection and analysis using out-of-lab tests, potentially including clinical environments. Validation of single marker location using the proposed method vs. motion capture showed height errors with bias less than 0.05 mm, and 95% confidence interval of − 8.18 to + 8.09 mm. The method is demonstrated in an example data set comparing different interventions for foot drop, and it shows clear differences among no intervention, functional electrical stimulation, and ankle–foot orthosis conditions. This method offers researchers and clinicians a rich understanding of a person’s gait by providing objective 3D foot kinematics and allowing a unique opportunity to view the regions of the foot where minimum clearance occurs. This information can contribute to a more informed recommendation of specific interventions or assistive technology than is currently possible in standard clinical practice.

Evaluation and Optimization of a Microcavity Plate-Based Human Hepatocyte Spheroid Model for Predicting Clearance of Slowly Metabolized Drug Candidates.

In vitro clearance assays are routinely conducted in drug discovery to predict in vivo clearance, but low metabolic turnover compounds are often difficult to evaluate. Hepatocyte spheroids can be cultured for days, achieving higher drug turnover, but have been hindered by limitations on cell number per well. Corning Elplasia microcavity 96-well microplates enable the culture of 79 hepatocyte spheroids per well. In this study, microcavity spheroid properties (size, hepatocyte function, longevity, culturing techniques) were assessed and optimized for clearance assays, which were then compared with microsomes, hepatocyte suspensions, two-dimensional-plated hepatocytes, and macrowell spheroids cultured as one per well. Higher enzyme activity coupled with greater hepatocyte concentrations in microcavity spheroids enabled measurable turnover of all 17 test compounds, unlike the other models that exhibited less drug turnover. Microcavity spheroids also predicted intrinsic clearance (CLint) and blood clearance (CLb) within threefold for 53% [9/17; average absolute fold error (AAFE), 3.9] and 82% (14/17; AAFE, 2.6) of compounds using a linear regression correction model, respectively. An alternate method incorporating mechanistic modeling that accounts for mass transport (permeability and diffusion) within spheroids demonstrated improved predictivity for CLint (12/17; AAFE, 4.0) and CLb (14/17; AAFE, 2.1) without the need for empirical scaling factors. The estimated fraction of drug metabolized by cytochrome P450 3A4 (fm,CYP3A4) using 3 μM itraconazole was within 25% of observed values for 6 of 8 compounds, with 5 of 8 compounds within 10%. In sum, spheroid cultures in microcavity plates permit the ability to test and predict clearance as well as fm,CYP3A4 of low metabolic turnover compounds and represent a valuable complement to conventional in vitro clearance assays. SIGNIFICANCE STATEMENT: Culturing multiple spheroids in ultralow attachment microcavities permits accurate quantitation of metabolically stable compounds in substrate depletion assays, overcoming limitations with singly cultured spheroids. In turn, this permits robust estimates of intrinsic clearance, which is improved with the consideration of mass transport within the spheroid. Incubations with 3 μM itraconazole enabled assessments of CYP3A4 involvement in hepatic clearance.

Model-Informed Precision Dosing of Intravenous Busulfan in Thai Pediatrics Undergoing Hematopoietic Stem Cell Transplantation.

Conditioning bifunctional agent, busulfan, is commonly used on children before hematopoietic stem cell transplantation. Currently, at the Ramathibodi hospital, Bangkok, Thailand, initial dosing is calculated according to age and body surface area, and 7 samples per day are used for therapeutic drug monitoring (TDM). This study aimed to identify the best strategies for individual dosages a priori from patient characteristics and a posteriori based on TDM. The pharmacokinetic data set consisted of 2018 plasma concentrations measured in 135 Thai (n = 135) pediatric patients (median age = 8 years) and were analyzed using a population approach. Body weight, presence of malignant disease, and genetic polymorphism of Glutathione S-transferase Alpha-1 (GSTA1) were predictors of clearance. The optimum sampling times for TDM concentration measurements were 0.25, 2, and 5 hours after a 3-hour infusion. This was sufficient to obtain a Bayesian estimate of clearance a posteriori. Simulations showed the poor performance of a priori formula-based dose calculations with 90% of patients demonstrating a 69%-151% exposure interval around the target. This interval shrank to 85%-124% if TDM was carried out only at day 1 and to 90%-116% with TDM at days 1 and 3. This comprehensive study reinforces the interest of TDM in managing interindividual variability in busulfan exposure. Therapeutic drug monitoring can reliably be implemented from 3 samples using the Bayesian approach, preferably over 2 days. If using the latter is not possible, the formulas developed herein could present an alternative in Thai patients.

Utility of Serum Procalcitonin and Its Clearance in Predicting Outcomes in COVID-19 Patients.

Introduction Identification of coronavirus disease 2019 (COVID-19) patients at risk of worse clinical outcomes is crucial to improving patient care. Various biochemical markers have been used to predict outcomes in such patients. We aimed to evaluate the role of serum PCT (procalcitonin) and the utility of PCT clearance (PCTc) in predicting the outcome of patients with COVID-19 illness. Methods We prospectively included 39 patients with severe or critical COVID-19 illness with an age equal to more than 18 years. In addition to routine baseline investigations, serum PCT was measured at admission (PCT1) and day 5 of hospitalization (PCT2). PCTc was calculated using the formula [Formula: see text]. Results We observed that serum PCT at admission was significantly higher in non-survivors (median: 1.9 ng/ml IQR: 0.51-4.23) compared to survivors (median 0.35 (IQR: 0.1-1.2), p 0.002). On serial serum-PCT estimation, non-survivors had persistently elevated serum-PCT (median PCT1:1.9 ng/ml (IQR: 0.51-4.23) to median PCT2: 1.9ng/ml (IQR: 0.83-2.72), p 0.51) than survivors (median PCT1:0.35ng/ml (IQR: 0.1-1.19) to median PCT2: 0.15ng/ml (IQR: 0.05-0.29), p 0.01). However, no difference in serum PCTc was observed between the two groups (median: 35.3% (IQR: 12.5-84.9) in survivors vs. 71.7% (33.3-91.7) in non-survivors, p = 0.165). Conclusion Serum PCT is a potential biochemical marker that could predict outcomes in COVID-19 patients. Measurement of serial serum PCT and estimation of PCT clearance may serve as better predictors than a single value; however, well-designed studies are required to identify the definite role of serum PCT in COVID-19 patients of varying severity.

Population pharmacokinetics of nirmatrelvir in Chinese patients with COVID-19: Therapeutic drug monitoring and dosing regimen selection in clinical practice

ObjectivesTo establish a population pharmacokinetics (PopPK) model of nirmatrelvir in Chinese COVID-19 patients and provide reference for refining the dosing strategy of nirmatrelvir in patients confirmed to be infected with SARS-CoV-2. MethodsA total of 80 blood samples were obtained from 35 mild to moderate COVID-19 patients who were orally administered nirmatrelvir/ritonavir tablets. The PopPK model of nirmatrelvir was developed using a nonlinear mixed effects modelling approach. The stability and prediction of the final model were assessed through a combination of goodness-of-fit and bootstrap method. The exposure of nirmatrelvir across various clinical scenarios was simulated using Monte Carlo simulations. ResultsThe pharmacokinetics of nirmatrelvir was well characterised by a one-compartment model with first-order absorption, and with creatinine clearance (Ccr) as the significant covariate. Typical population parameter estimates of apparent clearance and distribution volume for a patient with a Ccr of 95.5 mL·min−1were 3.45 L·h−1 and 48.71 L, respectively. The bootstrap and visual predictive check procedures demonstrated satisfactory predictive performance and robustness of the final model. ConclusionThe final model was capable of offering an early prediction of drug concentration ranges for different nirmatrelvir dosing regimens and optimise the dose regimen of nirmatrelvir in individuals with confirmed SARS-CoV-2 infection.

Diagnostic accuracy of estimated glomerular filtration rate in pediatric oncology patients.

Objective: To compare eGFR using different equations with 24-hour creatinine clearance Methodology: We collected data of standardized 24-hour creatinine clearance of pediatric oncology patients for a period of one year and compared the efficiency of various equations for estimation of creatinine clearance with it. For error estimation we used mean relative prediction error (MRPE) and root mean square error (RMSE) and for accuracy estimation we used Lin’s correlation. Results: Out of 100 study participants, 57 were males and 43 were females. Mean age of the population studied was 11.8 while mean BMI was 13.95. Most common tumor reported was osteosarcoma. Out of 18 equations evaluated only 5 showed an accuracy of 0.80 or more, while SEM of none of the equation is near to the desired value (zero). Minimum SEM was found to be for Schwartz (2012) equation. Conclusions: According to our study none of the equations in current clinical practices showed a good correlation with creatinine clearance adjusted according to body surface area. Keywords: eGFR, creatinine clarence, renal function, pediatric oncology.

Saliva monitoring of prednisolone in children with first onset steroid-sensitive nephrotic syndrome: Is it possible?

Prednisolone is the cornerstone of treatment for idiopathic nephrotic syndrome in children, but is associated with marked side-effects. Therapeutic drug monitoring using saliva would be a patient-friendly option to monitor prednisolone treatment. To assess the feasibility of saliva monitoring, we described the pharmacokinetics (PK) of unbound prednisolone in plasma and saliva of children with first onset steroid-sensitive nephrotic syndrome (SSNS). Children (age 2-16 years) with SSNS participating in a randomized, placebo-controlled trial with levamisole were treated with an 18-week tapering schedule of prednisolone. Five serial samples were collected at 4 (saliva) and 8weeks (saliva and plasma) after first onset. A nonlinear mixed-effects model was used to estimate the PK parameters of unbound prednisolone and the saliva-to-plasma ratio. Monte Carlo simulations were performed to assess the predictive performance of saliva monitoring. From 39 children, 109 plasma and 275 saliva samples were available. Estimates (relative squared error) of unbound plasma clearance and volume of distribution were 93 (5%) L h-1 70 kg-1 and 158 (7%) L 70 kg-1, respectively. Typical saliva-to-plasma ratio was 1.30 (8%). Monte Carlo simulations demonstrated that on basis of 4 saliva samples and a single plasma sample unbound plasma area-under-the-concentration-time curve can be predicted within 20% imprecision in 79% of the patients compared to 87% based on 4 plasma samples. Saliva proved to be a reliable and patient-friendly option to determine prednisolone plasma exposure in children with SSNS. This opens opportunities for further PK and pharmacodynamics studies of prednisolone in a variety of paediatric conditions.

Population pharmacokinetics and dosing optimization of perampanel in children with epilepsy: A real-world study.

The purposes of this study were to explore the pharmacokinetics of perampanel (PER) in children with epilepsy, identify factors that contribute to pharmacokinetic variations among subjects, evaluate the connection between PER exposure and clinical outcome, and establish an evidence-based approach for tailoring individualized antiepileptic treatment in this specific population. In this prospective study, PER plasma concentrations and genetic information on metabolic enzymes were obtained from 194 patients younger than 18 years. The disposition kinetics of PER in pediatric patients following oral dosing were characterized using nonlinear mixed effect models. The effective range for the plasma concentration of PER was determined by assessing the efficacy and safety of PER treatment and analyzing the relationship between drug exposure and clinical response. Monte Carlo simulations were then performed to evaluate and optimize the current dosing regimens. The pharmacokinetic profile of PER was adequately described by a one-compartment model with first-order absorption and elimination. Body weight, total bilirubin level, and concomitant oxcarbazepine were found to have significant influences on PER pharmacokinetics. Model estimates of apparent clearance and volume of distribution were .016 ± .009 L/h/kg and 1.47 ± .78 L/kg, respectively. The effective range predicted from plasma concentration data in responders was 215-862 μg/L. Dosing scenarios stratified according to essential covariates were proposed through simulation analysis. In this study, we captured the pharmacokinetic/pharmacodynamic characteristics of PER in pediatric epilepsy patients through analysis of real-world data and adopted a pharmacometric approach to support an individualized dosing strategy for PER in this specific population.

Cystatin C Outperforms Creatinine in Predicting Cefepime Clearance in Pediatric Stem Cell Transplant Recipients

BackgroundPediatric hematopoietic stem cell transplant (HSCT) patients are at risk of developing both sepsis and altered kidney function. Cefepime is used for empiric coverage post-HSCT and requires dose adjustment based on kidney function. Since cefepime's anti-microbial efficacy is determined by the time free concentrations exceed bacterial minimum inhibitory concentration (MIC), it is important to assess kidney function accurately to ensure adequate concentrations. Serum creatinine (SCr) is routinely used to estimate glomerular filtration rate (eGFR) but varies with muscle mass, which can be significantly lower in HSCT patients, making SCr an inaccurate kidney function biomarker. Cystatin C (CysC) eGFR is independent of muscle mass, though steroid use increases CysC. ObjectivesTo describe how eGFR impacts cefepime pharmacokinetic/pharmacodynamic (PK/PD) target attainment in pediatric HSCT patients, to investigate which method of estimating GFR (SCr, CysC, combined) best predicts cefepime clearance, and to explore additional predictors of cefepime clearance. Study DesignPatients admitted to the pediatric HSCT unit who received ≥2 cefepime doses were prospectively enrolled. We measured total cefepime peak/trough concentrations between the 2nd-4th cefepime doses and measured SCr and CysC if not already obtained clinically within 24h of cefepime samples. eGFRs were calculated with Chronic Kidney Disease in Children U25 equations. Bayesian estimates of cefepime clearance were determined with a pediatric cefepime PK model and PK software MwPharm++. Simple linear regression was used to compare cefepime clearance normalized to body surface area (BSA) to BSA-normalized SCr-, CysC-, and SCr-/CysC-eGFRs, while multiple linear regression was used to account for additional predictors of cefepime clearance. For target attainment, we assessed the percentage of time free cefepime concentrations exceeded 1x MIC (%fT>1x MIC) and 4x MIC (%fT>4x MIC) using a susceptibility breakpoint of 8 mg/L for Pseudomonas aeruginosa. ResultsWe enrolled 53 patients (ages 1-30 years, median 8.9 years). SCr- and CysC-eGFRs were lower in patients who attained 100% fT>1xMIC compared to those who did not attain this target: 115 vs 156 mL/min/1.73m2 (p=0.01) for SCr-eGFR and 73.5 vs 107 mL/min/1.73m2 (p<0.001) for CysC-eGFR. SCr-eGFR was weakly positively correlated with cefepime clearance (adjusted [a]r2=0.14), while CysC-eGFR and SCr-/CysC-eGFR had stronger positive correlations (ar2=0.30 CysC, ar2=0.28 combo. There was a weak, significant linear association between increasing CysC-eGFR and decreased %fT>1xMIC (ar2=0.32) and %fT>4xMIC (ar2=0.14). No patients with a CysC-eGFR >120 mL/min/1.73 m2 achieved 100% fT>1xMIC or 50% fT>4x MIC. In multiple regression models, underlying diagnosis of hemoglobinopathy (in all models) and being pre-transplant (in SCr and combined models) were associated with increased cefepime clearance, while concomitant use of calcineurin inhibitors was associated with decreased cefepime clearance in all models. Overall, the combo-eGFR model with timing pre-transplant, hemoglobinopathy, and use of calcineurin inhibitors had the best performance (ar2=0.63). ConclusionsCysC-based eGFRs (CysC alone and combined) predicted cefepime clearance better than SCr-eGFR, even after considering steroid use. Increasing CysC eGFR correlated with decreased probability of PD target attainment, raising concerns for underdosing at high eGFRs. CysC should be included when estimating kidney function to provide adequate dosing of cefepime in pediatric HSCT patients.

The Effect of Polymorphisms and Other Biomarkers on Infliximab Exposure in Paediatric Inflammatory Bowel Disease: Development of a Population Pharmacokinetic Model.

Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough concentrations for individualized dosing. The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance. This observational and ambispective single-centre study was conducted in paediatric patients with IBD treated with infliximab between July 2016 and July 2022 in the Paediatric Gastroenterology Service of the Hospital Universitari Vall d'Hebron (HUVH) (Spain). Demographic, clinical, and analytical variables were collected. Twenty SNPs potentially associated with variations in the response to infliximab plasma concentrations were analysed. infliximab serum concentrations and antibodies to infliximab (ATI) were determined by ELISA. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM). Thirty patients (21 males) were included. The median age (range) at the start of infliximab treatment was 13 years (16 months to 16 years). A total of 190 samples were obtained for model development (49 [25.8%] during the induction phase). The pharmacokinetics (PK) of infliximab were described using a two-compartment model. Weight, erythrocyte sedimentation rate (ESR), faecal calprotectin (FC), and the SNP rs1048610 (ADAM17) showed statistical significance for clearance (CL), and albumin for inter-compartmental clearance (Q). Estimates of CL1 (genotype 1-AA), CL2 (genotype 2-AG), CL3 (genotype 3-GG), Q, Vc, and Vp (central and peripheral distribution volumes) were 0.0066L/h/46.4kg, 0.0055L/h/46.4kg, 0.0081L/h/46.4kg, 0.0029L/h/46.4kg, 0.6750L/46.4kg, and 1.19L/46.4kg, respectively. The interindividual variability (IIV) estimates for clearance, Vc, and Vp were 19.33, 16.42, and 36.02%, respectively. A popPK model utilising weight, albumin, FC, ESR, and the SNP rs1048610 accurately predicted infliximab trough concentrations in children with IBD.

Targeted amplicon deep sequencing of ama1 and mdr1 to track within-host P. falciparum diversity throughout treatment in a clinical drug trial

Introduction Antimalarial therapeutic efficacy studies are routinely conducted in malaria-endemic countries to assess the effectiveness of antimalarial treatment strategies. Targeted amplicon sequencing (AmpSeq) uniquely identifies and quantifies genetically distinct parasites within an infection. In this study, AmpSeq of Plasmodium falciparum apical membrane antigen 1 (ama1), and multidrug resistance gene 1 (mdr1), were used to characterise the complexity of infection (COI) and drug-resistance genotypes, respectively. Methods P. falciparum-positive samples were obtained from a triple artemisinin combination therapy clinical trial conducted in 30 children under 13 years of age between 2018 and 2019 in Kilifi, Kenya. Nine of the 30 participants presented with recurrent parasitemia from day 26 (624h) onwards. The ama1 and mdr1 genes were amplified and sequenced, while msp1, msp2 and glurp data were obtained from the original clinical study. Results The COI was comparable between ama1 and msp1, msp2 and glurp; overall, ama1 detected more microhaplotypes. Based on ama1, a stable number of microhaplotypes were detected throughout treatment until day 3. Additionally, a recrudescent infection was identified with an ama1 microhaplotype initially observed at 30h and later in an unscheduled follow-up visit. Using the relative frequencies of ama1 microhaplotypes and parasitemia, we identified a fast (&lt;1h) and slow (&gt;5h) clearing microhaplotype. As expected, only two mdr1 microhaplotypes (NF and NY) were identified based on the combination of amino acid polymorphisms at codons 86 and 184. Conclusions This study highlights AmpSeq as a tool for highly-resolution tracking of parasite microhaplotypes throughout treatment and can detect variation in microhaplotype clearance estimates. AmpSeq can also identify slow-clearing microhaplotypes, a potential early sign of selection during treatment. Consequently, AmpSeq has the capability of improving the discriminatory power to distinguish recrudescences from reinfections accurately.

Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis.

Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups. Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM ® was used to analyze the data. Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin's absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid's clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide's clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts, as well as hospitalized patients who survived vs who died within 12 weeks of hospitalization.

Population Pharmacokinetics of Valproate in Children: The Importance of Total Daily Dose, Compliance and Co-Treatment

Abstract Valproate represents one of the most commonly used anticonvulsants worldwide, whose narrow therapeutic range and high potential for drug-drug interactions leads to pronounced intra- and inter-individual variability in plasma concentration and response. The aim of our study was to apply population pharmacokinetics analysis to comprehensively investigate and detect the most important factors affecting pharmacokinetics of valproate in Serbian children with epilepsy. This retrospective observational study was based on demographic and medical data retrieved from the medical records on epileptic patients treated with valproate at the pediatric department of the Clinical Centre, Kragujevac, Serbia. Valproate serum concentrations were obtained as a part of routine medical practice. Population pharmacokinetics analysis was performed by MonolixSuite 2019R1 (Lixoft, Antony, France) software, using one-compartment model with first order absorption and linear elimination. The study included 1642 valproate concentrations obtained from 232 patients, of which 201 (1420 concentrations) were included in the index set used for the modelling, while the other 31 (222 concentrations) were the validation set used for external validation of the final model. Covariate testing based on the whole index set revealed that only total daily valproate dose significanly affected the clearance of valproate: Cl (l/h)= 0.135×1.002DD. When only compliant patients were included, co-treatment with carbamazepine was shown to be of significance as well: Cl(l/h)=0.121×1.002DD×1.2CBZ. Our study demonstrated that valproate clearance correlates with total valproate daily dose. The influence of co-treatment with carbamazepine on valproate pharmacokinetics can be observed and used for clearance estimation only in compliant patients.

Therapeutic drug monitoring in pregnancy: Levetiracetam.

Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women. This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020-2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1-2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance. A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the 3rd trimester, the most significant C/D decrease was observed at the 1st trimester (slope = .85), with no significant change in the 2nd trimester (slope = .11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (μg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the 3rd trimester. LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period.

Improving In Vitro-In Vivo Extrapolation of Clearance Using Rat Liver Microsomes for Highly Plasma Protein-Bound Molecules.

It is common practice in drug discovery and development to predict in vivo hepatic clearance from in vitro incubations with liver microsomes or hepatocytes using the well-stirred model (WSM). When applying the WSM to a set of approximately 3000 Novartis research compounds, 73% of neutral and basic compounds (extended clearance classification system [ECCS] class 2) were well-predicted within 3-fold. In contrast, only 44% (ECCS class 1A) or 34% (ECCS class 1B) of acids were predicted within 3-fold. To explore the hypothesis whether the higher degree of plasma protein binding for acids contributes to the in vitro-in vivo correlation (IVIVC) disconnect, 68 proprietary compounds were incubated with rat liver microsomes in the presence and absence of 5% plasma. A minor impact of plasma on clearance IVIVC was found for moderately bound compounds (fraction unbound in plasma [fup] ≥1%). However, addition of plasma significantly improved the IVIVC for highly bound compounds (fup <1%) as indicated by an increase of the average fold error from 0.10 to 0.36. Correlating fup with the scaled unbound intrinsic clearance ratio in the presence or absence of plasma allowed the establishment of an empirical, nonlinear correction equation that depends on fup Taken together, estimation of the metabolic clearance of highly bound compounds was enhanced by the addition of plasma to microsomal incubations. For standard incubations in buffer only, application of an empirical correction provided improved clearance predictions. SIGNIFICANCE STATEMENT: Application of the well-stirred liver model for clearance in vitro-in vivo extrapolation (IVIVE) in rat generally underpredicts the clearance of acids and the strong protein binding of acids is suspected to be one responsible factor. Unbound intrinsic in vitro clearance (CLint,u) determinations using rat liver microsomes supplemented with 5% plasma resulted in an improved IVIVE. An empirical equation was derived that can be applied to correct CLint,u-values in dependance of fraction unbound in plasma (fup) and measured CLint in buffer.