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

AIMS: 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). METHODS: 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 8 weeks (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. RESULTS: 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. CONCLUSION: 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 of Adalimumab in Juvenile Idiopathic Arthritis Patients: A Retrospective Cohort Study Using Clinical Care Data.

BACKGROUND AND OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disorder that primarily affects the joints in children. Notably, it is known to co-occur with uveitis. Adalimumab, a monoclonal anti-TNF antibody, is effective in treating both conditions. A deeper understanding of the pharmacokinetics (PK) of adalimumab in JIA is crucial to advance in more personalized treatment approaches. The objective of this study is to evaluate the population PK profile of adalimumab in JIA and to explain causes for its variability. MATERIALS AND METHODS: Adalimumab and antidrug antibody concentrations were retrospectively retrieved from the charts of patients with JIA. Initially, five literature-based population PK models of adalimumab were evaluated to assess their ability to describe the observed concentration-time profiles in the JIA cohort. These models included one specifically for the pediatric Crohn's disease population and four derived from studies in adult populations in healthy subjects and rheumatoid arthritis patients. Subsequently, a novel population PK model tailored to the JIA population was developed using NONMEM software. Monte Carlo simulations were then conducted utilizing the final PK model to visualize the concentration-time profile of adalimumab in patients with JIA and the impact of covariates. RESULTS: A cohort of 50 patients with JIA with 78 available adalimumab samples was assessed. The mean age was 11.8 ± 3.9 years, with a median body weight of 49 kg (interquartile range 29.4-59.8 kg). All literature models adequately described the concentration-time profiles in JIA. The best model, which was developed in patients with rheumatoid arthritis during the maintenance phase of treatment, served as a basis for estimating clearance in JIA, resulting in a value of 0.37 L per day per 70 kg. Patient body weight, antidrug antibodies, methotrexate use, CRP level, and comorbidity of uveitis were found to have a significant impact on adalimumab clearance, and these reduced the inter-patient variability from 58.6 to 28.0%. On steady state in the simulated patient population, the mean trough level was 7.4 ± 5.5 mg/L. The two dosing regimens of 20 and 40 mg every other week, based on patients' body weight, resulted in comparable simulated overall drug exposure. CONCLUSIONS: Five literature models effectively described adalimumab PK in this pediatric cohort, highlighting the potential for extrapolating existing models to the pediatric population. The new JIA model confirmed the effect of several known covariates and found a novel association for drug clearance with methotrexate use (lower) and uveitis (higher), which might have clinical relevance for personalized dosing in JIA.

On inductive biases for the robust and interpretable prediction of drug concentrations using deep compartment models.

Conventional pharmacokinetic (PK) models contain several useful inductive biases guiding model convergence to more realistic predictions of drug concentrations. Implementing similar biases in standard neural networks can be challenging, but might be fundamental for model robustness and predictive performance. In this study, we build on the deep compartment model (DCM) architecture by introducing constraints that guide the model to explore more physiologically realistic solutions. Using a simulation study, we show that constraints improve robustness in sparse data settings. Additionally, predicted concentration-time curves took on more realistic shapes compared to unconstrained models. Next, we propose the use of multi-branch networks, where each covariate can be connected to specific PK parameters, to reduce the propensity of models to learn spurious effects. Another benefit of this architecture is that covariate effects are isolated, enabling model interpretability through the visualization of learned functions. We show that all models were sensitive to learning false effects when trained in the presence of unimportant covariates, indicating the importance of selecting an appropriate set of covariates to link to the PK parameters. Finally, we compared the predictive performance of the constrained models to previous relevant population PK models on a real-world data set of 69 haemophilia A patients. Here, constrained models obtained higher accuracy compared to the standard DCM, with the multi-branch network outperforming previous PK models. We conclude that physiological-based constraints can improve model robustness. We describe an interpretable architecture which aids model trust, which will be key for the adoption of machine learning-based models in clinical practice.

Correlation between trough concentration and AUC for elexacaftor, tezacaftor and ivacaftor.

Therapeutic drug monitoring (TDM) of elexacaftor, tezacaftor, ivacaftor (ETI) could be a useful tool to increase efficacy and decrease the risk of adverse effects in people with Cystic Fibrosis (pwCF). It is however unclear whether drug exposure should be monitored by assessment of trough (Cmin) levels or determination of the area under the curve (AUC). Hence, in this study the correlation between measured Cmin concentration and AUC was evaluated. Serial plasma samples, including Cmin, were drawn after administration of ETI in order to calculate the AUC and assess the correlation between the two parameters. A linear correlation between Cmin and AUC0-24h was found, with Pearson's r correlation coefficients of 0.963, 0.908 and 0.860 for elexacaftor, tezacaftor and ivacaftor, respectively. Exposure of ETI may be monitored by assessment of Cmin levels.

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia.

AIMS: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. METHODS: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400-600 mg*h/L was used as target range. RESULTS: Sixteen patients received vancomycin (median gestational age: 41 [range: 38-42] weeks, postnatal age: 4.4 [2.5-5.5] days, birth weight: 3.5 [2.3-4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20-0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. CONCLUSION: Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.

Smaller nadroparin dose reductions required for patients with renal impairment: A multicenter cohort study.

BACKGROUND: Guidelines advise 50 % and 25 % dose reduction of the therapeutic nadroparin dose (86 IU/kg) in patients with eGFR 15-29 and 30-60 ml/min respectively. For monitoring, peak anti-Xa levels are suggested. Data lack whether this results in therapeutic anti-Xa levels or in anti-Xa levels that are comparable to those of patients without renal impairment. AIMS: To determine dose ranges in patients with renal impairment that result in therapeutic anti-Xa levels and to determine the percentage of the 86 IU/kg dose that results in anti-Xa levels normally occurring in patients without renal impairment. METHODS: A retrospective cohort study was conducted in five hospitals. Patients ≥18 years of age, with an eGFR ≥ 15 ml/min were included. The first correctly sampled peak (i.e. 3-5 h after ≥ third administration, regardless of dose per patient) was included. Simulated prediction models were developed using multiple linear regression. RESULTS: 770 patients were included. eGFR and hospital affected the association between dose and anti-Xa level. The doses for peak anti-Xa levels of 0.75 IU/ml differed substantially between hospitals and ranged from 55 to 91, 65-359 and 68-168 IU/kg in eGFR 15-29, 30-60 and > 60 ml/min/1.73m2, respectively. In eGFR 15-29 and 30-60 ml/min/1.73m2, doses of 75 % and 91 % of 86 IU/kg respectively, were needed for anti-Xa levels normally occurring in patients with eGFR > 60 ml/min. CONCLUSION: We advise against anti-Xa based dose-adjustments as long as anti-Xa assays between laboratories are not harmonized and an anti-Xa target range is not validated. A better approach might be to target levels similar to eGFR > 60 ml/min/1.73m2, which are achieved by smaller dose reductions.

A Generative and Causal Pharmacokinetic Model for Factor VIII in Hemophilia A: A Machine Learning Framework for Continuous Model Refinement.

In rare diseases, such as hemophilia A, the development of accurate population pharmacokinetic (PK) models is often hindered by the limited availability of data. Most PK models are specific to a single recombinant factor VIII (rFVIII) concentrate or measurement assay, and are generally unsuited for answering counterfactual ("what-if") queries. Ideally, data from multiple hemophilia treatment centers are combined but this is generally difficult as patient data are kept private. In this work, we utilize causal inference techniques to produce a hybrid machine learning (ML) PK model that corrects for differences between rFVIII concentrates and measurement assays. Next, we augment this model with a generative model that can simulate realistic virtual patients as well as impute missing data. This model can be shared instead of actual patient data, resolving privacy issues. The hybrid ML-PK model was trained on chromogenic assay data of lonoctocog alfa and predictive performance was then evaluated on an external data set of patients who received octocog alfa with FVIII levels measured using the one-stage assay. The model presented higher accuracy compared with three previous PK models developed on data similar to the external data set (root mean squared error = 14.6 IU/dL vs. mean of 17.7 IU/dL). Finally, we show that the generative model can be used to accurately impute missing data (< 18% error). In conclusion, the proposed approach introduces interesting new possibilities for model development. In the context of rare disease, the introduction of generative models facilitates sharing of synthetic data, enabling the iterative improvement of population PK models.

Peri-operative desmopressin combined with pharmacokinetic-guided factor VIII concentrate in non-severe haemophilia A patients.

INTRODUCTION: Non-severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated. AIM: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients. METHODS: Non-severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri-operative combination treatment. In the single-arm DAVID study intravenous desmopressin (0.3 µg/kg) once-a-day was, after sampling, immediately followed by PK-guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK-guided combination treatment (intervention arm) or PK-guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL. RESULTS: In total 32 patients (33 procedures) were included. In the DAVID study (n = 21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n = 12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C > 1.00 IU/mL. CONCLUSION: Peri-operative combination treatment with desmopressin and PK-guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption.

Pharmacokinetic-Pharmacodynamic Modelling in Hemophilia A: Relating Thrombin and Plasmin Generation to Factor VIII Activity After Administration of a VWF/FVIII Concentrate.

BACKGROUND: Hemophilia A patients are treated with factor (F) VIII prophylactically to prevent bleeding. In general, dosage and frequency are based on pharmacokinetic measurements. Ideally, an alternative dose adjustment can be based on the hemostatic potential, measured with a thrombin generation assay (TGA), like the Nijmegen hemostasis assay. OBJECTIVE: The objective of this study was to investigate the predicted performance of a previously developed pharmacokinetic-pharmacodynamic model for FVIII replacement therapy, relating FVIII dose and FVIII activity levels with thrombin and plasmin generation parameters. METHODS: Pharmacokinetic and pharmacodynamic measurements were obtained from 29 severe hemophilia A patients treated with pdVWF/FVIII concentrate (Haemate P®). The predictive performance of the previously developed pharmacokinetic-pharmacodynamic model was evaluated using nonlinear mixed-effects modeling (NONMEM). When predictions of FVIII activity or TGA parameters were inadequate [median prediction error (MPE) > 20%], a new model was developed. RESULTS: The original pharmacokinetic model underestimated clearance and was refined based on a two-compartment model. The pharmacodynamic model displays no bias in the observed normalized thrombin peak height and normalized thrombin potential (MPE of 6.83% and 7.46%). After re-estimating pharmacodynamic parameters, EC50 and Emax values were relatively comparable between the original model and this group. Prediction of normalized plasmin peak height was inaccurate (MPE 58.9%). CONCLUSION: Our predictive performance displayed adequate thrombin pharmacodynamic predictions of the original model, but a new pharmacokinetic model was required. The pharmacodynamic model is not factor specific and applicable to multiple factor concentrates. A prospective study is needed to validate the impact of the FVIII dosing pharmacodynamic model on bleeding reduction in patients.

Infliximab Monotherapy vs Combination Therapy for Pediatric Crohn's Disease Exhibit Similar Pharmacokinetics.

BACKGROUND: The use of concomitant azathioprine may improve efficacy and pharmacokinetic (PK) properties of infliximab (IFX) but is also associated with an increased risk of adverse events. Proactive therapeutic drug monitoring (pTDM) of IFX monotherapy is an alternative strategy to improve PK. The aim of this study was to evaluate whether IFX with an immunomodulator (combo) has PK benefits over IFX-pTDM (mono) in pediatric Crohn's disease (CD). METHODS: This PK analysis included pediatric CD patients who started either IFX combo (TISKids study) or IFX mono with pTDM (REFINE cohort). Combo and mono IFX trough levels (TLs) and antibodies-to-infliximab were assessed at infusion 3, 4, and 5. A population PK model was built to compare IFX PK outcomes (clearance [CL], TLs and cumulative exposure) between combo and mono groups at infusion 4 and 5. Clinical response and steroid-free clinical remission (SFCR) was assessed at infusion 4 and 5. RESULTS: This study included 128 pediatric CD patients (66 mono and 62 combo). At infusion 5, there was no significant difference between mono and combo median TLs 4.1 µg/mL (2.1, 7.8) vs 5.9 µg/mL (3.2, 9.4; P = .14) or median CL 0.26 L/d (0.21, 0.32) vs 0.26 L/d (0.21, 0.33; P = .81). Mono patients had a lower SFCR rate at infusion 5 (53% [31 of 59] vs 80% [32 of 40]; P = .01). Clinical response rates were significantly higher among combo than mono patients at both infusion 4 and 5. CONCLUSIONS: This study suggests that there are no PK differences (TLs and CL) between combo and mono therapy in pediatric CD patients who started IFX.

This study compared the pharmacokinetics of infliximab combination therapy with azathioprine vs infliximab with proactive therapeutic drug monitoring as monotherapy among pediatric patients with Crohn's disease within the first 22 weeks. No pharmacokinetic differences were found between monotherapy and combination therapy.

Predictive Performance of a Gentamicin Pharmacokinetic Model in Term Neonates with Perinatal Asphyxia Undergoing Controlled Therapeutic Hypothermia.

BACKGROUND: Model validation procedures are crucial when population pharmacokinetic (PK) models are used to develop dosing algorithms and to perform model-informed precision dosing. We have previously published a population PK model describing the PK of gentamicin in term neonates with perinatal asphyxia during controlled therapeutic hypothermia (TH), which showed altered gentamicin clearance during the hypothermic phase dependent on gestational age and weight. In this study, the predictive performance and generalizability of this model were assessed using an independent data set of neonates with perinatal asphyxia undergoing controlled TH. METHODS: The external data set contained a subset of neonates included in the prospective observational multicenter PharmaCool Study. Predictive performance was assessed by visually inspecting observed-versus-predicted concentration plots and calculating bias and precision. In addition, simulation-based diagnostics, model refitting, and bootstrap analyses were performed. RESULTS: The external data set included 323 gentamicin concentrations of 39 neonates. Both the model-building and external data set included neonates from multiple centers. The original gentamicin PK model predicted the observed gentamicin concentrations with adequate accuracy and precision during all phases of controlled TH. Model appropriateness was confirmed with prediction-corrected visual predictive checks and normalized prediction distribution error analyses. Model refitting to the merged data set (n = 86 neonates with 935 samples) showed accurate estimation of PK parameters. CONCLUSIONS: The results of this external validation study justify the generalizability of the gentamicin dosing recommendations made in the original study for neonates with perinatal asphyxia undergoing controlled TH (5 mg/kg every 36 or 24 h with gestational age 36-41 and 42 wk, respectively) and its applicability in model-informed precision dosing.

Stepwise Introduction of Elexacaftor-Tezacaftor-Ivacaftor in Patients With Cystic Fibrosis and Liver Cirrhosis Child-Pugh A or B Using Clinical and Therapeutic Drug Monitoring: A Case Series.

PURPOSE: Cystic fibrosis (CF) is a monogenetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein and affecting multiple organs, including the lungs and liver. Almost 90% of people affected carry at least 1 Phe508del CFTR mutation. Medical treatment with the CFTR-modulating drug elexacaftor-tezacaftor-ivacaftor (ETI) has been proven to be efficacious in carriers of at least 1 Phe508del CFTR mutation. Use of ETI in patients with CF (pwCF) and liver cirrhosis is still controversial. Therefore, stepwise introduction of ETI in pwCF and liver cirrhosis Child-Pugh A or B was evaluated using clinical and therapeutic drug monitoring. METHODS: Seven consecutive pwCF received ETI. Four dosing steps were defined, at each of which the patients underwent clinical examination, routine blood tests, and therapeutic drug monitoring. Exposure of elexacaftor, tezacaftor, and ivacaftor was assessed by means of determination of AUC. FINDINGS: ETI was successfully introduced and maintained in all pwCF. In those with Child-Pugh B cirrhosis (n = 2), diminishment of the dose as recommended by the label resulted in AUC values that were lower than the mean AUC values in pwCF without hepatic impairment, as reported previously. IMPLICATIONS: Despite the limitations of this small case series, stepwise elevation of ETI dose did not induce clinical adverse effects or increases in serum liver test results under strict clinical follow-up and therapeutic drug monitoring, and may allow tolerable introduction of this therapy in pwCF and cirrhosis Child-Pugh A and possibly B.

ChatGPT in pharmacometrics? Potential opportunities and limitations.

The potential of using ChatGPT in pharmacometrics was explored in this study, with a focus on developing a population pharmacokinetic (PK) model for standard half-life factor VIII. Our results demonstrated that ChatGPT can be utilized to accurately obtain typical PK parameters from literature, generate a population PK model in R and develop an interactive Shiny application to visualize the results. ChatGPT's language generation capabilities enabled the development of R codes with minimal programming knowledge and helped to identify as well fix errors in the code. While ChatGPT presents several advantages, such as its ability to streamline the development process, its use in pharmacometrics also has limitations and challenges, including the accuracy and reliability of AI-generated data, the lack of transparency and reproducibility regarding codes generated by ChatGPT. Overall, our study demonstrates the potential of using ChatGPT in pharmacometrics, but researchers must carefully evaluate its use for their specific needs.

A new population pharmacokinetic model for recombinant factor IX-Fc fusion concentrate including young children with haemophilia B.

AIMS: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real-world data. METHODS: We collected prospective and retrospective data from patients with haemophilia B treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling. RESULTS: Real-world data were obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of -48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P < .01). CONCLUSIONS: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.

Benzylpenicillin concentrations in umbilical cord blood and plasma of premature neonates following intrapartum doses for group B streptococcal prophylaxis.

BACKGROUND AND METHOD: Dutch obstetrics guideline suggest an initial maternal benzylpenicillin dose of 2,000,000 IU followed by 1,000,000 IU every 4 h for group-B-streptococci (GBS) prophylaxis. The objective of this study was to evaluate whether concentrations of benzylpenicillin reached concentrations above the minimal inhibitory concentrations (MIC) in umbilical cord blood (UCB) and neonatal plasma following the Dutch guideline. RESULTS: Forty-six neonates were included. A total of 46 UCB samples and 18 neonatal plasma samples were available for analysis. Nineteen neonates had mothers that received intrapartum benzylpenicillin. Benzylpenicillin in UCB corresponded to concentrations in plasma drawn directly postpartum (R2 = 0.88, p < 0.01). A log-linear regression suggested that benzylpenicillin concentrations in neonates remained above the MIC threshold 0.125 mg/L up to 13.0 h after the last intrapartum dose. CONCLUSIONS: Dutch intrapartum benzylpenicillin doses result in neonatal concentrations above the MIC of GBS.

Methotrexate Polyglutamates Exposure - Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate.

Methotrexate polyglutamates (MTX-PG) concentrations in red blood cells (RBCs) have been suggested as a biomarker of response in patients with rheumatoid arthritis (RA) receiving low-dose MTX therapy. We investigated the association and interpatient variability between RBC-MTX-PG3-5 -exposure and response in patients with RA starting MTX. Data of three prospective cohorts were available. The relationship between exposure and Disease Activity Score in 28 joints (DAS28) was analyzed using a population pharmacokinetic-pharmacodynamic model. Relevant covariates were tested using full covariate modeling and backward elimination. From 395 patients, 3,401 MTX-PG concentrations and 1,337 DAS28 measurements were available between 0 and 300 days after MTX treatment onset. The developed model adequately described the time course of MTX-PG3-5 and DAS28. The median MTX-PG3-5 level at month 1 was 30.9 nmol/L (interquartile range (IQR): 23.6-43.7; n = 41) and at month 3: 69.3 nmol/L (IQR: 17.9-41.2; n = 351). Clearance of MTX-PG3-5 from RBCs was 28% lower (95% confidence interval (CI): 23.6-32.8%) in a woman and 10% lower (95% CI: 7.7-12.4%) in a 65-year-old compared with a 35-year-old patient. MTX-PG3-5 concentrations associated with DAS28: half-maximal effective concentration (EC50 ) was 9.14 nmol/L (95% CI: 4.2 nmol/L-14.1 nmol/L). EF at 80% (EC80 ) above 47 nmol/L was regarded as the optimal response. Independent of the MTX-PG 3-5 - response association, co-administration of disease-modifying antirheumatic drugs and corticosteroids improved response (additive effect on maximum effect (Emax )), whereas smoking, high body mass index and low albumin decreased Emax . In patients with RA starting MTX, RBC-MTX-PG3-5 was associated with clinical response. A dose increase is suggested when MTX-PG3-5 at month 1 is below 9.15 nmol/L, continued with the same dose when the concentration is above 47 nmol/L, and consider other treatment options above 78 nmol/L from 3 months onwards.

The road to implementation of pharmacokinetic-guided dosing of factor replacement therapy in hemophilia and allied bleeding disorders. Identifying knowledge gaps by mapping barriers and facilitators.

Clinical guidelines and expert groups recommend the use of pharmacokinetic (PK)-guided dosing of factor replacement therapy for the treatment of bleeding disorders, especially for patients with hemophilia. Although PK-guided dosing is increasingly applied, it is generally not considered standard clinical practice. The aim of this scoping review is to map barriers and facilitators for the implementation of PK-guided dosing in clinical practice and to identify knowledge gaps. A literature search was performed and 110 articles were included that describe PK-guided dosing in patients with bleeding disorders, mostly hemophilia A. We defined two overarching themes, efficacy and feasibility, and discuss five topics within each theme. For each topic, barriers, facilitators and knowledge gaps were described. Although consensus was found with regard to some topics, contradicting reports were found for others, especially with respect to the efficacy of PK-guided dosing. These contradictions highlight the need for future research to elucidate current ambiguities.

Limited sampling strategies for individualized BAX 855 prophylaxis in severe hemophilia A: in silico evaluation.

OBJECTIVE: Limited sampling strategies (LSS) lower the burden of pharmacokinetic (PK)-guided dosing, but an extensive evaluation of LSS for BAX 855 (Adynovi) is currently lacking. This study aimed to develop a LSS for BAX 855 and combine this with a LSS of a standard half-life (SHL) factor VIII (FVIII) concentrate in a clinical setting. METHODS: Individual PK parameters of BAX 855 were estimated for 10 000 virtual patients with severe hemophilia A using Monte Carlo simulations. Several LSS consisting of 2-6 samples were examined based on patient burden, bias and accuracy of clearance, elimination half-life, volume of distribution and trough levels at 72 h (C72). Analyses were performed separately for adults and children <12 years. RESULTS: The preferred LSS for BAX 855 consisted of three sampling points at 15-30 min, 48 h and 72 h for both adults (mean accuracy C72: 14.0% vs. 10.8% using six samples) and children (mean accuracy C72: 14.9% vs. 11.4% using six samples). The best strategy with two samples (peak, 48 h) resulted in an adequate, but lower accuracy than strategies with ≥3 samples (mean accuracy C72: 22.3%). The optimal combination of the LSS of SHL FVIII and BAX 855 led to six samples during four clinical visits. CONCLUSION: This in silico study has identified that two to three samples are necessary to estimate the individual PK of BAX-855 adequately. These samples can be collected in one or two clinical visits. When combining PK profiling of SHL FVIII and BAX 855, six samples during four clinical visits are needed.

Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Term Asphyxiated Neonates during Controlled Therapeutic Hypothermia.

Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T>MIC) (for efficacy purposes and 100% T>4×MIC and 100% T>5×MIC to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T>MIC during hypothermia (33.7°C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T>MIC during normothermia (36.7°C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T>4×MIC and 100% T>5×MIC are desired.

Pharmacokinetic/Pharmacodynamic Target Attainment of Ceftazidime in Adult Patients on General Wards with Different Degrees of Renal Function: A Prospective Observational Bicenter Cohort Study.

No prospective evidence exists on the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of ceftazidime in adult patients on general wards. We aimed to investigate whether the PK/PD target of ceftazidime (50% T > MIC) is attained in adult patients on general wards with adequate and impaired renal function receiving regular and guideline-recommended reduced doses of ceftazidime. In this observational, prospective, bicenter cohort study, adult patients admitted to a general ward receiving ceftazidime as part of standard care were included. Three blood samples per patient within 72 h after start of treatment were collected. Data were analyzed with nonlinear mixed effects modeling. The primary endpoint was target attainment of 50% T > MIC during the first 24 h of treatment (50% T0-24 > MIC). Forty patients were included from whom 121 blood samples were obtained. All 25/25 patients with adequate renal function, 9/10 patients with moderately impaired renal function (eGFR 30-50 mL/min/1.73 m2) and 5/5 patients with severe impaired renal function (eGFR < 30 mL/min/1.73 m2) attained 50% T0-24 > MIC when applying the clinical breakpoint MIC for Pseudomonas aeruginosa of 8 mg/L. The one patient not attaining the PK/PD target did not differ in any of the collected patients' characteristics, except that this patient was the oldest in the study population. However, age was not statistically significantly associated with clearance or volume of distribution in the population pharmacokinetic model and, therefore, not likely the cause for this patient not attaining the PK/PD target. Our results suggest ≥90% probability of the PK/PD target attainment of ceftazidime in patients on general wards with adequate and impaired renal function receiving regular and guideline-recommended reduced doses of ceftazidime for treatment of infections with Pseudomonas aeruginosa and all bacteria with lower MIC-values.