Understanding hemoglobin contribution to high-dose methotrexate disposition-population pharmacokinetics in pediatric patients with hematological malignancies.

PURPOSE: The aim of the present study was to develop a population pharmacokinetic model for methotrexate (MTX) during high-dose treatment (HDMTX) in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) and to describe the influence of variability factors. METHODS: The study included 50 patients of both sexes (aged 1-18 years) who received 3 or 5 g/m2 of HDMTX. A nonlinear mixed effect modeling approach was applied for data analysis. Parameter estimation was performed by first-order conditional estimation method with interaction (FOCEI), whereas stepwise covariate modeling was used to assess variability factors. RESULTS: The final model is a two-compartment model that incorporates the effect of body surface area and the influence of hemoglobin and serum creatinine on MTX clearance (CL). Population pharmacokinetic values for a typical subject were estimated at 5.75 L/h/m2 for clearance (CL), 21.3 L/m2 for volume of the central compartment (V1), 8.2 L/m2 for volume of the peripheral compartment (V2), and 0.087 L/h/m2 for intercompartmental clearance (Q). According to the final model, MTX CL decreases with increasing serum creatinine, whereas a positive effect was captured for hemoglobin. A difference of almost 32% in MTX CL was observed among patients' hemoglobin values reported in the study. CONCLUSION: The developed population pharmacokinetic model can contribute to the therapy optimization during HDMTX in pediatric patients with ALL and NHL. In addition to renal function and body weight, it describes the influence of hemoglobin on CL, allowing better understanding of its contribution to the disposition of HDMTX.

Association of clozapine and norclozapine levels with patient and therapy characteristics-focus on interaction with valproic acid.

PURPOSE: The goal of the study was to examine clozapine (CLZ) and norclozapine (NCLZ) therapeutic drug monitoring (TDM) data and associated sources of pharmacokinetic variability, particularly the impact of valproic acid (VPA) use. METHODS: This study included 126 patients with psychiatric disorders on mono- or co-therapy with CLZ. Patients' data during routine TDM were collected retrospectively from clinical records. The descriptive and statistical analysis was computed using IBM SPSS Statistics software (version 22, NY, USA). Multiple linear regression, based on the last observations, was used to assess correlation between demographic characteristics, life habits and co-therapy with dose-corrected serum levels (C/D) of CLZ and NCLZ, as well as CLZ/NCLZ. RESULTS: A total of 295 CLZ concentrations were measured in 126 patients, with a mean of 275.5 ± 174.4 µg/L, while 124 NCLZ concentrations were determined in 74 patients, with a mean of 194.6 ± 149.8 µg/L. A statistically significant effect on ln-transformed CLZ C/D was confirmed for sex and smoking, whereas sex, smoking and VPA therapy were associated with ln-transformed NCLZ C/D. According to the final models, lower values of NCLZ C/D for about 45.9% can be expected in patients receiving VPA. Concomitant use of VPA was the only factor detected to contribute in CLZ/NCLZ variability. CONCLUSION: The results of this study may help clinicians interpret TDM data and optimize CLZ dosing regimens, especially in patients concomitantly treated with VPA. Our results show that VPA primarily decreases NCLZ levels, while alteration of the parent drug is not statistically significant.

Pharmacokinetic characterization, benefits and barriers of subcutaneous administration of monoclonal antibodies in oncology.

OBJECTIVE: Therapeutic monoclonal antibodies in oncology are slowly becoming the dominant treatment option for many different cancer types. The main route of administration, infusion, requires extensive product preparations, patient hospitalization and close monitoring. Patient comfort improvement, staff workload reduction and cost savings dictated the development of subcutaneous formulations. The aim of this review is to present pharmacokinetic characteristics of subcutaneous products, discuss the differences between intravenous and subcutaneous routes and to point out the advantages as well as challenges of administration route shift from the formulation development and pharmacometric angle. DATA SOURCES: Food and Drug administration's Purple book database and electronic medicines compendium were used to identify monoclonal antibodies in oncology approved as subcutaneous forms. Using keywords subcutaneous, monoclonal antibodies, pharmacokinetics, model, as well as specific drugs previously identified, both PubMed and ScienceDirect databases were researched. DATA SUMMARY: There are currently six approved subcutaneous onco-monoclonal antibodies on the market. For each of them, exposure to the drug was similar in relation to infusion, treatment effectiveness was the same, administration was well tolerated by the patients and costs of the medical service were reduced. CONCLUSION: Development of subcutaneous forms for existing and emerging new monoclonal antibodies for cancer treatment as well as shifting from administration via infusion should be encouraged due to patient preference, lower costs and overall lack of substantial differences in efficacy and safety between the two routes.

Methotrexate concentrations and associated variability factors in high dose therapy of children with acute lymphoblastic leukemia and non-Hodgkin lymphoma.

Monitoring and optimization procedures improved high dose methotrexate (HDMTX) treatment outcomes. However, there are still some concerns regarding unexplained concentration variability. The objective of this study was to evaluate drug concentrations and associated variability factors in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) on HDMTX. Fifty patients (aged 1-18 years), receiving in total 184 HDMTX cycles of 3 or 5 g/m2/24 h infusion, were included in the study. Comparisons of MTX concentrations and concentrations to dose ratio between two dosing groups were conducted by Mann-Whitney U test. Regression analysis was performed with transformed data to assess relationship between MTX concentration to dose ratio and patient characteristics, biochemical analysis and therapy data. Statistically significant difference in concentrations between 3 and 5 g/m2 dosing groups was detected only at 24 h after the start of infusion (p < 0.001), but not at 48 and 72 h (p > 0.05). There was no difference between dose-normalized concentrations. Regression analysis showed that 73.9% of variability in dependent variable can be explained by included variables: time since dose, creatinine clearance (CrCl), hemoglobin and certain concomitant therapy. Our results highlight the importance of not only renal function and concomitant therapy, but also hemoglobin in reducing the variation in MTX concentrations. Therefore, monitoring of aforementioned biochemical parameters during HDMTX is important not only to assess toxicity, but also in predicting their impact on drug level.

Characterizing HIV-Preventive, Plasma Tenofovir Concentrations-A Pooled Participant-level Data Analysis From Human Immunodeficiency Virus Preexposure Prophylaxis Clinical Trials.

BACKGROUND: Daily dosing of tenofovir disoproxil fumarate, with or without emtricitabine, has high efficacy in preventing human immunodeficiency virus (HIV) infection when individuals are adherent. The target protective plasma concentration of tenofovir (TFV), however, is not fully understood. The aim of this study is to estimate the protective TFV plasma concentration. METHODS: Participant data from TFV-based daily oral and topical active arms of phase 3 trials (iPrEx, VOICE, and Partners PrEP) were pooled (n = 2950). Individual specific risk scores (low and high risk) of acquiring HIV, based on an earlier placebo analysis, were created. Longitudinal TFV pharmacokinetics (PK), HIV outcome, individual risk scores and the effect of sex at birth data were integrated and analyzed using non-linear mixed effects models. RESULTS: Around 50% of the individuals were estimated to be adherent, which differed from self-reported adherence (∼90%) and large variation between longitudinal adherence patterns were identified. Following oral administration, the estimated protective TFV trough concentration was substantially higher in high-risk females (45.8 ng/mL) compared with high-risk males (16.1 ng/mL) and to low-risk individuals (∼7.5 ng/mL). Dosing simulations indicated that high-risk women require full adherence to maintain protective levels. CONCLUSIONS: Using the largest PK-HIV outcome database to date, we developed a population adherence-PK-risk-outcome model. Our results indicate that high-risk females need higher levels of plasma TFV to achieve HIV protection compared with males. HIV protection exceeds 90% in all populations if daily adherence is achieved.

Understanding variability in the pharmacokinetics of atypical antipsychotics - focus on clozapine, olanzapine and aripiprazole population models.

Antipsychotic medicines are widely used for the management of psychotic symptoms regardless of the underlying diagnosis. Most atypical antipsychotics undergo extensive metabolism prior to excretion. Various factors may influence their pharmacokinetics, particularly elimination, leading to highly variable drug concentrations between individual patients following the same dosing regimen. Population pharmacokinetic approach, based on nonlinear mixed effects modeling, is a useful tool to identify covariates explaining pharmacokinetic variability, as well as to characterize and distinguish unexplained residual and between-subject (interindividual) variability. In addition, this approach allows the use of both sparsely and intensively sampled data. In this paper, we reviewed the pharmacokinetic characteristics of clozapine, olanzapine and aripiprazole, focusing on a population modeling approach. In particular, models based on a nonlinear mixed effects approach performed by NONMEM® software in order to identify and quantify sources of pharmacokinetic variability are presented. Population models were identified through systematic searches of PubMed and sixteen studies were selected. Some of the factors identified that significantly contribute to variability in elimination among clozapine, olanzapine, and aripiprazole are demographic characteristics, body weight, genetic polymorphism, smoking and in some cases drug interactions. Scientific research based on pharmacometric modeling is useful to further characterize sources of variability and their combined effect.

Adjusted indirect comparisons to assess bioequivalence between generic clopidogrel products in Serbia.

AIMS: Generic products can be regarded as therapeutically equivalent and switchable with the reference product. However, switchability between generics is unknown, as direct comparisons between generics are not performed. The aim of this study was to investigate the bioequivalence between generic clopidogrel products by means of adjusted indirect comparisons (AICs). METHODS: AICs were conducted to assess bioequivalence between 4 generic clopidogrel products that are authorised in Serbia. Generics are considered equivalent to the reference if the 90% confidence intervals (CIs) for the ratios test/reference of the maximum concentration (Cmax ) and area under the curve up to the last measurable concentration (AUC0-t ) fall within the acceptance range 80.00-125.00%. However, for AICs between generics, the Canadian acceptance criterion for Cmax was employed, where only the point estimate of Cmax needs to be within 80.00-125.00%. RESULTS: The 90% CIs of the AICs demonstrated bioequivalence within 80.00-125.00% for all AUC0-t comparisons. The point estimates of Cmax in all AICs were also within this range. CONCLUSION: This study demonstrates that the bioavailability of these 4 generic clopidogrel products authorised in Serbia is very similar. Despite the limited power of AICs, bioequivalence was demonstrated for all 90% CIs of AUC0-t and all 90% CIs of Cmax comparisons were within or very close to the acceptance range, being able to comply with the acceptance criterion employed in Canada for Cmax . Therefore, these 4 generic clopidogrel products authorised in Serbia can be considered switchable with each other in clinical practice based on the adjusted indirect comparisons.

Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz.

Background: A monthly treatment course of dihydroartemisinin-piperaquine (DHA-PQ) effectively prevents malaria during pregnancy. However, a drug-drug interaction pharmacokinetic (PK) study found that pregnant human immunodeficiency virus (HIV)-infected women receiving efavirenz-based antiretroviral therapy (ART) had markedly reduced piperaquine (PQ) exposure. This suggests the need for alternative DHA-PQ chemoprevention regimens in this population. Methods: Eighty-three HIV-infected pregnant women who received monthly DHA-PQ and efavirenz contributed longitudinal PK and corrected QT interval (QTc) (n = 25) data. Population PK and PK-QTc models for PQ were developed to consider the benefits (protective PQ coverage) and risks (QTc prolongation) of alternative DHA-PQ chemoprevention regimens. Protective PQ coverage was defined as maintaining a concentration >10 ng/mL for >95% of the chemoprevention period. Results: PQ clearance was 4540 L/day. With monthly DHA-PQ (2880 mg PQ), <1% of women achieved defined protective PQ coverage. Weekly (960 mg PQ) or low-dose daily (320 or 160 mg PQ) regimens achieved protective PQ coverage for 34% and >96% of women, respectively. All regimens were safe, with ≤2% of women predicted to have ≥30 msec QTc increase. Conclusions: For HIV-infected pregnant women receiving efavirenz, low daily DHA-PQ dosing was predicted to improve protection against parasitemia and reduce risk of toxicity compared to monthly dosing. Clinical Trials Registration: NCT02282293.

Investigation of factors influencing radioiodine (131I) biokinetics in patients with benign thyroid disease using nonlinear mixed effects approach.

PURPOSE: Radioiodine (131I) therapy is the common treatment option for benign thyroid diseases. The objective of this study was to characterize 131I biokinetics in patients with benign thyroid disease and to investigate and quantify the influence of patients' demographic and clinical characteristics on intra-thyroidal 131I kinetics by developing a population model. METHODS: Population pharmacokinetic analysis was performed using a nonlinear mixed effects approach. Data sets of 345 adult patients with benign thyroid disease, retrospectively collected from patients' medical records, were evaluated in the analysis. The two-compartment model of 131I biokinetics representing the blood compartment and thyroid gland was used as the structural model. RESULTS: Results of the study indicate that the rate constant of the uptake of 131I into the thyroid (ktu) is significantly influenced by clinical diagnosis, age, functional thyroid volume, free thyroxine in plasma (fT4), use of anti-thyroid drugs, and time of discontinuation of therapy before administration of the radioiodine (THDT), while the effective half-life of 131I is affected by the age of the patients. Inclusion of the covariates in the base model resulted in a decrease of the between subject variability for ktu from 91 (3.9) to 53.9 (4.5)%. CONCLUSIONS: This is the first population model that accounts for the influence of fT4 and THDT on radioiodine kinetics. The model could be used for further investigations into the correlation between thyroidal exposure to 131I and the outcome of radioiodine therapy of benign thyroid disease as well as the development of dosing recommendations.

Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients.

PURPOSE: The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients. METHODS: In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model. RESULTS: According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F. CONCLUSIONS: Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.

Application of Counter-propagation Artificial Neural Networks in Prediction of Topiramate Concentration in Patients with Epilepsy.

PURPOSE: The application of artificial neural networks in the pharmaceutical sciences is broad, ranging from drug discovery to clinical pharmacy. In this study, we explored the applicability of counter-propagation artificial neural networks (CPANNs), combined with genetic algorithm (GA) for prediction of topiramate (TPM) serum levels based on identified factors important for its prediction. METHODS: The study was performed on 118 TPM measurements obtained from 78 adult epileptic patients. Patients were on stable TPM dosing regimen for at least 7 days; therefore, steady-state was assumed. TPM serum concentration was determined by high performance liquid chromatography with fluorescence detection. The influence of demographic, biochemical parameters and therapy characteristics of the patients on TPM levels were tested. Data analysis was performed by CPANNs. GA was used for optimal CPANN parameters, variable selection and adjustment of relative importance. RESULTS: Data for training included 88 measured TPM concentrations, while remaining were used for validation. Among all factors tested, TPM dose, renal function (eGFR) and carbamazepine dose significantly influenced TPM level and their relative importance were 0.7500, 0.2813, 0.0625, respectively. Relative error and root mean squared relative error (%) and their corresponding 95% confidence intervals for training set were 2.14 [(-2.41) - 6.70] and 21.5 [18.5 - 24.1]; and for test set were -6.21 [(-21.2) - 8.77] and 39.9 [31.7 - 46.7], respectively. CONCLUSIONS: Statistical parameters showed acceptable predictive performance. Results indicate the feasibility of CPANNs combined with GA to predict TPM concentrations and to adjust relative importance of identified variability factors in population of adult epileptic patients.

Pharmacokinetic variability of amikacin after once-daily and twice-daily dosing regimen in full-term neonates.

The purpose of the study was to compare peak (Cpeak) and trough (Ctrough) amikacin levels after twice-daily (TD) or once-daily dosing (OD) in full-term neonates. Additionally, the study aimed to address amikacin pharmacokinetics and its variability. Data included 31 patients born on term. Amikacin daily dose was 15 or 20 mg/kg depending on the neonate's age. Patients randomly received amikacin every 12 or 24 h. In all patients corresponding Cpeak and Ctrough were taken. Volume of distribution (Vd), clearance (CL) and half-life (t1/2) were calculated. Mean Cpeak of 21.79 µg/ml in the TD group was statistically different from Cpeak of 36.39 µg/ml in the OD group. Average Ctrough in TD (5.67 µg/ml) was statistically different from the corresponding 3.99 µg/ml in the OD group. Mean amikacin Vd, CL, and t1/2 were 0.78 ± 0.38 l/kg, 86.99 ± 48.22 ml/h∙kg, and 6.81 ± 2.51 h, respectively. High interindividual pharmacokinetic variability was observed. Further analysis showed that neonatal age contributed to the pharmacokinetic parameters' values. Statistically significant difference in CL and t1/2 was observed between patients age ≤ 2 and > 2 days on therapy initiation. As expected, amikacin given OD achieved higher Cpeak and lower Ctrough than TD. Based on the results, observed variability in amikacin pharmacokinetics was possibly due to the renal maturation process.

Effect of Long-term Topiramate Therapy on Serum Bicarbonate and Potassium Levels in Adult Epileptic Patients.

BACKGROUND: Topiramate (TPM) is a sulfamate-substituted monosaccharide that is structurally different from other antiepileptic drugs. TPM inhibits carbonic anhydrase activity, which is associated with loss of bicarbonate from the kidney and consequently metabolic acidosis or electrolyte imbalance. OBJECTIVE: The objectives of the study were to investigate the influence of TPM therapy on bicarbonate and potassium levels in adult epileptic patients. METHODS: Data were collected from 59 adult patients on monotherapy or co-therapy of TPM and other antiepileptic drugs. Serum bicarbonate and potassium levels were available from all patients. Steady-state TPM trough concentrations were determined in blood samples by high-performance liquid chromatography. Data analysis was performed by SPSS software (version 17, Chicago, IL). RESULTS: Patients were divided into group A (duration of therapy shorter than or equal to 5 years) and group B (duration of therapy longer than 5 years). Significant difference (P < 0.05) in serum bicarbonate levels was observed between these 2 groups. Bicarbonate levels were linearly related to the TPM therapy duration. No correlation was found between the TPM dose or patient age and bicarbonate or potassium levels, as well as between therapy duration and potassium level. Linear regression analysis showed no significant association among 54 available TPM trough concentrations and bicarbonate or potassium levels. CONCLUSIONS: Results highlight the frequent occurrence of lower bicarbonate level associated with prolonged TPM therapy. Monitoring bicarbonate levels in patients on long-term TPM therapy might be useful.

Pharmacokinetics of lamotrigine in paediatric and young adult epileptic patients--nonlinear mixed effects modelling approach.

PURPOSE: The purpose of the study was to examine and describe adjunctive lamotrigine (LTG) pharmacokinetics in paediatric and young adult patients using a nonlinear mixed effects modelling (NONMEM) approach. METHODS: The study included 53 patients (age range 3-35 years) who were concomitantly treated with carbamazepine (CBZ) and/or valproic acid (VPA). A total of 70 blood samples corresponding to trough levels were available for analysis. Data were modelled, and the final model was evaluated using NONMEM and auxiliary software tools. RESULTS: The final LTG population model included the effects of concomitant drugs and patient's weight (WT) which stratified the population into three groups: ≤25 kg, >25 to <60 kg and ≥60 kg. Based on the final model, the estimated LTG oral clearance (CL/F) for a typical patient weighing ≤25 kg, >25 to <60 kg or ≥60 kg who was concomitantly treated with CBZ was estimated to be 3.28, 4.23, or 7.15 l/h, respectively. If a patient was concomitantly treated with CBZ + VPA, the CL/F decreased on average by 69.5 % relative to LTG + CBZ co-therapy. VPA was found to decrease the LTG CL/F by 87.6 % compared to co-therapy with only CBZ. CONCLUSION: The LTG population pharmacokinetic model developed in this study may be a reliable method for individualising the LTG dosing regimen in paediatric and young adult patients on combination therapy during therapeutic drug monitoring.

Integrating Clopidogrel's First-Pass Effect in a Joint Semi-Physiological Population Pharmacokinetic Model of the Drug and Its Inactive Carboxylic Acid Metabolite.

Clopidogrel (CLO), a pro-drug for preventing thrombotic events, undergoes rapid absorption and extensive metabolism, with approximately 85-90% converted to an inactive carboxylic acid metabolite (CLO-CA) and the remaining to an active thiol (CLO-TH). Few pharmacokinetic models for the drug and its metabolites exist, with most focusing on CLO-TH. Although CLO-CA is inactive, its predominant (compared to its parent drug and metabolites) presence in plasma underscores the importance of characterizing its formation and pharmacokinetic profile. This study aimed to characterize the process of the absorption of CLO and its conversion to CLO-CA via developing a population pharmacokinetic model. Individual participants' data from two bioequivalence studies were utilized. Extensive blood samples were collected at predetermined intervals, including 841 concentrations of CLO and 1149 of CLO-CA. A nonlinear, mixed-effects modelling approach using NONMEM® software (v 7.5) was applied. A one-compartment model was chosen for CLO, while a two-compartment proved optimal for CLO-CA. Absorption from the depot compartment was modeled via two transit compartments, incorporating transit rate constants (Ktr). A semi-physiological model explained the first-pass effect of CLO, integrating a liver compartment. The estimated mean transit times (MTTs) for the studies were 0.470 and 0.410 h, respectively. The relative bioavailability for each study's generic medicine compared to the reference were 1.08 and 0.960, respectively. Based on the estimated parameters, the fractions metabolized to inactive metabolites (FiaM_st1 and FiaM_st2) were determined to be 87.27% and 86.87% for the two studies, respectively. The appropriateness of the final model was confirmed. Our model offers a robust framework for elucidating the pharmacokinetic profiles of CLO and CLO-CA.

Thrombocytopenia risks in ARDS COVID-19 patients treated with high-dose linezolid during vvECMO therapy: an observational study.

Patients treated with ECMO are at great risk of nosocomial infections, and around 10% of isolates are gram-positive pathogens. Linezolid (LZD) is effective in the treatment of these infections but appropriate dosing is challenging. The aim was to evaluate the occurrence of thrombocytopenia during ECMO when treated with LZD. An LZD trough concentration of 8 mg/L was set as the cutoff value for thrombocytopenia occurrence among critically ill patients who received parenteral LZD therapy at a dose of 600 mg every 8 h during ECMO. Eleven patients were included in this prospective observational study. Median LZD trough concentrations were 7.85 (interquartile range (IQR), 1.95-11) mg/L. Thrombocytopenia was found in 81.8% of patients. Based on the median LZD trough concentrations cutoff value, patients were divided into two groups, 1.95 (IQR, 0.91-3.6) and 10.3 (IQR, 9.7-11.7) mg/L, respectively. Median platelet values differed significantly between groups on admission, ECMO day 0, ECMO day 1, and LZD sampling day [194 and 152.5, (p < 0.05)], [113 and 214, (p < 0.05)], [76 and 147.5, (p < 0.01)], and [26 and 96.5, (p < 0.01)], respectively. Duration of LZD therapy was similar between the groups. Significant platelet reduction was observed in both groups, emphasizing the need for closer monitoring to prevent LZD-associated thrombocytopenia.

Population Pharmacokinetic Model of Linezolid and Probability of Target Attainment in Patients with COVID-19-Associated Acute Respiratory Distress Syndrome on Veno-Venous Extracorporeal Membrane Oxygenation-A Step toward Correct Dosing.

During veno-venous extracorporeal membrane oxygenation (vv ECMO) therapy, antimicrobial drugs are frequently used, and appropriate dosing is challenging due to there being limited data to support the dosage. Linezolid is effective against multidrug-resistant Gram-positive pathogens frequently isolated in ECMO patients. In total, 53 steady-state linezolid levels were obtained following 600 mg intravenous (IV) injections every 8 h, and these were used to develop a population pharmacokinetic (PopPK) model in patients with COVID-19-associated acute respiratory distress syndrome (CARDS) on vv ECMO. The data were analyzed using a nonlinear mixed-effects modelling approach. Monte Carlo simulation generated 5000 patients' individual PK parameters and corresponding concentration-time profiles using the PopPK model, following the administration of 600 mg/8 h (a higher-than-standard dosing) and 600 mg/12 h (standard). The probabilities of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) and the cumulative fraction of responses (CFR) for three pathogens were calculated and compared between the two dosing scenarios. Linezolid 600 mg/8 h was predicted to achieve greater than or equal to 85%Tf>MIC in at least 90% of the patients with CARDS on vv ECMO compared to only approximately two thirds of the patients after dosing every 12 h at a minimal inhibitory concentration (MIC) of 2 mg/L. In addition, for the same MIC, fAUC24/MIC ≥ 80 was achieved in almost three times the number of patients following an 8-h versus a 12-h interval. PopPK simulation predicted that a significantly higher proportion of the patients with CARDS on vv ECMO would achieve the PK/PD targets following the 8-h dosing interval compared to standard linezolid dosing. Nevertheless, the safety concern, in particular, for thrombocytopenia, with higher-than-standard linezolid dosage is reasonable, and consequently, monitoring is essential.

The Influence of Subclinical Active Inflammation on IFX Pharmacokinetic Modeling and Disease Progression Assessment: Findings from a Prospective Real-World Study in Inflammatory Bowel Disease Patients.

BACKGROUND AND AIMS: Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment. METHODS: The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model. RESULTS: The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in the majority of its definitions, when adjusted for several confounding factors. Additionally, alongside FC, both IFX and CL demonstrated a significant impact on the temporal aspect of disease progression. CONCLUSION: In this 2-year real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that subclinical active inflammation, as mirrored by FC or CRP, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of disease progression. These findings underscore the need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.

Lidocaine clearance as pharmacokinetic parameter of metabolic hepatic activity in patients with impaired liver.

Background: The study aimed to estimate lidocaine (LID) pharmacokinetic parameter values in patients with impaired liver function, level of correlation between the pharmacokinetic parameters and Child-Pugh class and change in pharmacokinetic parameters after liver tumor resection compared to the preoperative value. Methods: Patients with impaired liver function were subject to the LID test 1 day prior to, 3 and 7 days after the intervention. LID was administered in single i.v. dose of 1 mg/kg. Blood samples were collected at 15, 30 and 90 minutes after drug administration. Non-compartmental analysis was applied for calculating the pharmacokinetic parameters. Results: The study included 17 patients with the diagnosis of cirrhosis and 41 patients with liver tumor. In both groups of patients, the values of the coefficients of correlation show the best correlation between clearance (CL) and Child-Pugh score (-0.693, p<0.005) over other pharmacokinetic parameters. The results indicate worsening hepatic function on 3rd day after operation in comparison to the values of LID CL prior to operation (mean LID CL for patients with Child-Pugh class A are 25.91 L/h, 41.59 L/h, respectively; while for B class are 16.89 L/h, 22.65 L/h, respectively). On day 7th, the values of LID CL (mean value for patients with Child-Pugh class A and B are 40.98 L/h and 21.46 L/h, respectively) are increased in comparison to 3rd day after. Conclusions: LID pharmacokinetic parameters consequently changed according to the severity of liver impairment, assessed by Child-Pugh score. Values of LID CL and volume of distribution (Vd) coupled with standard biochemical parameters may be used for preoperative assessment of liver function and monitoring of its postoperative recovery.

A case study on the in silico absorption simulations of levothyroxine sodium immediate-release tablets.

The aim of this case study was to develop a drug-specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus™ software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentration-time profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate-release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitro-in vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets.