Population Pharmacokinetic Parameters Research Articles

Population Pharmacokinetic and Exposure-Safety Analyses of Ibrutinib for the Treatment of Chronic Graft-Versus-Host Disease.

The population pharmacokinetic (PK) and exposure-response (E-R) analyses for the safety of ibrutinib for the treatment of chronic graft-versus-host disease (cGVHD) is presented. This work aims to develop a population PK model for ibrutinib based on data from clinical studies in subjects with cGVHD, to evaluate the impact of intrinsic and extrinsic factors on PK parameters as well as systemic exposure levels, and to assess an E-R relationship for selected safety end points. Pooled data from 162 subjects with cGVHD enrolled in 4 clinical studies were included in the population PK analysis. In the studies, an ibrutinib dose of 420mg once daily was administered orally. With the exception of 1 study, the study protocols instructed for a reduction of the ibrutinib dose to 140 or 280mg once daily, depending on concomitant CYP3A inhibitor use. Concomitant CYP3A inhibitor use was found to be a primary covariate for relative bioavailability (F1): the F1 value increased 2.22-fold with concomitant moderate CYP3A inhibitors and 3.09-fold with concomitant strong CYP3A inhibitors, compared with the F1 value in the absence of CYP3A inhibitors. In addition, Japanese ethnicity led to an F1 value that was 1.70-fold higher than that in the non-Japanese population. Simulations using the final PK model suggest that ibrutinib exposure was appropriately controlled within the therapeutic range in the entire cGVHD population by applying dose reductions depending on the use of CYP3A inhibitors, and that additional dose modification for the Japanese population would not be required. The subsequent E-R analysis suggests no apparent association between the systemic exposure to ibrutinib and the selected safety end points.

Pediatric Population Pharmacokinetic Modeling and Exposure-Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data.

This study aimed to develop a population pharmacokinetic (PK) model of ambrisentan in pediatric patients (8 to <18 years) with pulmonary arterial hypertension (PAH) and compare pediatric ambrisentan systemic exposure with previously reported adult data. Association of ambrisentan exposure with efficacy (6-minute walking distance) and safety (adverse events) were exploratory analyses. A population PK model was developed using pediatric PK data. Steady-state systemic exposure metrics were estimated for the pediatric population and compared with previously reported data in adult patients with PAH and healthy subjects. No covariates had a significant effect on PK parameters; therefore, the final covariate model was the same as the base model. The pediatric population PK model was a 2-compartment model including the effect of body weight (allometric scaling),first-order absorption and elimination, and absorption lag time. Steady-state ambrisentan exposure was similar between the pediatric and adult population when accounting for body weight differences. Geometric mean area under the concentration-time curve at steady state in pediatric patients receiving ambrisentan low dose was 3% lower than in the adult population (and similar in both populations receiving high dose). Geometric mean maximum plasma concentration at steady state in pediatric patients receiving low and high doses was 11% and 18% higher, respectively, than in the adult population. There was no apparent association in the pediatric or adult population between ambrisentan exposure and change in 6-minute walking distance or incidence of ambrisentan-related adverse events in pediatric patients. The similar ambrisentan exposure and exposure-response profiles observed in pediatric and adult populations with PAH suggests appropriateness of body-weight-based dosing in the pediatric population with PAH.

Systematic-review-of-population-pharmacokinetic-models-of-isoniazid-in-children-and-adults-with-tuberculosis

Introduction: Isoniazid (INH) is one of the first-line anti-tuberculosis (anti-TB) drugs that have both bactericidal and bacteriostatic properties depending on the rate of mycobacterial growth. Several population pharmacokinetic (PPK) models of INH were established. This systemic review aims to summarise published PPK parameters of INH in the models and to identify covariates influencing the INH pharmacokinetic parameters of models. Method: A search of publications for PPK analyses of INH in volunteers or TB patients from 2011 to 2021 was conducted in PubMed and Scopus databases. Reviews, methodology articles, non-compartmental analysis, in vitro, and animal studies were excluded. Result: Twelve studies were included in this review. Most of the included studies described the pharmacokinetics of INH as two-compartmental with first-order absorption and elimination in most of the included studies. Eleven studies reported N-acetyltransferase 2 (NAT2) genotype polymorphism as the most common significant covariate affecting the pharmacokinetic parameters of INH. Other common significant covariates reported include body weight (n = 2) and body mass index (BMI) (n = 1). Conclusion: The variability of population clearance parameters of INH was explained mainly by the NAT2 genotype polymorphism. This indicates that to optimise and rationalise the dosing regimen of INH, a patient’s NAT2 genotype should be considered. At the same time, body weight and BMI values should be considered when making dosing adjustments for INH to achieve the therapeutic range.

418. Fosfomycin Dosing Regimens for The Treatment of Carbapenem-Resistant Enterobacteriaceae Infections in Patients Receiving Continuous Renal Replacement Therapy: a Monte Carlo Simulation

Abstract Background To predict the appropriate dosing of intravenous fosfomycin for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infection in continuous renal replacement therapy (CRRT) patients. Methods Minimum inhibitory concentration (MIC) values of all isolates were determined by E-test method. Population pharmacokinetic parameters were obtained from a previously published study. The percentages of a 24-hour period in which the drug concentration exceeded the MIC (%T &amp;gt;MIC) were defined to be 70% T &amp;gt;MIC and 100% T &amp;gt;MIC, respectively. In addition, the 24-hour area under the unbound concentration-time curve over the MIC (AUC0-24/MIC) of 45 mg·h/L was used as a target value. All dosing regimens were estimated for the probability of target attainment (PTA) using a Monte Carlo simulation. Results For the effluent rate of 20 mL/kg/h, the PTA for reaching 70% T &amp;gt;MIC, 100% T &amp;gt;MIC, and AUC0-24/MIC of 45 mg·h/L was achieved in pathogens with a MIC of 24 mg/L, 12 mg/L, and 24 mg/L in all regimens, respectively. Meanwhile for the effluent rate of 25 mL/kg/h, the PTA for reaching 70% T &amp;gt;MIC, 100% T &amp;gt;MIC, and AUC0-24/MIC of 45 mg·h/L was achieved in organisms with a MIC of 16 mg/L, 12 mg/L and 24 mg/L in all regimens, respectively. Conclusion The appropriate fosfomycin dosing regimens for CRE infections in critically ill patients receiving CRRT were suggested based on pharmacokinetic/pharmacodynamic targets, MIC values, and effluent rates. Clinical validation is warranted. Disclosures All Authors: No reported disclosures.

597. Are We Dosing Correctly? Population Pharmacokinetic Modeling of Cefepime, Piperacillin-Tazobactam, and Meropenem in Individuals with Cystic Fibrosis

Abstract Background Patients with cystic fibrosis (CF) experience recurrent bacterial pulmonary exacerbations. The management of these infections becomes increasingly complex due to decreased antimicrobial susceptibility and inadequate pharmacokinetic/pharmacodynamic (PK/PD) characterization of the most commonly used antimicrobial agents in this population. Methods One hundred fifty-five pediatric and adult participants receiving cefepime (n=82), meropenem (n=42), or piperacillin-tazobactam (n=31) were enrolled. Opportunistic blood samples were obtained during hospitalization. Population PK (PopPK) analysis was conducted using nonlinear mixed effects modeling in NONMEM, and clinical and demographic characteristics were evaluated as potential covariates. Monte Carlo simulations evaluated the probability of PK/PD target attainment (PTA) for different dosing regimens. Multiple targets, defined as percentage of a 24-h time period that the free drug concentration exceeds the MIC (fT &amp;gt; MIC), were selected based on prior studies of beta-lactam antibiotics. Results Preliminary PopPK modeling results show that lean body weight, creatinine clearance, daily dose, mode of administration (standard vs. extended infusion), and age affect PK parameters, with varying effects by drug. As anticipated, extended or continuous infusions resulted in higher PTA (Table 1). In the cefepime group, the 3-h infusion regimen achieved higher PTAs than the 0.5-h regimen across all age groups (Figure 1, Figure 2). Estimated breakpoints (in which ≥ 90% of patients are expected to achieve a PK/PD target) were 2-4 fold higher in pediatric participants receiving a 3-h infusion vs. 0.5-h infusion, based on age and target fT &amp;gt; MIC (Table 1). In the meropenem group, increased creatinine clearance led to reduced PTA, and in the piperacillin-tazobactam group, total daily dose and interval were the principal drivers of PTA. Table 1:Breakpoints (mg/L, highest minimum inhibitory concentration (MIC) with ≥ 90% PK target attainment) for different infusion durations, based on Monte Carlo simulations.Figure 1:Comparison of PTA between the two durations of infusion for 50 mg/kg (3 to 11 years) or 2 g (12 years and above) cefepime q8h at the target of 65% fT&amp;gt; MIC.Figure 2:Comparison of PTA between two durations of infusion for 50 mg/kg (3 to 11 years) or 2 g (12 years and above) cefepime q8h at the target of 100% fT&amp;gt; MIC. Conclusion To our knowledge, this is the largest PopPK study to date of these antimicrobials in individuals with CF. Clinicians should incorporate local antibiograms with these PopPK models to determine optimal dosing in patients with CF, since standard dosing regimens may fail to achieve specific PK/PD targets. This population may also benefit from beta-lactam therapeutic drug monitoring. Disclosures C. Buddy Creech, MD, MPH, Altimmune: Advisor/Consultant|Astellas: Advisor/Consultant|Merck: Grant/Research Support|Premier: Advisor/Consultant.

Population Pharmacokinetic Analysis for Model-Based Therapeutic Drug Monitoring of Tacrolimus in Chinese Han Heart Transplant Patients.

Tacrolimus has become the first-line immunosuppressant for preventing rejection after heart transplantation. The present study aimed to investigate genetic variants and clinical factors affecting the variability of tacrolimus in Chinese Han heart transplant patients using a population pharmacokinetic approach. The retrospective study included 53 hospitalized patients with 547 tacrolimus concentrations for analysis. Nonlinear mixed-effects modeling was used to develop the population pharmacokinetics model for tacrolimus in patients with heart transplants, followed by Monte Carlo simulations to design initial dosing regimens. In our study, the mutation rate of CYP3A4*18B (C>T) was 27.36%. An oral one-compartment model with first-order absorption and elimination was used to describe the pharmacokinetics of tacrolimus in heart transplant patients. In the final model, the estimated apparent clearance (CL/F) and volume of distribution (V/F) were 532.5L/h [12.20% interindividual variability, IIV] and 16.87 L (23.16% IIV), respectively. Albumin, postoperative time, and rs2242480 (CYP3A4*18B) gene polymorphisms were the significant covariates affecting CL/F, and creatinine clearance had significant effects on the V/F. The population pharmacokinetic model of tacrolimus in heart transplant patients can better estimate the population and individual pharmacokinetic parameters of patients and can provide a reference for the design of individualized dosing regimens.

Novel approach to adherence assessment based on parent drug and metabolite pharmacokinetics: pilot study with spironolactone.

The aim of this study was to evaluate adherence to spironolactone in a group of unselected patients with arterial hypertension by analysis of measured serum spironolactone and canrenone concentrations according to a proposed two-step decision scheme based on pharmacokinetic considerations. Simulation of serum concentration-time profiles of spironolactone and canrenone based on population pharmacokinetic parameters described in literature and a body weight-normalized spironolactone dose / canrenone level nomogram derived from a group of adherent patients with conservatively treated primary hyperaldosteronism, were used to create a two-step decision scheme. 71 outpatients treated with spironolactone for resistant hypertension with spironolactone and canrenone serum concentrations measured between 2018 and 2021 were analyzed according to the proposed scheme. We compared our proposed methodology to the standard approach for adherence testing. With the most sensitive traditional approach to adherence assessment through detectable serum concentrations of spironolactone and/or canrenone, 9 (12.7%) non-adherent patients were identified. With our two-step assessment of adherence, we were able to identify 18 (25.4%) non-adherent patients. Consideration of the pharmacokinetic properties of parental drug and its metabolite led to improved sensitivity in non-adherence detection in patients with arterial hypertension. This approach enables better interpretation of measured spironolactone and canrenone serum concentrations and should be used in clinical practice.

Estimating the In Vivo Function of CYP2D6 Alleles through Population Pharmacokinetic Modeling of Brexpiprazole.

Accurate prediction of CYP2D6 phenotype from genotype information is important to support safe and efficacious pharmacotherapy with CYP2D6 substrates. To facilitate accurate CYP2D6 genotype-phenotype translation, there remains a need to investigate the enzyme activity associated with individual CYP2D6 alleles using large clinical data sets. This study aimed to quantify and compare the in vivo function of different CYP2D6 alleles through population pharmacokinetic (PopPK) modeling of brexpiprazole using data from 13 clinical studies. A PopPK model of brexpiprazole and its two metabolites, DM-3411 and DM-3412, was developed based on plasma concentration samples from 826 individuals. As the minor metabolite, DM-3412, is formed via CYP2D6, the metabolic ratio of DM-3412:brexpiprazole calculated from the PopPK parameter estimates was used as a surrogate measure of CYP2D6 activity. A CYP2D6 genotype-phenotype analysis based on 496 subjects showed that the CYP2D6*2 allele (n=183) was associated with only 10% enzyme activity relative to the wild-type allele (CYP2D6*1) and a low enzyme activity was consistently observed across genotypes containing CYP2D6*2. Among the decreased function alleles, the following enzyme activities relative to CYP2D6*1 were estimated: 23% for CYP2D6*9 (n=20), 32% for CYP2D6*10 (n=62), 64% for CYP2D6*14 (n=1), 4% for CYP2D6*17 (n=37), 4% for CYP2D6*29 (n=13), and 9% for CYP2D6*41 (n=64). These findings imply that a lower functional value would more accurately reflect the in vivo function of many reduced function CYP2D6 alleles in the metabolism of brexpiprazole. The low enzyme activity observed for CYP2D6*2, which has also been reported by others, suggests that the allele exhibits substrate-specific enzyme activity.

Pharmacogenetics-based population pharmacokinetic analysis and dose optimization of valproic acid in Chinese southern children with epilepsy: Effect of ABCB1 gene polymorphism.

Objective: The aim of this study was to establish a population pharmacokinetic (PPK) model of valproic acid (VPA) in pediatric patients with epilepsy in southern China, and provide guidance for individualized medication of VPA therapy. Methods: A total of 376 VPA steady-state trough concentrations were collected from 103 epileptic pediatric patients. The PPK parameter values for VPA were calculated by using the nonlinear mixed-effects modeling (NONMEM) method, and a one-compartment model with first-order absorption and elimination processes was applied. Covariates included demographic information, concomitant medications and selected gene polymorphisms. Goodness-of-fit (GOF), bootstrap analysis, and visual predictive check (VPC) were used for model evaluation. In addition, we used Monte Carlo simulations to propose dose recommendations for different subgroup patients. Results: A significant effect of the patient age and ABCB1 genotypes was observed on the VPA oral clearance (CL/F) in the final PPK model. Compared with patients with the ABCB1 rs3789243 AA genotype, CL/F in patients with GG and AG genotypes was increased by 8% and reduced by 4.7%, respectively. The GOF plots indicated the satisfactory predictive performance of the final model, and the evaluation by bootstrap and VPC showed that a stable model had been developed. A table of individualized dosing regimens involving age and ABCB1 genotype was constructed based on the final PPK model. Conclusion: This study quantitatively investigated the effects of patient age and ABCB1 rs3789243 variants on the pharmacokinetic variability of VPA. The PPK models could be beneficial to individual dose optimization in epileptic children on VPA therapy.

Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis.

Single, high-dose liposomal amphotericin B (LAmB; AmBisome, Gilead Sciences) has demonstrated non-inferiority to amphotericin B deoxycholate in combination with other antifungals for averting all-cause mortality from HIV-associated cryptococcal meningitis. There are limited data on the pharmacokinetics (PK) of AmBisome. The aim of this study was to describe population PK of AmBisome and conduct a meta-analysis of the available studies to suggest the optimal dosing for cryptococcal meningoencephalitis. Data from a Phase II and Phase III trial of high-dose, short-course AmBisome for cryptococcal meningoencephalitis were combined to develop a population PK model. A search was conducted for trials of AmBisome monotherapy and meta-analysis of clinical outcome data was performed. A two-compartment model with first-order clearance of drug from the central compartment fitted the data best and enabled the extent of inter-individual variability in PK to be quantified. Mean (SD) population PK parameter estimates were: clearance 0.416 (0.363) L/h; volume of distribution 4.566 (4.518) L; first-order transfer of drug from central to peripheral compartments 2.222 (3.351) h-1, and from peripheral to central compartment 2.951 (4.070) h-1. Data for the meta-analysis were insufficient to suggest optimal dosing of AmBisome for cryptococcal meningoencephalitis. This study provides novel insight into the PK of AmBisome at the population level and the variability therein. Our analysis also serves to highlight the paucity of data available on the pharmacodynamics (PD) of AmBisome and underscores the importance of thorough and detailed PK/PD analysis in the development of novel antifungals, by demonstrating the challenges associated with post hoc PK/PD analysis.

Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Target Attainment Analyses for Dalbavancin in Pediatric Patients.

Dalbavancin, approved for the treatment of pediatric and adult patients with acute bacterial skin and skin structure infections, has a terminal half-life of >14 days allowing administration as a single-dose regimen. We developed a population pharmacokinetic (PK) model using 1124 dalbavancin concentrations from 211 pediatric patients, with allometric scaling of clearance and volume parameter exponents fixed at 0.75 and 1, respectively. Serum albumin was included as a covariate on all PK parameters; creatinine clearance or estimated glomerular filtration rate was a covariate on clearance. The final model, qualified by visual predictive checks and bootstrapping, was used to simulate 1000 PK profiles for a range of pediatric age groups. PK/pharmacodynamic target attainment (PTA) was calculated for targets associated with stasis, 1-log kill, and 2-log kill of Staphylococcus aureus (neutropenic murine thigh infection model). Dalbavancin PK was well characterized by a three-compartment model. No additional significant covariates were identified. Simulations showed that single-dose (30-minute intravenous infusion) regimens of 22.5 mg/kg (patients <6 years) and 18 mg/kg (patients 6 years to <18 years) resulted in PTA ≥94% for minimal inhibitory concentrations ≤2 mg/L and ≤0.5 mg/L for the stasis and 2-log kill targets, respectively. PTA for pediatric patients was similar to adults with exposures within the range for adults administered 1500 mg dalbavancin. Dalbavancin PK in pediatric patients was well characterized by a three-compartment model. Simulations with the final model demonstrated adequate PTA across the entire age range for the approved pediatric dalbavancin doses.

Population Pharmacokinetics of Doxycycline, Administered Alone or with N-Acetylcysteine, in Chickens with Experimental Mycoplasma gallisepticum Infection.

Mycoplasmosis is a bacterial infection that significantly affects poultry production, and it is often controlled with antibiotics, including doxycycline. The conducted study aimed to determine population pharmacokinetic (PopPk) parameters of doxycycline in healthy (n = 12) and in Mycoplasma gallisepticum-challenged (n = 20) chickens after its oral administration via drinking water at the registered dose rate of 20 mg/kg b.w./24 h for five days, without or with co-administration of N-acetylcysteine (NAC, a dose of 100 mg/kg b.w./24 h) via the feed. Doxycycline concentrations in plasma were analyzed with the LC-MS/MS method. The values of tvV/F and tvke were 4.73 L × kg-1 and 0.154 h-1, respectively, and they showed low BSV. A high BSV of 93.17% was calculated for the value of tlag of 0.8 h, which reflects the inter-individual differences in the water consumption. PTA was computed after Monte Carlo simulation with the registered dose for doxycycline. The target of %fT &gt; MIC ≥ 80% and 100% can be achieved in 90% of the broiler population, after a correction for protein binding, for bacteria with MIC ≤ 0.5 mg × L-1 and 0.25 mg × L-1, respectively. The applied PopPk model did not reveal significant effect of M. gallisepticum infection and co-administration of NAC on pharmacokinetic parameters of doxycycline.

Acetaminophen pharmacokinetics in infants and children with congenital heart disease.

Acetaminophen is routinely used for perioperative analgesia in children undergoing major surgical procedures. There are few estimates of acetaminophen pharmacokinetic parameters in children with congenital heart disease, especially those with cyanotic heart disease. The current study prospectively investigated differences in acetaminophen pharmacokinetics following surgery using cardiopulmonary bypass in children with cyanotic and acyanotic congenital heart disease. Children (2-6 years, 9-23 kg) presenting for median sternotomy for Fontan palliation (cyanotic patients) or two ventricle surgical repair (acyanotic patients) were eligible for inclusion. A single intravenous dose of acetaminophen (15 mg/kg) was administered at the start of sternal closure after separation from cardiopulmonary bypass. The time-course of acetaminophen concentrations were described using non-linear mixed effects models. One and two-compartment disposition models with first-order elimination were tested. Pharmacokinetic parameter estimates were scaled using allometry and standardized to a 70 kg person. There were 208 acetaminophen concentrations assayed from 30 children, 15 with cyanotic, and 15 with acyanotic heart disease. A 2-compartment model best described acetaminophen PK. Parameter estimates (population parameter variability, PPV%; 95% confidence interval, CI) were clearance CL 15.3L.h-1.70 kg-1 (22.2%; 13.8-16.7), intercompartment clearance Q 45.4L.h-1.70 kg-1 (22.4%; 25.2-61.9), central volume of distribution V1 33.5L.70 kg-1 (23.2%; 25.9-38.8), peripheral volume of distribution V2 32.1L.70 kg-1 (21.7%; 25.9-38.8). Neither clearance nor volume parameters differed between cyanotic and acyanotic patients. Acetaminophen pharmacokinetics were characterized using a 2-compartment model with first-order elimination following cardiac bypass surgery in children. Population pharmacokinetic parameter estimates were similar to other studies in children. No differences were detected between patients with cyanotic and acyanotic heart disease.

Population Pharmacokinetics/Pharmacodynamics and Clinical Outcomes of Meropenem in Critically Ill Patients.

Several pathophysiological changes can alter meropenem pharmacokinetics in critically ill patients, thereby increasing the risk of subtherapeutic concentrations and affecting therapeutic outcomes. This study aimed to characterize the population pharmacokinetic (PPK) parameters of meropenem, evaluate the relationship between the pharmacokinetic/pharmacodynamic index of meropenem and treatment outcomes, and evaluate the different dosage regimens that can achieve 40%, 75%, and 100% of the dosing interval for which the free plasma concentrations remain above the MIC of the pathogens (fT>MIC) targets. Critically ill adult patients treated with meropenem were recruited for this study. Five blood samples were collected from each patient. PPK models were developed using a nonlinear mixed-effects modeling approach, and the final model was subsequently used for Monte Carlo simulations to determine the optimal dosage regimens. A total of 247 concentrations from 52 patients were available for analysis. The two-compartment model with linear elimination adequately described the data. The mean PPK parameters were clearance (CL) of 4.8 L/h, central volume of distribution (VC) of 11.4 L, peripheral volume of distribution (VP) of 14.6 L, and intercompartment clearance of 10.5 L/h. Creatinine clearance was a significant covariate affecting CL, while serum albumin level and shock status were factors influencing VC and VP, respectively. Although 75% of the drug-resistant infection patients had fT>MIC values of >40%, approximately 83% of them did not survive the infection. Therefore, 40% fT>MIC might not be sufficient for critically ill patients, and a higher target, such as 75 to 100% fT>MIC, should be considered for optimizing therapy. A 75% fT>MIC could be reached using approved doses administered via a 3-h infusion.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Spotlight commentary: Navigating between financial risks and improved treatment outcomes with immune checkpoint inhibitors in cancer patients: The need for biomarker identification and dose optimization.

Bayesian forecasting of tumor size metrics and overall survival.

The tumor size ratio (TSR), time-to-tumor growth (TTG), and tumor growth rate (kG) are frequently suggested as model-based predictors of overall survival (OS) for different types of tumors. When the tumor metrics are applied in forecasting of the outcome for individual patients at an early stage, the tumor data might be sparse resulting in imprecise prediction. This simulation study aimed to investigate how the tumor follow-up data and estimation approaches influence the accuracy in the tumor size metrics and the predicted hazard of death for individual patients. Longitudinal tumor size and OS data were simulated using tumor growth inhibition and Weibull distribution models, respectively. Based on the model and increasing measurement durations, the accuracy (defined as 80-125% of the simulated "true" value) in individual metrics and hazard was computed. TSR week 6 (TSRw6) accuracy was adequate for 91% of the patients when tumor size was measured up to 12 weeks. For TTG and kG metrics, the highest accuracy observed was lower (43 and 77%, respectively) and occurred later (42 and 60 weeks, respectively). The simultaneous (joint) and sequential estimation approaches resulted in similar accuracies, however, in general, the sequential approach where individual tumor size parameters are fixed, demonstrated inferior estimation properties. The TSRw6 and the model-predicted tumor time course (absolute or relative change) had better forecasting properties than TTG or kG. The population pharmacokinetic (PK) parameters and data approach performed similarly or better than the simultaneous approach and had a better accuracy in estimating individuals' hazard of death than the individual PK parameters method.

Population pharmacokinetics and pharmacodynamics of imipenem in neutropenic adult patients

ObjectiveImipenem is recommended in patients with chemotherapy-induced febrile neutropenia. Although alterations of antibiotic pharmacokinetic parameters have been reported in such patients, little data is available on imipenem. MethodsProspective, single-center, non-interventional pharmacokinetic cohort study in adults with chemotherapy-induced febrile neutropenia. Critically ill patients were excluded. Imipenem was administered as a 30-min infusion of 1000 mg/8h. Total imipenem plasma concentrations were assayed by high-performance liquid chromatography during neutropenia and just after neutrophil recovery. We estimated population pharmacokinetic parameters of imipenem by non-linear mixed-effect modelling using the SAEM algorithm. ResultsSixteen patients were included in the study, including nine women (56.3%), median age 37 years (range, 18.3; 78.3). Eight patients had an hematological malignancy (50.0%) and seven had a solid tumor (43.8%). Imipenem pharmacokinetics were best described by a one-compartment model with first-order elimination. Mean values for imipenem were: clearance 14.3L/h and 10.9L/h and volume of distribution 20.7L and 14.5 L during neutropenia and after recovery, respectively. Imipenem plasma area under the curve at steady state was reduced by 23% during neutropenia. However, all patients achieved a pharmacodynamic target of %fT>MIC ≥ 40% with a regimen of 1000 mg/8 h or 500 mg/6 h, for MICs up to 2 mg/L. The pharmacodynamics profile for a target of %fT > MIC = 100% was however less favorable with 500 mg/6 h or 1000 mg/8 h either during or after neutropenia. ConclusionPharmacokinetic/pharmacodynamic goals for imipenem were similar in patients during and after neutropenia, despite reduced plasma exposure.

Levobupivacaine plasma concentrations following repeat caudal anesthetics.

A single caudal anesthetic at the start of lower abdominal surgery is unlikely to provide prolonged analgesia. A second caudal at the end of the procedure extends the analgesia duration but total plasma concentrations may be associated with toxicity. Our aim was to measure total plasma levobupivacaine concentrations after repeat caudal anesthesia in infants and to generate a pharmacokinetic model for prediction of plasma concentrations after repeat caudal anesthesia in neonates, infants and children. Infants undergoing definitive repair of anorectal malformations or Hirschsprung's disease received a second caudal anesthesia at the end of the procedure. Total levobupivacaine concentrations were assayed 3-4 times in the first 6h after the initial caudal. These data were pooled with data from four studies describing plasma concentrations after levobupivacaine caudal or spinal anesthesia. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects models. Covariates included postmenstrual age and body weight. Parameter estimates were used to simulate concentrations after a repeat levobupivacaine 2.5mg kg-1 caudal at 3 or 4h following an initial levobupivacaine 2.5mg kg-1 caudal. Twenty-one infants (postnatal age 11-32 weeks, gestation 37-39 weeks, weight 5.2-8.6kg) were included. The measured peak plasma concentration after repeat caudal levobupivacaine 2.5mg kg-1 4 h after initial caudal was 1.38 mg L-1 (95% prediction interval 0.60-2.6mg L-1 ) and 3 h after initial caudal was 1.46 mg L-1 (0.60-2.80)mg L-1 . Simulation of total plasma concentrations in neonates (7kg, 57 weeks postmenstrual age) given caudal levobupivacaine 4 h after the initial caudal were 1.76 mg L-1 (0.68-3.50) mg L-1 if 2.5mg kg-1 levobupivacaine was used and 0.88 mg L-1 (0.34-1.73)mg L-1 if 1.25 mg kg-1 of 0.125% levobupivacaine was used. In simulated older children (20 kg, 6 years), the mean maximum concentration was 1.43 mg L-1 (0.60-2.70)mg L-1 if 2.5mg kg-1 levobupivacaine was repeated at 3h. Repeat caudal levobupivacaine 2.5mg kg-1 at 3h after an initial 2.5mg kg-1 dose does not exceed the concentration associated with systemic local anesthetic toxicity. In 2.5% of simulated neonates (weight 3.8kg, PMA 40 weeks), repeat caudal anesthesia demonstrates broaching of the lower concentration limit associated with toxicity at both 3 and 4 h after initial caudal.

Population Pharmacokinetics and Exposure–Response Analyses of Ustekinumab in Patients With Moderately to Severely Active Crohn's Disease

Ustekinumab, a fully human immunoglobulin G1κ monoclonal antibody that antagonizes human interleukin-12/23p40, is an effective therapy for several immune-mediated inflammatory diseases, including Crohn's disease (CD). This work characterizes the population pharmacokinetic (PK) and exposure-response (E-R) relationships of ustekinumab in patients with CD using data from four Phase IIb/III clinical studies. Serum ustekinumab concentration-time data from 1673 patients after IV and/or SC administration of ustekinumab were fitted simultaneously using nonlinear mixed effects modeling to develop a population PK model, which was subsequently used to evaluate simulation scenarios. Logistic regression E-R models were used to assess relationships between serum ustekinumab concentrations and clinical remission after induction (n=1910) and maintenance (n=387) treatment. Ustekinumab PK properties are well described by a two-compartment model with first-order absorption and elimination. Typical values of PK parameters for a 70-kg patient were: clearance, 0.192 L/d; volume of distribution at steady state, 4.62 L; and intercompartmental clearance, 0.287 L/d. Ustekinumab terminal elimination t1/2 was 19days, and bioavailability after SC administration was 78.3%. Ustekinumab clearance was not affected by coadministration of immunosuppressive agents or corticosteroids. Body weight, serum albumin, and C-reactive protein (CRP) concentrations, tumor necrosis factor (TNF) antagonist failure status, sex, race (Asian vs non-Asian), and anti-ustekinumab antibody status significantly affected ustekinumab disposition; however, the effects of these covariates on ustekinumab exposure were not clinically relevant. The population PK model predicts that a milligram/kilogram dosing approach will result in lower ustekinumab exposure in patients with lower body weight. A positive E-R relationship was established between ustekinumab concentration and efficacy outcomes. The treatment effect of ustekinumab after induction therapy was more pronounced among patients with higher baseline CRP concentrations relative to those with lower values. In patients with CD, ustekinumab disposition after IV and SC administration was biexponential and consistent with those in patients with ulcerative colitis. Prior treatment with TNF antagonists or the concomitant use of immunosuppressive agents or corticosteroids had no effect on ustekinumab disposition. None of the covariates that affected ustekinumab clearance had a clinically meaningful impact on ustekinumab exposure. E-R models support recommended posology of ustekinumab in adults with CD; however, an ∼6 mg/kg IV induction dose in pediatric patients with lower body weights may not provide exposure that matches that in adult patients. gov identifiers: NCT00771667, NCT01369329, NCT01369342, and NCT01369355.

Pharmacokinetics of hydroxychloroquine in Japanese systemic lupus erythematosus patients with renal impairment.

Reduction of the hydroxychloroquine (HCQ) dosage is recommended in systemic lupus erythematosus (SLE) patients with renal impairment, but a pharmacokinetics (PK) study of patients with renal impairment has not yet been performed. We investigated the PK of both single and multiple doses of HCQ and its metabolites in SLE patients with renal impairment who newly started HCQ at a daily dose of 300 mg based on an ideal body weight dosage of 6.5 mg/kg. Population PK analysis was performed using a non-linear mixed-effects model. In total, 219 samples from 21 patients were analysed. The PK of HCQ in blood after single and multiple oral administrations followed the two-compartment model. At steady state, the concentration ratio of HCQ to each metabolite was HCQ:desethylhydroxychloroquine:desethylchloroquine:bisdesethylchloroquine = 1:0.28:0.1:0.06. The HCQ concentration correlated positively with that of each metabolite. The estimated values (relative standard error) of the population PK parameters were the total clearance at 110 l/h (31%) and a central volume of distribution of 398 l (19%). Co-administration of prednisolone and age, but not renal impairment, were factors affecting the total clearance of HCQ. From the PK perspective, a dosage reduction is unnecessary in SLE patients with impaired renal function.