Zero-order Input Research Articles

Time-Varying Clearance in Milrinone Pharmacokinetics from Premature Neonates to Adolescents.

Milrinone is an inotrope and vasodilator used for prophylaxis or treatment of low cardiac output syndrome after weaning from cardiopulmonary bypass (CPB). It is renally eliminated and has an acceptable therapeutic range of 100-300μg/L, but weight-based dosing alone is associated with poor target attainment. We aimed to develop a population pharmacokinetic model for milrinone from premature neonates to adolescents, and to evaluate how age, renal function and recovery from CPB may impact dose selection. Fifty paediatric patients (aged 4 days to 16 years) were studied after undergoing cardiac surgery supported by CPB. Data from 29 premature neonates (23-28 weeks' postmenstrual age) treated for prophylaxis of low systemic blood flow were available for a pooled pharmacokinetic analysis. Population parameters were estimated using non-linear mixed effects modelling (NONMEM 7.5.1). There were 369 milrinone measurements available for analysis. A one-compartment model with zero-order input and first-order elimination was used to describe milrinone disposition. Population parameters were clearance 17.8L/70kg [95% CI 15.8-19.9] and volume 20.4L/h/70kg [95% CI 17.8-22.1]. Covariates included size, postmenstrual age and renal function for clearance, and size and postnatal age for volume. Milrinone clearance is reduced by 39.5% [95% CI 24.0-53.7] immediately after bypass, and recovers to baseline clearance with a half-time of 12.0h [95% CI 9.7-15.2]. Milrinone volume was 2.07 [95% CI 1.87-2.27] times greater at birth than the population standard and decreased over the first days of life with a half-time of 0.977days [95% CI 0.833-1.12]. Milrinone is predominately renally eliminated and so renal function is an important covariate describing variability in clearance. Increasing clearance over time likely reflects increasing cardiac output and renal perfusion due to milrinone and return to baseline following CPB.

Pharmacokinetics of desflurane uptake and disposition in piglets.

Many respiratory but few arterial blood pharmacokinetics of desflurane uptake and disposition have been investigated. We explored the pharmacokinetic parameters in piglets by comparing inspiratory, end-tidal, arterial blood, and mixed venous blood concentrations of desflurane. Seven piglets were administered inspiratory 6% desflurane by inhalation over 2h, followed by a 2-h disposition phase. Inspiratory and end-tidal concentrations were detected using an infrared analyzer. Femoral arterial blood and pulmonary artery mixed venous blood were sampled to determine desflurane concentrations by gas chromatography at 1, 3, 5, 10, 20, 30, 40, 50, 60, 80, 100, and 120min during each uptake and disposition phase. Respiratory and hemodynamic parameters were measured simultaneously. Body uptake and disposition rates were calculated by multiplying the difference between the arterial and pulmonary artery blood concentrations by the cardiac output. The rates of desflurane body uptake increased considerably in the initial 5min (79.8ml.min-1) and then declined slowly until 120min (27.0ml.min-1). Similar characteristics of washout were noted during the subsequent disposition phase. Concentration-time curves of end-tidal, arterial, and pulmonary artery blood concentrations fitted well to zero-order input and first-order disposition kinetics. Arterial and pulmonary artery blood concentrations were best fitted using a two-compartment model. After 2h, only 21.9% of the desflurane administered had been eliminated from the body. Under a fixed inspiratory concentration, desflurane body uptake in piglets corresponded to constant zero-order infusion, and the 2-h disposition pattern followed first-order kinetics and best fitted to a two-compartment model.

Evaluation of body weight–based dosing, alternative dosing regimens, and treatment interruptions for α1-proteinase inhibitors and implications on biochemical efficacy in patients with α1-antitrypsin deficiency

IntroductionThe recommended standard dose for α1-proteinase inhibitor (A1PI) augmentation therapy is 60 mg/kg once-weekly (QW) intravenous (IV) infusions that aim to maintain systemic A1PI levels >11 μM, the biochemical efficacy threshold, in patients with α1-antitrypsin deficiency (AATD). However, this standard dose may not be optimal for all patients. Body weight–based dosing, alternative dosing regimens, and treatment interruption periods were evaluated using population pharmacokinetic (PopPK) modeling and simulations. MethodsA nonlinear mixed-effects PopPK model with covariate effects was developed using data from 3 clinical studies investigating 60 mg/kg QW IV A1PI infusions in patients with AATD (n = 65) to evaluate A1PI pharmacokinetic (PK) characteristics. Model-based simulations were conducted for predefined body weight categories, alternative dosing regimens (60–180 mg/kg QW or once every 2 weeks [Q2W]), and treatment interruption periods ranging from 3 to 14 days. ResultsA1PI PK characteristics were well described by a 2-compartment turnover model with zero-order input and linear elimination. Body weight was a statistically significant determinant of variability in central volume of distribution. Model-based simulations suggested that patients with a higher body weight may attain the 11 μM threshold quicker than patients with a lower body weight and that QW dosing was better at maintaining A1PI levels >11 μM, even when higher Q2W doses were administered. Missing a dose for as few as 3 days could result in A1PI levels <11 μM. DiscussionFindings suggest that doses higher than 60 mg/kg administered QW might be more clinically beneficial in some patients with AATD, and that body weight should be considered in dose optimization.

Population pharmacokinetics and target attainment analyses to identify a rational empirical dosing strategy for cefepime in critically ill patients.

We aimed to identify rational empirical dosing strategies for cefepime treatment in critically ill patients by utilizing population pharmacokinetics and target attainment analysis. A prospective and opportunistic pharmacokinetic (PK) study was conducted in 130 critically ill patients in two ICU sites. The plasma concentrations of cefepime were determined using a validated LC-MS/MS method. All cefepime PK data were analysed simultaneously using the non-linear mixed-effects modelling approach. Monte Carlo simulations were performed to evaluate the PTA of cefepime at different MIC values following different dose regimens in subjects with different renal functions. The PK of cefepime in critically ill patients was best characterized by a two-compartment model with zero-order input and first-order elimination. Creatinine clearance and body weight were identified to be significant covariates. Our simulation results showed that prolonged 3 h infusion does not provide significant improvement on target attainment compared with the traditional intermittent 0.5 h infusion. In contrast, for a given daily dose continuous infusion provided much higher breakpoint coverage than either 0.5 h or 3 h intermittent infusions. To balance the target attainment and potential neurotoxicity, cefepime 3 g/day continuous infusion appears to be a better dosing regimen than 6 g/day continuous infusion. Continuous infusion may represent a promising strategy for cefepime treatment in critically ill patients. With the availability of institution- and/or unit-specific cefepime susceptibility patterns as well as individual patients' renal function, our PTA results may represent useful references for physicians to make dosing decisions.

Population pharmacokinetics and model-based dosing evaluation of bedaquiline in multidrug-resistant tuberculosis patients.

Aims: Bedaquiline is now recommended to all patients in the treatment of multidrug-resistant tuberculosis (MDR-TB) using standard dosing regimens. As the ability to measure blood drug concentrations is very limited, little is known about drug exposure and treatment outcome. Thus, this study aimed to model the population pharmacokinetics as well as to evaluate the currently recommended dosage. Methodology: A bedaquiline population pharmacokinetic (PK) model was developed based on samples collected from the development cohort before and 1, 2, 3, 4, 5, 6, 8, 12, 18, and 24h after drug intake on week 2 and week 4 of treatment. In a prospective validation cohort of patients with MDR-TB, treated with bedaquiline-containing standardized regimen, drug exposure was assessed using the developed population PK model and thresholds were identified by relating to 2-month and 6-month sputum culture conversion and final treatment outcome using classification and regression tree analysis. In an exploratory analysis by the probability of target attainment (PTA) analysis, we evaluated the recommended dosage at different MIC levels by Middlebrook 7H11 agar dilution (7H11). Results: Bedaquiline pharmacokinetic data from 55 patients with MDR-TB were best described by a three-compartment model with dual zero-order input. Body weight was a covariate of the clearance and the central volume of distribution, albumin was a covariate of the clearance. In the validation cohort, we enrolled 159 patients with MDR-TB. The 7H11 MIC mode (range) of bedaquiline was 0.06mg (0.008-0.25mg/L). The study participants with AUC0-24h/MIC above 175.5 had a higher probability of culture conversion after 2-month treatment (adjusted relative risk, aRR:16.4; 95%CI: 5.3-50.4). Similarly, those with AUC0-24h/MIC above 118.2 had a higher probability of culture conversion after 6-month treatment (aRR:20.1; 95%CI: 2.9-139.4), and those with AUC0-24h/MIC above 74.6 had a higher probability of successful treatment outcome (aRR:9.7; 95%CI: 1.5-64.8). Based on the identified thresholds, simulations showed that the WHO recommended dosage (400mg once daily for 14 days followed by 200mg thrice weekly) resulted in PTA >90% for the majority of isolates (94%; MICs ≤0.125mg/L). Conclusion: We established a population PK model for bedaquiline in patients with MDR-TB in China. Based on the thresholds and MIC distribution derived in a clinical study, the recommended dosage of bedaquiline is sufficient for the treatment of MDR-TB.

Biphasic burst and sustained transdermal delivery in vivo using an AI-optimized 3D-printed MN patch

The objective of the present study was to fabricate microneedles for delivering lipophilic active ingredients (APIs) using digital light processing (DLP) printing technology and quality by design (QbD) supplemented by artificial intelligence (AI) algorithms. In the present study, dissolvable microneedle (MN) patches using ibuprofen (IBU) as a model drug were successfully fabricated with DLP printing technology at ∼ 750 μm height, ∼250 μm base diameter, and tip with radius of curvature (RoC) of ∼ 15 μm. MN patches were comprised of IBU, photoinitiator, Lithium phenyl (2,4,6-trimethylbenzoyl) phosphinate (LAP), polyethylene glycol dimethacrylate (PEGDAMA)550 and distilled water and were developed using the QbD optimization approach. Optimization of print fidelity and needle morphology were achieved using AI implementing a semi-supervised machine learning approach. Mechanical strength tests demonstrated that IBU MNs formed pores both on Parafilm M® and human cadaver skin. IBU-MNs consisting of 0.23 %w/v and 0.49 %w/v LAP with 10 %w/v water showed ∼ 2 mg/cm2 sustained drug permeation at 72 h in skin permeation experiments with flux of ∼ 40 μg/cm2/h. Pharmacokinetic studies in rats displayed biphasic rapid first-order absorption with sustained zero-order input of Ko = 150ug/hr, AUC0-48h = 62812.02 ± 11128.39 ng/ml*h, Tmax = 2.66 ± 1.12 h, and Cmax = 3717.43 ± 782.25 ng/ml (using 0.23 %w/v LAP IBU MN patch). An in vitro in vivo relation (IVIVR) was conducted identifying a polynomial relationship between patch release and fraction absorbed in vivo. This study demonstrates fabrication of dissolvable DLP-printed microneedle patches for lipophilic API delivery with biphasic rapid first-order and sustained zero-order release.

Population Pharmacokinetics of Piperacillin/Tazobactam Across the Adult Lifespan.

Piperacillin/tazobactam is one of the most frequently used antimicrobials in older adults. Using an opportunistic study design, we evaluated the pharmacokinetics of piperacillin/tazobactam as a probe drug to evaluate changes in antibacterial drug exposure and dosing requirements, including in older adults. A total of 121 adult patients were included. The population pharmacokinetic models that best characterized the observed plasma concentrations of piperacillin and tazobactam were one-compartment structural models with zero-order input and linear elimination. Among all potential covariates, estimated creatinine clearance had the most substantial impact on the elimination clearance for both piperacillin and tazobactam. After accounting for renal function and body size, there was no remaining impact of frailty on the pharmacokinetics of piperacillin and tazobactam. Monte Carlo simulations indicated that renal function had a greater impact on the therapeutic target attainment than age, although these covariates were highly correlated. Frailty, using the Canadian Study of Health and Aging Clinical Frailty Scale, was assessed in 60 patients who were ≥65 years of age. The simulations suggested that adults ≤50 years of age infected with organisms with higher minimum inhibitory concentrations may benefit from continuous piperacillin/tazobactam infusions (12 g/day of piperacillin component) or extended infusions of 4 g every 8 hours. However, for a target of 50% fT + minimum inhibitory concentration, dosing based on renal function is generally preferable to dosing by age, and simulations suggested that patients with creatinine clearance ≥120 mL/min may benefit from infusions of 4 g every 8 hours for organisms with higher minimum inhibitory concentrations.

Population Pharmacokinetics (PPK) and Exposure-Response to Support Body Surface Area (BSA)-Based Dosing of Brentuximab Vedotin in Pediatric Patients with Advanced-Stage Newly-Diagnosed Hodgkin Lymphoma (HL)

Introduction Brentuximab vedotin is an antibody-drug conjugate (ADC), consisting of antibody cAC10 specific to human CD30 and the antimicrotubule agent monomethyl auristatin E (MMAE), conjugated by a protease-cleavable linker. PPK models were developed to identify factors impacting the pharmacokinetics of ADC and MMAE, and exposure-response analyses were performed to assess the risk-benefit profiles of brentuximab vedotin combined with doxorubicin, vinblastine, and dacarbazine (A+AVD) to support BSA-based dosing of brentuximab vedotin in pediatric patients with advanced-stage newly-diagnosed HL. Methods Data from two open-label phase 1/2 pediatric studies were included in the PPK analysis: study C25002 (NCT01492088), which was a dose-escalation study (brentuximab vedotin 1.4-1.8 mg/kg every 3 weeks) in patients with relapsed or refractory systemic anaplastic large cell lymphoma or HL, and study C25004 (NCT02979522) in patients with advanced-stage, newly-diagnosed HL (brentuximab vedotin 48 mg/m2 every 2 weeks [Q2W] +AVD; A 25 mg/m2, V 6 mg/m2, D 375 mg/m2). Samples for measuring ADC and MMAE concentrations and immunogenicity assessment were collected. Sources of brentuximab vedotin pharmacokinetic variability were quantified using nonlinear mixed-effects modeling. ADC exposures achieved by BSA-based dosing of brentuximab vedotin in pediatric patients were compared to those in adults who received weight-based dosing of brentuximab vedotin in the ECHELON-1 trial (NCT01712490). Exposure-response analyses included patients in study C25004 treated with brentuximab vedotin 48 mg/m2 Q2W in combination with AVD. Relationships between ADC/MMAE exposures, progression-free survival (PFS), and incidence of adverse events (AEs) were analyzed by logistic regression in patients receiving A+AVD. Results Data from 95 patients (6-17 years) informed pharmacokinetics models of ADC (linear 3-compartment with zero-order input and first-order elimination) and MMAE (2-compartment with first-order elimination and formation of MMAE from ADC). BSA (0.79-2.03 m2) and albumin level (23-51 g/L) were significant covariates for clearance of ADC and MMAE. Age, body weight, sex, and race were not identified as covariates for ADC and MMAE pharmacokinetics. Albumin concentrations did not result in clinically meaningful change in clearance of ADC and MMAE. BSA-based brentuximab vedotin dosing resulted in similar systemic exposures of ADC and MMAE across age groups (<12 [n=23], 12-16 [n=56], and >16 years [n=16]). In exposure-response analyses (n=59), steady-state ADC exposures (area under the curve [AUC]) with BSA-based dosing of brentuximab vedotin at 48 mg/m2 Q2W in pediatric patients were comparable to those with weight-based dosing of brentuximab vedotin at 1.2 mg/kg Q2W in adults in the ECHELON-1 trial (Figure). A significant increase (p<0.05) in the incidence of febrile neutropenia was related to increasing exposure of MMAE, consistent with what has been observed in adult patients. No apparent relationship was identified between ADC exposure and the incidence of peripheral neuropathy, grade ≥3 neutropenia, febrile neutropenia, or grade ≥3 treatment-emergent AEs, or between ADC/MMAE exposure and PFS. Conclusions PPK and exposure-response analyses support brentuximab vedotin 48 mg/m2 Q2W in combination with AVD as a treatment option for pediatric patients with advanced-stage newly-diagnosed HL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Population pharmacokinetic/pharmacodynamic analysis of PEG-rhGH enhances confidence in exploring dosing schemes with longer intervals

Background and objectivesPEG-rhGH (Jintrolong®, 0.2 mg/kg/week) is approved in China for the treatment of growth hormone deficiency (GHD) in children. Although 0.2 mg/kg/2 weeks PEG-rhGH failed the non-inferiority threshold of 20% compared with 0.2 mg/kg/week PEG-rhGH, it notably increases serum IGF-1 levels and height velocity in a phase IV trial. In the absence of investigation on the relationship between pharmacokinetics and pharmacodynamics, this analysis aimed to build a population pharmacokinetic/pharmacodynamic (PopPK/PD) model to characterize the relationship between serum PEG-rhGH concentration and serum insulin-like growth factor-1 (IGF-1) levels after subcutaneously administration of PEG-rhGH and to explore the possibility of flexible dosing schemes and improve the clinical monitor practice of IGF-1 levels. MethodsA total of 41 subjects were included for the PopPK analysis, consisting of 30 healthy adults (single dose of 0.1–0.4 mg/kg) and 11 GHD children (multiple doses of 0.2 mg/kg/2 weeks for 26 consecutive weeks). Only GHD children were included for the PopPK/PD analysis. The time courses of serum PEG-rhGH concentrations in healthy adults and GHD children and those of serum IGF-1 levels stimulated by serum PEG-rhGH were well developed with non-linear mixed-effects modeling. ResultsSerum PEG-rhGH pharmacokinetics after subcutaneous administration were adequately described by a one-compartment model with a zero-order input into the absorption compartment followed by first-order absorption dictating absorption into the central compartment, with a dual elimination process consisting of a capacity limited process and a non-capacity limited process. Body weight was a significant covariate. The drug effects on IGF-1 levels were adequately described by a turnover model with saturable effect relationship. IGF-1 responses at the various dosing scheme scenarios were simulated, and illustrated that dosing schemes with intervals longer than the approved one week could be promising, which may provide comparable peaks and average IGF-1 levels and IGF-1 SDS to dosing schemes that have been clinically proven to be tolerated and effective. An accurate prediction of the time course of the effect of various dosing schemes may assist the clinical monitoring practice. ConclusionsThis pharmacokinetic/pharmacodynamic analysis suggested that longer intervals or higher dosing strengths (e.g., 0.3 mg/kg/10 days) in children with GHD are promising compared with the approved dosing scheme (0.2 mg/kg/week). Our simulation may assist the clinical monitoring of the PEG-rhGH therapy.

Comparison of Race-Based and Non-Race-Based Equations for Kidney Function Estimation in Critically Ill Thai Patients for Vancomycin Dosing.

Empiric antibiotic dosing frequently relies on an estimate of kidney function based on age, serum creatinine, sex, and race (on occasion). New non–race‐based estimated glomerular filtration rate (eGFR) equations have been published, but their role in supporting dosing is not known. Here, we report on a population pharmacokinetic model of vancomycin that serves as a useful probe substrate of eGFR in critically ill Thai patients. Data were obtained from medical records during a 10‐year period. A nonlinear mixed‐effects modeling approach was conducted to estimate vancomycin parameters. Data from 208 critically ill patients (58.2% men and 36.0% septic shock) with 398 vancomycin concentrations were collected. Twenty‐three covariates including 12 kidney function estimates were tested and ranked on the basis of the model performance. The median (min, max) age, weight, and serum creatinine was 69 (18, 97) years, 60.0 (27, 120) kg, and 1.53 (0.18, 7.15) mg/dL, respectively. The best base model was a 1‐compartment linear elimination with zero‐order input and proportional error model. A Thai‐specific eGFR equation not indexed to body surface area model best predicted vancomycin clearance (CL). The typical value for volume of distribution and CL was 67.5 L and 1.22 L/h, respectively. A loading dose of 2000 mg followed by maintenance dose regimens based on eGFR is suggested. The Thai GFR not indexed to BSA model best predicts vancomycin CL and dosing in the critically ill Thai population. A 5% to 10% absolute gain in the vancomycin probability of target attainment is expected with the use of this population‐specific eGFR equation.

Pharmacokinetic analysis of meropenem therapeutic drug monitoring data (TDM) in critically ill adult patients

Meropenem is a carbapenem antibiotic widely used in treatment of severe infections in ICU. Critically ill patients’ pathophysiological features may cause changes in the pharmacokinetics of meropenem, such as augmented/impaired renal clearance, as well as an increase in the volume of distribution of the drug. Considerable variability in meropenem concentration for the same dosage regimen, severity of the diseases and the escalating antibiotic resistance support the need for an individualization of the dosing in critically ill patients. Estimation of meropenem pharmacokinetic (PK) parameters was performed using the NPAG (non-parametric adaptive grid) program from the Pmetrics package based on peak-trough TDM data. A one-compartment linear PK model with zero-order input and first-order elimination was used to analyze data of the 36 critically ill patients (66 measured meropenem concentrations totally) and to predict pharmacodynamic (PD) parameter values (%T&gt;MIC) based on the time course of free meropenem concentration for empirically prescribed dosage regimens by MIC level. The estimated PK parameters of the meropenem model were in good agreement with those published in the literature earlier. A great interindividual variability for PK parameters from 44.5% up to 167% was revealed. Different regression lines between meropenem clearance and clearance creatinine (CLCr) were registered in patients with CLCr [1] 7 L/h versus &gt; 7 L/h: statistically significant regression (n=30, p=0.015) versus no correlation (n=6, р=0.85), respectively. Bayesian feedback TDM-based meropenem dose personalization is the most practical approach to ensure adequate drug exposure in critically ill patients, especially in patients with augmented renal clearance.

Population Pharmacokinetics of Meropenem in Preterm Infants

Background. Meropenem, a broad spectrum carbapenem antibiotic, is often used for newborns despite of limited data available on neonatal pharmacokinetics. Due to pharmacokinetic and pharmacodynamic differences as well as to significant changes in the human body related to growth and maturation of organs and systems, direct scaling and dosing extrapolation from adults or older children with adjustment on patients weight can result in increased risk of toxicity or treatment failures. Aims to evaluate the pharmacokinetics of meropenem in premature neonates based on therapeutic drug monitoring data in real clinical settings. Materials. Of 53 pre-term neonates included in the pharmacokinetic/pharmacodynamic analysis, in 39 (73.6%) patients, gestational age ranged from 23 to 30 weeks. Population and individual pharmacokinetic parameter values were estimated by the NPAG program from the Pmetrics package based on peak-trough therapeutic drug monitoring. Samples were assayed by high-performance liquid chromatography. One-compartment pharmacokinetic model with zero-order input and first-order elimination was used to fit concentration data and to predict pharmacokinetic parameter (%T MIC of free drug) for virtual patients with simulated fast, moderate and slow meropenem elimination received different dosage by minimum inhibitory concentration (MIC) level. Univariate and multivariate regression analysis was used to evaluate the influence of patients covariates (gestational age, postnatal age, postconceptual age, body weight, creatinine clearance calculated by Schwartz formula, etc) on estimated meropenem pharmacokinetic parameters. Results. The identified population pharmacokinetic parameters of meropenem in pre-term newborns (elimination half-lives T1/2 = 1.93 0.341 h; clearance CL = 0.26 0.085 L/h/ kg; volume of distribution V = 0.71 0.22 L/h) were in good agreement with those published in the literature for adults, neonates and older children. Pharmacokinetic/pharmacodynamic modeling demonstrated that a meropenem dosage regimen of 90 mg/kg/day administered using prolonged 3-hour infusion every 8 hours should be considered as potentially effective therapy if nosocomial infections with resistant organisms (MIC 8 mg/L) are treated. Conclusions. Neonates and especially pre-term neonates have a great pharmacokinetic variability. Meropenem dosing in premature newborns derived from population pharmacokinetic/pharmacodynamic model can partly overcome the variability, but not all pharmacokinetic variability can be explained by covariates in a model. Further personalizing based on Bayesian forecasting approach and a patients therapeutic drug monitoring data can help to achieve desired pharmacodynamic target.

Experimental Validation of a Mathematical Framework to Simulate Antibiotics with Distinct Half-Lives Concurrently in an In Vitro Model.

Antimicrobial resistance has been steadily increasing in prevalence, and combination therapy is commonly used to treat infections due to multidrug resistant bacteria. Under certain circumstances, combination therapy of three or more drugs may be necessary, which makes it necessary to simulate the pharmacokinetic profiles of more than two drugs concurrently in vitro. Recently, a general theoretical framework was developed to simulate three drugs with distinctly different half-lives. The objective of the study was to experimentally validate the theoretical model. Clinically relevant exposures of meropenem, ceftazidime, and ceftriaxone were simulated concurrently in a hollow-fiber infection model, with the corresponding half-lives of 1, 2.5, and 8 h, respectively. Serial samples were obtained over 24 h and drug concentrations were assayed using validated LC-MS/MS methods. A one-compartment model with zero-order input was used to characterize the observed concentration-time profiles. The experimentally observed half-lives corresponding to exponential decline of all three drugs were in good agreement with the respective values anticipated at the experiment design stage. These results were reproducible when the experiment was repeated on a different day. The validated benchtop setup can be used as a more flexible preclinical tool to explore the effectiveness of various drug combinations against multidrug resistant bacteria.

ПОПУЛЯЦИОННЫЙ ФАРМАКОКИНЕТИЧЕСКИЙ АНАЛИЗ ДАННЫХ ТЕРАПЕВТИЧЕСКОГО ЛЕКАРСТВЕННОГО МОНИТОРИНГА ЛЕВЕТИРАЦЕТАМА У НЕДОНОШЕННЫХ НОВОРОЖДЕННЫХ С НЕОНАТАЛЬНЫМИ СУДОРОГАМИ

Neonatal seizures remain a significant neurologic condition with higher incidences in preterm newborns. There still is a lack of evidence-based recommendations for the optimal choice of antiseizure drug (ASD) and effective dosing in term and preterm neonates. Phenobarbital continues to be widely used as the first-line ASD in neonates. Levetiracetam (LEV) is a relatively new ASD with favorable safety profile and positive efficacy outcomes for neonatal seizures. LEV is increasingly being used to treat seizures in newborns. Objective of the research: the population PK modeling based on TDM data assessed at intravenous (IV) LEV monotherapy as the first-line ASD in preterm newborns. Materials and methods: of 45 preterm neonates included in the LEV retrospective PK analysis, gestational age (GA) ranged from 22 to 36 weeks, in 30 (67%) patients GA was 22–28 weeks. Population and individual PK parameter values were estimated by the NPAG program from the Pmetrics package based on peak-trough TDM. Samples were assayed by high-performance liquid chromatography. One-compartment PK model with zero-order input and first-order elimination was used to fit LEV concentration data from 101 TDM occasions (201 measured concentrations totally). In the majority of cases, the LEV daily doses were 30 mg/kg/day (ranged from 20 up to 50 mg/kg/day), administered twice a day with 12-hour dosing interval in divided doses. Univariate and multivariate regression analysis was used to evaluate the influence of patient’s covariates on distribution of the estimated LEV PK parameters. Results: when compared to adults and older children, preterm newborns were found to have in average a higher volume of distribution (V), longer half-life (T1/2) and lower clearance (CL). Taking into consideration the lower GA and PCA of the neonates included into this PK study, the identified population PK parameters of LEV in preterm newborns were in good agreement with those published in the literature for neonates: the estimated T1/2 values have a 20% to 80% range of 11 to 32 hrs, the median values for CL and V were 1,22 ml/min/kg and 1,5 L/kg, respectively. LEV was tolerated well in the study age-group, no serious adverse events were evident during or after 30-min IV LEV infusions. Conclusion: the study revealed significant variability in the estimated PK parameters in preterm infants. The results of regression analysis showed that it is not possible to fully explain PK variability using covariates in a statistical model. Personalizing of the LEV anti-seizure treatment for the preterm newborns can be based on the Bayesian forecasting approach and a patient’s TDM data.

Population Pharmacokinetics of Cariprazine and its Major Metabolites.

Background and ObjectivesCariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is approved for the treatment of adults with schizophrenia (1.5–6 mg/day) and manic/mixed (3–6 mg/day) episodes associated with bipolar I disorder. This population pharmacokinetic analysis describes the concentration-time profiles of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). Additionally, the potential impact of patient characteristics, creatinine clearance, and cytochrome P450 2D6 (CYP2D6) metabolizer status on the pharmacokinetics of cariprazine and its metabolites was evaluated.MethodsData from three phase 1 and ten phase 2/3 studies in adult patients with schizophrenia or bipolar mania were included. Nonlinear mixed-effects pharmacokinetic modeling was performed using the NONMEM software package. Compartmental modeling was performed sequentially with the cariprazine elimination rate used as the DCAR formation rate and likewise the elimination rate of DCAR used with a delay as the DDCAR formation rate.ResultsCariprazine pharmacokinetics were described by a three-compartment model with zero-order input of the dose to a depot compartment followed by first-order absorption and first-order elimination. DCAR and DDCAR pharmacokinetics were described by two-compartment models with linear elimination. Statistically significant predictors of pharmacokinetic parameters included weight, sex, and race, though differences in exposures were not large enough to require an adjustment in dose. Creatinine clearance was not a statistically significant predictor of drug clearance, and a post hoc analysis found that CYP2D6 metabolizer status was not associated with changes in exposure levels for cariprazine, DCAR, or DDCAR. The median time to 90% of steady state was approximately 1 week for cariprazine and DCAR and 3 weeks for DDCAR.ConclusionsPopulation pharmacokinetic modeling provided a quantitative description of the concentration-time profile of cariprazine and its metabolites.Electronic supplementary materialThe online version of this article (10.1007/s13318-020-00650-4) contains supplementary material, which is available to authorized users.

Population Pharmacokinetics of Brentuximab Vedotin in Adult and Pediatric Patients With Relapsed/Refractory Hematologic Malignancies: Model-Informed Hypothesis Generation for Pediatric Dosing Regimens.

Prior pharmacokinetic (PK) analyses of the antibody‐drug conjugate (ADC) brentuximab vedotin (1.8 mg/kg every 3 weeks) in pediatric patients with relapsed/refractory hematologic malignancies found that patients aged <12 years exhibited decreased ADC area under the curve (AUC) compared with those aged ≥12 years. This population PK (POPPK) analysis used data from pediatric (NCT01492088) and adult (NCT00430846) studies of brentuximab vedotin to quantify body size effects on ADC exposure. Data were collected from 84 patients with a median age of 25.7 years (range, 7.7‐87.3 years), 34 of whom (40.5%) were aged <18 years; median patient weight was 67 kg (range, 21‐154 kg), and median body surface area was 1.8 m2 (range, 0.87‐2.81 m2). ADC PK was described by a linear 3‐compartment model with zero‐order input and first‐order elimination. POPPK modeling indicated that dosing brentuximab vedotin at 1.8 mg/kg every 3 weeks or 1.2 mg/kg every 2 weeks resulted in lower ADC AUC values in small/moderate‐sized pediatric patients (<28 kg and 28‐49 kg, respectively) compared with large pediatric/adult patients (50‐100 kg). Dosing at 71.5 mg/m2 every 3 weeks and 47.7 mg/m2 every 2 weeks was predicted to achieve comparable AUC values across all body weight ranges and a similar AUC to that in the 50‐ to 100‐kg group at the standard doses of 1.8 mg/kg every 3 weeks and 1.2 mg/kg every 2 weeks, respectively. These results have generated a hypothesis to support evaluation of brentuximab vedotin at 48 mg/m2 every 2 weeks in combination with adriamycin, vinblastine, and dacarbazine chemotherapy in an ongoing pediatric trial in frontline Hodgkin lymphoma (NCT02979522).

Need for Bioequivalence Standards that Reflect the Clinical Importance of the Complex Pharmacokinetics of Paliperidone Palmitate Long-Acting Injectable Suspension.

Paliperidone palmitate is a second generation antipsychotic, approved for the treatment of schizophrenia in the form of the long-acting injectable (LAI) products INVEGA SUSTENNA® (once monthly injection) and INVEGA TRINZA® (once every 3 months injection). Paliperidone palmitate dissolves slowly after deep intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. The pharmacokinetic (PK) profile of the INVEGA SUSTENNA® formulation is biphasic, comprised of an initial relatively fast zero-order input, which allows rapid attainment of therapeutic concentrations without oral supplementation; and a subsequent maintained second-stage, first-order input, allowing for once monthly administration. Changes to the manufacturing processes can substantially alter the release characteristics of paliperidone palmitate LAI and consequently its PK profile. As an example, larger or smaller particle sizes of paliperidone palmitate can result in a delayed or accelerated release of paliperidone into the systemic circulation, respectively. Such changes are clinically relevant, as transient excursions above therapeutic plasma concentrations can be associated with an increased risk of adverse effects, including tachycardia, hypotension, QT prolongation, and extrapyramidal symptoms. Conversely, a delay in attaining therapeutic plasma concentrations of paliperidone on initiation of treatment, or a return to low plasma concentrations before the end of a dosing interval during repeated dosing, increases the risk of relapse. Given the integral relationship of the PK profile to the product's clinical effects, it is important to have bioequivalence standards that reflect the complexity of the paliperidone palmitate LAI PK profile if one is to consider therapeutic equivalence based on simple bioequivalence testing. Although both the EMA and U.S. FDA have product-specific guidelines to determine bioequivalence, their requirements differ substantially. In Canada, no LAI product-specific bioequivalence guidance exists for multiphasic medication delivery systems, and the recently revised Comparative Bioavailability Standards: Formulations Used for Systemic Effects guidance applies only to oral and non-injectable formulations. We recommend that new Canadian standards be developed for multiphasic and biphasic intramuscular / subcutaneous (IM/SC) products, including paliperidone palmitate LAI products, because, similar to modified-release oral dosage forms, a different PK profile in modified-release IM/SC products can result in clinically meaningful differences in safety, efficacy, and tolerability. To ensure bioequivalence for both newly initiated and switch patients, this paper proposes bioequivalence standards that could be adopted in Canada that include two studies, a multiple-dose cross-over study, and a single-dose study with partial AUC metrics.

Vancomycin Population Pharmacokinetics in Critically Ill Adults During Sustained Low-Efficiency Dialysis

Sustained low-efficiency dialysis (SLED) is a hybrid form of dialysis that is increasingly used in critically ill patients with kidney injury and hemodynamic instability. Antimicrobial dosing for patients receiving SLED is informed by pharmacokinetic studies that describe the drug clearance. Studies available to assist in the dosing of vancomycin in the context of SLED are lacking. The objective of this prospective observational study was to describe the population pharmacokinetics of vancomycin in critically ill patients receiving SLED, and use simulation studies to propose dosing strategies. Serial serum samples were obtained from 31 critically ill patients prescribed vancomycin while receiving SLED. Vancomycin concentrations were quantified in plasma using a validated liquid chromatography mass spectrometry/mass spectrometry method. A population pharmacokinetic model was developed, and Monte Carlo simulation was used to determine the probability of target attainment at different doses. From a total of 335 serum samples from 31 patients receiving 52 sessions of SLED therapy, a two-compartment linear model with zero-order input was developed. The mean (standard deviation) clearance of vancomycin on and off SLED was 5.97 (4.04) and 2.40 (1.46)L/h, respectively. Using pharmacodynamic targets for efficacy (area under the concentration-time curve from time zero to 24h [AUC24]/minimum inhibitory concentration [MIC] ≥ 400) and safety (AUC24 ≥ 700), a loading dose of 2400mg followed by daily doses of 1600mg is recommended. Subsequent dosing should be informed by therapeutic drug monitoring of vancomycin levels. In critically ill patients receiving SLED, vancomycin clearance is highly variable with a narrow therapeutic window. Empiric dosing is proposed but subsequent dosing should be guided by drug levels.

Optimized meropenem dosage regimens using a pharmacokinetic/pharmacodynamic population approach in patients undergoing continuous venovenous haemodiafiltration with high-adsorbent membrane.

The pharmacokinetics (PK) of antibiotics change during sepsis and continuous renal replacement therapies in critically ill patients. Limited evidence exists on the use of the oXiris® high-adsorbent membrane. To develop a PK/pharmacodynamic (PD) model for meropenem in critically ill sepsis patients undergoing continuous venovenous haemodiafiltration (CVVHDF) with the oXiris® membrane, and to design an optimal dosing regimen assessed according to the PTA. A prospective, open-label, observational PK trial was performed (EUDRACT 2011-005902-30). We conducted PK studies (plasma and ultrafiltrate) for at least 24 h after concomitant administration of CVVHDF and meropenem 1 g q8h. We constructed a PK model using the non-linear mixed-effects approach (NONMEM 7.3). We evaluated the suitability of different dosage regimens using Monte Carlo simulations and calculated the PTA as the percentage of subjects achieving a given percentage of time above the MIC (fT>MIC). The PK of meropenem was best captured by a two-open-compartment model with zero-order input kinetics and first-order elimination. Extracorporeal CL was 7.78 L/h [relative standard error (RSE) 16.45 L/h] and central compartment V (Vc) was 24.9 L (RSE 13.73 L). Simulations showed that, for susceptible Pseudomonas aeruginosa isolates (EUCAST MIC ≤2 mg/L) and attainment of 100%fT>MIC, 500 mg q8h given as extended (EI) or continuous infusion (CI) would be sufficient. For a target of 100%fT>4×MIC, CI of 3000 mg q24h or 2000 mg q8h administered as EI or CI would be required. We have constructed a PK model of meropenem in sepsis patients undergoing CVVHDF using the oXiris® membrane. This tool will support physicians when calculating the optimal initial dose.

Piperacillin Population Pharmacokinetics in Critically Ill Adults During Sustained Low-Efficiency Dialysis.

Sustained low-efficiency dialysis (SLED), is increasingly being used in intensive care units (ICUs) but studies informing drug dosing for such patients is lacking. To describe the population pharmacokinetics (PKs) of piperacillin/tazobactam in critically ill adults receiving SLED and to provide dosing recommendations. This prospective population PK study was conducted in adult ICU patients prescribed piperacillin/tazobactam while receiving SLED; 321 blood samples were obtained from 34 participants during and between approximately 50 SLED treatments for quantification of piperacillin and tazobactam concentrations in plasma. A population PK model was developed. Monte Carlo simulation was used to determine the probability of target attainment and pathogen-specific fractional target attainment at different doses. From a 2-compartment linear model with zero-order input, the mean (SD) clearance of piperacillin on SLED and off SLED were 4.81 (8.48) and 1.42 (1.54) L/h, respectively. Tazobactam concentrations were not sufficient for analysis. For the target of 50% fT>MIC (unbound concentrations of drug are above the minimum inhibitory concentration for >50% of the dosing interval), 3-g of piperacillin infused over 0.5 hours every 8 hours was appropriate for susceptible organisms with MIC ≤16 mg/L. For life-threatening infections where the target of 100% fT>MIC is preferred, a 9-g dose administered as a continuous infusion every 24 hours was appropriate for susceptible organisms with MIC ≤32 mg/L. In critically ill patients receiving SLED, piperacillin doses need to be guided by the frequency of SLED treatments and susceptibility of the known or suspected pathogen.