Nonlinear Mixed-effect Modeling Approach Research Articles

Comprehensive population pharmacokinetic modelling of sugemalimab, an anti-programmed death-ligand 1 (PD-L1) human monoclonal antibody, in patients with solid tumours or lymphomas across multiple Phase I-III studies.

The aim of this study was to develop a population pharmacokinetics model for sugemalimab, a monoclonal antibody that targets programmed death-ligand 1 (PD-L1), using data from Phase I-III trials and to assess clinical factors affecting sugemalimab exposure. A nonlinear mixed-effect modelling approach was employed to analyse pooled data from nine studies involving 1628 subjects to characterize the PopPK of sugemalimab. This investigation examined the influence of various covariates on sugemalimab pharmacokinetics (PK), encompassing demographics, baseline hepatic and renal function-related covariates, and others (including anti-drug antibody [ADA], combination treatment, Eastern Cooperative Oncology Group [ECOG] performance score, tumour burden and tumour type). Estimation accuracy and predictive ability of the final model were evaluated using various methods. The influence of covariates on sugemalimab exposure was assessed by simulation from the final model. A two-compartment model with first-order elimination and time-varying clearance effectively described the PK of sugemalimab. Covariate analyses revealed significant relationships between sugemalimab clearance and body weight, albumin, gender, ADA, tumour burden and tumour type. The statistically significant covariates on central volume were body weight, albumin, gender and tumour type. No significant relationships were found in the final model for age, race, alanine aminotransferase, aspartate aminotransferase, creatinine, total bilirubin, alkaline phosphatase, combination treatment, creatinine clearance, ECOG, renal function or hepatic function. All significant covariates demonstrated less than a 20% effect on sugemalimab exposure. The PopPK model adequately described the pharmacokinetic profile of sugemalimab with no clinically meaningful impact observed on its exposure across all covariates. Dose adjustment does not appear to be necessary.

Population pharmacokinetics of nirmatrelvir/ritonavir in critically ill Chinese COVID-19 patients and recommendations for medication use: a two-center retrospective study

ABSTRACT Background This study aimed to establish population pharmacokinetics (PPK) models of nirmatrelvir/ritonavir in critically ill Chinese patients with the coronavirus disease 2019 (COVID-19) infection, explore factors affecting the pharmacokinetics (PK) of nirmatrelvir/ritonavir. Methods A total of 285 serum samples and clinical data were collected from 152 patients. The PPK models of nirmatrelvir/ritonavir were analyzed using nonlinear mixed-effect modeling (NONMEM) approach. The optimal dosing regimen for patients with different renal function was determined using Monte Carlo simulations. Results The population typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) of nirmatrelvir were 2.26 L/h and 15.3 L, respectively. Notably, creatinine clearance (CrCL) significantly influenced the PK variation of nirmatrelvir. Monte Carlo simulations suggested that patients with mild-to-moderate renal impairment experienced a 22.0–59.9% increase in the area under the curve (AUC) when they were administered a standard dose of nirmatrelvir compared to those with normal renal function. The AUC in patients with severe renal impairment after administration of 150 mg q12h nirmatrelvir was similar to that in patients with normal renal function after administration of 300 mg q12h nirmatrelvir. Conclusions PPK modeling and simulation provided a reference for the rational clinical application of nirmatrelvir/ritonavir in critically ill Chinese patients.

Population pharmacokinetic/target engagement modelling of tozorakimab in healthy volunteers and patients with chronic obstructive pulmonary disease.

This study describes the pharmacokinetic (PK)/target engagement (TE) relationship of tozorakimab, an anti-interleukin (IL)-33 antibody, by building a mechanistic population PK/TE model using phase 1 biomarker data. The analysis included tozorakimab PK and TE in serum assessed in 60 tozorakimab-treated participants, including healthy adults and patients with mild chronic obstructive pulmonary disease. Scenarios evaluated three dose frequencies (once every 2, 4 or 6weeks) administered subcutaneously at seven doses of tozorakimab (30, 60, 90, 120, 150, 300 or 600 mg). For each dose, simulations were performed with 5000 virtual individuals to predict systemic TE. Inhibition of IL-33/soluble ST2 (sST2) complex levels at trough PK at steady state was assessed in each dosing scenario. The PK/TE modelling analyses were performed using a nonlinear mixed-effect modelling approach. The final two-compartment PK model with tozorakimab binding IL-33 in the central compartment adequately described the systemic PK and TE of tozorakimab at population and individual levels. The mean PK parameter estimates of absorption rate, central volume of distribution and clearance were 0.48 (90% confidence interval [CI]: 0.40-0.59, 1/day), 12.64 (90% CI: 8.60-18.62, L) and 0.87 (90% CI: 0.65-1.16, L/day), respectively. Consistent with the observed value, tozorakimab bioavailability was 45%. For all three dose frequencies, predicted inhibition of systemic IL-33/sST2 levels was more than 95% at doses greater than 90 mg. The PK/TE model reliably quantified the relationship between PK and systemic TE of tozorakimab, with potential utility for predicting clinical dose-response relationships and supporting clinical dose selection.

Item Response Theory Quantifies the Relationship Between Improvements in Serum Phosphate and Patient-Reported Outcomes in Adults With X-Linked Hypophosphatemia.

Burosumab is indicated for treatment of a rare bone disease, X-linked hypophosphatemia (XLH). The aim of this analysis was to evaluate the relationship between a treatment response biomarker and patient-reported outcomes (PROs). Longitudinal data for PROs were obtained from adults with XLH from a phase III study. Individual rich time profiles of the biomarker, serum phosphate were simulated using a prior population pharmacokinetic-pharmacodynamic model to calculate serum phosphate exposure metrics for each 28-day treatment cycle, which were then merged with PROs data. Item response theory parameters were first estimated to map a latent variable, ψ, that is, disability score, relative to baseline. Next, the relationships between serum phosphate exposures and ψ were modeled using a nonlinear mixed-effect (NLME) modeling approach. A combined item response theory-NLME model with average serum phosphate as a predictor of ψ described PROs data well. The model estimates suggested 28%, 31%, and 25% reduction in Western Ontario and McMaster Universities Osteoarthritis Index, brief pain inventory, and brief fatigue inventory scores, respectively, with every unit increase in average serum phosphate from the lower limit of normal (2.5 mg/dL). Additionally, a time effect of ~ 0.08% improvements each week was estimated. The analysis suggested that burosumab treatment-induced improvements in serum phosphate levels are associated with improvements in PROs in adults with X-linked hypophosphatemia. The analyses confirmed the importance of prolonged serum phosphate level correction in adult patients with XLH. These results can be useful to guide the design of further studies and to design treatment optimization strategies.

Redefining Statin Dosage Post-Gastric Bypass: Insights from a Population Pharmacokinetics-Pharmacodynamics Link Approach.

Roux-en-Y gastric bypass (RYGB) involves creating a small stomach pouch, bypassing part of the small intestine, and rerouting the digestive tract. These alterations can potentially change the drug exposure and response. Our primary aim was to assess the impact of RYGB on the pharmacokinetics of simvastatin lactone (SV) and its active metabolite, simvastatin hydroxy acid (SVA). Ultimately, we aimed to optimize dosing for this understudied population by employing a population pharmacokinetic-pharmacodynamic link approach. The study comprised patients who had undergone RYGB surgery and individuals without a previous history of RYGB. All participants received a single oral dose of simvastatin. Plasma concentration data were analyzed with a nonlinear mixed-effect modeling approach. A parent-metabolite model with first-order absorption, 2-compartments for SV and 1-compartment for SVA, linear elimination, and enterohepatic circulation best described the data. The model was linked to the turnover pharmacodynamic model to describe the SVA inhibition on LDL-cholesterol production. Our simulations indicated that following RYGB surgery, the exposure to SV and SVA decreased by 40%. Consequently, for low-intensity statin patients, we recommend increasing the dose from 10 to 20 mg in post-RYGB patients to maintain a comparable response to that of non-operated subjects. Moderate-intensity statin patients should require increasing doses to 40 or 60 mg or the addition of a non-statin medication to achieve similar therapeutic outcomes. In conclusion, individuals post-RYGB exhibit diminished exposure to SV and may benefit from increasing the dose or adjunctive therapy with non-statin drugs to attain equivalent responses and mitigate potential adverse events.

Five multivariate Duchenne muscular dystrophy progression models bridging six-minute walk distance and MRI relaxometry of leg muscles.

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T2 modelvariables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T2. Sigmoid Imax and Emax models best captured the profiles of 6MWD and MRI-T2 over age. Steroid use, baseline 6MWD, and baseline MRI-T2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T2, supporting the use of MRI-T2. The developed models will guide drug developers in using the MRI-T2 to most efficient use in DMD clinical trials.

Population pharmacokinetics of a novel PCSK9 antisense oligonucleotide.

The aim of this study was to characterize the population pharmacokinetics of AZD8233, an antisense oligonucleotide (ASO) that targets the PCSK9 transcript to reduce hepatocyte PCSK9 protein production and plasma levels. AZD8233 utilizes generation 2.5S-constrained ethyl motif (cET) chemistry and is conjugated to a triantennary N-acetylgalactosamine (GalNAc3) ligand for targeted hepatocyte uptake. A non-linear mixed-effect modelling approach utilizing NONMEM software was applied to AZD8233 concentration-time data from 3416 samples in 219 participants from four phase 1-2 studies, one in healthy volunteers (NCT03593785) and three in patients with dyslipidaemia (NCT04155645, NCT04641299 and NCT04823611). The final model described the AZD8233 plasma concentration-time profile from four phase 1-2 studies in healthy volunteers or participants with dyslipidaemia, covering a dose range of 4 to 120 mg. The pharmacokinetics of AZD8233 were adequately described by a two-compartment model with first-order absorption. The supra-proportional increase in maximum plasma concentration (Cmax) across the observed dose range was described by non-linear Michaelis-Menten elimination (maximum elimination rate, 9.9mg/h [12% relative standard error]; concentration yielding half-maximal elimination rate, 4.8mg/L [18% relative standard error]). Body weight, sex, estimated glomerular filtration rate and disease status (healthy participant vs. patient with dyslipidaemia) were identified as factors affecting exposure to AZD8233. Covariate analysis showed body weight to be the main factor affecting exposure to AZD8233, which largely explained the higher Cmax observed in the Asian population relative to non-Asians.

PK Modeling of L-4-Boronophenylalanine and Development of Bayesian Predictive Platform for L-4-Boronophenylalanine PKs for Boron Neutron Capture Therapy.

L-4-[(10B)]Boronophenylalanine (BPA) is an amino acid analogue with a boron-10 moiety. It is most widely used as a boron carrier in boron neutron capture therapy. In this study, a Bayesian predictive platform of blood boron concentration based on a BPA pharmacokinetic (PK) model was developed. This platform is user-friendly and can predict the individual boron PK and optimal time window for boron neutron capture therapy in a simple way. The present study aimed to establish a PK model of L-4-boronophenylalanine and develop a Bayesian predictive platform for blood boron PKs for user-friendly estimation of boron concentration during neutron irradiation of neutron capture therapy. Whole blood boron concentrations from seven previous reports were graphically extracted and analyzed using the nonlinear mixed-effects modeling (NONMEM) approach. Model robustness was assessed using nonparametric bootstrap and visual predictive check approaches. The visual predictive check indicated that the final PK model is able to adequately predict observed concentrations. The Shiny package was used to input real-time blood boron concentration data, and during the following irradiation session blood boron was estimated with an acceptably short calculation time for the determination of irradiation time. Finally, a user-friendly Bayesian estimation platform for BPA PKs was developed to optimize individualized therapy for patients undergoing BNCT.

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

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. The study included 50 patients of both sexes (aged 1-18years) who received 3 or 5g/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. 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. 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.

Radial increment dynamics of Maritime pine (Pinus pinaster Ait.) in pure and mixed stands with Scots pine (Pinus sylvestris L.) under changing environmental conditions

Forest dynamics are undergoing profound alteration due to the fact that climate change is increasing the frequency and severity of abiotic and biotic forest disturbances. Because of the unpredictable nature of the drought periods and the variation in their severity, Mediterranean forests are typically more vulnerable. Mediterranean Pinus pinaster forests are showing decay symptoms linked to climate change. There is clear evidence that promoting mixtures can serve as an effective forest adaptation strategy. In this regard, we sought to better understand the responses of P. pinaster radial growth dynamics to various factors, in both mixed and pure forest stands, and provide valuable insights into P. pinaster dynamics when mixed with P. sylvestris. In this study, we examined the variation of intra-annual cumulative radial increment patterns in response to the climate of P. pinaster between pure and mixed stands with P. sylvestris. Using data from band dendrometers collected over five consecutive climatically distinct years (2016–2020), a nonlinear mixed-effect model approach was used to analyze the differences in intra-annual cumulative radial increment patterns for P. pinaster between years in mixed and pure stands. The intra-annual radial increment pattern of P. pinaster showed significant year-to-year variation and varied with tree size, with greater increment in larger trees. Trees in mixed stands had a higher mean radial increment compared to corresponding ones in pure stands. Increased summer maximum temperatures negatively affected tree cumulative annual increment regardless of composition, but with a lower impact on trees in pure stands. Spring precipitation increased the length of the growing season, while higher spring maximum temperatures triggered an earlier inflection point. Our results highlight the high plasticity of P. pinaster in adapting to varying intra- and inter-annual environmental conditions and competition with other species and suggest that promoting mixtures with P. sylvestris may be an interesting management strategy for adaptation to climate change.

Population Pharmacokinetic Analysis of Atomoxetine and its Metabolites in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

Atomoxetine (ATX) is a non-stimulant used to treat attention-deficit/hyperactivity disorder (ADHD) and systemic exposure is highly variable due to polymorphic cytochrome P450 2D6 (CYP2D6) activity. The objective of this study was to characterize the time course of ATX and metabolites (4-hydroxyatomoxetine (4-OH); N-desmethylatomoxetine (NDA); and 2-carboxymethylatomoxetine (2-COOH)) exposure following oral ATX dosing in children with ADHD to support individualized dosing. A nonlinear mixed-effect modeling approach was used to analyze ATX, 4-OH, and NDA plasma and urine, and 2-COOH urine profiles obtained over 24-72 hours from children with ADHD (n = 23) following a single oral ATX dose. Demographics and CYP2D6 activity score (AS) were evaluated as covariates. Simulations were performed to explore the ATX dosing in subjects with various CYP2D6 AS. A simultaneous pharmacokinetic modeling approach was used in which a model for ATX, 4-OH, and NDA in plasma and urine, and 2-COOH in urine was developed. Plasma ATX, 4-OH, and NDA were modeled using two-compartment models with first-order elimination. CYP2D6 AS was a significant determinant of ATX apparent oral clearance (CL/F), fraction metabolized to 4-OH, and systemic exposure of NDA. CL/F of ATX varied almost 7-fold across the CYP2D6 AS groups: AS 2: 20.02 L/hour; AS 1: 19.00 L/hour; AS 0.5: 7.47 L/hour; and AS 0: 3.10 L/hour. The developed model closely captures observed ATX, 4-OH, and NDA plasma and urine, and 2-COOH urine profiles. Application of the model shows the potential for AS-based dosing recommendations for improved individualized dosing.

A validated UPLC-MS/MS method for quantification of pyrotinib and population pharmacokinetic study of pyrotinib in HER2-positive breast cancer patients.

Pyrotinb has been approved for the treatment of HER2-positive advanced or metastatic breast cancer in China. However, the plasma concentration of pyrotinb in different patients varies greatly, and in the course of treatment, if patients have intolerable adverse reactions, the drug dosage will be reduced or even stopped. This study set out to establish an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the determination of pyrotinb in human plasma, analyze the population pharmacokinetics (PPK) of pyrotinib and assess the influence of patient variables on PK of pyrotinib in patients with HER2 positive breast cancer. An UPLC-MS/MS method was developed to measure pyrotinib in human plasma. Utilizing a gradient elution procedure and a Kinetex C18 column (2.1mm × 100mm, 1.7μm), sample separation was accomplished in 5.5min. Pyrotinb extraction via protein precipitation was used as a sample pre-treatment technique. In total, 50 patients provided 158 plasma samples, which were identified and used in the PPK investigation. The non-linear mixed-effects modeling (NONMEM) approach was used to assess the plasma concentrations and covariates information. For the final PPK model evaluation, external evaluation, non-parametric bootstrap, visual predictive check (VPC), and goodness-of-fit (GOF) were used. The UPLC-MS/MS method for determining plasma concentration of pyrotinib in patients had good selectivity and linearity in the range of 1-1,000ng/mL. Pyrotinib concentration profile in HER2-positive breast cancer patients was well described by a single-compartment PPK model with first-order absorption and elimination. The formulas for the final estimated values of overall parameters of CL/F and Vd/F and Ka are respectively: , , . No dosage adjustment was advised, despite the possibility that the total protein levels could have a substantial impact on the apparent distribution volume of pyrotinib with limited magnitude. In this study, an UPLC-MS/MS method was established to determine the concentration of pyrotinib in human plasma. A population pharmacokinetic model of pyrotinib in HER2 positive breast cancer patients suggested that low serum total protein reduced the clearance rate of pyrotinib in patients. Clinical medical staff should pay attention to the liver function of patients with abnormal serum total protein and be alert to the occurrence of adverse drug reactions.

Development and internal validation of a clinical prediction model for individualized dosing of BAY 81-8973, A full-length recombinant factor VIII, in pediatric patients with haemophilia A

BackgroundAs the most commonly used coagulation factor VIII (FVIII) concentrate in China, the individualized dosing prediction model of Kovaltry (BAY81–8973) is not fully investigated in pediatric patients. The prophylaxis tailored by population pharmacokinetic (PopPK) model can optimize dosing regimens. ObjectivesThis study aimed to develop PopPK models of BAY 81–8973 in pediatric patients, identify quantitative relationships of blood type (as a substitution for von Willebrand factor) on FVIII clearance and provide model-informed precision dosing (MIPD) procedures. MethodsPediatric patients with severe hemophilia A were enrolled and PK tests were conducted. The blood samples were collected at six time point. One-stage-based activated partial thromboplastin time was used for FVIII activity. Basic demographics and key covariates (blood type and von Willebrand factor antigen) were collected. A nonlinear mixed-effect modeling (NONMEM) approach was employed to establish PopPK model. Simulations were performed to evaluate current dosing regimens and present MIPD strategies. ResultsA total of 30 pediatric patients were included in the analysis. In the final model, Fat-free mass calculated from weight, age, and height was included as a size descriptor which affect FVIII apparent volume of distribution and clearance. Both von Willebrand factor antigen (VWF:Ag) and blood type accounted for the interindividual variability of FVIII clearance, but only one can retain in the final model. Therefore, two PopPK models based on VWF:Ag or blood type were developed. When the VWF:Ag value is doubled, the FVIII clearance is reduced by 35 %. Compared with blood type non-O, the clearance in pediatric patients with blood type O increased by 25.9 %. Weight-based dosing without regard to age and blood type resulted in large differences in FVIII trough activity. Patient demographics, dosing information, sparse blood samples and PopPK model together with Bayesian estimate constituted the MIPD workflow. Using it, the individual parameters and optimized dosing regimen could be achieved. ConclusionThis is the first predictive model designed to predict individualized dosing of BAY 81–8973 in pediatric patients with Hemophilia A. These results are useful in the PK-guided prophylaxis among pediatric patients and hold great potential to improve their long-term clinical outcomes.

Population pharmacokinetic modeling and dosing simulation of avalglucosidase alfa for selecting alternative dosing regimen in pediatric patients with late-onset pompe disease

Avalglucosidase alfa (AVAL) was approved in the United States (2021) for patients with late-onset Pompe disease (LOPD), aged ≥ 1 year. In the present study, pharmacokinetic (PK) simulations were conducted to propose alternative dosing regimens for pediatric LOPD patients based on a bodyweight cut-off. Population PK (PopPK) analysis was performed using nonlinear mixed effect modeling approach on pooled data from three clinical trials with LOPD patients, and a phase 2 study (NCT03019406) with infantile-onset Pompe disease (IOPD: 1–12 years) patients. A total of 2257 concentration-time points from 91 patients (LOPD, n = 75; IOPD, n = 16) were included in the analysis. The model was bodyweight dependent allometric scaling with time varying bodyweight included on clearance and distribution volume. Simulations were performed for two dosing regimens (20 mg/kg or 40 mg/kg) with different bodyweight cut-off (25, 30, 35 and 40 kg) by generating virtual pediatric (1–17 years) and adult patients. Corresponding simulated individual exposures (maximal concentration, Cmax and area under the curve in the 2-week dosing interval, AUC2W), and distributions were calculated. It was found that dosing of 40 mg/kg and 20 mg/kg in pediatric patients < 30 kg and ≥ 30 kg, respectively, achieved similar AVAL exposure (based on AUC2W) to adult patients receiving 20 mg/kg. PK simulations conducted on the basis of this model provided supporting data for the currently approved US labelling for dosing adapted bodyweight in LOPD patients ≥ 1 year by USFDA.

Vancomycin population pharmacokinetics analysis in Chinese paediatric patients with varying degrees of renal function and ages: development of new practical dosing recommendations.

To describe the pharmacokinetics of vancomycin in a large Chinese paediatric cohort with varying degrees of renal function and ages and to develop practical dosing guidelines. We conducted a retrospective population pharmacokinetic study using data from paediatric patients who received vancomycin between June 2013 and June 2022. A non-linear mixed-effect modelling approach with a one-compartment model structure was applied. Monte Carlo simulations were used to stimulate an optimal dosage regimen to achieve the target of AUC24/MIC between 400 and 650. We analysed a total of 673 paediatric patients and 1547 vancomycin serum concentrations. Covariate analysis revealed that physiological maturation, renal function, albumin and cardiothoracic surgery (CTS) significantly affected vancomycin pharmacokinetics. The typical clearance and volume of distribution, standardized to 70 kg, were 7.75 L/h (2.3% relative standard error, RSE) and 36.2 L (1.7% RSE), respectively. Based on the model, we proposed an optimal dosing regimen that considers the patient's age and estimate glomerular filtration rate (eGFR) to achieve a target AUC24/MIC for CTS and non-CTS patients. We also found that a loading dose of 20 mg/kg can help patients with an eGFR of <60 mL/min/1.73 m2 achieve the target AUC on the first day of treatment. We established vancomycin pharmacokinetic parameters in Chinese paediatric patients and proposed a dosing guideline integrating eGFR, age and CTS status, potentially improving clinical outcomes and reducing nephrotoxicity risk.

Population Pharmacokinetics of Total Rabbit Anti-thymocyte Globulin in Non-obese Adult Patients Undergoing Hematopoietic Cell Transplantation for Hematologic Malignancy.

Rabbit anti-thymocyte globulin (rATG), a therapeutic polyclonal antibody against human T cells, is commonly used in conditioning therapy prior to allogeneic hematopoietic cell transplantation (HCT). Previous studies successfully developed an individualized rATG dosing regimen based on "active" rATG population PK (popPK) analysis, while "total" rATG can be a more logistically favorable alternative for early HCT outcomes. We conducted a novel popPK analysis of total rATG. Total rATG concentration was measured in adult human-leukocyte antigen (HLA) mismatched HCT patients who received a low-dose rATG regimen (total 2.5-3mg/kg) within 3days prior to HCT. PopPK modeling and simulation was performed using nonlinear mixed effect modeling approach. A total of 504 rATG concentrations were available from 105 non-obese patients with hematologic malignancy (median age 47years) treated in Japan. The majority had acute leukemia or malignant lymphoma (94%). Total rATG PK was described by a two-compartment linear model. Influential covariate relations include ideal body weight [positively on both clearance (CL) and central volume of distribution], baseline serum albumin (negatively on CL), CD4+ T cell dose (positively on CL), and baseline serum IgG (positively on CL). Simulated covariate effects predicted that early total rATG exposures were affected by ideal body weight. This novel popPK model described the PK of total rATG in the adult HCT patients who received a low-dose rATG conditioning regimen. This model can be used for model-informed precision dosing in the settings with minimal baseline rATG targets (T cells), and early clinical outcomes are of interest.

A pharmacokinetic analysis of amisulpride in adult Chinese patients with schizophrenia: Impact of creatinine clearance.

To develop a stable population pharmacokinetic (PPK) model of amisulpride and to investigate the effects of covariates on the pharmacokinetic parameters in adult Chinese patients with schizophrenia. This retrospective study was carried out using 168 serum samples from 88 patients collected during routine clinical monitoring. Covariates recorded included demographic parameters (gender, age, weight), clinical parameters (serum creatinine, creatinine clearance), and intake of co-medications. The amisulpride PPK model was established using a nonlinear mixed effects modeling (NONMEM) approach. Goodness-of-fit (GOF) plots, bootstrap validation (1,000 runs), and normalized prediction distribution error (NPDE) were used in the evaluation of the final model. A one-compartment model with first-order absorption and elimination was developed. The population estimates for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 32.6 L/h and 391 L, respectively. Estimated creatinine clearance (eCLcr) was a significant covariate for CL/F. The established model was: CL/F = 32.6 × (eCLcr/114.3)0.485 (L/h). The stability of the model was confirmed using GOF plots, bootstrap, and NPDE. Creatinine clearance is a major covariate which is positively correlated with CL/F. Therefore, additional dose adjustments of amisulpride may be required on the basis of eCLcr. An ethnic difference may exist in the pharmacokinetics of amisulpride, but further research is needed in order to confirm this possibility. The PPK model of amisulpride for adult Chinese schizophrenic patients established here using NONMEM, is potentially an important tool for individualizing drug dosage and therapeutic drug monitoring.

New Recommendations of a Height-Based Dosing Regimen of Tobramycin for Cystic Fibrosis in Adults: A Population Pharmacokinetic Analysis.

Acute pulmonary exacerbations (APEs) in patients with adult cystic fibrosis (CF) are treated with a beta-lactam and an aminoglycoside for activity against Pseudomonas aeruginosa (PA). Emerging drug resistance and changing pharmacokinetic profile in an aging population involve a reevaluation of tobramycin dosing recommendations. The objective of this study was to develop a population pharmacokinetic model and establish optimal dosing recommendations for tobramycin using Monte Carlo simulations. This retrospective clinical study and data collection were performed at the CF center of the McGill University Health Center (MUHC), Canada. Model development and simulations were performed using a nonlinear mixed-effect modeling approach (NONMEM, version 7.4.2). The ratios of maximal concentration (C max ) to the minimal inhibitory concentration (MIC) (C max /MIC ≥8 and ≥10) and area under the curve (AUC) to the MIC (AUC/MIC ≥70 and ≥100) were evaluated. Adult patients with CF (n = 51) treated with tobramycin were included in the study. Plasma concentrations of tobramycin were obtained for 699 samples from the MUHC database. The two-compartmental model best described the pharmacokinetics of tobramycin. The association of patient height with the central volume of distribution significantly improved this model. Height, rather than weight, induced the best reduction in objective function. According to simulations, doses between 3.4 mg/cm and 4.4 mg/cm were necessary to achieve C max /MIC values of ≥8 and ≥10, respectively. However, higher doses were required to achieve the AUC/MIC targets. This study demonstrated that height of the patients seems to be more suitable than their weight for dosing adjustments in adult patients with CF. According to this model, initial doses of tobramycin between 3.4 and 4.4 mg/cm should be recommended for patients with a median height of 164 cm and weight of 55 kg to achieve the target plasma concentrations.

Safety, pharmacokinetics and exploratory exposure-response analysis of CX3002, a novel inhibitor of Xa, in Chinese healthy subjects

Background and objectiveCX3002 is a structurally novel inhibitor of factor Xa, with promising prospects. This study aims to report the results of a first-in-human ascending-dose study of CX3002 in Chinese healthy subjects, and to establish an exploratory population pharmacokinetic/pharmacodynamic (PK/PD) model to investigate the exposure-response relationship of CX3002. MethodsThe randomized, double-blind, placebo-controlled study included six single-dose groups and three multiple-dose groups, with a dose range of 1–30 mg. Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of CX3002 were evaluated. PK of CX3002 was analyzed using both non-compartment method and population modeling. PK/PD model was developed using nonlinear mixed effect modeling approach and was evaluated by prediction-corrected visual predictive check and bootstrap methods. ResultsA total of 84 subjects were enrolled and all participants completed the study. CX3002 exhibited satisfactory safety and tolerability in healthy subjects. Cmax and AUC of CX3002 increased with dose from 1 to 30 mg, but less-than-proportional increases were observed. There was no obvious accumulation with multiple doses. Anti-Xa activity showed dose-related increases after administration of CX3002 but not placebo. The PK of CX3002 was well described by a two-compartment model with a modification of bioavailability according to dose, and anti-Xa activity was described by a Hill function. No covariate was identified significant based on the limited data in this study. ConclusionsCX3002 was well tolerated and resulted in dose-related anti-Xa activity across the dose range. The PK of CX3002 were predictable, and correlated with PD effects. Continued clinical investigation of CX3002 was supported. Chinadrugtrials.org.cn identifier: CTR20190153.

Investigating the contribution of residual unexplained variability components on bias and imprecision of parameter estimates in population pharmacokinetic mixed-effects modeling.

In a nonlinear mixed-effects modeling (NLMEM) approach of pharmacokinetic (PK) and pharmacodynamic (PD) data, two levels of random effects are generally modeled: between-subject variability (BSV) and residual unexplained variability (RUV). The goal of this simulation-estimation study was to investigate the extent to which PK and RUV model misspecification, errors in recording dosing and sampling times, and variability in drug content uniformity contribute to the estimated magnitude of RUV and PK parameter bias. A two-compartment model with first-order absorption and linear elimination was simulated as a true model. PK parameters were clearance 5.0 L/h; central volume of distribution 35 L; inter-compartmental clearance 50 L/h; peripheral volume of distribution 50 L. All parameters were assumed to have a 30% coefficient of variation (CV). One hundred in-silico subjects were administered a labeled dose of 120mg under 4 sample collection designs. PK and RUV model misspecifications were associated with relatively larger increases in the magnitude of RUV compared to other sources for all levels of sampling design. The contribution of dose and dosing time misspecifications have negligible effects on RUV but result in higher bias in PK parameter estimates. Inaccurate sampling time data results in biased RUV and increases with the magnitude of perturbations. Combined perturbation scenarios in the studied sources will propagate the variability and accumulate in RUV magnitude and bias in PK parameter estimates. This work provides insight into the potential contributions of many factors that comprise RUV and bias in PK parameters.