Distribution Of Central Compartment Research Articles

Population pharmacokinetics and limited sampling strategies of polymyxin B in critically ill patients.

To characterize the pharmacokinetics (PK) of polymyxin B in Chinese critically ill patients. The factors significantly affecting PK parameters are identified, and a limited sampling strategy for therapeutic drug monitoring of polymyxin B is explored. Thirty patients (212 samples) were included in a population PK analysis. A limited sampling strategy was developed using Bayesian estimation, multiple linear regression and modified integral equations. Non-linear mixed-effects models were developed using Phoenix NLME software. A two-compartment population PK model was used to describe polymyxin B PK. Population estimates of the volumes of central compartment distribution (V) and peripheral compartment distribution (V2), central compartment clearance (CL) and intercompartmental clearance (Q) were 7.857 L, 12.668 L, 1.672 L/h and 7.009 L/h. Continuous renal replacement therapy (CRRT) significantly affected CL, and body weight significantly affected CL and Q. The AUC0-12h of polymyxin B in patients with CRRT was significantly lower than in patients without CRRT. CL and Q increased with increasing body weight. A limited sampling strategy was suggested using a two-sample scheme with plasma at 0.5h and 8h after the end of infusion (C0.5 and C8) for therapeutic drug monitoring in the clinic. A dosing regimen should be based on body weight and the application of CRRT. A two-sample strategy for therapeutic drug monitoring could facilitate individualized treatment with polymyxin B in critically ill patients.

Population Pharmacokinetics and Dosing Regimen Optimization of Latamoxef in Chinese Children.

The present study aimed to establish population pharmacokinetic models of latamoxef, as well as its R- and S-epimers, and generate findings to guide the individualized administration of latamoxef in pediatric patients. A total of 145 in-hospital children aged 0.08–10.58 years old were included in this study. Three population pharmacokinetic models of latamoxef and its R- and S-epimers were established. The stability and predictive ability of the final models were evaluated by utilizing goodness-of-fit plots, nonparametric bootstrapping, and normalized prediction distribution errors. The final model of total latamoxef was considered as a basis for the dosing regimen. A two-compartment model with first-order elimination best described the pharmacokinetics of total latamoxef. The population typical values of total latamoxef were as follows: central compartment distribution volume (V1) of 4.84 L, peripheral compartment distribution volume (V2) of 16.18 L, clearance (CL) of 1.00 L/h, and inter-compartmental clearance (Q) of 0.97 L/h. Moreover, R-epimer has a higher apparent volume of distribution and lower clearance than S-epimer. Body surface area (BSA) was identified as the most significant covariate to V, CL, and Q. Specific recommendations are given for dosage adjustment in pediatric patients based on BSA. This study highlights that a BSA-normalized dose of latamoxef was required when treating different bacteria to reach the therapeutic target more effectively.

Intrapulmonary pharmacokinetics of high doses of tigecycline in patients with ventilator-associated pneumonia

Tigecycline is commonly used for infections by multidrug-resistant bacteria. However, it is not approved for ventilator-associated pneumonia (VAP) as increased mortality has been reported in VAP patients treated with conventional doses. The purpose of this study was to prospectively evaluate the intrapulmonary pharmacokinetics of off-label high-dose tigecycline in patients with VAP. Nine mechanically ventilated patients received tigecycline intravenously (loading dose 200 mg followed by 100 mg every 12 h). After ≥5 doses, two bronchoscopies were performed in each patient on consecutive days and eight blood samples were collected. Tigecycline concentrations in plasma and bronchoalveolar lavage fluid were determined by liquid chromatography. The urea dilution method was used to calculate epithelial lining fluid (ELF) concentrations. A two-compartmental pharmacokinetic (PK) model with linear elimination was used to estimate PK parameters. Mean patient age was 69 ± 11.86 years and mean APACHE II score was 21. The estimated population mean PK parameters (relative standard error) were: clearance, 11.64 L/h (54%); volume of distribution in central compartment, 79.01 L (37%); volume of distribution in peripheral compartment, 92.95 L (17%); intercompartmental clearance, 62.81 L/h (34%); and ELF penetration ratio, 2.41 (40%). Cmax, Cmin, plasma AUC0-12, plasma fAUC0-12 and ELF AUC0-12 were 1.99 ± 1.82 μg/mL, 0.81 ± 1.27 μg/mL, 12.89 ± 17.25 μg•h/mL, 3.24 ± 3.09 μg•h/mL and 7.13 ± 2.61 μg•h/mL, respectively. The increased plasma and ELF AUC0-12 achieved with a 200 mg daily tigecycline dose, combined with high ELF penetration, support the effectiveness of off-label high-dose tigecycline in VAP.

441 Population pharmacokinetics of an anti-PD-1 antibody, Penpulimab in patients with advanced malignancies

BackgroundPenpulimab is a humanized IgG1 monoclonal antibody targeting PD-1 and is being evaluated in a variety of malignancies. The objective of the present study was to develop a population pharmacokinetic (PopPK) model of penpulimab in patients with hematologic malignancies and solid tumors, and to characterize the impact of demographic and disease factors on the pharmacokinetics.MethodsPharmacokinetic data in patients with advanced malignancies were analyzed from six clinical studies with doses of 1, 3, 10 mg/kg, 200 mg every 2 weeks (Q2W), or 200 mg every 3 weeks (Q3W) of penpulimab (N=332). Noncompartmental analyses were performed on PK data from a subset of participants and the pharmacokinetic characteristics of penpulimab were summarized.ResultsThe PopPK of penpulimab was adequately described with a two-compartment model with first-order elimination using a non-linear mixed effects model (NONMEM). Typical values for these PK parameters were estimated at 0.232 L/day for Clearance (CL), 3.42 L for the volume of distribution of central compartment (V1). There was no clinical correlation between penpulimab pharmacokinetics and baseline covariates, such as age, race, immunogenicity, hepatic function, creatinine clearance, tumor type, and ECOG score. Several indicators, including the impact of albumin, lactic dehydrogenase, and gender on CL, and the impact of weight and gender on V1, were found to be statistically significant, but the geometric mean ratios for the PK parameters ranged between 0.7 and 1.3, with a difference of less than 30% and no clinically significant relevance. Drug exposure increased proportionally with dose from 1.0 mg/kg to 10.0 mg/kg, and at 1mg/kg or more, the PD-1 receptor occupancy reached 80% to 100% two days after penpulimab infusion. PopPK simulation showed that concentration ranges of penpulimab following administration at a fixed dose (200 mg Q2W) or by body weight (3.0 mg/kg Q2W) were basically consistent. More than 97.5% of the patients, at either dosing regimen (200 mg Q2W or Q3W), had steady-state trough concentrations >10 µg/mL, which is much higher than the concentration (0.5 µg/mL) needed for reaching 90% to 100% PD-1 receptor occupancy.ConclusionsThe PopPK model adequately assessed the pharmacokinetic characteristics and impact factors of penpulimab in the hematologic malignancies as well as solid tumors. This simulation indicates that both weight-based dose and fixed dose (200mg Q2W or Q3W) are appropriate for penpulimab.Ethics ApprovalThese studies were conducted in accordance with the protocol, good clinical practice standards and the Declaration of Helsinki. The protocols and subsequent amendments were approved by the appropriate institutional review board (IRB) or ethics committee at each participating institution. All patients provided voluntary written informed consent.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Abstract 1366: Integrated population modeling of loncastuximab tesirine (Lonca) exposure in B-cell non-Hodgkin lymphoma (B-NHL)

Abstract Lonca is an antibody (Ab) drug conjugate comprising a humanized monoclonal Ab directed against B-cell antigen CD19, conjugated with a potent pyrrolobenzodiazepine (PBD) dimer toxin. In a Phase 1 (NCT02669017) study in relapsed or refractory (R/R) B-NHL, a recommended Phase 2 dosing regimen for Lonca of 150 µg/kg once every 3 weeks (Q3W) for two doses, followed by 75 µg/kg Q3W was identified then evaluated in a Phase 2 (NCT03589469) study in R/R diffuse large B-cell lymphoma (DLBCL). A population pharmacokinetic (PPK) model was developed to characterize the pharmacokinetics (PK) of the Lonca dosing regimen and evaluate exposure covariates. The integrated PPK model was used to describe drug concentrations for Lonca PBD-conjugated Ab (5,301 samples), total Ab (5,241 samples), and unconjugated warhead SG3199 (239 samples) in serum from 328 patients. Samples were taken pre-dose, at end of infusion and at pre-determined timepoints post-infusion throughout the trials. Analysis was performed using non-linear mixed-effects modeling (NONMEM, v7.4 [ICON Solutions]). Subgroup analyses were conducted on model-predicted exposure metrics derived from simulation of Lonca PK profiles based on empirical Bayesian estimates of individual PK parameters. Concentration-time data of Lonca PBD-conjugated Ab and total Ab were best characterized by a two-compartment model with parallel linear clearance (0.218 L/day), and a time-dependent clearance component which approached zero by ~15 weeks. The estimated volume of distribution of central compartment was 3.86 L and the estimated typical half-life at steady state of Lonca is ~3 weeks. The effect of body weight, age, sex, race, renal impairment, drug formulation, anti-drug Ab, ECOG, and concomitant P-gp inhibitors did not show clinically important influence on exposure (< ±30% change relative to reference). Based on model-predicted Cycle 1 average concentration (Cavg) patients with low albumin (<35 g/L, n=49) had 52% lower Cavg than patients with normal albumin levels (≥35 g/L, n=279). Patients with non-DLBCL (n=44) had 61% lower Cavg than patients with DLBCL (n=284). Trends of lower exposures with baseline mild/moderate hepatic impairment and ECOG status >1 were noted but did not appear to be of clinical relevance. In conclusion, Lonca exposure was well described by a two-compartment model with linear and time-dependent clearance; the latter is thought to reflect reduction of tumor cells. Lonca exposure was lower in non-DLBCL patients, and lower in patients with hypoalbuminemia secondary to enhanced protein clearance in patients with critical illness. Overall, modeling demonstrates rapid attainment of steady-state exposure for Lonca given 150 µg/kg Q3W for two doses, and a sustaining profile for Lonca given 75 µg/kg Q3W thereafter for patients with DLBCL. Citation Format: Melhem Solh, Juan Pablo Alderuccio, Anastasios Stathis, David Ungar, Sam Liao, Lisa Khouri, Xiaoyan Zhang, Joseph Boni. Integrated population modeling of loncastuximab tesirine (Lonca) exposure in B-cell non-Hodgkin lymphoma (B-NHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1366.

A systematic review of population pharmacokinetic analyses of polyclonal immunoglobulin G therapy

BackgroundPopulation pharmacokinetics (popPK) using the nonlinear mixed-effect (NLME) modeling approach is an essential tool for guiding dose individualization. Several popPK analyses using the NLME have been conducted to characterize the pharmacokinetics of immunoglobulin G (IgG). ObjectiveTo summarize the current information on popPK of polyclonal IgG therapy. MethodA systematic search was conducted in the PubMed and Web of Science databases from inception to December 2020. Additional relevant studies were also included by reviewing the reference list of the reviewed articles. All popPK studies that employed the NLME modeling approach were included and data were synthesized descriptively. ResultsThis review included seven studies. Most of the popPK models were developed in patients with primary immunodeficiency (PID). IgG pharmacokinetics was described as a two-compartment model in five studies, while it was described as a one-compartment model in two other studies. Among all tested covariates, weight was consistently identified as a significant predictor for clearance (CL) of IgG. Whereas, weight and disease type were found to be significant predictors for the volume of distribution in central compartment (Vc). In a typical 70 kg adult, the median estimated values of Vc and CL were 4.04 L and 0.144 L/day, respectively. The between subject variability of Vc was considered large. Only two studies evaluated their models using external data. ConclusionsSeven popPK studies of IgG were found and discussed, with only weight being a significant covariate across all studies. Future studies linking pharmacokinetics with pharmacodynamics in PID and other patient populations are required.

Population Pharmacokinetics and Pharmacodynamics of Norvancomycin in Children With Malignant Hematological Disease.

Knowledge of pharmacokinetic (PK) behavior of norvancomycin (NVCM) in pediatric patients is lacking, which leads to empirical therapy in clinical practice. This study developed a population PK model of children aged 0-15 years; 112 opportunistic samples in total from 90 children were analyzed. The stability and prediction of the final model were evaluated by goodness-of-fit plots, nonparametric bootstrap, visual predictive check, and normalized prediction distribution errors. The PKs of NVCM in children was described by a 2-compartment model with first-order elimination along with body weight and estimated glomerular filtration rate as significant covariates on clearance. The population typical values of the PK parameters were as follows: clearance 0.12 L/kg/h, central compartment distribution volume 0.17 L/kg, peripheral compartment distribution volume 0.38 L/kg, and intercompartmental clearance 0.35 L/kg/h. Logistic analysis showed that the ratio of area under the concentration-time curve over 24 hours (AUC0-24 ) to minimum inhibitory concentration (MIC) had the strongest correlation with clinical efficacy, and at least 80% clinical efficiency could be achieved when AUC0-24 /MIC ≥ 221.06 was defined as the target. Monte Carlo simulation results suggested that a higher dose was required for this pediatric population in order to reach the target. The dosing regimen was optimized based on the final model. A population PK model of NVCM was first characterized in children with hematologic malignancy, and an evidence-based approach for NVCM dosage individualization was provided.

483P - Population pharmacokinetics of tislelizumab in patients with advanced tumors

BackgroundTislelizumab, an investigational humanized IgG4 monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcgR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. It has shown robust antitumor activity and was generally well-tolerated in patients with advanced solid tumors and with classical Hodgkin lymphoma (cHL). The objectives of this analysis were to develop a population pharmacokinetics (popPK) model and quantify the impact of demographic and disease characteristics on tislelizumab PK. MethodsPopPK analysis was conducted using pooled data from three studies (001, 102, 203) in patients with advanced solid tumors and cHL. The dataset contained 5935PK observations from 798 patients. A nonlinear mixed-effects modeling approach with first-order conditional estimation with interaction (FOCEI) method in NONMEM was used for the analysis. Covariates related to baseline demographics, tumor type, and tumor size on tislelizumab PK were investigated. Covariates were selected using a forward addition and backward elimination method. ResultsTislelizumab PK exhibited linearity over a dose range of 0.5 - 10mg/kg without time‐varying clearance. A three-compartment model with first-order elimination from the central compartment, and redistribution into the peripheral compartments best described the PK of tislelizumab. Clearance (CL), volume of distribution of central compartment (Vc), and terminal half-life were estimated to be 0.164L/day, 2.92L, and 25.9 days, respectively. Baseline tumor size, albumin and tumor type were significant covariates on CL, while body weight, sex and tumor type were significant covariates on Vc. However, sensitivity analysis showed that the impact of these covariates on tislelizumab exposures (area under the curve, maximum and trough concentrations) was not clinically significant. ConclusionsThe final popPK model adequately described the observed tislelizumab PK. Results support the use of the current clinical dose of 200mg Q3W and no dose adjustment is necessary based on patients’ age, body weight, race, sex, tumor type and tumor size. Clinical trial identificationBGB-A317-Study-001: NCT02407990 BGB-A317-203: NCT03209973 BGB-A317-102: CTR20160872. Legal entity responsible for the studyBeiGene, Ltd. FundingBeiGene. DisclosureC-Y. Wu: Full / Part-time employment: BeiGene, Ltd. T. Tang: Full / Part-time employment: BeiGene, Ltd. Y. Ben: Full / Part-time employment: BeiGene, Ltd. S. Sahasranaman: Full / Part-time employment: BeiGene, Ltd. All other authors have declared no conflicts of interest.

Abstract LB-268: Assessment of flat dosing strategy for INCMGA00012 in patients with advanced tumors

Abstract Background: INCMGA00012, a humanized, hinge-stabilized, IgG4κ monoclonal antibody that recognizes human PD-1, is being developed for the treatment of multiple solid tumor types, both as monotherapy and in combination with other potentially immunoactive agents. Flat dosing is preferred to weight-based dosing for multiple reasons, including convenience of preparation and administration, reduced errors in preparation calculation, and minimization of drug waste. A modeling and simulation approach was employed to support flat doses for later phase studies. Patients and Methods: INCMGA00012 has been administered to approximately 200 participants in a Phase 1 study (Study INCMGA 0012-101) at weight-based doses ranging from 1 to 10 mg/kg Q2W or Q4W and at flat doses of 500 mg Q4W and 750 mg Q4W. PK data from weight-based doses were used for population PK model development and data from flat doses were used for model validation. Simulations were performed to support the selection of RP2 flat dose. Results: The concentrations of INCMGA00012 were adequately described by a 2-compartment model with first-order elimination. Higher clearance was estimated for 1 mg/kg (23.5 mL/h) than the other dose groups (13.5 mL/h). Body weight dependence of clearance and volume of distribution for central compartment were characterized by power relationships with exponents of 0.911 and 0.493, respectively. The model was validated using PK data from participants who received INCMGA00012 500 mg Q4W and 750 mg Q4W, respectively, in the cohort expansion phase. Median steady state trough concentrations of 500 mg Q4W and 750 mg Q4W exceeded the target value. Conclusion: Modeling and simulation provide justification for 500 mg Q4W for further clinical development of INCMGA00012 based upon favorable safety, PK characteristics and presumed flat exposure-response relationships for efficacy. Citation Format: Xuejun chen, Phil Wang, Sanjeev Kaul, Bradley Sumrow, Swamy Yeleswaram. Assessment of flat dosing strategy for INCMGA00012 in patients with advanced tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-268.

Population pharmacokinetics of PF-05280014 (a trastuzumab biosimilar) and reference trastuzumab (Herceptin\xae) in patients with HER2-positive metastatic breast cancer

PurposePF-05280014 is a biosimilar to trastuzumab (Herceptin®). Following demonstration of pharmacokinetic (PK) similarity in healthy volunteers, a comparative clinical study in patients with HER2-positive metastatic breast cancer (mBC) compared the efficacy, safety and immunogenicity of PF-05280014 and trastuzumab sourced from the EU (trastuzumab-EU), both with paclitaxel.MethodsPopulation PK of PF-05280014 and trastuzumab-EU was evaluated.ResultsOverall, 702 patients were treated: PF-05280014 (n = 349) and trastuzumab-EU (n = 353). Peak-and-trough serum drug concentration samples were collected (selected doses) following repeated intravenous administration of PF-05280014 or trastuzumab-EU. Population PK analysis was performed with drug concentration–time data to cycle 17 for each compound, using nonlinear mixed effect modeling. Potential baseline covariates (circulating HER2 concentrations, body weight, Japanese race, Eastern Cooperative Oncology Group status, number of metastatic sites and antidrug antibody status) were evaluated. Concentration–time data of PF-05280014 and trastuzumab-EU were adequately described by a two-compartment model with first-order elimination, with inter-individual variability (IIV) on clearance (CL), volumes of distribution in central compartment (V1) and peripheral compartments, and intercompartment clearance. Similar estimated PK parameters and IIV were obtained for both treatments. For PF-05280014 and trastuzumab-EU, baseline body weight was an influential covariate on CL and V1; the magnitude was comparable between treatments. PK was consistent between the limited number of Japanese and non-Japanese patients for both compounds.ConclusionsPF-05280014 and trastuzumab-EU had similar PK parameters and influential PK covariates in patients with HER2-positive mBC. These results provided further evidence in patients for PK similarity between PF-05280014 and trastuzumab-EU.Clinical trial registrationClinicalTrials.gov, NCT01989676.

Population pharmacokinetic modeling to establish the role of P-glycoprotein on ciprofloxacin distribution to lung and prostate following intravenous and intratracheal administration to Wistar rats

Ciprofloxacin (CIP) is indicated for clinical treatment of urinary and respiratory tract infections. Poor infection site penetration and consequent insufficient exposure to the antimicrobial agent may be the reason for some therapeutic failures. Ciprofloxacin is reported as a substrate for efflux transporters, such as P-glycoprotein, which could be related to the presence of sub-therapeutic drug concentration at the infection site. In the present work we evaluated CIP pharmacokinetics (PK) in plasma and lung and prostate tissues of Wistar rats after intravenous (i.v.) and intratracheal (i.t.) dosing (7 mg/Kg) in the presence and absence of P-gp inhibitor tariquidar (TAR, 15 mg/Kg). Microdialysis was applied to determine free tissue concentration-time profiles and the obtained data were analyzed by non-compartmental and population PK (popPK) analysis. A sequential strategy was used to develop the popPK model: characterization of CIP PK in tissues (Tissue model) was performed subsequently to CIP PK modeling in plasma (Plasma model). Two and three compartmental models were used to simultaneously characterize plasma concentrations after i.t. and i.v. dosing; the distribution model was developed by separating the central compartment into venous and arterial compartment and by adding lung and prostate; TAR was identified as a significant covariate for clearance and volume of distribution of central compartment as well as for inter-compartmental clearance. Our results indicate an impact of P-gp on plasma PK, likely by acting on renal active secretion of CIP. Regarding CIP exposure in lung and prostate tissues, our results suggest a complex interplay between drug transporters; P-gp inhibition by TAR was likely counterbalanced by the activity of other efflux/influx transporters, which could not be fully characterized by our model.

Determination of vancomycin pharmacokinetics in critically ill intensive care unit patients in Malaysia: A population pharmacokinetic analysis with a nonparametric approach

Background: The pharmacokinetics (PK) of vancomycin in critically ill intensive care unit (ICU) patients is difficult to predict due to the scarcity of data and the variable physiology of the patient cohort. Aims and Objectives: Since there are limited studies worldwide, this study is, therefore, intended to explore vancomycin population PK parameters in critically ill ICU patients in Hospital Raja Perempuan Zainab II, Kelantan, Malaysia. Materials and Methods: Vancomycin population PK in ICU patients was modeled with Pmetrics. A total of 92 samples from 45 ICU patients were included in the model building and validation. The median observations per patient were three with a range of one to four observations. The median parameters estimates obtained from the final model were used to predict individual vancomycin clearance (CL) in the validation dataset. Results: The PK of vancomycin was adequately described with a two-compartment model. Parameters included CL of 1.64 L/h, volume of distribution in central compartment of 20.0 L, rate of constant from central out to the peripheral compartment of 2.92/h, and the rate constant back from the peripheral to central compartment of 7.17/h. The developed model adequately estimated CL in the validation dataset. Conclusion: A model to describe the PK of vancomycin was developed which adequately describes vancomycin population PK in critically ill ICU patients in Kelantan. The model might be used in initiating a vancomycin dosage regimen in the type of patients similar to the present study.

Population Pharmacokinetics of Sirolimus in Healthy Chinese Subjects

Sirolimus is metabolized by the CYP3A subfamily and is a substrate of the P-glycoprotein. CYP3A5 and MDR1 gene polymorphisms have been reported to influence plasma concentrations of this drug and dose requirements, but some recent studies reported conflicting results. The aim of this study was to develop population pharmacokinetics to identify the potential influencing factors that explain pharmacokinetic variability in healthy Chinese adults. Twenty seven healthy Chinese subjects were enrolled into this study and were genotyped for CYP3A5 (6986A>G), MDR1 (3435C>T). Blood samples at different time point were collected from each subject and blood concentrations were measured. The population pharmacokinetic model was established using the non-linear mixed-effects model method, CYP3A5, MDR1, gender and other factors were evaluated in the model as covariates. The results indicated that CYP3A5 polymorphisms significantly influenced the clearance, the central compartment distribution volume was larger in male than that in female subjects, body surface area showed remarkable impact on peripheral compartment volume. All parameters were estimated with acceptable precision. Visual predictive check and bootstrap indicated that the population model adequately captured the observed profiles. This model may be useful in guiding clinicians to adjust drug dosing regimen.

Population pharmacokinetics of moxifloxacin and its concentration-QT interval relationship modeling in Chinese healthy volunteers.

Moxifloxacin (MX) is an 8-methoxyquinolone antimicrobial drug, which is often used as a positive control in thorough QT (TQT) studies. In the present study we established the population pharmacokinetics model of MX and the relationship of MX concentrations with the QT and various corrected QT (QTc) intervals, and compared the results with other ethnicities. The MX data used for modeling were obtained from a published TQT interval prolongation study of antofloxacin with MX as the positive control. In this four-period crossover study, 24 adult Chinese healthy volunteers received either 200 or 400 mg of oral antofloxacin once daily, 400 mg of MX, or a placebo. Population concentration-effect models were used to investigate the relationship between MX concentrations and QT interval prolongation, baseline-adjusted QTc (ΔQTc), or ΔQTc adjusted with time-matched placebo corrections (ΔΔQTc). The influencing factors of MX PK and the concentration-QTc relationship were determined through covariate screening. Simulation studies were conducted in R2.30 by using the final model with the estimated population mean and intra-individual and inter-individual variability. The estimated pharmacokinetic parameters and the estimated slope of the MX concentration-QT/ΔQTc/ΔΔQTc relationship were described using models and were compared to results for other ethnicities from the literature. We showed that the population pharmacokinetic parameter estimates for total plasma clearance (CL/F), the volume of distribution of central compartment (Vc/F), the distributional clearance in plasma (Q), the volume of distribution of peripheral compartment (Vp/F), and the absorption rate constant (Ka) were 8.22 L/h, 104 L, 3.98 L/h, 37.7 L, and 1.81 1/h, respectively. There was no significant covariate included in the final model. QT interval prolongation of MX estimates ranging from 9.77 to 12.91 ms at the mean average maximum concentration of MX (4.36 μg/mL) and a mean slope ranging from 2.33 to 2.96 ms per μg/mL. In conclusion, no ethnic differences were observed for the MX pharmacokinetic parameters and QT interval prolongation.

Antigenic burden and serum IgG concentrations influence rituximab pharmacokinetics in rheumatoid arthritis patients.

Rituximab is a monoclonal antibody directed against CD20, which is approved in rheumatoid arthritis (RA). This study aimed at assessing the influence of CD19+ cell counts as target-antigen amount, and of immunoglobulin G (IgG) serum concentrations on rituximab pharmacokinetics in RA patients. In a cohort of 64 RA patients who had received repetitive courses of rituximab, the influence of CD19+ cell count, IgG serum concentration, body surface area, sex and disease activity score in 28 joints on rituximab pharmacokinetic parameters was assessed using a population pharmacokinetic analysis. A two-compartment model, with first-order distribution and elimination best described the data. The volume of distribution of central compartment and clearance of rituximab were estimated at 4.7l and 0.56lday-1 , respectively. Distribution and elimination half-lives were 0.9days and 17.3days, respectively. As expected, the central volume of distribution increased with body surface area (P=0.012) and was higher in male than in female (P=0.004). We found that the elimination rate constant (k10 ) increased with CD19+ count (P=0.00022) and IgG concentration (P=7.4 × 10-8 ), and that k10 decreased with time (P=0.00015), partly explained by a change in target-antigen amount. The association between CD19+ count and k10 may be explained by target-mediated drug disposition, while the association between IgG serum concentration and k10 may be explained by a saturation of the neonatal Fc receptor at high IgG concentrations, resulting in decreased recycling of rituximab.

Modification of the Fc Region of a Human Anti-oncostatin M Monoclonal Antibody for Higher Affinity to FcRn Receptor and Extension of Half-life in Cynomolgus Monkeys.

The purpose of this study was to evaluate the pharmacokinetics (PK) of anti-oncostatin M (OSM) IgG1 monoclonal antibodies, CNTO 1119 and its Fc variant (CNTO 8212), which incorporates the LS(Xtend) mutation to extend terminal half-life (T1/2 ), after a single intravenous (IV) or subcutaneous (SC) administration in cynomolgus monkeys, and to predict human PK. In study 1, single doses of CNTO 1119 and CNTO 8212 were administered IV or SC at 3 mg/kg to cynomolgus monkeys (n = 3 per group). In study 2, single doses of CNTO 8212 were administered IV at 1, 5 or 20 mg/kg, or SC at 5 mg/kg to cynomolgus monkeys (n = 5 per group). Serial blood samples were collected for assessment of serum concentrations of CNTO 1119 and/or CNTO 8212. A two-compartment population PK model with first-order elimination was utilized to simultaneously describe the serum concentrations of CNTO 1119 and CNTO 8212 over time after IV and SC administration in cynomolgus monkeys. The typical population PK parameter estimates for CNTO 1119 in cynomolgus monkeys were clearance (CL) = 2.81 mL/day/kg, volume of distribution of central compartment (V1 ) = 31.3 mL/kg, volume of distribution of peripheral compartment (V2 ) = 23.3 mL/kg, absolute bioavailability (F) = 0.84 and T1/2 = 13.4 days. In comparison, the typical population PK parameter estimates for CNTO 8212 in cynomolgus monkeys were CL = 1.41 mL/day/kg, V1 = 39.8 mL/kg, V2 = 32.6 mL/kg, F = 0.75 and T1/2 = 35.7 days. The mean CL of CNTO 8212 was ~50% lower compared with that for CNTO 1119 in cynomolgus monkeys. The overall volume of distribution (V1 +V2 ) for CNTO 8212 was about 32% larger compared with that for CNTO 1119, but generally similar to the vascular volume in cynomolgus monkeys. The T1/2 of CNTO 8212 was significantly (p < 0.05) longer by about 2.7-fold than that for CNTO 1119 in cynomolgus monkeys. Thus, the modification of the Fc portion of an anti-OSM IgG1 mAb for higher FcRn binding affinity resulted in lower systemic clearance and a longer terminal half-life in cynomolgus monkeys. CNTO 8212 demonstrated linear PK after a single IV dose (1-20 mg/kg) in cynomolgus monkeys. The predicted human PK parameters suggest that CNTO 8212 is likely to exhibit slow clearance and long terminal half-life in human beings and may likely allow less frequent dosing in the clinical setting.

A Nonparametric Pharmacokinetic Approach to Determine the Optimal Dosing Regimen for 30-Minute and 3-Hour Meropenem Infusions in Critically Ill Patients.

Pharmacokinetics of meropenem differ widely in the critically ill population. It is imperative to maintain meropenem concentrations above the inhibitory concentrations for most of the interdose interval. A population pharmacokinetic/pharmacodynamic model was developed to determine the probability of target attainment for 3-hour and 30-minute infusion regimens in this population. This study was performed in an intensive care setting among adult patients who were initiated on meropenem at a dose of 1000 mg. Multiple blood specimens were collected at predetermined time points during the interdose period, and meropenem concentrations were measured using high performance liquid chromatography. Using Pmetrics, a pharmacokinetic/pharmacodynamic model was developed and validated. Monte Carlo simulation was performed, and probability of target attainment (100% T > minimum inhibitory concentration (MIC), with a probability >0.9) for doubling MICs was determined for different regimens of meropenem. A 2-compartment multiplicative gamma error model best described the population parameters from 34 patients. The pharmacokinetic parameters used in the final model were Ke (elimination rate constant from the central compartment), Vc (volume of distribution of central compartment), KCP and KPC (intercompartmental rate constants), and IC2 (the fitted amount of meropenem in the peripheral compartment). Inclusion of creatinine clearance (CLcreat) and body weight as covariates improved the model prediction (Ke = Ke0 × (Equation is included in full-text article.), Vc = Vc0 × Weight). The Ke and Vc [geometric mean (range)] of the individuals were 0.54 (0.01-2.61)/h and 9.36 (4.35-21.62) L, respectively. The probability of attaining the target, T > MIC of 100%, was higher for 3-hour infusion regimens compared with 30-minute infusion regimens for all ranges of CLcreat. This study emphasizes that extended regimens of meropenem are preferable for treating infections caused by bacteria with higher MICs. The nonparametric analysis using body weight and CLcreat as covariate adequately predicted the pharmacokinetics of meropenem in critically ill patients with a wide range of renal function.

Target-Mediated Drug Disposition of Daratumumab Following Intravenous Infusion in Relapsed or Refractory Multiple Myeloma after Prior Proteasome Inhibitors and Immunomodulatory Drugs: A Population Pharmacokinetic Analysis

Introduction: Daratumumab is a first-in-class human anti-CD38 IgG1 monoclonal antibody in clinical development across the multiple myeloma (MM) disease spectrum. A population pharmacokinetics (PK) analysis was conducted (1) to characterize the target-mediated drug disposition (TMDD) and the variability associated with daratumumab disposition, (2) to evaluate the effects of individual demographic characteristics and other factors (e.g., laboratory tests and baseline disease status) on the disposition of daratumumab, (3) to understand daratumumab exposure in special populations (e.g., patients with renal or hepatic impairment and elderly patients), and (4) to predict target saturation and its relationship with daratumumab exposure.Methods: A total of 2,572 daratumumab concentration measurements from 223 patients enrolled in a Phase 1/2 study (GEN501 [NCT00574288]) and a Phase 2 study (MMY2002 [NCT01985126]) were included in the population PK modeling. Daratumumab doses ranged from 0.1 to 24 mg/kg, and 150 of these patients received 16 mg/kg. A mixed-effects 2-compartment pharmacokinetic model based on Michaelis-Menten approximation TMDD was developed. Model-based covariate analyses and simulations were conducted to evaluate the influence of individual characteristics/factors on exposure to daratumumab.Results: The population PK model suggested that the disposition of daratumumab was concentration- and dose-dependent, i.e., lower clearance at higher daratumumab concentrations. The model further revealed that the nonlinear concentration-dependent clearance decreased over time, which could be described as a first-order process. The concentration- and time-dependency of daratumumab clearance suggested that the dynamics of target/tumor burden significantly influenced daratumumab disposition in MM patients. The estimated target binding affinity (ie, concentration at 50% target saturation) was 2.38 µg/mL. The population PK model predicted that a concentration of 21.4 µg/mL and 236 µg/mL would be needed to achieve 90% and 99% target saturation, respectively. The estimated linear clearance (0.17 L/day) was very close to the clearance of non-specific endogenous IgG described in the literature and the volume of distribution of central compartment (V1) approached plasma volume, confirming the robustness of the model.The clearance and V1 of daratumumab significantly increased with increasing body weight. Consequently, exposure to daratumumab was relatively consistent across the range of body weights of MM patients after administration on a mg/kg basis. Age, race, renal impairment, and mild hepatic impairment had neither statistically significant nor clinically relevant effects on exposure to daratumumab. In addition, exposure was consistent across the different subgroups for performance status (ECOG), refractory status, and number of prior lines of therapy. Although baseline albumin levels, type of myeloma (IgG vs non-IgG), sex, and drug products had a statistically significant effect on daratumumab pharmacokinetics, further analyses demonstrated that these covariates had no clinically relevant impact on efficacy or safety profiles.Conclusion: The population PK model revealed a concentration- and time-dependent clearance of daratumumab, suggesting the presence of TMDD. A serum daratumumab concentration of 236 μg/mL was predicted to yield 99% target (CD38) saturation. This analysis suggests that body weight-based dosing is a feasible strategy for MM patients. No clinically relevant demographic or clinical characteristics were identified. Therefore, no dose adjustment based on these factors is recommended. DisclosuresYan:Janssen: Employment. Clemens:Janssen: Employment. Puchalski:Janssen: Employment. Lonial:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Lokhorst:Genmab: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Orlowski:Millennium Pharaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acetylon Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Research Funding; Biotheryx: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Losic:Genmab A/S: Employment. Khan:Janssen: Employment. Jansson:Janssen: Employment. Ahmadi:Janssen: Employment. Lantz:Janssen: Employment. Perez Ruixo:Janssen: Employment. Zhou:Janssen: Employment. Xu:Janssen: Employment.

Pharmacokinetics and pharmacodynamics of piperacillin/tazobactam during high volume haemodiafiltration in patients with septic shock.

The purpose of the study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of piperacillin and tazobactam during high-volume haemodiafiltration (HVHDF). A single dose of piperacillin/tazobactam (4/0.5 g) was administered as 30 minute infusion during HVHDF to 10 patients with acute kidney injury due to septic shock. Arterial blood samples were collected before and at 30 or 60 min intervals over 8 h (12 samples) after study drug administration. Concentrations of piperacillin and tazobactam were determined by HPLC-MS/MS. R software was used for population PK analysis and Monte Carlo Simulation of probability of PK/PD target attainment (PTA) in 1000 subjects. A total of 101 samples were collected during HVHDF. The median (IQR) estimated glomerular filtration rate of the patients was 16 (11.25-27.5) ml/min/1.73 m(2) and HVHDF effluent rate was 208 (146.3-298.3) ml/kg/h. A final two-compartment population PK model predicted mean (%SE) total piperacillin clearance on HVHDF was 6.9 (6.4) l/h, volume of distribution of central compartment 9.0 (10.1) l and of peripheral compartment 11.2 (12.2) l. The PTA of 50% fT>MIC for piperacillin 4 g/tazobactam 0.5 g dosed every 8 h as 0.5-h and 4-h infusion was 84.3% and 100% for MIC of 16 mg/l respectively. Aiming 100% fT>MIC of 16 mg/l, the PTA values were 88.6% and 61.0%, for piperacillin 4 g/tazobactam 0.5 g 4-h infusion every 6 and 8 h respectively. For bactericidal PK/PD target attainment piperacillin/tazobactam doses of 4/0.5 g every 8 h appear appropriate in septic shock patients with minimal residual renal function during HVHDF.

Population Pharmacokinetics of Cefazolin in Serum and Tissue for Patients with Complicated Skin and Soft Tissue Infections (cSSTI).

IntroductionCefazolin is commonly used to treat complicated skin and soft tissue infections (cSSTI) caused by methicillin-susceptible Staphylococcus aureus (MSSA) and Enterobacteriaceae. We aimed to determine the variability of cefazolin exposure in interstitial fluid (ISF) of tissue and evaluate its dosing recommendations.MethodsPopulation pharmacokinetics were performed to co-model serum and ISF concentration data from six patients enrolled in a previous in vivo microdialysis study. A 5,000 patient Monte Carlo simulation was then conducted for 1 and 2 g every 8 h (q8h) regimens to calculate the penetration ratio and probability of target attainment (PTA) at 30% and 50% of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT > MIC) in ISF of tissue.ResultsA three-compartment model, with one of the compartments representing ISF concentrations, fits the data best. The final model resulted in the mean ± SD parameter values: Clearance = 3.8 ± 2.1 L/h, volume of distribution in central compartment = 8.6 ± 6.4 L and volume of distribution in ISF = 36.6 ± 17.9 L. The mean ± SD and median penetration ratios were 1.36 ± 4.57 and 0.80, respectively. At the MIC90 for MSSA of 1 mg/L, PTAs for the 1 g q8h dose in ISF were 96% and 91% for 30% and 50% fT > MIC targets, respectively, which decreased to 87% and 71% at 2 mg/L. For the same respective targets, a 2 g q8h dosing regimen increased PTA to 96% and 91% at 2 mg/L.ConclusionCefazolin penetration into the ISF of a lower limb infection varied across this simulated patient population. Based on these data, a 1 g q8h regimen should be sufficient to obtain 30% fT > MIC exposure against most MSSA causing cSSTI. However, a 2 g q8h dose is required to obtain 50% fT > MIC pharmacodynamic targets at the current breakpoint for Enterobacteriaceae (2 mg/L).Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0049-3) contains supplementary material, which is available to authorized users.