Pharmacokinetic-pharmacodynamic Model Research Articles

Pharmacokinetic and pharmacodynamic properties of once-weekly insulin icodec in individuals with type 2 diabetes.

To characterize the pharmacokinetic and pharmacodynamic properties of once-weekly insulin icodec in type 2 diabetes (T2D). In an open-label trial, 46 individuals with T2D (18-75 years; body mass index 18.0-38.0 kg/m2 ; glycated haemoglobin ≤75 mmol/mol [≤9%]; basal insulin-treated) received subcutaneous once-weekly icodec for ≥8 weeks at individualized doses, aiming at a pre-breakfast plasma glucose concentration of 4.4 to 7.0 mmol/L (80-126 mg/dL) on the last three mornings of each weekly dosing interval. Frequent blood sampling to assess total serum icodec concentration (ie, albumin-bound and unbound) occurred from first icodec dose until 35 days after last dose. Icodec trough concentrations following initiation of once-weekly dosing were predicted by pharmacokinetic modelling. During the final 3 weeks of icodec treatment, while at steady state, the icodec glucose-lowering effect was assessed in three glucose clamps (target 7.5 mmol/L [135 mg/dL]): 0 to 36, 40 to 64 and 144 to 168 h post-dose, thus covering the initial, middle and last part of the 1-week dosing interval. Glucose-lowering effect during a complete dosing interval was predicted by pharmacokinetic-pharmacodynamic modelling. Model-predicted icodec steady state was attained after 3 to 4 weeks. At steady state, model-predicted daily proportions of glucose-lowering effect on days 1 to 7 of the 1-week dosing interval were 14.1%, 16.1%, 15.8%, 15.0%, 14.0%, 13.0% and 12.0%, respectively. Icodec duration of action was at least 1 week in all participants. Once-weekly icodec was overall safe and well tolerated in the current trial. The pharmacokinetic and pharmacodynamic characteristics of icodec in individuals with T2D support its potential as a once-weekly basal insulin.

Pharmacokinetic-pharmacodynamic modeling of the active components of Shenkang injection in rats with chronic renal failure and its protective effect on damaged renal cells.

The study aimed to explore the pharmacokinetic and pharmacodynamic alterations of the active components of Shenkang injection (i.e. hydroxy saffron yellow pigment A [HSYA], tanshinol, rheum emodin, and astragaloside IV) in rats with chronic renal failure (CRF), and establish a pharmacokinetic-pharmacodynamic model (PK-PD model) in order to provide a scientific and theoretical basis for the rational clinical use of Shenkang injection. Sprague-Dawley (SD) rats were randomly divided into a normal group, model group, and Shenkang injection group. A rat model of CRF was induced by adenine gavage and then followed by drug administration via tail vein injection. Orbital blood was collected at different timepoints and the blood concentrations of the four active components were measured by UHPLC-Q-Orbitrap HRMS. Serum levels of creatinine (Scr), urea nitrogen (BUN), and uric acid (UA) were determined using an automatic biochemical analyzer. A PK-PD model was established, and DAS 3.2.6 software was used for model fitting as well as statistical analysis. TGF-β1 was utilized to induce normal rat kidney cells to construct a renal fibrosis model to investigate the protective effect of the pharmacological components on renal fibrosis. The pharmacokinetic analysis of hydroxy saffron yellow pigment A, tanshinol, rheum emodin, and astragaloside IV based on UHPLC-Q-Orbitrap HRMS was stable. The linear regression equations for the four active components were as follows: Y=0.031X+0.0091 (R2 =0.9986) for hydroxy saffron yellow pigment A, Y=0.0389X+0.164 (R2 =0.9979) for tanshinol, Y=0.0257X+0.0146 (R2 =0.9973) for rheum emodin, and Y=0.0763X+0.0139 (R2 =0.9993) for astragaloside IV, which indicated good linear relationships. The methodological investigation was stable, with the interday and intraday precision RSD <10%. Meanwhile, the recoveries ranged between 90% and 120%, in accordance with the requirements for in vivo analysis of drugs. Compared with the model group, the levels of Scr, BUN, and UA were significantly decreased after 20min in the Shenkang injection group (p<0.01). The PK-PD model showed that the four active components in the Shenkang injection group could fit well with the three effect measures (i.e. Scr, BUN, and UA), with the measured values similar to the predicted values. The cell model of renal fibrosis showed that the connective tissue growth factor and FN1 protein expression levels were significantly lower in the Shenkang injection group than those in the model group, and the cell fibrosis was improved. The established method for in vivo analysis of Shenkang injection was highly specific, with good separation of the components and simple operation. The total statistical moment could well integrate the pharmacokinetic parameters of the four active components. After treatment with Shenkang injection, all indexes in the administered group improved and showed significant inhibition of renal cell fibrosis in vitro. This study could provide scientific reference ideas for the clinical rational use of traditional Chinese medicine.

Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide administration in healthy participants.

Lysergic acid diethylamide (LSD) is currently investigated for several neurological and psychiatric illnesses. Various studies have investigated the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationship of LSD in healthy participants, but data on urinary recovery and confirmatory studies are missing. The present study characterized the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship and urinary recovery of LSD at doses of 85 and 170 μg administered orally in 28 healthy participants. The plasma concentrations and subjective effects of LSD were continuously evaluated over a period of 24 h. Urine was collected during 3 time intervals (0-8, 8-16 and 16-24 h after LSD administration). Pharmacokinetic parameters were determined using compartmental modelling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modelling. Mean (95% confidence interval) maximal LSD concentrations were 1.8ng/mL (1.6-2.0) and 3.4ng/mL (3.0-3.8) after the administration of 85 and 170 μg LSD, respectively. Maximal concentrations were achieved on average after 1.7h. Elimination half-lives were 3.7h (3.4-4.1) and 4.0h (3.6-4.4), for 85 and 170 μg LSD, respectively. Only 1% of the administered dose was recovered from urine unchanged within the first 24 h, 16% was eliminated as 2-oxo-3-hydroxy-LSD. Urinary recovery was dose proportional. Mean (±standard deviation) durations of subjective effects were 9.3±3.2 and 11 ±3.7h, and maximal effects (any drug effects) were 77 ± 18% and 87 ± 13% after 85 and 170 μg of LSD, respectively. The present novel study validates previous findings. LSD exhibited dose-proportional pharmacokinetics and first-order elimination kinetics and dose-dependent duration and intensity of subjective effects. LSD is extensively metabolized and shows dose-proportional urinary recovery.

Pharmacodynamic Model of the Dynamic Response of Pseudomonas aeruginosa Biofilms to Antibacterial Treatments.

Accurate pharmacokinetic-pharmacodynamic (PK-PD) models of biofilm treatment could be used to guide formulation and administration strategies to better control bacterial lung infections. To this end, we developed a detailed pharmacodynamic model of P. aeruginosa treatment with the front-line antibiotics, tobramycin and colistin, and validated it on a detailed dataset of killing dynamics. A compartmental model structure was developed in which the key features are the diffusion of the drug through a boundary layer to the bacteria, concentration-dependent interactions with bacteria, and the passage of the bacteria through successive transit states before death. The number of transit states employed was greater for tobramycin, which is a ribosomal inhibitor, than for colistin, which disrupts bacterial membranes. For both drugs, the experimentally observed delay in the killing of bacteria following drug exposure was consistent with the sum of the diffusion time and the time for passage through the transit states. For each drug, the PD model with a single set of parameters described data across a ten-fold range of concentrations and for both continuous and transient exposure protocols, as well as for combined drug treatments. The ability to predict drug response over a range of administration protocols allows this PD model to be integrated with PK descriptions to describe in vivo antibiotic response dynamics and to predict drug delivery strategies for the improved control of bacterial lung infections.

Semimechanistic pharmacokinetic-pharmacodynamic model of tripegfilgrastim for pediatric patients after chemotherapy.

Tripegfilgrastim is a long-acting granulocyte colony-stimulating factor (G-CSF) that has been used to prevent chemotherapy-induced neutropenia in adults. This study aimed to establish a pharmacokinetic (PK)-pharmacodynamic (PD) model to explore the impact of chemotherapy and tripegfilgrastim on absolute neutrophil counts (ANCs) and to further propose a fixed-dose regimen in pediatric patients. Because neutrophils affect the clearance of tripegfilgrastim, the semimechanistic PK-PD model was developed simultaneously by using data from 40 healthy adults and 27 pediatric patients with solid tumors. Tripegfilgrastim PK and ANC dynamics were described with a pharmacodynamics-mediated drug disposition model assuming quasi-equilibrium with five transit compartments mimicking neutrophil granulopoiesis. The effect of chemotherapy on neutrophils was included by stimulating the elimination of the G-CSF receptor at the mitotic cells. Healthy adult and pediatric patients showed significantly different value for dissociation constant of the tripegfilgrastim-G-CSF receptor complex (Kd ) and apparent volume of distribution (Vd /F). Patients treated with chemotherapy had a higher Vd /F and 62% lower Kd than healthy adults. As the age increased, the absorption rate of tripegfilgrastim was decreased. Body weight affected the G-CSF receptor-mediated internalization of tripegfilgrastim, and the baseline ANC value impacted the production rate of G-CSF receptors. Simulations from the developed model suggested that 1.5, 2.5, 4, and 6 mg single subcutaneous tripegfilgrastim doses for the respective weight groups of 10-20, 21-30, 31-44, and more than 45 kg significantly reduced the duration of Grade 4 neutropenia similar to tripegfilgrastim weight-based treatment with 100 μg/kg.

The pharmacokinetic-pharmacodynamic modelling framework as a tool to predict drug resistance evolution.

Pharmacokinetic-pharmacodynamic (PKPD) models, which describe how drug concentrations change over time and how that affects pathogen growth, have proven highly valuable in designing optimal drug treatments aimed at bacterial eradication. However, the fast rise of antimicrobial resistance calls for increased focus on an additional treatment optimization criterion: avoidance of resistance evolution. We demonstrate here how coupling PKPD and population genetics models can be used to determine treatment regimens that minimize the potential for antimicrobial resistance evolution. Importantly, the resulting modelling framework enables the assessment of resistance evolution in response to dynamic selection pressures, including changes in antimicrobial concentration and the emergence of adaptive phenotypes. Using antibiotics and antimicrobial peptides as an example, we discuss the empirical evidence and intuition behind individual model parameters. We further suggest several extensions of this framework that allow a more comprehensive and realistic prediction of bacterial escape from antimicrobials through various phenotypic and genetic mechanisms.

Assessment of ibrutinib scheduling on leukocyte, lymph node size and blood pressure dynamics in chronic lymphocytic leukemia through pharmacokinetic-pharmacodynamic models.

Ibrutinib is a Bruton tyrosine kinase (Btk) inhibitor for treating chronic lymphocytic leukemia (CLL). It has also been associated with hypertension. The optimal dosing schedule for mitigating this adverse effect is currently under discussion. A quantification of relationships between systemic ibrutinib exposure and efficacy (i.e., leukocyte count and sum of the product of perpendicular diameters [SPD] of lymph nodes) and hypertension toxicity (i.e., blood pressure), and their association with overall survival is needed. Here, we present a semi-mechanistic pharmacokinetic-pharmacodynamic modeling framework to characterize such relationships and facilitate dose optimization. Data from a phase Ib/II study were used, including ibrutinib plasma concentrations to derive daily 0-24-h area under the concentration-time curve, leukocyte count, SPD, survival, and blood pressure measurements. A nonlinear mixed effects modeling approach was applied, considering ibrutinib's pharmacological action and CLL cell dynamics. The final framework included (i) an integrated model for SPD and leukocytes consisting of four CLL cell subpopulations with ibrutinib inhibiting phosphorylated Btk production, (ii) a turnover model in which ibrutinib stimulates an increase in blood pressure, and (iii) a competing risk model for dropout and death. Simulations predicted that the approved dosing schedule had a slightly higher efficacy (24-month, progression-free survival [PFS] 98%) than de-escalation schedules (24-month, average PFS ≈ 97%); the latter had, on average, ≈20% lower proportions of patients with hypertension. The developed modeling framework offers an improved understanding of the relationships among ibrutinib exposure, efficacy and toxicity biomarkers. This framework can serve as a platform to assess dosing schedules in a biologically plausible manner.

Real-Time Personalised Pharmacokinetic-Pharmacodynamic Modelling in Propofol Anesthesia through Bayesian Inference.

Pharmacological models describe a patient's response to the administration of a medicinal drug based on parameters derived from population studies. However, considerable inter-patient variability exists, such that population models may underperform when used to predict the actual response of a specific individual. In applications which demand predictive accuracy-such as target-controlled infusion of anesthetic agents-modeling uncertainty may reduce system dependability and introduce clinical risk. Our work investigates the use of Bayesian inference, implemented through a particle filter algorithm, to refine a prior model of propofol pharmacokinetics-pharmacodynamics and estimate patient-specific parameters in real-time. We report here on an observational clinical study conducted on 40 adults undergoing general anesthesia, where we evaluated the performance of Bayesian inference-personalized models in forecasting forward trends of depth of anesthesia (Bispectral Index) measurements and compared it with that of a traditional population-based pharmacological model. Our results show a significant reduction in prediction error metrics for the patient-specific models. Our study demonstrates the viability and practical implementability of Bayesian inference as a tool for real-time intra-operative estimation of personalized pharmacological models in anesthesia applications.

Pharmacokinetic–pharmacodynamic modeling of maintenance therapy for childhood acute lymphoblastic leukemia

In the treatment of childhood acute lymphoblastic leukemia (ALL), current protocols combine initial high-dose multiagent chemotherapy with prolonged oral therapy with 6-mercaptopurine (6MP) and low-dose methotrexate (MTX) maintenance therapy. Decades of research on ALL treatment have resulted in survival rates of approximately 90%. However, dose-response relationships vary widely between patients and insight into the influencing factors, that would allow for improved personalized treatment management, is insufficient. We use a detailed data set with measurements of thioguanine nucleotides and MTX in red blood cells and absolute neutrophil count (ANC) to develop pharmacokinetic models for 6MP and MTX, as well as a pharmacokinetic–pharmacodynamic (PKPD) model capable of predicting individual ANC levels and thus contributing to the development of personalized treatment strategies. Here, we show that integrating metabolite measurements in red blood cells into the full PKPD model improves results when less data is available, but that model predictions are comparable to those of a fixed pharmacokinetic model when data availability is not limited, providing further evidence of the quality of existing models. With this comprehensive model development leading to dynamics similar to simpler models, we validate the suitability of this model structure and provide a foundation for further exploration of maintenance therapy strategies through simulation and optimization.

Methotrexate Polyglutamates Exposure - Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate.

Methotrexate polyglutamates (MTX-PG) concentrations in red blood cells (RBCs) have been suggested as a biomarker of response in patients with rheumatoid arthritis (RA) receiving low-dose MTX therapy. We investigated the association and interpatient variability between RBC-MTX-PG3-5 -exposure and response in patients with RA starting MTX. Data of three prospective cohorts were available. The relationship between exposure and Disease Activity Score in 28 joints (DAS28) was analyzed using a population pharmacokinetic-pharmacodynamic model. Relevant covariates were tested using full covariate modeling and backward elimination. From 395 patients, 3,401 MTX-PG concentrations and 1,337 DAS28 measurements were available between 0 and 300 days after MTX treatment onset. The developed model adequately described the time course of MTX-PG3-5 and DAS28. The median MTX-PG3-5 level at month 1 was 30.9 nmol/L (interquartile range (IQR): 23.6-43.7; n = 41) and at month 3: 69.3 nmol/L (IQR: 17.9-41.2; n = 351). Clearance of MTX-PG3-5 from RBCs was 28% lower (95% confidence interval (CI): 23.6-32.8%) in a woman and 10% lower (95% CI: 7.7-12.4%) in a 65-year-old compared with a 35-year-old patient. MTX-PG3-5 concentrations associated with DAS28: half-maximal effective concentration (EC50 ) was 9.14 nmol/L (95% CI: 4.2 nmol/L-14.1 nmol/L). EF at 80% (EC80 ) above 47 nmol/L was regarded as the optimal response. Independent of the MTX-PG 3-5 - response association, co-administration of disease-modifying antirheumatic drugs and corticosteroids improved response (additive effect on maximum effect (Emax )), whereas smoking, high body mass index and low albumin decreased Emax . In patients with RA starting MTX, RBC-MTX-PG3-5 was associated with clinical response. A dose increase is suggested when MTX-PG3-5 at month 1 is below 9.15 nmol/L, continued with the same dose when the concentration is above 47 nmol/L, and consider other treatment options above 78 nmol/L from 3months onwards.

Total intravenous anaesthesia in neonatal surgery: a case series using the Eleveld model

The practice of total intravenous anaesthesia (TIVA) target-controlled infusion of propofol (TCI-propofol) during neonatal surgery was limited by the lack of an appropriate pharmacokinetic-pharmacodynamic model and safety concerns. This is due to the physiological differences between the adult and neonate populations as well as inter-individual pharmacodynamic variation. Eleveld is the latest propofol pharmacokinetic model commercially available and the only model with the neonatal population in its algorithm design. We present a case series of neonates that underwent neonatal surgery under TIVA TCI-propofol utilising the Eleveld pharmacokinetic model. There was no observable clinically significant hypotension intraoperatively. Careful titration of TCI-propofol was necessary for timely emergence and maintaining haemodynamic stability. All neonates were extubated well postoperatively and recovered uneventfully. These demonstrated good and desirable anaesthetic effects using TCI-propofol without undesirable short-term side effects, especially clinically significant hypotension.

Pharmacokinetic pharmacodynamic modeling of analgesics and sedatives in children.

Pharmacokinetic pharmacodynamic modeling is an important tool which uses statistical methodology to provide a better understanding of the relationship between concentration and effect of drugs such as analgesics and sedatives. Pharmacokinetic pharmacodynamic models also describe between-subject variability that allows identification of subgroups and dose adjustment for optimal pain management in individual patients. This approach is particularly useful in the pediatric population, where most drugs have received limited evaluation and dosing is extrapolated from adult practice. In children, the covariates of weight and age are used to describe size- and maturation-related changes in pharmacokinetics. It is important to consider both size and maturation in order to develop an accurate model and determine the optimal dose for different age groups. An adequate assessment of analgesic and sedative effect using pain scales or brain activity measures is essential to build reliable pharmacokinetic pharmacodynamic models. This is often challenging in children due to the multidimensional nature of pain and the limited sensitivity and specificity of some measurement tools. This review provides a summary of the pharmacokinetic and pharmacodynamic methodology used to describe the dose-concentration-effect relationship of analgesics and sedation in children, with a focus on the different pharmacodynamic endpoints and the challenges of pharmacodynamic modeling.

Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors

BackgroundKN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK),...

Population pharmacokinetic-pharmacodynamic model of nirogacestat effects on B-cell maturation antigen in healthy subjects.

8027 Background: B-cell maturation antigen (BCMA) is expressed on the membrane of normal plasma cells (PCs) and multiple myeloma (MM) cells and is the target of several investigational agents and approved products for MM treatment. Mechanistically, BCMA is cleaved from the cell surface by the enzyme gamma secretase, resulting in reduced levels of membrane-bound BCMA (mbBCMA) and release of soluble BCMA. Gamma secretase inhibitors (GSIs) have been shown to increase BCMA receptor density and potentiate the activity of several BCMA-targeted therapies in both clinical trials and in vitro studies. Although the effect of GSIs on BCMA receptor density has been well characterized in vitro, their effect on BCMA dynamics is incompletely understood in humans. This study sought to evaluate the pharmacodynamics (PD) of the GSI nirogacestat on mbBCMA in healthy subjects. Methods: A total of 23 healthy subjects were administered single doses of 50, 150, or 300 mg nirogacestat or multiple doses of 100 mg every 12 hours. Density of mbBCMA on PCs isolated from whole blood and bone marrow was measured by flow cytometry at baseline and 1, 2, 4, 8, 24, and 48 hours after single doses and 24 and 48 hours after the first dose in subjects receiving multiple doses. Nirogacestat serum concentrations were also measured at multiple time points to fully characterize the pharmacokinetics (PK). A population PK-PD model of the effect of nirogacestat on BCMA dynamics in humans was developed and used to simulate various administration dose levels and schedules to find an optimal nirogacestat regimen that continually increases mbBCMA over the dosing interval. Results: A 2-compartment model with linear absorption and elimination described serum nirogacestat in healthy subjects. A sequential PK-PD model that included an effect compartment and drug effect on mbBCMA cleavage rate described mbBCMA values. Simulations indicated that a 100-mg dose administered twice daily sufficiently maintained elevated and clinically relevant mbBCMA levels. Exposure and efficacy benchmarks from in vitro experiments and published clinical studies were used to contextualize simulations and hypothesize various dose and schedule scenarios to minimize dose of the BCMA-targeting therapy while maximizing BCMA potentiation. Conclusions: These results suggest that nirogacestat dose and schedule may have direct implications on the potentiation of BCMA-targeting therapies. Simulations suggest that the 100-mg, twice-daily nirogacestat dose results in elevated mbBCMA levels that could even allow for use of lower doses of BCMA-targeted agents while maintaining or improving efficacy. Study results along with this PK-PD model will be used to support nirogacestat dose and schedule in ongoing and planned studies in patients with MM.

Population pharmacokinetic and pharmacokinetic-pharmacodynamic modeling of bempedoic acid and low-density lipoprotein cholesterol in healthy subjects and patients with dyslipidemia

Population pharmacokinetics (popPK) of bempedoic acid and the popPK/pharmacodynamic (popPK/PD) relationship between bempedoic acid concentrations and serum low-density lipoprotein cholesterol (LDL-C) from baseline were characterized. A two-compartment disposition model with a transit absorption compartment and linear elimination best described bempedoic acid oral pharmacokinetics (PK). Multiple covariates, including renal function, sex, and weight, had statistically significant effects on the predicted steady-state area under the curve. Mild (estimated glomerular filtration rate (eGFR) 60 to < 90 mL/min vs. ≥ 90 mL/min) and moderate (eGFR 30 to < 60 mL/min vs. ≥ 90 mL/min) renal impairment, female sex, low (< 70 kg vs. 70–100 kg) and high (> 100 kg vs. 70–100 kg) body weight were predicted to have a 1.36-fold (90% confidence interval (CI) 1.32, 1.41), 1.85-fold (90% CI 1.74, 2.00), 1.39-fold (90% CI 1.34, 1.47), 1.35-fold (90% CI 1.30, 1.41), and 0.75-fold (90% CI 0.72, 0.79) exposure difference relative to their reference populations, respectively. An indirect response model described changes in serum LDL-C with a model-predicted 35% maximal reduction and bempedoic acid IC50 of 3.17 µg/mL. A 28% reduction from LDL-C baseline was predicted for a steady-state average concentration of 12.5 µg/mL after bempedoic acid (180 mg/day) dosing, accounting for approximately 80% of the predicted maximal LDL-C reduction. Concurrent statin therapy, regardless of intensity, reduced the maximal effect of bempedoic acid but resulted in similar steady-state LDL-C levels. While multiple covariates had statistically significant effects on PK and LDL-C lowering, none were predicted to warrant bempedoic acid dose adjustment.

Prediction of Omeprazole Pharmacokinetics and its Inhibition on Gastric Acid Secretion in Humans Using Physiologically Based Pharmacokinetic-Pharmacodynamic Model Characterizing CYP2C19 Polymorphisms.

To develop a whole physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model to describe the pharmacokinetics and anti-gastric acid secretion of omeprazole in CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs) and ultrarapid metabolizers (UMs) following oral or intravenous administration. A PBPK/PD model was built using Phoenix WinNolin software. Omeprazole was mainly metabolized by CYP2C19 and CYP3A4 and the CYP2C19 polymorphism was incorporated using in vitro data. We described the PD by using a turn-over model with parameter estimates from dogs and the effect of a meal on the acid secretion was also implemented. The model predictions were compared to 53 sets of clinical data. Predictions of omeprazole plasma concentration (72.2%) and 24h stomach pH after administration (85%) were within 0.5-2.0-fold of the observed values, indicating that the PBPK-PD model was successfully developed. Sensitivity analysis demonstrated that the contributions of the tested factors to the plasma concentration of omeprazole were Vmax,2C19 ≈ Papp > Vmax,3A4 > Kti, and contributions to its pharmacodynamic were Vmax,2C19 > kome > kms > Papp > Vmax,3A4. The simulations showed that while the initial omeprazole dose in UMs, EMs, and IMs increased 7.5-, 3- and 1.25-fold compared to those of PMs, the therapeutic effect was similar. The successful establishment of this PBPK-PD model highlights that pharmacokinetic and pharmacodynamic profiles of drugs can be predicted using preclinical data. The PBPK-PD model also provided a feasible alternative to empirical guidance for the recommended doses of omeprazole.

Physiologically-based pharmacokinetic pharmacodynamic parent-metabolite model of edoxaban to predict drug-drug-disease interactions: M4 contribution.

This study aimed to develop a physiologically-based pharmacokinetic pharmacodynamic (PBPK/PD) parent-metabolite model of edoxaban, an oral anticoagulant with a narrow therapeutic index, and to predict pharmacokinetic (PK)/PD profiles and potential drug-drug-disease interactions (DDDIs) in patients with renal impairment. A whole-body PBPK model with a linear additive PD model of edoxaban and its active metabolite M4 was developed and validated in SimCYP for healthy adults with or without interacting drugs. The model was extrapolated to situations including renal impairment and drug-drug interactions (DDIs). Observed PK and PD data in adults were compared with predicted data. The effect of several model parameters on the PK/PD response of edoxaban and M4 was investigated in sensitivity analysis. The PBPK/PD model successfully predicted PK profiles of edoxaban and M4 as well as anticoagulation PD responses with or without the influence of interacting drugs. For patients with renal impairment, the PBPK model successfully predicted the fold change in each impairment group. Inhibitory DDI and renal impairment had a synergistic effect on the increased exposure of edoxaban and M4, and their downstream anticoagulation PD effect. Sensitivity analysis and DDDI simulation show that renal clearance, intestinal P-glycoprotein activity, and hepatic OATP1B1 activity are the major factors affecting edoxaban-M4 PK profiles and PD responses. Anticoagulation effect induced by M4 cannot be ignored when OATP1B1 is inhibited or downregulated. Our study provides a reasonable approach to adjust the dose of edoxaban in several complicated scenarios especially when M4 cannot be ignored due to decreased OATP1B1 activity.

Sutimlimab Pharmacokinetics and Pharmacodynamics in Patients with Cold Agglutinin Disease.

Sutimlimab, a humanized monoclonal antibody targeting the classical complement pathway, is approved in the US, Japan, and EU for the treatment of hemolytic anemia in adults with cold agglutinin disease. The objectives of this study were to support dose selection for Phase 3 studies, assess dose recommendations, and establish the relationship between sutimlimab exposure and clinical outcome (hemoglobin [Hb] levels). Clinically meaningful biomarkers were graphically analyzed and the exposure-response relationship was proposed. The pharmacokinetic (PK) characteristics of sutimlimab were best described by a two-compartment model with parallel linear and non-linear clearance terms. Body weight was a significant covariate for the volume of distribution in the central compartment (Vc) and total body clearance of sutimlimab. Ethnicity (Japanese, non-Japanese) was a covariate on Vc and maximal non-linear clearance. There were no PK differences between healthy participants and patients. Following graphical exposure-response analysis for biomarkers, a pharmacokinetic-pharmacodynamic model was developed by integrating an indirect response/turnover model for Hb with a maximum effect (Emax) model, relating the Hb-elevating effect of sutimlimab to plasma exposure. Renal function and occurrence of blood transfusion were identified as covariates on Hb change from baseline. Simulations showed that Emax was attained with the approved dosing (6.5 g in patients <75 kg, and 7.5 g in patients {greater than or equal to}75 kg), independent of covariate characteristics, and provided adequate sutimlimab exposure to maximize effects on Hb, bilirubin, and total complement component C4 levels. A change in Hb from baseline at steady state of 2.2 g/dL was projected, consistent with Phase 3 study observations. Significance Statement The final validated population PK and PK/PD models confirm that the approved dosing regimen for sutimlimab (6.5 g in patients <75 kg, and 7.5 g in patients ≥75 kg) is sufficient, without the need for further dose adjustments in populations of patients with cold agglutinin disease.

Pharmacokinetic-pharmacodynamic (PK/PD) modeling to study the hepatoprotective effect of Perilla Folium on the acute hepatic injury rats

Ethnopharmacological relevancePerilla Folium (PF), is a traditional medicinal material with the homology of medicine and food in China and has been widely used due to its rich nutritional content and medicinal value. The hepatoprotective effects of PF extract include their protection against acute hepatic injury, tert-butylhydroperoxide (t-BHP) induced oxidative damage, and Lipopolysaccharide (LPS) and D-galactosamine (D-GalN) induced hepatic injury have been well studied. However, there are few reports on the pharmacokinetics studies of PF extract in acute hepatic injury model rats, and the anti-hepatic injury activity of PF is still unclear. Aim of the studyThe differences in the plasma pharmacokinetic of 21 active compounds between the normal and model groups were compared， and established pharmacokinetics/pharmacodynamics (PK/PD) modeling was to analyze the hepatoprotective effects of PF. Materials and methodsThe acute hepatic injury model was induced with an intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-GalN), and the plasma pharmacokinetics of 21 active compounds of PF were analyzed in the normal and model groups using ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS). The correlation between plasma components and hepatoprotective effects indicators (the alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactic dehydrogenase (LDH)) in the model group was also investigated and established a Pharmacokinetic/pharmacodynamic (PK/PD) correlation analysis of the hepatoprotective effects of PF. ResultsThe results revealed that organic acid compounds possessed the characteristics of faster absorption, shorter peak time and slower metabolism, while the flavonoid compounds had slower absorption and longer peak time, and the pharmacokinetics of various components were significantly affected after modeling. The results of PK/PD modeling analysis demonstrated that the plasma drug concentration of each component existed a good correlation with the three AST, ALT, and LDH, and the lag time of the efficacy of each component is relatively long. ConclusionsThe plasma drug concentration of each component existed a good correlation with the three AST, ALT, and LDH, and the lag time of the efficacy of each component is relatively long in vivo.

Develop adult extrapolation to pediatrics and pediatric dose optimization based on the physiological pharmacokinetic model of azithromycin.

Physiologically-based pharmacokinetic (PBPK) models are more frequently used for supporting pediatric dose selection in small-molecule drugs. Through literature research, drug parameters of azithromycin and clinical data from different studies were obtained. Through parameter optimization of the absorption and dissolution process, the adult intravenous model was extended to the adult oral model. The adult intravenous and oral PBPK models are precise to meet the AAFE<2 standard, and the pharmacokinetic parameters of the predicted values of the model are all within the mean standard deviation of the clinical observations. The values of plasma protein unbound fraction, renal clearance, and gastric juice pH between adults and pediatrics were changed by using the age-dependent pediatric organ maturity formula, and the adult model was extrapolated to the pediatric model. The final developed pediatric PBPK model was used to evaluate optimal dosing for children of different developmental ages. The relationship between the frist dose and age was as follows: 8.8mg/kg/day from 0.5 to 2years old, 9.2mg/kg/day from 3 to 6years old, 9.4mg/kg/day from 7 to 12years old, and 8.2mg/kg/day from 13 to 18years old, taken in half for 2-5days. Simultaneously, the simulated exposures achieved with the dosing regimen proposed were comparable to adult plasma exposures for treatment of community-acquired pneumonia. A reasonable azithromycin pharmacokinetic-pharmacodynamic model for adults and pediatrics has been established, which can be demonstrated by the use of literature pediatric data to develop pediatric PBPK models, expanding the scope of this powerful modeling tool.