Comparing Model Performance in Characterizing the PK/PD of the Anti-Myostatin Antibody Domagrozumab.
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ABSTRACT:
SUBMITTER: Tiwari A
PROVIDER: S-EPMC6951913 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tryptase, a protease implicated in asthma pathology, is secreted from mast cells upon activation during an inflammatory allergic response. MTPS9579A is a novel monoclonal antibody that inhibits tryptase activity by irreversibly dissociating the active tetramer into inactive monomers. This study assessed the relationship between MTPS9579A concentrations in healthy subjects and tryptase levels in serum and nasal mucosal lining fluid from healthy subjects and patients with moderate-to-severe asthma. These data were used to develop a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model that quantitatively inter-relates MTPS9579A exposure and inhibition of active tryptase in the airway of patients with asthma. From initial estimates of airway tryptase levels and drug partitioning, the PK/PD model predicted almost complete neutralization of active tryptase in the airway of patients with asthma with MTPS9579A doses of 900 mg and greater, administered intravenously (i.v.) once every 4 weeks (q4w). Suppression of active tryptase during an asthma exacerbation event was also evaluated using the model by simulating the administration of MTPS9579A during a 100-fold increase in tryptase secretion in the local tissue. The PK/PD model predicted that 1800 mg MTPS9579A i.v. q4w results in 95.7% suppression of active tryptase at the steady-state trough concentration. Understanding how the exposure-response relationship of MTPS9579A in healthy subjects translates to patients with asthma is critical for future clinical studies assessing tryptase inhibition in the airway of patients with moderate-to-severe asthma.
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Project description:Lonicerae japonicae Flos (LJF) possesses a good anti-respiratory syncytial virus (RSV) effect. However, the material basis of LJF in treating RSV is still unclear. In this study, a sensitive and accurate quantitative method based on UHPLC-QQQ MS was established and validated for the simultaneous determination of the 15 ingredients from LJF in RSV-infected mice plasma. Multiple reaction monitoring was performed for quantification of the standards and of the internal standard in plasma. All the calibration curves show good linear regression within the linear range (r2 > 0.9918). The method validation results, including specificity, linearity, accuracy, precision, extraction recovery, matrix effect, and stability of 15 ingredients, are all within the current acceptance criteria. This established method was successfully applied to the pharmacokinetic study of 15 compounds from LJF. Furthermore, the repair rate of lung index and the improvement rate of IFN-γ and IL-6 improved after administration of the LJF, indicating that LJF possessed a positive effect on the treatment of RSV infection. Finally, by combining Spearman and Grey relation analysis, isochlorogenic acid B, isochlorogenic acid C, secoxyloganin, chlorogenic acid, and loganic acid are speculated to be the main effective ingredients of LJF in treating RSV. This study lays the foundation for attempts to reveal the mechanisms of the anti-RSV effect of LJF.
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Project description:BackgroundPharmacokinetic models are evaluated using three types of metrics: those based on estimating the typical pharmacokinetic parameters, those based on predicting individual pharmacokinetic parameters and those that compare data and model distributions. In the third groups of metrics, the best-known methods are Visual Predictive Check (VPC) and Normalised Prediction Distribution Error (NPDE). Despite their usefulness, these methods have some limitations, especially for the analysis of dependent concentrations, i.e., evaluated in the same patient.ObjectiveIn this work, we propose an evaluation method that accounts for the dependency between concentrations.MethodsThanks to the study of the distribution of simulated vectors of concentrations, the method provides one probability per individual that its observations (i.e., concentrations) come from the studied model. The higher the probability, the better the model fits the individual. By examining the distribution of these probabilities for a set of individuals, we can evaluate the model as a whole.ResultsWe demonstrate the effectiveness of our method through two examples. Our approach successfully detects misspecification in the structural model and identifies outlier kinetics in a set of kinetics.ConclusionWe propose a straightforward method for evaluating models during their development and selecting a model to perform therapeutic drug monitoring. Based on our preliminary results, the method is very promising but needs to be validated on a larger scale.
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Project description:We sought to characterize the population pharmacokinetic/pharmacodynamic (PK/PD) relationship of bococizumab (RN316/PF-04950615), a humanized IgG2Δa monoclonal antibody that binds to secreted human proprotein convertase subtilisin kexin type 9 (PCSK9), using data derived from 16 phase I, II, and III clinical studies (36,066 bococizumab observations, 46,790 low-density lipoprotein cholesterol [LDL-C] measurements, 3499 participants). A two-compartment disposition model with parallel linear and Michaelis-Menten elimination and an indirect response model was used to characterize the population PK and LDL-C response of bococizumab. Potential model parameters and covariate relationships were explored, and visual predictive checks were used for model assessment and validation. Key covariates included the effect of anti-drug antibodies (ADAs) on exposure through impact on clearance and bioavailability; impact of statins on bococizumab elimination (maximal rate of metabolism); and impact of statins, Asian race, and male sex on LDL-C efficacy (maximum effect). ADAs and neutralizing ADAs did not have additional effects on LDL-C beyond the influence on bococizumab exposure. In conclusion, the population PK/PD model adequately describes bococizumab concentration and LDL-C efficacy. The covariate effects are consistent with the presumed mechanism of action of PCSK9 inhibitors. With increasing availability of antibody-based therapeutics, improved understanding of the effect of ADAs and statins on bococizumab PK/PD adds to the literature and enhances our pharmacological understanding of how immunogenicity and concomitant medications may impact the PK/PD of biotherapeutics.
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Project description:An in-house antibody generation campaign identified a diverse, high affinity set of anti-interleukin-11 (IL-11) monoclonal antibodies (mAbs) to enable successful development of novel, custom ultra-sensitive target engagement assays for detection of "free" (unbound to the dosed anti-IL-11 therapeutic mAb) and "total" (free and mAb-IL-11 complexed form) IL-11 in preclinical species and human. Antibody hits from distinct epitope communities were screened on various platforms, including enzyme-linked immunosorbent assay, Meso Scale Discovery, Simoa HD-1 and Simoa Planar Array (SP-X), and used for assay development and sensitivity optimization. The ultra-sensitive SP-X format achieved a lower limit of quantitation of 0.006 pg/mL, enabling the first reported baseline levels of IL-11 in healthy control plasma determined by custom bioanalytical assays. These newly established baseline levels supported mechanistic pharmacokinetic/pharmacodynamic modeling in mouse, cynomolgus monkey, and human for a greater understanding of preclinical study design and in vivo dynamic interaction of soluble IL-11 with an anti-IL-11 antibody therapeutic candidate. Modeling and simulation also helped refine the utility of assays with respect to their potential use as target engagement biomarkers in the clinic.Abbreviations IL-11: Interleukin-11, TE: Target engagement, PK/PD: Pharmacokinetic/pharmacodynamic, mAb: Monoclonal antibody, NHP: Non-human primate, IgG: Immunoglobulin G, Cyno: Cynomolgulus monkey, GFR: Glomerular filtration rate, BQL: Below quantitation levels, DRM: Disease relevant model, kDa: kilodaltons, SPR: Surface plasmon resonance, pSTAT3: phosphorylated STAT3, IL-11R: Interleukin-11 receptor, TPP: Target product protein, LLOQ: Lower limit of quantitation, RLU: Relative light units.
| S-EPMC9348130 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma(PDAC) does not respond to single-agent immune checkpoint inhibitor therapy, including anti-PD-1 antibody(aPD-1) therapy. Higher plasma levels of IL-8 are associated with poorer outcomes in patients who receive aPD-1 therapies, providing a rationale for combination immunotherapy with an anti-IL-8 antibody(aIL-8) and aPD-1. We thus investigated whether human aIL-8 therapy can potentiate the antitumor activity of aPD-1 and further investigated how the combination affects the immune response by regulating myeloid cells in the tumor microenvironment in a humanized murine model of PDAC with a reconstituted immune system consisting of human T cells and a combination of CD14+ and CD16+ myeloid cells. The results show that the combination of aIL-8 and aPD-1 treatment significantly enhanced antitumor activity following the infusion of myeloid cells. Our results further showed that the target of IL-8 is mainly present in CD16+ myeloid cells and is likely to be granulocytes. FACS analysis showed that aIL-8 treatment increased granulocytic myeloid cells in tumors. Consistently, single-nuclear RNA-sequencing analysis of tumor tissue showed that the innate immune response and cytokine response pathways in the myeloid cell cluster were activated by aIL-8 treatment. This is the first preclinical study using a humanized mouse model for new combination immunotherapeutic development and supports the further clinical testing of aIL-8 in combination with aPD-1 for PDAC treatment. This study also suggests that peripherally derived myeloid cells can potentiate the antitumor response of T cells, likely through the innate immune response, and aIL-8 re-educates tumor-infiltrating myeloid cells by activating the innate immune response.
| S-EPMC9485862 | biostudies-literature
Project description:ObjectiveErtugliflozin is approved in the US and European Union as a stand-alone product for adults with type 2 diabetes mellitus as once daily (QD) dosing. The approved fixed-dose combination (FDC) of ertugliflozin and immediate-release metformin is dosed twice daily (BID). This study assessed steady-state pharmacokinetics (PK; area under the concentration-time curve over 24 hours (AUC24)) and pharmacodynamics (PD; urinary glucose excretion over 24 hours (UGE24)) for ertugliflozin 5 and 15 mg total daily doses administered BID or QD.Materials and methodsIn this open-label, two-cohort, randomized, multiple-dose, crossover study, healthy subjects received ertugliflozin 2.5 mg BID and 5 mg QD (n = 28) or ertugliflozin 7.5 mg BID and 15 mg QD (n = 22) for 6 days. Plasma and urine samples were collected for 24 hour post morning dose on day 6 in each period.ResultsThe geometric mean ratio (GMR) (90% CI) of ertugliflozin AUC24 was 100.8% (98.8%, 102.8%) for 2.5 mg BID vs. 5 mg QD, and 99.7% (97.1%, 102.5%) for 7.5 mg BID vs. 15 mg QD. GMR (90% CI) of UGE24 for BID vs. QD administration was 110.2% (103.0%, 117.9%) at a total daily dose of 5 mg, and 102.8% (97.7%, 108.1%) at 15 mg. The 90% CIs of the GMR of AUC24 and UGE24 for BID vs. QD dosing were within the acceptance range for equivalence (80 - 125%) and the prespecified criterion for similarity (70 - 143%), respectively. All treatments were well tolerated.ConclusionThere are no clinically meaningful differences in steady-state PK or PD between ertugliflozin BID and QD regimens at total daily doses of 5 and 15 mg, supporting BID administration of ertugliflozin as a component of the ertugliflozin/metformin (immediate-release) FDC.
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Project description:The efficacy of programmed cell death‑ligand 1 (PD‑L1)/programmed cell death protein 1 (PD‑1) blockade therapy has been demonstrated but is limited in patients with PD‑L1low or immune desert tumors. This limitation can be overcome by combination therapies that include anti‑vascular endothelial growth factor (VEGF) therapy. Such combinations have been investigated in clinical trials for a number of cancer types; however, evidence on the mechanisms underlying their effects in these types of patients is still not sufficient. Therefore, the present study investigated the efficacy and effects on CD8+ T cell and C‑X‑C motif chemokine receptor 3 (CXCR3) ligand expression in tumors by combining anti‑PD‑L1 and anti‑VEGF antibodies using an OV2944‑HM‑1 mouse model with PD‑L1low and immune desert‑like phenotypes. Although the model exhibited anti‑PD‑L1 insensitivity, anti‑PD‑L1 antibody treatment combined with anti‑VEGF antibody inhibited tumor growth compared with anti‑VEGF monotherapy, which itself inhibited tumor growth compared with the control treatment on Day 25. In combination‑treated mice, a higher percentage of CD8+ T cells and higher levels of CXCR3 ligands were observed in tumor tissues compared with those in the anti‑VEGF antibody treatment group, which was not significantly different from control treatment on Day 8. The increase in the intratumoral percentage of CD8+ T cells following the combination treatment was reversed by CXCR3 blocking to the same level as the control. In an anti‑PD‑L1 insensitive model with PD‑L1low and immune desert‑like phenotypes, although anti‑PD‑L1 antibody alone was not effective, anti‑PD‑L1 antibody in combination with anti‑VEGF antibody exhibited antitumor combination efficacy with an increase of CD8+ T cell infiltration, which was suggested to be dependent on the increase of intratumoral CXCR3 ligands. This mechanism could explain the efficacy of anti‑PD‑L1 antibody and anti‑VEGF antibody combination therapy in the clinical setting.
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Project description:More than 2,000 genes appear to be upregulated or downregulated in skeletal muscle of mice with constitutive knockout of myostatin (Steelman et al., FASEB J 20:580-2, 2006). This study was done to determine whether inhibition of myostatin activity in mature mice has similar effects on the pattern of gene expression. Keywords: Differential expression in treated and control mice
2008-11-22 | GSE13707 | GEO
Project description:Apramycin represents a subclass of aminoglycoside antibiotics that has been shown to evade almost all mechanisms of clinically relevant aminoglycoside resistance. Model-informed drug development may facilitate its transition from preclinical to clinical phase. This study explored the potential of pharmacokinetic/pharmacodynamic (PK/PD) modeling to maximize the use of in vitro time-kill and in vivo preclinical data for prediction of a human efficacious dose (HED) for apramycin. PK model parameters of apramycin from four different species (mouse, rat, guinea pig, and dog) were allometrically scaled to humans. A semimechanistic PK/PD model was developed from the rich in vitro data on four Escherichia coli strains and subsequently the sparse in vivo efficacy data on the same strains were integrated. An efficacious human dose was predicted from the PK/PD model and compared with the classical PK/PD index methodology and the aminoglycoside dose similarity. One-compartment models described the PK data and human values for clearance and volume of distribution were predicted to 7.07 L/hour and 26.8 L, respectively. The required fAUC/MIC (area under the unbound drug concentration-time curve over MIC ratio) targets for stasis and 1-log kill in the thigh model were 34.5 and 76.2, respectively. The developed PK/PD model predicted the efficacy data well with strain-specific differences in susceptibility, maximum bacterial load, and resistance development. All three dose prediction approaches supported an apramycin daily dose of 30 mg/kg for a typical adult patient. The results indicate that the mechanistic PK/PD modeling approach can be suitable for HED prediction and serves to efficiently integrate all available efficacy data with potential to improve predictive capacity.
| S-EPMC8048880 | biostudies-literature