Testing Extrapolation of a Biologically Based Exposure–Response Model from in Vitro to in Vivo Conditions

2002 ◽  
Vol 35 (1) ◽  
pp. 72-79 ◽  
Author(s):  
M. Mebust ◽  
D. Crawford-Brown ◽  
W. Hofmann ◽  
H. Schöllnberger
Keyword(s):  
Response Model ◽  
Exposure Response

scholarly journals Trematocidal Activity of Praziquantel and Artemisinin Derivatives: In Vitro and In Vivo Investigations with Adult Echinostoma caproni

2006 ◽  
Vol 50 (2) ◽  
pp. 803-805 ◽  
Author(s):  
Jennifer Keiser ◽  
Reto Brun ◽  
Bernard Fried ◽  
Jürg Utzinger
Keyword(s):  
Body Weight ◽  
Worm Burden ◽  
Echinostoma Caproni ◽  
Artemisinin Derivatives ◽  
Exposure Response ◽  
Oral Doses

ABSTRACT We examined the effects of praziquantel and the artemisinins on adult Echinostoma caproni. In vitro, both praziquantel and the artemisinins exhibited exposure-response relationships. In vivo, worm burden reductions of 100% were achieved with single oral doses of praziquantel, artesunate, and artemether at 50, 700, and 1,100 mg/kg of body weight, respectively.

scholarly journals Exposure–response modelling approaches for determining optimal dosing rules in children

2020 ◽  
Vol 29 (9) ◽  
pp. 2583-2602
Author(s):  
Ian Wadsworth ◽  
Lisa V Hampson ◽  
Björn Bornkamp ◽  
Thomas Jaki
Keyword(s):  
Recursive Partitioning ◽  
Age Groups ◽  
In Vitro Study ◽  
Model Parameters ◽  
Response Model ◽  
B Splines ◽  
Model Based ◽  
Exposure Response ◽  
Optimal Dosing

Within paediatric populations, there may be distinct age groups characterised by different exposure–response relationships. Several regulatory guidance documents have suggested general age groupings. However, it is not clear whether these categorisations will be suitable for all new medicines and in all disease areas. We consider two model-based approaches to quantify how exposure–response model parameters vary over a continuum of ages: Bayesian penalised B-splines and model-based recursive partitioning. We propose an approach for deriving an optimal dosing rule given an estimate of how exposure–response model parameters vary with age. Methods are initially developed for a linear exposure–response model. We perform a simulation study to systematically evaluate how well the various approaches estimate linear exposure–response model parameters and the accuracy of recommended dosing rules. Simulation scenarios are motivated by an application to epilepsy drug development. Results suggest that both bootstrapped model-based recursive partitioning and Bayesian penalised B-splines can estimate underlying changes in linear exposure–response model parameters as well as (and in many scenarios, better than) a comparator linear model adjusting for a categorical age covariate with levels following International Conference on Harmonisation E11 groupings. Furthermore, the Bayesian penalised B-splines approach consistently estimates the intercept and slope more accurately than the bootstrapped model-based recursive partitioning. Finally, approaches are extended to estimate Emax exposure–response models and are illustrated with an example motivated by an in vitro study of cyclosporine.

scholarly journals Application of Pharmacokinetic-Pharmacodynamic Modeling to Inform Translation of In Vitro NaV1.7 Inhibition to In Vivo Pharmacological Response in Non-human Primate

2020 ◽  
Vol 37 (10) ◽  
Author(s):  
Jeanine E. Ballard ◽  
Parul Pall ◽  
Joshua Vardigan ◽  
Fuqiang Zhao ◽  
Marie A. Holahan ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Pharmacodynamic Modeling ◽  
Effect Compartment ◽  
Individual Compound ◽  
Preclinical Development ◽  
Initial Exposure ◽  
Exposure Response ◽  
Staged Approach

Abstract Purpose This work describes a staged approach to the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling in the voltage-gated sodium ion channel (NaV1.7) inhibitor drug discovery effort to address strategic questions regarding in vitro to in vivo translation of target modulation. Methods PK-PD analysis was applied to data from a functional magnetic resonance imaging (fMRI) technique to non-invasively measure treatment mediated inhibition of olfaction signaling in non-human primates (NHPs). Initial exposure-response was evaluated using single time point data pooled across 27 compounds to inform on in vitro to in vivo correlation (IVIVC). More robust effect compartment PK-PD modeling was conducted for a subset of 10 compounds with additional PD and PK data to characterize hysteresis. Results The pooled compound exposure-response facilitated an early exploration of IVIVC with a limited dataset for each individual compound, and it suggested a 2.4-fold in vitro to in vivo scaling factor for the NaV1.7 target. Accounting for hysteresis with an effect compartment PK-PD model as compounds advanced towards preclinical development provided a more robust determination of in vivo potency values, which resulted in a statistically significant positive IVIVC with a slope of 1.057 ± 0.210, R-squared of 0.7831, and p value of 0.006. Subsequent simulations with the PK-PD model informed the design of anti-nociception efficacy studies in NHPs. Conclusions A staged approach to PK-PD modeling and simulation enabled integration of in vitro NaV1.7 potency, plasma protein binding, and pharmacokinetics to describe the exposure-response profile and inform future study design as the NaV1.7 inhibitor effort progressed through drug discovery.

Model-Based Dose-Exposure-Response Assessment for Lead and Backup Spectinamide in a Mouse Model of Tuberculosis

2020 ◽  
Author(s):  
◽  
Santosh Wagh ◽  
Keyword(s):  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Response Relationship ◽  
Exposure Response ◽  
Antibiotic Effect ◽  
Post Antibiotic Effect

Despite decades of research, tuberculosis remains the oldest pathogen-based disease that is the leading cause of death from a single infectious agent. Among many anti-tubercular therapies under investigation, the semisynthetic compounds spectinamides are a promising novel class of anti-tuberculosis agents. One such lead candidate, spectinamide 1810, and backup spectinamide 1599 have demonstrated excellent efficacy, safety, and drug-like properties in various in vitro and in vivo assessments. The dose-ranging and dose fractionation studies were designed to characterize the dose-exposure-response relationship for lead and backup spectinamide in a mouse model of Mycobacterium tuberculosis infection. In this current study, we used 26 and 23 combinations of dose level and dosing frequency for the lead and backup spectinamide, respectively. The dedicated pharmacokinetic studies with a collection of series of blood samples were conducted in healthy animals. Population pharmacokinetic analysis was performed using non-linear mixed effect modeling to estimate pharmacokinetic parameters in healthy animals. The Bayesian principles were applied for reliable pharmacokinetic estimation in infected animals by using informed priors obtained from healthy animals. The individual pharmacokinetic parameters were obtained for infected animals through post-hoc estimation and subsequently used for pharmacokinetic/-pharmacodynamic (PK/PD) indices and mechanism-based PK/PD modeling. The obtained data on spectinamides’ plasma concentrations and counts of colony-forming units were analyzed using a PK/PD approach as well as classical anti-infective PK/PD indices. The population pharmacokinetic analysis results suggest that there is no difference in the pharmacokinetic parameters of lead and backup spectinamide in infected animals as compared to healthy animals. The PK/PD index analysis showed that the efficacy of spectinamide 1810 is largely driven by concentration (Cmax/MIC) and exposure (AUC/MIC) rather than a threshold minimum inhibitory level (T>MIC). Although similar results were obtained for spectinamide 1599 in previously performed in vitro experiments, in the present in vivo studies, spectinamide 1599 did not demonstrate the expected correlation between efficacy and PK/PD indices. Therefore, we could not identify major drivers for the efficacy of this compound. Additionally, a novel mechanism-based PK/PD model with consideration to post-antibiotic effect could adequately describe the exposure-response relationship for lead and backup spectinamide. This supports the idea that the in vitro observed post-antibiotic effect of these spectinamides can translate to the in vivo situation, as well. Altogether we suggest, the obtained results and pharmacometric model for the exposure-response relationship of lead and backup spectinamides provide a rational basis for dose selection for future efficacy studies of these compounds against Mycobacterium tuberculosis in mice and other animal species.

scholarly journals Prediction of Human Drug-Drug Interactions

2020 ◽  
Author(s):  
Ulrika Simonsson
Keyword(s):  
Drug Interactions ◽  
Limited Data ◽  
Treatment Development ◽  
Drug Discovery And Development ◽  
Exposure Response ◽  
Novel Drugs ◽  
Integrate Data

Patients suffering from complex diseases (infectious diseases, oncology) or several conditions (co-morbidities) require combination therapies of different drugs. Combining different drugs will potentially lead to drug-drug interactions, influencing the efficacy and safety of the treatment. Development of novel drugs that are intended to be used in combination should consider drug-drug interactions as early as possible. Even with limited data, drug-drug interactions in humans can be predicted using model-informed drug discovery and development (MID3). The concept to utilize and integrate data from in vitro combination experiments combined with preclinical in vivo data on the exposure-response relationships of the drugs in combination through a computational model-informed approach, is introduced here with tuberculosis as case study.

scholarly journals Pharmacokinetics and pharmacodynamics of clofazimine for treatment of cryptosporidiosis

2021 ◽  
Author(s):  
Cindy X. Zhang ◽  
Melissa S. Love ◽  
Case W. McNamara ◽  
Victor Chi ◽  
Ashley K. Woods ◽  
...  
Keyword(s):  
Treatment Effect ◽  
Large Scale ◽  
Oral Absorption ◽  
Diarrheal Disease ◽  
Pharmacodynamic Modeling ◽  
Great Promise ◽  
Preclinical Model ◽  
Exposure Response

Infection with Cryptosporidium spp. can cause severe diarrhea leading to long-term adverse impacts and even death in malnourished children and immunocompromised patients. The only FDA-approved drug for treating cryptosporidiosis, nitazoxanide, has limited efficacy in the populations impacted the most by the diarrheal disease, and safe, effective treatment options are urgently needed. Initially identified by a large-scale phenotypic screening campaign, the antimycobacterial therapeutic clofazimine demonstrated great promise in both in vitro and in vivo preclinical models of Cryptosporidium infection. Unfortunately, a Phase 2a clinical trial in HIV infected adults with cryptosporidiosis did not identify any clofazimine treatment effect on Cryptosporidium infection burden or clinical outcomes. To explore whether clofazimine’s lack of efficacy in the Phase 2a trial may have been due to subtherapeutic clofazimine concentrations, a pharmacokinetic/pharmacodynamic modeling approach was undertaken to determine the relationship between clofazimine in vivo concentrations and treatment effects in multiple preclinical infection models. Exposure-response relationships were characterized using E max and logistic models which allowed predictions of efficacious clofazimine concentrations for the control and reduction of disease burden. After establishing exposure-response relationships for clofazimine treatment of Cryptosporidium infection in our preclinical model studies, it was unmistakable that the clofazimine levels observed in the Phase 2a study participants were well below concentrations associated with anti- Cryptosporidium efficacy. Thus, despite a dosing regimen above the highest doses recommended for mycobacterial therapy, it is very likely the lack of treatment effect in the Phase 2a trial was at least partially due to clofazimine concentrations below those required for efficacy against cryptosporidiosis. It is unlikely that clofazimine will provide a remedy for the large number of cryptosporidiosis patients currently without a viable treatment option unless alternative, safe clofazimine formulations with improved oral absorption are developed.

Model-Based Exposure-Response Assessment for Spectinamide 1810 in a Mouse Model of Tuberculosis

2021 ◽  
Author(s):  
Santosh Wagh ◽  
Chetan Rathi ◽  
Pradeep B. Lukka ◽  
Keyur Parmar ◽  
Zaid Temrikar ◽  
...  
Keyword(s):  
Mouse Model ◽  
Plasma Concentrations ◽  
Dose Fractionation ◽  
Population Pharmacokinetic ◽  
Response Relationship ◽  
Postantibiotic Effect ◽  
Bacterial Killing ◽  
Exposure Response

Despite decades of research, tuberculosis remains a leading cause of death from a single infectious agent. Spectinamides are a promising novel class of anti-tuberculosis agents, and lead spectinamide 1810 has demonstrated excellent efficacy, safety and drug-like properties in numerous in vitro and in vivo assessments in mouse models of tuberculosis. In the current dose ranging and dose fractionation study, we used 29 different combinations of dose level and dosing frequency to characterize the exposure-response relationship for spectinamide 1810 in a mouse model of M. tuberculosis infection and in healthy animals. The obtained data on 1810 plasma concentrations and counts of colony-forming units in lungs were analyzed using a population pharmacokinetic/pharmacodynamic (PK/PD) approach as well as classical anti-infective PK/PD indices. The analysis results indicate that there was no difference in the PK of 1810 in infected compared to healthy, uninfected animals. The PK/PD index analysis showed that bacterial killing of 1810 in mice was best predicted by fC max /MIC and fAUC/MIC rather than f%T MIC . A novel PK/PD model with consideration of postantibiotic effect could adequately describe the exposure-response relationship for 1810 and supports the notion that the in vitro observed postantibiotic effect of this spectinamide also translates to the in vivo situation in mice. The obtained results and pharmacometric model for the exposure-response relationship of 1810 provide a rational basis for dose selection in future efficacy studies of this compound against M. tuberculosis .

Induction and Differentiation of Dental Epithelium in Vivo and in Vitro

1982 ◽  
Vol 40 ◽  
pp. 142-145
Author(s):  
E. J. Kollar
Keyword(s):  
Connective Tissue ◽  
Oral Mucosa ◽  
Basal Lamina ◽  
Functional Derivatives ◽  
Specific Source ◽  
Dental Epithelium ◽  
Connective Tissue Stroma

The differentiation and maintenance of many specialized epithelial structures are dependent on the underlying connective tissue stroma and on an intact basal lamina. These requirements are especially stringent in the development and maintenance of the skin and oral mucosa. The keratinization patterns of thin or thick cornified layers as well as the appearance of specialized functional derivatives such as hair and teeth can be correlated with the specific source of stroma which supports these differentiated expressions.

Ultrastructural Correlations between Clonal Human Tumor Colonies and in Vivo Neoplasms

1982 ◽  
Vol 40 ◽  
pp. 210-211
Author(s):  
M.J. Murphy ◽  
R.R. Price ◽  
J.C. Sloman
Keyword(s):  
Cultured Cells ◽  
Human Tumor ◽  
Cell Type ◽  
Tumor Mass ◽  
Initial Cell ◽  
Cloning Assay ◽  
Human Tumor Cloning ◽  
The Relationship

The in vitro human tumor cloning assay originally described by Salmon and Hamburger has been applied recently to the investigation of differential anti-tumor drug sensitivities over a broad range of human neoplasms. A major problem in the acceptance of this technique has been the question of the relationship between the cultured cells and the original patient tumor, i.e., whether the colonies that develop derive from the neoplasm or from some other cell type within the initial cell population. A study of the ultrastructural morphology of the cultured cells vs. patient tumor has therefore been undertaken to resolve this question. Direct correlation was assured by division of a common tumor mass at surgical resection, one biopsy being fixed for TEM studies, the second being rapidly transported to the laboratory for culture.

Ultrastructure of melanocyte-keratinocyte interactions and pigment transfer in vitro

1978 ◽  
Vol 36 (2) ◽  
pp. 650-651
Author(s):  
Raul I. Garcia ◽  
Evelyn A. Flynn ◽  
George Szabo
Keyword(s):  
Direct Injection ◽  
Skin Pigmentation ◽  
Freeze Fracture ◽  
Pigment Granule ◽  
Time Lapse ◽  
Ultrastructural Level ◽  
Lanthanum Tracer ◽  
A Cell

Skin pigmentation in mammals involves the interaction of epidermal melanocytes and keratinocytes in the structural and functional unit known as the Epidermal Melanin Unit. Melanocytes(M) synthesize melanin within specialized membrane-bound organelles, the melanosome or pigment granule. These are subsequently transferred by way of M dendrites to keratinocytes(K) by a mechanism still to be clearly defined. Three different, though not necessarily mutually exclusive, mechanisms of melanosome transfer have been proposed: cytophagocytosis by K of M dendrite tips containing melanosomes, direct injection of melanosomes into the K cytoplasm through a cell-to-cell pore or communicating channel formed by localized fusion of M and K cell membranes, release of melanosomes into the extracellular space(ECS) by exocytosis followed by K uptake using conventional phagocytosis. Variability in methods of transfer has been noted both in vivo and in vitro and there is evidence in support of each transfer mechanism. We Have previously studied M-K interactions in vitro using time-lapse cinemicrography and in vivo at the ultrastructural level using lanthanum tracer and freeze-fracture.

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