273 Application of pharmacokinetic-pharmacodynamic modeling to select the optimal dose of ALX148, a CD47 blocker

BackgroundALX148 is a fusion protein comprised of a high-affinity CD47 blocker linked to an inactive immunoglobulin Fc region. Optimal doses selection is increasingly important in clinical setup and can be guided by an assessment of target receptor occupancy (RO) and pharmacodynamics (PD) effect in the site of action. However, direct measurement of RO and PD effect in the tumor tissue is challenging. A mechanistic pharmacokinetic (PK)-PD model was developed to predict CD47 occupancy and PD effect in tumor tissues for ALX148.MethodsThe developed semi-mechanistic PK/RO/PD model describes the PK of ALX148 and its distribution to non-Hodgkin lymphoma tumor tissues (lymph nodes, spleen, and bone marrow). The model includes non-linear clearance of ALX148 due to target CD47 receptor binding and further internalization of the complex. CD47 RO was described on red blood cells and tumor cells taking into account the number of cells and CD47 expression (molecules per cell). Parameters were fitted against clinical PK and in vitro data. In vitro data on stimulation of phagocytosis by ALX148 in the presence of antibodies inducing antibody-dependent cellular phagocytosis (ADCP) was used to estimate the RO-PD relationship. Clinical data on RO in the periphery was used for model validation.ResultsThe model successfully described dose-dependence ALX148 clinical PK and RO data. Predicted trough median CD47 occupancy in the spleen, lymph nodes, and bone marrow during the treatment with 10 mg/kg QW ALX148 was 98% (95% confidence bands: 95%–99%), whereas 30 mg/kg Q2W resulted in 99% CD47 occupancy (95% confidence bands: 98%–99%). ADCP of cancer cells was predicted to be increased by ~1.8 times during the treatment with both regimens of ALX148: 10 mg/kg QW and 30 mg/kg Q2W. Dose 3 mg/kg resulted in the lower induction of ADCP than 10 mg/kg: 1.6 vs 1.8 (p-value < 0.001).ConclusionsThe model was successfully calibrated and validated against both in vitro and clinical data on ALX148. It was predicted that 10 mg/kg QW is an optimal dose of ALX148 to occupy more than 90% of CD47 in the tumor tissues to achieve maximal induction of phagocytosis caused by ADCP stimulating antibodies such as rituximab. This approach can be applied for the optimal dose selection of other anti-CD47 agents taking into account their specific features as binding properties, size, etc.

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MATURATION OF HEMOLYSIN-PRODUCING CELL CLONES

Journal of Experimental Medicine ◽

10.1084/jem.131.6.1261 ◽

1970 ◽

Vol 131 (6) ◽

pp. 1261-1270 ◽

Cited By ~ 4

Author(s):

George C. Saunders ◽

Douglas Swartzendruber

Keyword(s):

Bone Marrow ◽

Doubling Time ◽

Sheep Erythrocyte ◽

Mature Animal ◽

Cell Clones ◽

Initial Appearance ◽

Vitro Data ◽

In Vitro Data

Cells capable of reacting with sheep erythrocyte (SRBC) antigen to maturate and produce hemolysin appear simultaneously in the bone marrow and spleen of 1-day old Swiss-Webster mice. However, hemolysin-producing cell clones (HPCC) do not result. Complete functional precursor units generally appear in the spleens of mice older than 3 days. In vivo and in vitro data correlate well in this regard. Complete precursor units are not seen in the bone marrow and only very rarely in the thymus. The efficiency of precursor units of neonatal mice when they become functional approximates that of the mature animal when based on the doubling time of plaque-forming cells (PFC). Possible explanations of the initial appearance of incomplete precursor units have been discussed.

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In Vitro Data Reveals Potential Novel Mechanism of Action of Teriflunomide on CNS Microglia and Astrocytes

10.26226/morressier.59a3eda8d462b8028d8951bb ◽

2017 ◽

Author(s):

Andrea Edling

Keyword(s):

Mechanism Of Action ◽

Vitro Data ◽

In Vitro Data

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Faculty Opinions recommendation of Simulation and prediction of in vivo drug metabolism in human populations from in vitro data.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1091007.544382 ◽

2007 ◽

Author(s):

Marival Bermejo

Keyword(s):

Drug Metabolism ◽

Human Populations ◽

In Vivo Drug Metabolism ◽

Vitro Data ◽

In Vitro Data

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Use of Toxicokinetics in Risk Assessment Based on In Vitro Data

Alternatives to Laboratory Animals ◽

10.1177/026119299302100209 ◽

1993 ◽

Vol 21 (2) ◽

pp. 173-180

Author(s):

Gunnar Johanson

Keyword(s):

Risk Assessment ◽

Whole Body ◽

External Exposure ◽

Target Dose ◽

Toxic Response ◽

Route Of Exposure ◽

Vitro Data ◽

In Vitro Data

This presentation addresses some aspects of the methodology, advantages and problems associated with toxicokinetic modelling based on in vitro data. By using toxicokinetic models, particularly physiologically-based ones, it is possible, in principle, to describe whole body toxicokinetics, target doses and toxic effects from in vitro data. Modelling can be divided into three major steps: 1) to relate external exposure (applied dose) of xenobiotic to target dose; 2) to establish the relationship between target dose and effect (in vitro data, e.g. metabolism in microsomes, partitioning in tissue homogenates, and toxicity in cell cultures, are useful in both steps); and 3) to relate external exposure to toxic effect by combining the first two steps. Extrapolations from in vitro to in vivo, between animal and man, and between high and low doses, can easily be carried out by toxicokinetic simulations. In addition, several factors that may affect the toxic response by changing the target dose, such as route of exposure and physical activity, can be studied. New insights concerning the processes involved in toxicity often emerge during the design, refinement and validation of the model. The modelling approach is illustrated by two examples: 1) the carcinogenicity of 1,3-butadiene; and 2) the haematotoxicity of 2-butoxyethanol. Toxicokinetic modelling is an important tool in toxicological risk assessment based on in vitro data. Many factors, some of which can, and should be, studied in vitro, are involved in the expression of toxicity. Successful modelling depends on the identification and quantification of these factors.

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Lymphocutaneous spread of Mycobacterium elephantis in an immunocompetent individual: A case report

SAGE Open Medical Case Reports ◽

10.1177/2050313x211034913 ◽

2021 ◽

Vol 9 ◽

pp. 2050313X2110349

Author(s):

Brett D Edwards ◽

Ranjani Somayaji ◽

Dina Fisher ◽

Justin C Chia

Keyword(s):

Case Report ◽

Chronic Lung Disease ◽

Contaminated Soil ◽

Lung Abscess ◽

Immunocompetent Individual ◽

First Case ◽

Antimycobacterial Agents ◽

Vitro Data ◽

In Vitro Data

Mycobacterium elephantis was first described when isolated from an elephant that succumbed to lung abscess. However, despite this namesake, it is not associated with animals and has been described most often as a probable colonizer rather than pathogen in humans with chronic lung disease. In this report, we describe the first case of lymphocutaneous infection from M. elephantis, likely as a result of cutaneous inoculation with contaminated soil. This offers further evidence to its capabilities as a pathogen. We provide a review of the limited prior reports of M. elephantis and outline the available in vitro data on efficacy of various antimycobacterial agents.

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Prediction of CYP2D6 Drug Interactions from In Vitro Data: Evidence for Substrate-Dependent Inhibition

Drug Metabolism and Disposition ◽

10.1124/dmd.111.041210 ◽

2011 ◽

Vol 40 (1) ◽

pp. 47-53 ◽

Cited By ~ 43

Author(s):

Brooke M. VandenBrink ◽

Robert S. Foti ◽

Dan A. Rock ◽

Larry C. Wienkers ◽

Jan L. Wahlstrom

Keyword(s):

Drug Interactions ◽

Dependent Inhibition ◽

Vitro Data ◽

In Vitro Data

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Pharmacokinetics and Pharmacodynamics of Antistaphylococcal Antibiotics in Continuous Ambulatory Peritoneal Dialysis Patients

Peritoneal Dialysis International ◽

10.1177/089686089301302s92 ◽

1993 ◽

Vol 13 (2_suppl) ◽

pp. 367-371 ◽

Cited By ~ 3

Author(s):

Erich Keller

Keyword(s):

Peritoneal Dialysis ◽

Continuous Ambulatory Peritoneal Dialysis ◽

Inhibitory Concentration ◽

Pharmacokinetic Data ◽

Pharmacokinetics And Pharmacodynamics ◽

Antistaphylococcal Activity ◽

Cure Rates ◽

Vitro Data ◽

In Vitro Data

Staphylococci are the leading pathogens In continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis. Vancomycin appears to be an outstanding antistaphylococcal drug because resistance to It Is nearly absent. The pharmacokinetics of vancomycin and clinical cure rates of peritonitis with different dosing guidelines have been studied extensively. Different dosing guidelines with IP or IV loading doses followed or not followed by IP maintenance doses are used successfully, despite the fact that some of the dosing schemes produce apparently suboptimal drug levels referring to In vitro data like the MIC value (minimum Inhibitory concentration). Alternatively, amlnoglycosldes, cephalosporlns, Isoxazolyl penicillins, and broad-spectrum penicillins combined with betalactamase Inhibitors may be used for the treatment of gram-positive peritonitis. For the above panicillins pharmacokinetic data are scarce, and clinical experience is limited. Rifampin has excellent Intracellular antistaphylococcal activity and should be used In combination with other antibiotics. Although pharmacokinetic data are lacking, rifampin dosages do not require adaptation to renal function or replacement therapy.

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Kenyan Plasmodium falciparum Field Isolates: Correlation between Pyrimethamine and Chlorcycloguanil Activity In Vitro and Point Mutations in the Dihydrofolate Reductase Domain

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.1.164 ◽

1998 ◽

Vol 42 (1) ◽

pp. 164-169 ◽

Cited By ~ 65

Author(s):

A. Nzila-Mounda ◽

E. K. Mberu ◽

C. H. Sibley ◽

C. V. Plowe ◽

P. A. Winstanley ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Dihydrofolate Reductase ◽

Drug Response ◽

Point Mutations ◽

Distinct Group ◽

Wild Type ◽

Field Isolates ◽

Vitro Data ◽

In Vitro Data

ABSTRACT Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P< 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 ± 6.94 and 0.24 ± 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).

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