Predicting in vivo effect levels for repeat-dose systemic toxicity using chemical, biological, kinetic and study covariates

Abstract Background Fostemsavir (FTR) is an oral prodrug of the first-in-class attachment inhibitor temsavir (TMR) which is being evaluated in patients with multidrug resistant HIV-1 infection. In vitro studies indicated that TMR and its 2 major metabolites are inhibitors of organic cation transporters (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs). To assess the clinical relevance, of OCT and MATE inhibition, mechanistic static DDI prediction with calculated Imax,u/IC50 ratios was below the cut-off limits for a DDI flag based on FDA guidelines and above the cut-off limits for MATEs based on EMA guidelines. Methods Metformin is a commonly used probe substrate for OCT1, OCT2 and MATEs. To predict the potential for a drug interaction between TMR and metformin, a physiologically based pharmacokinetic (PBPK) model for TMR was developed based on its physicochemical properties, in vitro and in vivo data. The model was verified and validated through comparison with clinical data. The TMR PBPK model accurately described AUC and Cmax within 30% of the observed data for single and repeat dose studies with or without food. The SimCYP models for metformin and ritonavir were qualified using literature data before applications of DDI prediction for TMR Results TMR was simulated at steady state concentrations after repeated oral doses of FTR 600 mg twice daily which allowed assessment of the potential OCT1, OCT2, and MATEs inhibition by TMR and metabolites. No significant increase in metformin systemic exposure (AUC or Cmax) was predicted with FTR co-administration. In addition, a sensitivity analysis was conducted for either hepatic OCT1 Ki, or renal OCT2 and MATEs Ki values. The model output indicated that, a 10-fold more potent Ki value for TMR would be required to have a ~15% increase in metformin exposure Conclusion Based on mechanistic static models and PBPK modeling and simulation, the OCT1/2 and MATEs inhibition potential of TMR and its metabolites on metformin pharmacokinetics is not clinically significant. No dose adjustment of metformin is necessary when co-administered with FTR Disclosures Xiusheng Miao, PhD, GlaxoSmithKline (Employee) Mindy Magee, Doctor of Pharmacy, GlaxoSmithKline (Employee, Shareholder) Peter D. Gorycki, BEChe, MSc, PhD, GSK (Employee, Shareholder) Katy P. Moore, PharmD, RPh, ViiV Healthcare (Employee)

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The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing

Molecular Informatics ◽

10.1002/minf.201200114 ◽

2013 ◽

Vol 32 (1) ◽

pp. 47-63 ◽

Cited By ~ 25

Author(s):

Pekka Kohonen ◽

Emilio Benfenati ◽

David Bower ◽

Rebecca Ceder ◽

Michael Crump ◽

...

Keyword(s):

Data Warehouse ◽

Toxicity Testing ◽

Systemic Toxicity ◽

Repeated Dose

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Considerable Improvement of Ursolic Acid Water Solubility by Its Encapsulation in Dendrimer Nanoparticles: Design, Synthesis and Physicochemical Characterization

Nanomaterials ◽

10.3390/nano11092196 ◽

2021 ◽

Vol 11 (9) ◽

pp. 2196 ◽

Cited By ~ 1

Author(s):

Silvana Alfei ◽

Anna Maria Schito ◽

Guendalina Zuccari

Keyword(s):

Ursolic Acid ◽

Water Solubility ◽

Drug Loading ◽

Physicochemical Characterization ◽

Systemic Toxicity ◽

Water Soluble ◽

Design Synthesis ◽

Pentacyclic Triterpenoid

Ursolic acid (UA) is a pentacyclic triterpenoid found in many medicinal plants and aromas endowed with numerous in vitro pharmacological activities, including antibacterial effects. Unfortunately, UA is poorly administered in vivo, due to its water insolubility, low bioavailability, and residual systemic toxicity, thus making urgent the development of water-soluble UA formulations. Dendrimers are nonpareil macromolecules possessing highly controlled size, shape, and architecture. In dendrimers with cationic surface, the contemporary presence of inner cavities and of hydrophilic peripheral functions, allows to encapsulate hydrophobic non-water-soluble drugs as UA, to enhance their water-solubility and stability, and to promote their protracted release, thus decreasing their systemic toxicity. In this paper, aiming at developing a new UA-based antibacterial agent administrable in vivo, we reported the physical entrapment of UA in a biodegradable not cytotoxic cationic dendrimer (G4K). UA-loaded dendrimer nanoparticles (UA-G4K) were obtained, which showed a drug loading (DL%) much higher than those previously reported, a protracted release profile governed by diffusion mechanisms, and no cytotoxicity. Also, UA-G4K was characterized by principal components analysis (PCA)-processed FTIR spectroscopy, by NMR and elemental analyses, and by dynamic light scattering experiments (DLS). The water solubility of UA-G4K was found to be 1868-fold times higher than that of pristine UA, thus making its clinical application feasible.

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Continuous intravenous infusions of bromodeoxyuridine as a clinical radiosensitizer.

Journal of Clinical Oncology ◽

10.1200/jco.1984.2.10.1144 ◽

1984 ◽

Vol 2 (10) ◽

pp. 1144-1150 ◽

Cited By ~ 52

Author(s):

T J Kinsella ◽

J B Mitchell ◽

A Russo ◽

M Aiken ◽

G Morstyn ◽

...

Keyword(s):

Bone Marrow ◽

Tumor Cells ◽

Normal Skin ◽

Systemic Toxicity ◽

Constant Infusion ◽

Local Toxicity ◽

Arterial Plasma ◽

Infusion Period

Twelve patients were treated with continuous intravenous (24-hour) infusions of bromodeoxyuridine (BUdR) at 650 or 1,000 mg/m2/d for up to two weeks. Myelosuppression, especially thrombocytopenia, was the major systemic toxicity and limited the infusion period to nine to 14 days. However, bone marrow recovery occurred within seven to ten days, allowing for a second infusion in most patients. Local toxicity (within the radiation field) was minimal, with the exception of one of four patients, who underwent abdominal irradiation. Pharmacology studies revealed a steady-state arterial plasma level of 6 X 10(-7) mol/L and 1 X 10(-6) mol/L during infusion of 650 and 1,000 mg/m2/d, respectively. In vivo BUdR uptake into normal bone marrow was evaluated in two patients by comparison of preinfusion and postinfusion in vitro radiation survival curves of marrow CFUc with enhancement ratios (D0-pre/D0-post) of 1.8 (with 650 mg/m2/d) and 2.5 (with 1,000 mg/m2/d). In vivo BUdR incorporation into normal skin and tumor cells using an anti-BUdR monoclonal antibody and immunohistochemistry was demonstrated in biopsies from three patients revealing substantially less cellular incorporation into normal skin (less than 10%) compared with tumor (up to 50% to 70%). We conclude that local and systemic toxicity of continuous infusion of BUdR at 1,000 mg/m2/d for approximately two weeks is tolerable. The observed normal tissue toxicity is comparable with our previous clinical experience with intermittent (12 hours every day for two weeks) infusions of BUdR. Theoretically, a constant infusion should allow for greater incorporation of BUdR into cycling tumor cells and thus, for further enhancement of radiosensitization.

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Ameliorative effect of DRDE 07 and its analogues on the systemic toxicity of sulphur mustard and nitrogen mustard in rabbit

Human & Experimental Toxicology ◽

10.1177/0960327109359641 ◽

2010 ◽

Vol 29 (9) ◽

pp. 747-755 ◽

Cited By ~ 7

Author(s):

Pravin Kumar ◽

Anshoo Gautam ◽

Prakash Chandra Jatav ◽

Abdhesh kumar ◽

K. Ganeshan ◽

...

Keyword(s):

Animal Model ◽

Nitrogen Mustard ◽

Protective Efficacy ◽

Systemic Toxicity ◽

Skin Injury ◽

Sulphur Mustard ◽

Therapeutic Drugs ◽

Differential Toxicity ◽

Ameliorative Effect

Despite extensive research efforts, there is no unanimous approval of any animal model to evaluate the toxicity of sulphur mustard [SM; bis (2-chloroethyl) sulphide] or nitrogen mustard [HN-3; tris-(2-chloroethyl) amine] and screening of various prophylactic and therapeutic agents against them. In this study, differential toxicity of mustard agents in higher animal model that is male rabbit was determined. Protective efficacy of DRDE 07 [S-2(2-aminoethylamino) ethyl phenyl sulphide] and its analogues were also evaluated against SM and HN-3 toxicity. Differential toxicity study of SM and HN-3 reveals that both the compounds were more toxic by percutaneous route as compared to subcutaneous route. Till date, there is no recommended drug to counteract SM induced toxicity or mortality in vivo. However, DRDE 07 (an amifostine analogue) and its analogues are found to be very effective protective agents against percutaneously exposed SM in rabbits. The present experiments also showed that SM does not cause skin injury alone but also can cause systemic toxicity as well. DRDE 07 and many of its analogues may prove as prototype compounds for the development of better prophylactic and therapeutic drugs to counter the toxicity of SM or HN-3. In conclusion, rodents and rabbits can be used for the screening of drugs against the blistering agents.

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Deposition of Doxorubicin in Rats following Administration of Three Newly Synthesized Doxorubicin Conjugates

BioMed Research International ◽

10.1155/2013/926584 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Menglei Huan ◽

Shuang Tian ◽

Han Cui ◽

Bangle Zhang ◽

Dan Su ◽

...

Keyword(s):

Polyethylene Glycol ◽

Antitumor Activity ◽

Tumor Targeting ◽

Circulatory System ◽

Systemic Toxicity ◽

Chemical Structures ◽

Low Levels ◽

Acid Labile

We previously reported the synthesis of three DOX conjugates that represented different targeting vehicles and showed them to have antitumor activity bothin vitroandin vivo. However, the relationships between the pharmacokinetics of these DOX conjugates and their chemical structures were not characterized. In the current study, free DOX derived from each of the conjugates was found at low levels in the rat circulatory system, with conjugated DOX being the major form. The two polyethylene glycol (PEG) conjugates slowly released DOX, andt1/2βfor total DOX from DOX-LNA, PEG-ami-DOX, and PEG-hyd-DOX was 5.79, 10.22, and 15.18 h, respectively. All three conjugates also deposited less DOX into normal organs than did an equivalent dose of free DOX, and theCmaxvalue of free DOX released by DOX- LNA, PEG-ami-DOX, and PEG-hyd-DOX was 32.5, 9.5, and 4.7 μg/g, respectively. Among the conjugates, the compound with an acid-labile bond between PEG and DOX exhibited the lowest free DOX deposition in healthy tissues, which should decrease the systemic toxicity of free DOX while allowing for tumor targeting by PEG.

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Novel Arylimidamides for Treatment of Visceral Leishmaniasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00250-10 ◽

2010 ◽

Vol 54 (6) ◽

pp. 2507-2516 ◽

Cited By ~ 44

Author(s):

Michael Zhuo Wang ◽

Xiaohua Zhu ◽

Anuradha Srivastava ◽

Qiang Liu ◽

J. Mark Sweat ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Leishmania Major ◽

Oral Treatment ◽

Antileishmanial Activity ◽

Repeat Dose ◽

Lead Discovery ◽

Preclinical Development

ABSTRACT Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC50], <1 μM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro and in vivo antileishmanial activities, pharmacokinetics, mutagenicities, and toxicities of two novel AIAs, DB745 and DB766. They were exceptionally active (IC50 ≤ 0.12 μM) against intracellular L. donovani, Leishmania amazonensis, and Leishmania major and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models, L. donovani-infected mice and hamsters. Most notably, DB766 (100 mg/kg of body weight/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen) and had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from 1 to 2 days in mice. In a repeat-dose toxicity study of mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possess good antileishmanial activity and desirable pharmacokinetics and should be considered for further preclinical development as an oral treatment for VL.

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Modification of primary amines to higher order amines reduces in vivo hematological and immunotoxicity of cationic nanocarriers through TLR4 and complement pathways

10.1101/647305 ◽

2019 ◽

Author(s):

Randall Toy ◽

Pallab Pradhan ◽

Vijayeetha Ramesh ◽

Nelson C. Di Paolo ◽

Blake Lash ◽

...

Keyword(s):

Polymeric Nanoparticles ◽

Neutrophil Infiltration ◽

Systemic Toxicity ◽

Innate Immune ◽

Primary Amines ◽

Nucleic Acid Delivery ◽

Toxicity Response ◽

Branched Polyethylenimine

ABSTRACTFor decades, cationic polymer nanoparticles have been investigated for nucleic acid delivery. Despite promising in vitro transfection results, most formulations have failed to translate into the clinic due to significant in vivo toxicity – especially when delivered intravenously. To address this significant problem, we investigated the detailed mechanisms that govern the complex in vivo systemic toxicity response to common polymeric nanoparticles. We determined that the toxicity response is material dependent. For branched polyethylenimine (bPEI) nanoparticles – toxicity is a function of multiple pathophysiological responses – triggering of innate immune sensors, induction of hepatic toxicity, and significant alteration of hematological properties. In contrast, for chitosan-based nanoparticles – systemic toxicity is primarily driven through innate immune activation. We further identified that modification of primary amines to secondary and tertiary amines using the small molecule imidazole-acetic-acid (IAA) ameliorates in vivo toxicity from both nanocarriers by different, material-specific mechanisms related to Toll-like receptor 4 activation (for bPEI) and complement activation driven neutrophil infiltration (for chitosan), respectively. Our results provide a detailed roadmap for evaluating in vivo toxicity of nanocarriers and identifies potential opportunities to reduce toxicity for eventual clinical translation.Graphical Abstract

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BST-236, a Novel Cytarabine Prodrug, Is Safer and As Effective As Cytarabine in In Vivo Leukemia Models

Blood ◽

10.1182/blood-2018-99-112092 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1451-1451 ◽

Cited By ~ 1

Author(s):

Shoshi Tessler ◽

Inbal Mishalian ◽

Ronny Peri-Naor ◽

Stela Gengrinovitch ◽

Raphael Mayer ◽

...

Keyword(s):

Weight Loss ◽

Cell Death ◽

Systemic Toxicity ◽

In Vivo Studies ◽

Leukemia Cells ◽

Severe Toxicity ◽

Unfit Patients ◽

Kinetics Of

Abstract Introduction: Acute myeloid leukemia (AML) is associated with poor outcomes in older and medically unfit patients, largely due to the severe toxicity associated with cytarabine treatment, which precludes the administration of effective cytarabine doses. BST-236 is a prodrug of cytarabine, inactive in its prodrug form and designed to deliver cytarabine to leukemia cells with reduced systemic toxicity, thus to enable delivery of high cytarabine doses to leukemia cells with relative sparing of normal tissues. Results: BST-236 is a conjugate of cytarabine and asparagine (Figure 1). It was demonstrated that BST-236 is inactive as an intact prodrug and that its activity is exerted by release of cytarabine via non-enzymatic hydrolysis. Unlike free cytarabine, the bound cytarabine in BST-236 is not phosphorylated into its active metabolite Ara-CTP and it is protected by the asparagine residue from deamination into its inactive form Ara-U. In vitro studies demonstrate that BST-236 enters into leukemia cells, accompanied by cellular accumulation of free cytarabine, which is released from BST-236 (Figure 2). Like cytarabine, treatment with BST-236 result in induction of cell death of various leukemia cell lines via apoptosis, an activity which is dependent on the human equilibrative nucleoside transporter 1 (hENT1). The in vitro kinetics of BST-236-induced toxicity were found to be delayed compared to administration of free cytarabine, correlating with an observed delayed cellular availability of cytarabine. In vivo studies in mice and dogs demonstrate that BST-236 concentrations in the plasma are dose-proportional, with a prodrug-typical profile and only ~5% of free cytarabine present in the plasma. The maximal tolerated dose of BST-236 was found to be several-fold higher than reported for cytarabine, with mainly hematological effects and no unexpected toxicities. In vivo head-to-head studies in human leukemia mouse models with equimolar doses of cytarabine and BST-236 demonstrate similar efficacy of complete elimination of the leukemia cells in the bone marrow, spleen, and peripheral blood by both molecules (Figure 3A). However, while cytarabine treatment was associated with significant toxicity including weight loss, dramatic reduction in spleen size and number of mouse spleen cells, and delayed normal murine white blood cell recovery, equimolar BST-236 doses enabled spleen and BM recovery with minimal weight loss and no observed clinical signs (Figure 3B, 3C). Summary: in vitro and in vivo studies demonstrate that BST-236 is a prodrug of cytarabine, which enables the delivery of cytarabine to target cells, resulting in elimination of the leukemia with reduced systemic toxicity compared to free cytarabine. The data also suggest that while the mechanism of cell death induced by BST-236 and cytarabine is similar, the observed differential kinetics of the delivery of cytarabine by BST-236 and its metabolism may explain its reduced systemic toxicity. Our nonclinical findings are in line with the clinical results of the BST-236 Phase 1/2 study (ASH 2017 abstract no 893, manuscript in preparation) and suggest that BST-236 may enable delivery of high cytarabine doses to older and medically-unfit patients who currently cannot benefit from an effective cytarabine therapy. This suggestion is to be confirmed by an ongoing Phase 2b study. Disclosures Tessler: Biosight: Employment. Gengrinovitch:Biosight: Employment. Ben Yakar:Biosight: Employment. Peled:Cellect Biotherapeutics Ltd: Consultancy. Flaishon:Biosight: Employment.

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The ROMP: A Powerful Approach to Synthesize Novel pH-Sensitive Nanoparticles for Tumor Therapy

Biomolecules ◽

10.3390/biom9020060 ◽

2019 ◽

Vol 9 (2) ◽

pp. 60 ◽

Cited By ~ 6

Author(s):

Philippe Bertrand ◽

Christophe Blanquart ◽

Valérie Héroguez

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Tumor Therapy ◽

Systemic Toxicity ◽

Oxide Shell ◽

Cancer Drugs ◽

Native Form ◽

In Vivo Models ◽

Anti Cancer

Fast clearance, metabolism, and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects, despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo models of cancer. The specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. This paper deals with the synthesis of the polymeric nanoparticle platform, which was produced by Ring-Opening Metathesis Polymerization (ROMP), able to release anti-cancer drugs in dispersion, such as histone deacetylase inhibitors, into mesothelioma tumors. The core-shell nanoparticles (NPs) have stealth properties due to their poly(ethylene oxide) shell and can be viewed as universal nano-carriers on which any alkyne-modified anti-cancer molecule can be grafted by click chemistry. A cleavage reaction of the chemical bond between NPs and drugs through the contact of NPs with a medium presenting an acidic pH, which is typically a cancer tumor environment or an acidic intracellular compartment, induces a controlled release of the bioactive molecule in its native form. In our in vivo syngeneic model of mesothelioma, a highly selective accumulation of the particles in the tumor was obtained. The release of the drugs led to an 80% reduction of tumor weight for the best compound without toxicity. Our work demonstrates that the use of theranostic nanovectors leads to an optimized delivery of epigenetic inhibitors in tumors, which improves their anti-tumor properties in vivo.

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