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1.
Clin Pharmacol Ther ; 113(2): 310-320, 2023 02.
Article in English | MEDLINE | ID: mdl-35355254

ABSTRACT

During development of a drug, the requirement of evaluating the proarrhythmic risk and delayed repolarization needs to be fulfilled. Would it be possible to create an alternative to a thorough QT (TQT) study or is there a need to perform a dedicated TQT study? How is an alternative approach generated, what information is available, and which instructions are considered missing today to generate such an approach? This tutorial describes the considerations and path followed to create an early and feasible alternative to a TQT study using experience-based insights from a successful application to the US Food and Drug Administration for GLPG1972, an ADAMTS-5 inhibitor, and discusses the approach used in light of the current guidelines and literature.


Subject(s)
Long QT Syndrome , Humans , Dose-Response Relationship, Drug , Electrocardiography , Long QT Syndrome/chemically induced , Long QT Syndrome/diagnosis , Pharmaceutical Preparations , United States , United States Food and Drug Administration
2.
CPT Pharmacometrics Syst Pharmacol ; 10(11): 1396-1411, 2021 11.
Article in English | MEDLINE | ID: mdl-34708556

ABSTRACT

MET receptor tyrosine kinase inhibitors (TKIs) can restore sensitivity to gefitinib, a TKI targeting epidermal growth factor receptor (EGFR), and promote apoptosis in non-small cell lung cancer (NSCLC) models resistant to gefitinib treatment in vitro and in vivo. Several novel MET inhibitors are currently under study in different phases of development. In this work, a novel tumor-in-host modeling approach, based on the Dynamic Energy Budget (DEB) theory, was proposed and successfully applied to the context of poly-targeted combination therapies. The population DEB-based tumor growth inhibition (TGI) model well-described the effect of gefitinib and of two MET inhibitors, capmatinib and S49076, on both tumor growth and host body weight when administered alone or in combination in an NSCLC mice model involving the gefitinib-resistant tumor line HCC827ER1. The introduction of a synergistic effect in the combination DEB-TGI model allowed to capture gefitinib anticancer activity enhanced by the co-administered MET inhibitor, providing also a quantitative evaluation of the synergistic drug interaction. The model-based comparison of the two MET inhibitors highlighted that S49076 exhibited a greater anticancer effect as well as a greater ability in restoring sensitivity to gefitinib than the competitor capmatinib. In summary, the DEB-based tumor-in-host framework proposed here can be applied to routine combination xenograft experiments, providing an assessment of drug interactions and contributing to rank investigated compounds and to select the optimal combinations, based on both tumor and host body weight dynamics. Thus, the combination tumor-in-host DEB-TGI model can be considered a useful tool in the preclinical development and a significant advance toward better characterization of combination therapies.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Drug Resistance, Neoplasm , ErbB Receptors/metabolism , Gefitinib/pharmacology , Gefitinib/therapeutic use , Heterografts , Humans , Lung Neoplasms/drug therapy , Mice , Xenograft Model Antitumor Assays
3.
Environ Int ; 120: 584-592, 2018 11.
Article in English | MEDLINE | ID: mdl-30212803

ABSTRACT

Bisphenol S (BPS) is widely used as a substitute for Bisphenol A in consumer products. Despite its potential endocrine-disrupting effects and widespread exposure, toxicokinetic data, particularly during the critical period of pregnancy, are not available for BPS. The objectives of our study were to evaluate the mechanisms determining fetal exposure to BPS and to BPS glucuronide (BPSG) and to compare them with those prevailing for BPA. The disposition of BPS and BPSG was evaluated in the materno-fetal unit of the catheterized pregnant ewe model, following intravenous administrations of BPS and BPSG to mothers and their fetuses. In a second experiment, the rate of BPS accumulation in the fetal compartment was determined under steady-state conditions after repeated intravenous BPS administrations to the mother. In the maternal compartment, BPS was mainly metabolized into BPSG and totally eliminated in urine. Only 0.40% of the maternal dose was transferred to the fetus. However, once in the fetal compartment, 26% of the fetal dose was rapidly eliminated through placental transfer, while 46% of BPS was metabolized into BPSG which remained trapped in the fetal compartment. Thus, the elimination of BPSG from the fetal compartment required its back-conversion into bioactive BPS, leading to an 87% enhancement of the fetal BPS exposure. Our findings demonstrate that, despite the low materno-fetal placental transfer of BPS, this substitute for BPA is able to accumulate in the fetal compartment after repeated maternal exposure, leading to chronic fetal exposure to BPS in a range of concentrations similar to those of BPA.


Subject(s)
Benzhydryl Compounds/pharmacokinetics , Endocrine Disruptors/pharmacokinetics , Phenols/pharmacokinetics , Placenta/metabolism , Sulfones/pharmacokinetics , Animals , Benzhydryl Compounds/toxicity , Endocrine Disruptors/toxicity , Female , Fetus/metabolism , Glucuronides/metabolism , Humans , Male , Maternal-Fetal Exchange , Phenols/toxicity , Pregnancy , Sheep , Sulfones/toxicity , Toxicokinetics
4.
Sci Rep ; 7(1): 15330, 2017 11 10.
Article in English | MEDLINE | ID: mdl-29127374

ABSTRACT

Bisphenol A (BPA) risk assessment is hampered by the difficulty of determining the extent of internal exposure in the human fetus and uncertainties regarding BPA toxicokinetics (TK) in the maternal-fetal unit. A feto-maternal TK model describing BPA and BPA glucuronide (BPAG) disposition in sheep was humanized, using human TK data obtained after d6-BPA administration on a cookie, to predict BPA and BPAG kinetics in the human mother-fetus unit. Validation of the model predictions included the assessed dose proportionality of BPA and BPAG disposition and the similarity between the simulated and measured time courses of BPA and BPAG in fetal rhesus monkeys after BPA maternal dosing. The model predicted fluctuations in fetal BPA concentrations associated with typical maternal exposure to BPA through the diet, with similar trough (0.011 ng/L vs 0.014 ng/L) and lower peak BPA concentrations (0.023 ng/L vs 0.14 ng/L) in fetal than in maternal plasma. BPAG concentrations in fetal plasma were predicted to increase over time to reach a steady value (29 ng/L) reflecting the cumulative BPA dose received by the fetus. Model-predicted BPAG concentrations in fetal plasma are consistent with reported levels in human cord blood that may be considered as relevant markers of the BPA dose entering blood throughout fetal life.


Subject(s)
Benzhydryl Compounds/toxicity , Fetus/metabolism , Glucuronides/toxicity , Maternal Exposure/adverse effects , Models, Biological , Phenols/toxicity , Prenatal Exposure Delayed Effects/metabolism , Animals , Female , Fetus/pathology , Humans , Pregnancy , Prenatal Exposure Delayed Effects/pathology , Sheep , Toxicokinetics
5.
Food Chem Toxicol ; 93: 82-8, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27090580

ABSTRACT

The gavage route is often used for the toxicological evaluation of food contaminants. This route does not take into account absorption of the toxicants through the buccal mucosa, as evidenced in dogs for bisphenol A (BPA). Our goal was to determine the functional significance of buccal BPA absorption during dietary exposure. Four ewes received BPA by nasogastric gavage (100 mg/kg) and through food pellets (10 mg/kg), 13 days apart. The time course of serum concentrations of BPA and its main metabolite BPA-G was submitted to non-compartmental analysis. The dietary route led to 3-fold higher bioavailability as compared to gavage. The ratio of BPA-G to BPA concentrations varied greatly over time after the food administration, but not after gavage, suggesting a delayed metabolism of BPA after dietary exposure. The maximum entrance rate of BPA in the systemic circulation, determined by deconvolution analysis, was much higher after dietary administration than after gavage and a biphasic pattern of BPA entry was observed in 3 of the 4 ewes. Our results evidenced a dual mechanism of BPA absorption (buccal and digestive) after dietary exposure and highlight the necessity to take buccal absorption into account when evaluating food contaminants.


Subject(s)
Benzhydryl Compounds/pharmacokinetics , Diet , Free Radical Scavengers/pharmacokinetics , Mouth Mucosa/metabolism , Oral Mucosal Absorption/drug effects , Phenols/pharmacokinetics , Animals , Benzhydryl Compounds/pharmacology , Dogs , Free Radical Scavengers/pharmacology , Mouth Mucosa/drug effects , Phenols/pharmacology , Sheep , Tissue Distribution
6.
Environ Int ; 86: 52-9, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26540084

ABSTRACT

Previous studies in experimental animals have shown that maternal exposure to bisphenol A (BPA) during late pregnancy leads to high plasma concentrations of BPA glucuronide (BPAG) in fetus compared to mother due to the inability of BPAG to cross the placental barrier. A recent in vitro study has reported that BPAG can exert adipogenic effect underlining the need for characterization of the fetal disposition of BPAG. Experiments were conducted in chronically catheterized fetal sheep to determine the contribution of BPAG hydrolysis to BPA to the elimination of BPAG from the fetal compartment and its resulting effect on the overall fetal exposure to free BPA. Serial sampling of fetal arterial blood, amniotic fluid, maternal venous blood and urine was performed following separate single doses of BPA and BPAG administered intravenously to eight fetal/maternal pairs after cesarean section, and repeated BPAG doses given to two fetal sheep. On average 67% of the BPA entering the fetal circulation was rapidly eliminated through fetal to maternal clearance, with a very short half-life (20 min), while the remaining fraction (24%) was glucuronoconjugated. BPA conjugation-deconjugation cycling was responsible for a 43% increase of the overall fetal exposure to free BPA. A very specific pattern of fetal exposure to free BPA was observed due to its highly increased persistence with a hydrolysis-dependent plasma terminal free BPA half-life of several tens of hours. These findings suggest that although the high fetal to maternal clearance of free BPA protects the fetus from transient increases in free BPA plasma concentrations associated with maternal BPA intake, low but sustained basal free BPA concentrations are maintained in the fetus through BPA conjugation-deconjugation cycling. The potential health implications of these low but sustained basal concentrations of free BPA in fetal plasma should be addressed especially when considering time-dependent effects.


Subject(s)
Benzhydryl Compounds/blood , Fetus/metabolism , Glucuronides/blood , Maternal Exposure , Maternal-Fetal Exchange , Phenols/blood , Sheep, Domestic/blood , Animals , Female , Half-Life , Humans , Kinetics , Male , Placenta/metabolism , Pregnancy , Sheep, Domestic/embryology
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