Is it important to correct apparent drug tissue concentrations for blood contamination in the dog?

Giudicelli, Christine; Dricot, Eric; Moati, F.; Strolin‐Benedetti, M.; Giudicelli, Jean‐François

doi:10.1111/j.1472-8206.2004.00246.x

Cited by 12 publications

(11 citation statements)

References 6 publications

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“…Additionally, others [17] have suggested that no correction of apparent drug tissue concentrations for blood contamination was necessary for brain tissue, unless the brain-to-plasma ratio is below 0.1. The pharmacokinetic parameters Tmax (the time to reach peak concentration) and Cmax (the peak concentration) were thus calculated accordingly by non-compartmental analysis of mean concentration time data with WinNonlin (version 5.2, Pharsight, Mountain View, CA).…”

Section: Methodsmentioning

confidence: 99%

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Verreault

Schmitt

Goldwirt

et al. 2016

Clinical Cancer Research

101

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Rationale p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM. Methods We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCLs), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models. Results MDM2-amplified PDCLs were 44 times more sensitive than TP53 mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 μM vs 21.9 μM). MDM4 amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 μM), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 μM). In MDM2-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood-brain and the blood-tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival. Conclusion These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2 amplified models suggests that additional markers of response to MDM2 inhibitors must be identified.

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Section: Methodsmentioning

confidence: 99%

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Verreault

Schmitt

Goldwirt

et al. 2016

Clinical Cancer Research

101

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“…One potential confounding factor associated with the tissue/blood concentration ratio is the possibility of residual blood trapped in the tumor. However, because temsirolimus tissue concentration is greater than its ng/g blood concentration (mean tissue concentration of 220 ng/g versus mean whole blood concentration of 174 ng/mL) and its volume of distribution (533-699 L) is much greater than blood volume (6 L), the correction of tissue concentration for blood contamination is theoretically unnecessary (16). Correlative analyses of the tumor tissue (pending) for the inhibition of the key regulators (p70 S6 kinase, eIF4E, PTEN, etc.)…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Tumor Distribution Characteristics of Temsirolimus in Patients with Recurrent Malignant Glioma

Kuhn

Chang

Wen

et al. 2007

Clinical Cancer Research

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Purpose: To characterize the pharmacokinetics of temsirolimus and its major metabolite, sirolimus, in patients receiving enzyme-inducing antiepileptic drugs (EIAED) compared with patients receiving non-EIAEDs. An additional objective was to determine whether concentrations of temsirolimus or sirolimus were achieved in brain tumor tissue. Experimental Design: Patients with recurrent malignant gliomas not receiving EIAEDs initially received temsirolimus weekly at a dose of 250 mg i.v. The dose was subsequently reduced to 170 mg due to intolerable side effects. For patients taking EIAEDs, the starting dose of temsirolimus was 250 mg with standard dose escalation until the maximal tolerated dose was established. Ten whole blood samples were obtained over a period of 24 h after administration of temsirolimus for pharmacokinetic assessments. Patients eligible for cytoreductive surgery received temsirolimus before tumor resection.Whole blood and tumor tissue were obtained for analysis.Results: Significant differences in the pharmacokinetic variables for temsirolimus and sirolimus were observed between the two patient groups at a comparable dose level of 250 mg. For patients receiving EIAEDs, the systemic exposure to temsirolimus was lower by 1.5-fold. Likewise, peak concentrations and exposure to sirolimus were lower by 2-fold. Measurable concentrations of temsirolimus and sirolimus were observed in brain tumor specimens. The average tissue to whole blood ratio for temsirolimus was 1.43 and 0.84 for sirolimus. Conclusions: Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of patients at their respective dose levels. Correlative analyses of the tissue for the inhibition of the key regulators (p70 S6 kinase and 4E-binding protein 1) of mammalian target of rapamycin are necessary to define the therapeutic significance of the altered exposure to temsirolimus.Temsirolimus Torisel) is an ester of sirolimus (rapamycin). Both temsirolimus and its major metabolite, sirolimus, bind with equipotency to the cytosolic protein FKBP-12 (1). This protein-drug complex inhibits mammalian target of rapamycin -mediated phosphorylation of p70 S6 kinase and the eukaryotic initiation factor 4E-binding protein 1, which are involved in the regulation of key molecules involved in cell cycle control and apoptosis (2, 3). Phosphatidylinositol 3-kinase and AKT are the upstream key regulators of the phosphorylation and activation of mammalian target of

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“…Blood contamination is another consideration as a source of variability in tissue concentrations, particularly for FNA samples, for which forceful suction is applied to a small yet very-well-perfused mass (21,27,28). In a study that investigated the error associated with blood contamination in measuring liver tissue drug concentrations in dogs, measurements were slightly underestimated if they were not corrected for residual blood (28).…”

Section: Discussionmentioning

confidence: 99%

“…In a study that investigated the error associated with blood contamination in measuring liver tissue drug concentrations in dogs, measurements were slightly underestimated if they were not corrected for residual blood (28). Correction of tissue concentrations for blood contamination is less of a concern for compounds with high tissue-to-plasma ratios, such as paritaprevir and ritonavir.…”

Section: Discussionmentioning

confidence: 99%

Paritaprevir and Ritonavir Liver Concentrations in Rats as Assessed by Different Liver Sampling Techniques

Venuto

Markatou

Woolwine-Cunningham

et al. 2017

Antimicrob Agents Chemother

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The liver is crucial to pharmacology, yet substantial knowledge gaps exist in the understanding of its basic pharmacologic processes. An improved understanding for humans requires reliable and reproducible liver sampling methods. We compared liver concentrations of paritaprevir and ritonavir in rats by using samples collected by fine-needle aspiration (FNA), core needle biopsy (CNB), and surgical resection. Thirteen Sprague-Dawley rats were evaluated, nine of which received paritaprevir/ritonavir at 30/20 mg/kg of body weight by oral gavage daily for 4 or 5 days. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry on samples collected via FNA (21G needle) with 1, 3, or 5 passes (FNA 1 , FNA 3 , and FNA 5 ); via CNB (16G needle); and via surgical resection. Drug concentrations in plasma were also assessed. Analyses included noncompartmental pharmacokinetic analysis and use of Bland-Altman techniques. All liver tissue samples had higher paritaprevir and ritonavir concentrations than those in plasma. Resected samples, considered the benchmark measure, resulted in estimations of the highest values for the pharmacokinetic parameters of exposure (maximum concentration of drug in serum [C max ] and area under the concentration-time curve from 0 to 24 h [AUC 0 -24 ]) for paritaprevir and ritonavir. Bland-Altman analyses showed that the best agreement occurred between tissue resection and CNB, with 15% bias, followed by FNA 3 and FNA 5 , with 18% bias, and FNA 1 and FNA 3 , with a 22% bias for paritaprevir. Paritaprevir and ritonavir are highly concentrated in rat liver. Further research is needed to validate FNA sampling for humans, with the possible derivation and application of correction factors for drug concentration measurements.KEYWORDS hepatocyte isolation, liver biopsy, liver drug concentration, liver fineneedle aspiration T he liver is the primary site of drug metabolism, and hepatocytes are principally responsible for hepatic metabolic capacity as a result of the abundance of phase I and II drug-metabolizing enzymes and transporters (1-3). Due to the liver's fundamental role in drug metabolism, understanding the relationship between intrahepatic and plasma drug concentrations is potentially important for predicting drug-drug interactions, hepatotoxicity, and therapeutic efficacy. To date, most methods used to determine intrahepatic drug concentrations have relied on in vitro techniques (e.g., microsomal experiments and sandwich cultures) that work well as isolated systems. Inaccuracies develop, however, when these models are used for other purposes, as they

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Is it important to correct apparent drug tissue concentrations for blood contamination in the dog?

Cited by 12 publications

References 6 publications

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Pharmacokinetic and Tumor Distribution Characteristics of Temsirolimus in Patients with Recurrent Malignant Glioma

Paritaprevir and Ritonavir Liver Concentrations in Rats as Assessed by Different Liver Sampling Techniques

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