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Your search keyword '"Siccardi, Marco"' showing total 21 results
Start Over Author "Siccardi, Marco" Publisher american society for microbiology
21 results on '"Siccardi, Marco"'

2. Analysis of clinical drug-drug interaction data to predict uncharacterized interaction magnitudes between antiretroviral drugs and co-medications

Author

Stader, Felix, Kinvig, Hannah, Battegay, Manuel, Khoo, Saye, Owen, Andrew, Siccardi, Marco, and Marzolini, Catia

Subjects
virus diseases
Abstract

Despite their high potential for drug-drug interactions (DDI), clinical DDI studies of antiretroviral drugs (ARVs) are often lacking, because the full range of potential interactions cannot feasibly or pragmatically be studied, with some high-risk DDI studies also being ethically difficult to undertake. Thus, a robust method to screen and to predict the likelihood of DDIs is required. We developed a method to predict DDIs based on two parameters: the degree of metabolism by specific enzymes, such as CYP3A, and the strength of an inhibitor or inducer. These parameters were derived from existing studies utilizing paradigm substrates, inducers, and inhibitors of CYP3A to assess the predictive performance of this method by verifying predicted magnitudes of changes in drug exposure against clinical DDI studies involving ARVs. The derived parameters were consistent with the FDA classification of sensitive CYP3A substrates and the strength of CYP3A inhibitors and inducers. Characterized DDI magnitudes (; n; = 68) between ARVs and comedications were successfully quantified, meaning 53%, 85%, and 98% of the predictions were within 1.25-fold (0.80 to 1.25), 1.5-fold (0.66 to 1.48), and 2-fold (0.66 to 1.94) of the observed clinical data. In addition, the method identifies CYP3A substrates likely to be highly or, conversely, minimally impacted by CYP3A inhibitors or inducers, thus categorizing the magnitude of DDIs. The developed effective and robust method has the potential to support a more rational identification of dose adjustment to overcome DDIs, being particularly relevant in an HIV setting, given the treatment's complexity, high DDI risk, and limited guidance on the management of DDIs.

Published
2018
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5. Simulating Intestinal Transporter and Enzyme Activity in a Physiologically Based Pharmacokinetic Model for Tenofovir Disoproxil Fumarate

Author

Moss, Darren M., primary, Domanico, Paul, additional, Watkins, Melynda, additional, Park, Seonghee, additional, Randolph, Ryan, additional, Wring, Steve, additional, Rajoli, Rajith Kumar Reddy, additional, Hobson, James, additional, Rannard, Steve, additional, Siccardi, Marco, additional, and Owen, Andrew, additional

Published
2017
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12. Pharmacokinetics of Lamivudine and Lamivudine-Triphosphate after Administration of 300 Milligrams and 150 Milligrams Once Daily to Healthy Volunteers: Results of the ENCORE 2 Study

Author

Else, Laura J., primary, Jackson, Akil, additional, Puls, Rebekah, additional, Hill, Andrew, additional, Fahey, Paul, additional, Lin, Enmoore, additional, Amara, Alieu, additional, Siccardi, Marco, additional, Watson, Victoria, additional, Tjia, John, additional, Emery, Sean, additional, Khoo, Saye, additional, Back, David J., additional, and Boffito, Marta, additional

Published
2012
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15. Population Pharmacokinetic Modeling of the Association between 63396C→T Pregnane X Receptor Polymorphism and Unboosted Atazanavir Clearance

Author

Schipani, Alessandro, primary, Siccardi, Marco, additional, D'Avolio, Antonio, additional, Baietto, Lorena, additional, Simiele, Marco, additional, Bonora, Stefano, additional, Rodríguez Novoa, Sonia, additional, Cuenca, Lorena, additional, Soriano, Vincent, additional, Chierakul, Nitipatana, additional, Saguenwong, Natpratou, additional, Chuchuttaworn, Charoen, additional, Hoskins, Janelle M., additional, Dvorak, Anne M., additional, McLeod, Howard L., additional, Davies, Gerry, additional, Khoo, Saye, additional, Back, David J., additional, Di Perri, Giovanni, additional, and Owen, Andrew, additional

Published
2010
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16. Development, Validation, and Routine Application of a High-Performance Liquid Chromatography Method Coupled with a Single Mass Detector for Quantification of Itraconazole, Voriconazole, and Posaconazole in Human Plasma

Author

Baietto, Lorena, primary, D'Avolio, Antonio, additional, Ventimiglia, Giusi, additional, De Rosa, Francesco Giuseppe, additional, Siccardi, Marco, additional, Simiele, Marco, additional, Sciandra, Mauro, additional, and Di Perri, Giovanni, additional

Published
2010
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18. Tipranavir (TPV) Genotypic Inhibitory Quotient Predicts Virological Response at 48 Weeks to TPV-Based Salvage Regimens

Author

de Requena, Daniel Gonzalez, primary, Bonora, Stefano, additional, Calcagno, Andrea, additional, D'Avolio, Antonio, additional, Siccardi, Marco, additional, Fontana, Silvia, additional, Milia, Maria Grazia, additional, Sciandra, Mauro, additional, Garazzino, Silvia, additional, Di Garbo, Antonio, additional, Baietto, Lorena, additional, Trentini, Laura, additional, and Di Perri, Giovanni, additional

Published
2008
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19. Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico, In Vitro, and In Vivo Investigation.

Author

Curley P, Rajoli RK, Moss DM, Liptrott NJ, Letendre S, Owen A, and Siccardi M

Subjects
Administration, Oral, Alkynes, Animals, Anti-HIV Agents blood, Anti-HIV Agents cerebrospinal fluid, Benzoxazines blood, Benzoxazines cerebrospinal fluid, Computer Simulation, Cyclopropanes, Drug Administration Schedule, Drug Dosage Calculations, Humans, Male, Nerve Tissue Proteins metabolism, Protein Binding, Rats, Rats, Wistar, Tissue Distribution, Anti-HIV Agents pharmacokinetics, Benzoxazines pharmacokinetics, Brain metabolism, Models, Statistical
Abstract

Adequate concentrations of efavirenz in the central nervous system (CNS) are necessary to suppress viral replication, but high concentrations may increase the likelihood of CNS adverse drug reactions. The aim of this investigation was to evaluate the efavirenz distribution in the cerebrospinal fluid (CSF) and the brain by using a physiologically based pharmacokinetic (PBPK) simulation for comparison with rodent and human data. The efavirenz CNS distribution was calculated using a permeability-limited model on a virtual cohort of 100 patients receiving efavirenz (600 mg once daily). Simulation data were then compared with human data from the literature and with rodent data. Wistar rats were administered efavirenz (10 mg kg of body weight -1 ) once daily over 5 weeks. Plasma and brain tissue were collected for analysis via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The median maximum concentrations of drug (C max ) were predicted to be 3,184 ng ml -1 (interquartile range [IQR], 2,219 to 4,851 ng ml -1 ), 49.9 ng ml -1 (IQR, 36.6 to 69.7 ng ml -1 ), and 50,343 ng ml -1 (IQR, 38,351 to 65,799 ng ml -1 ) in plasma, CSF, and brain tissue, respectively, giving a tissue-to-plasma ratio of 15.8. Following 5 weeks of oral dosing of efavirenz (10 mg kg -1 ), the median plasma and brain tissue concentrations in rats were 69.7 ng ml -1 (IQR, 44.9 to 130.6 ng ml -1 ) and 702.9 ng ml -1 (IQR, 475.5 to 1,018.0 ng ml -1 ), respectively, and the median tissue-to-plasma ratio was 9.5 (IQR, 7.0 to 10.9). Although it is useful, measurement of CSF concentrations may give an underestimation of the penetration of antiretrovirals into the brain. The limitations associated with obtaining tissue biopsy specimens and paired plasma and CSF samples from patients make PBPK modeling an attractive tool for probing drug distribution., (Copyright © 2016 American Society for Microbiology.)

Published
2016
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21. Population pharmacokinetic modeling of the association between 63396C->T pregnane X receptor polymorphism and unboosted atazanavir clearance.

Author

Schipani A, Siccardi M, D'Avolio A, Baietto L, Simiele M, Bonora S, Rodríguez Novoa S, Cuenca L, Soriano V, Chierakul N, Saguenwong N, Chuchuttaworn C, Hoskins JM, Dvorak AM, McLeod HL, Davies G, Khoo S, Back DJ, Di Perri G, and Owen A

Subjects
ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Adult, Aged, Atazanavir Sulfate, Circadian Rhythm, Cytochrome P-450 CYP3A genetics, Female, Gene Frequency, Genotype, HIV Infections drug therapy, HIV Infections genetics, Humans, Liver-Specific Organic Anion Transporter 1, Male, Middle Aged, Oligopeptides therapeutic use, Organic Anion Transporters genetics, Pregnane X Receptor, Pyridines therapeutic use, Young Adult, Oligopeptides pharmacokinetics, Polymorphism, Single Nucleotide genetics, Pyridines pharmacokinetics, Receptors, Steroid genetics
Abstract

Atazanavir (ATV) plasma concentrations are influenced by CYP3A4 and ABCB1, which are regulated by the pregnane X receptor (PXR; NR1I2). PXR expression is correlated with CYP3A4 in liver in the absence of enzyme inducers. The PXR single nucleotide polymorphism (SNP) 63396C→T (rs2472677) alters PXR expression and CYP3A4 activity in vitro, and we previously showed an association of this polymorphism with unboosted ATV plasma concentrations. The aim of this study was to develop a population pharmacokinetic analysis to quantify the impact of 63396C→T and diurnal variation on ATV clearance. A population analysis was performed with 323 plasma samples from 182 randomly selected patients receiving unboosted ATV. Two hundred fifty-nine of the blood samples were collected at random time points, and 11 patients had a full concentration-time profile at steady state. Nonlinear mixed effects modeling was applied to explore the effects of PXR 63396C→T, patient demographics, and diurnal variation. A one-compartment model with first-order absorption and lag time best described the data. Population clearance was 19.7 liters/h with interpatient variability or coefficient of variation (CV) of 21.5%. Homozygosity for the T allele for PXR 63396 was associated with a 17.0% higher clearance that was statistically significant. Evening dosing was associated with 34% higher bioavailability than morning dosing. Patient demographic factors had no effect on ATV clearance. These data show an association of PXR 63396C→T and diurnal variation on unboosted ATV clearance. The association is likely to be mediated through an effect on hepatic PXR expression and therefore expression of its target genes (e.g., CYP3A4, SLCO1B1, and ABCB1), which are known to be involved in ATV clearance.

Published
2010
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