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Your search keyword '"Henry E. Pertinez"' showing total 3 results
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3 results on '"Henry E. Pertinez"'

1. Determination of the Pharmacokinetics and Pharmacodynamics of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol in a Cross-Over Cynomolgus Macaque Model of Mycobacterium tuberculosis Infection

Author

Laura Sibley, Andrew D. White, Charlotte Sarfas, Jennie Gullick, Fergus Gleeson, Faye Lanni, Simon Clark, Emma Rayner, Santiago Ferrer-Bazaga, Fatima Ortega-Muro, Laura Alameda, Joaquin Rullas, Veronica Sousa, Marisa Martinez, Inigo Angulo-Barturen, Adolfo Garcia, Juan José Vaquero, Henry E. Pertinez, Geraint Davies, Mike Dennis, Ann Williams, and Sally Sharpe

Subjects
tuberculosis, antibiotics, pharmacokinetics, pharmacodynamics, primates, Pharmacy and materia medica, RS1-441
Abstract

Innovative cross-over study designs were explored in non-human primate (NHP) studies to determine the value of this approach for the evaluation of drug efficacy against tuberculosis (TB). Firstly, the pharmacokinetics (PK) of each of the drugs Isoniazid (H), Rifampicin (R), Pyrazinamide (Z) and Ethambutol (E), that are standardly used for the treatment of tuberculosis, was established in the blood of macaques after oral dosing as a monotherapy or in combination. Two studies were conducted to evaluate the pharmacokinetics and pharmacodynamics of different drug combinations using cross-over designs. The first employed a balanced, three-period Pigeon design with an extra period; this ensured that treatment by period interactions and carry-over could be detected comparing the treatments HR, HZ and HRZ using H37Rv as the challenge strain of Mycobacterium tuberculosis (M. tb). Although the design accounted for considerable variability between animals, the three regimens evaluated could not be distinguished using any of the alternative endpoints assessed. However, the degree of pathology achieved using H37Rv in the model during this study was less than expected. Based on these findings, a second experiment using a classical AB/BA design comparing HE with HRZ was conducted using the M. tb Erdman strain. More extensive pathology was observed, and differences in computerized tomography (CT) scores and bacteriology counts in the lungs were detected, although due to the small group sizes, clearer differences were not distinguished. Type 1 T helper (Th1) cell response profiles were characterized using the IFN-γ ELISPOT assay and revealed differences between drug treatments that corresponded to decreases in disease burden. Therefore, the studies performed support the utility of the NHP model for the determination of PK/PD of TB drugs, although further work is required to optimize the use of cross-over study designs.

Published
2022
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2. Pharmacokinetic-Pharmacodynamic Modeling of Alpha Interferon Response Induced by a Toll-Like 7 Receptor Agonist in Mice

Author

Piet H. van der Graaf, Jonathan Duckworth, Jaiessh Rawal, Henry E. Pertinez, Joost de Jongh, Neil Benson, Hannah M. Jones, and Tamara J. van Steeg

Subjects
Agonist, medicine.drug_class, medicine.medical_treatment, Hepatitis C virus, Alpha interferon, Hepacivirus, Pharmacology, Biology, medicine.disease_cause, Antiviral Agents, Mice, Immune system, Interferon, Cell Line, Tumor, Animals, Outbred Strains, medicine, Animals, Humans, Pharmacology (medical), Receptor, Interferon alfa, Adenine, Interferon-alpha, Hepatitis C, Infectious Diseases, Cytokine, Toll-Like Receptor 7, Models, Animal, Immunology, medicine.drug
Abstract

Recombinant alpha interferon (IFN-α) is used in the treatment of hepatitis C virus (HCV)-infected patients but is not optimal in terms of efficacy or tolerability. Toll-like 7 receptor (TLR-7) agonists stimulate the innate immune system to produce, among other cytokines, IFN-α and are being evaluated as alternative drugs to treat HCV infection. This paper describes the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling to understanding the behavior of a TLR-7 agonist [9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (BHMA)] in mice, using IFN-α as a biomarker. This is the first report of such a PK-PD model, and the conclusions may be of utility in the clinical development of TLR-7 agonists for HCV infection.

Published
2010
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3. Empirical and semi-mechanistic modelling of double-peaked pharmacokinetic profile phenomenon due to gastric emptying

Author

Kayode Ogungbenro, Henry E. Pertinez, and Leon Aarons

Subjects
Levodopa, Time Factors, Gastric emptying, Chemistry, Stomach, Pharmacology toxicology, digestive, oral, and skin physiology, Pharmaceutical Science, Pharmacology, Models, Biological, medicine.anatomical_structure, Pharmacokinetics, Gastric Emptying, Plasma concentration, medicine, Humans, Radionuclide imaging, Effect compartment, Radionuclide Imaging, medicine.drug, Acetaminophen, Research Article
Abstract

Models have been developed to explain double-peaked plasma concentration-time profiles using mechanisms such as variable absorption and enterohepatic recirculation. Interruption of gastric emptying has also been shown to produce double-peaks, and this work proposes models for analysis of such data. In the presence of levodopa, gastric emptying is interrupted at times associated with double-peaks in pharmacokinetic profiles. Data from a simultaneous scintigraphy and paracetamol absorption study with levodopa was obtained, and models with compartments for stomach, intestine, central and peripheral tissue were developed to describe levodopa and paracetamol pharmacokinetics, including the double-peak phenomenon. The empirical model uses two gastric emptying parameter rates which are applied over separate time periods to describe the varying gastric emptying rate. The semi-mechanistic model uses a feedback mechanism acting via an effect compartment to link the plasma concentration of levodopa to the rate of gastric emptying, allowing levodopa pharmacokinetics to vary the rate of gastric emptying and give rise to a multiple-peaked plasma pharmacokinetic profile. The models were applied to plasma levodopa and paracetamol pharmacokinetic data with and without simultaneous analysis of scintigraphy data, in both cases giving a good fit and in the absence of scintigraphy data adequately predicting the stomach profile. For the semi-mechanistic model, the first-order constant governing gastric emptying was shown to switch between fast and slow values at a critical levodopa effect compartment concentration. New models have thus been proposed for analysis of plasma concentration profiles that exhibit double-peak phenomenon and applied successfully to levodopa data.

Published
2014

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