scholarly journals Predicting Pharmacokinetics of a Tenofovir Alafenamide Subcutaneous Implant Using Physiologically Based Pharmacokinetic Modelling

2020 ◽  
Vol 64 (8) ◽  
Author(s):  
Rajith K. R. Rajoli ◽  
Zach R. Demkovich ◽  
Charles Flexner ◽  
Andrew Owen ◽  
Marco Siccardi
Keyword(s):  
Peripheral Blood ◽  
Pbpk Model ◽  
Mononuclear Cells ◽  
Plasma Concentrations ◽  
Antiretroviral Drugs ◽  
Release Rates ◽  
Peripheral Blood Mononuclear ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Tenofovir Alafenamide

ABSTRACT Long-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV preexposure prophylaxis (PrEP). Daily drug release requirements were then ascertained by averaging across the dosing interval. A TAF physiologically based pharmacokinetic (PBPK) model was developed and partially qualified against available oral single- and multiple-dose pharmacokinetics. The models were assumed to be qualified when simulated values were within 2-fold of the observed mean. TAF s.c. implants were simulated in five hundred individuals, reporting predicted TAF plasma and tenofovir (TFV) plasma concentrations for various release rates. Intracellular TFV diphosphate (TFV-DP) concentrations were also simulated in peripheral blood cells and cervical and rectal tissues. The minimum dose predicted to achieve intracellular TFV-DP levels above a target concentration of 48 fmol/106 cells for a month was identified. TAF, TFV, and TFV-DP concentrations for release rates between 1.0 and 1.6 mg/day were simulated. The PBPK model indicated that a minimum release of 1.4 mg/day TAF is necessary to achieve TFV-DP concentrations above the identified target in peripheral blood mononuclear cells (PBMCs). TFV-DP cervical and rectal tissue concentrations were predicted to be between 1.5 and 2.0 fmol/106 cells and 0.9 and 1.1 fmol/106 cells, respectively, for release rates between 1.3 and 1.6 mg/day. These simulations provide target minimum doses for LA TAF PrEP in humans. Based on the generated results, multiple implants delivering a total of 1.4 mg/day of TAF subcutaneously could provide protection levels for approximately 6 months to 1 year. This modeling may inform future design of s.c. implants to mitigate adherence issues for effective PrEP applications.

scholarly journals No Evidence for Induction of ABC Transporters in Peripheral Blood Mononuclear Cells in Humans after 14 Days of Efavirenz Treatment

2010 ◽  
Vol 54 (10) ◽  
pp. 4185-4191 ◽  
Author(s):  
Jürgen Burhenne ◽  
Anne-Kathrin Matthée ◽  
Ivana Pasáková ◽  
Claudia Röder ◽  
Tilman Heinrich ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Abc Transporters ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Plasma Concentrations ◽  
Antiretroviral Drugs ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Intracellular Concentrations

ABSTRACT Intracellular concentrations of antiretroviral drugs in peripheral blood mononuclear cells (PBMCs) are an important determinant of therapeutic success. In vitro data indicate that efavirenz induces several ATP-binding cassette (ABC) transporters, and pharmacogenetic studies found an association between ABCB1(C3435T) and efavirenz exposure and between this polymorphism and improved virological outcomes. We therefore aimed to clarify whether efavirenz also induces ABC transporters in vivo in PBMCs and whether intracellular concentrations might be altered after induction. Twelve healthy individuals received multiple oral doses of efavirenz over 14 days (400 mg once daily). Blood samples were drawn on study days 1 (single dose) and 14 (multiple dose), and efavirenz concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Expression of P glycoprotein (P-gp) and of the multidrug resistance-associated proteins 1 and 2 as well as P-gp activity was analyzed in PBMCs on day 1 and day 14 using real-time reverse transcription-PCR (RT-PCR) and rhodamine 123 efflux. Although a clear autoinduction could be confirmed by a significant decrease of efavirenz exposure from day 1 to day 14, efavirenz did not change expression of the ABC transporters or P-gp activity in PBMCs. Moreover, intracellular concentrations of efavirenz were 1.3- to 1.8-fold higher than the corresponding plasma concentrations, and the intracellular/plasma concentration ratio remained constant during the treatment and did not correlate with ABC transporter expression or function. In conclusion, our study confirmed that intracellular concentrations of efavirenz are independent from these efflux transporters and demonstrated for the first time that the transporters are not induced in PBMCs in vivo after 2 weeks of treatment with efavirenz.

scholarly journals Physiologically Based Pharmacokinetic Model of Rifapentine and 25-Desacetyl Rifapentine Disposition in Humans

2016 ◽  
Vol 60 (8) ◽  
pp. 4860-4868
Author(s):  
Todd J. Zurlinden ◽  
Garrett J. Eppers ◽  
Brad Reisfeld
Keyword(s):  
Time Course ◽  
Pbpk Model ◽  
Plasma Concentrations ◽  
Optimal Dose ◽  
Tissue Level ◽  
Pharmacokinetic Data ◽  
Rat Tissues ◽  
Content Type ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

ABSTRACTRifapentine (RPT) is a rifamycin antimycobacterial and, as part of a combination therapy, is indicated for the treatment of pulmonary tuberculosis (TB) caused byMycobacterium tuberculosis. Although the results from a number of studies indicate that rifapentine has the potential to shorten treatment duration and enhance completion rates compared to other rifamycin agents utilized in antituberculosis drug regimens (i.e., regimens 1 to 4), its optimal dose and exposure in humans are unknown. To help inform such an optimization, a physiologically based pharmacokinetic (PBPK) model was developed to predict time course, tissue-specific concentrations of RPT and its active metabolite, 25-desacetyl rifapentine (dRPT), in humans after specified administration schedules for RPT. Starting with the development and verification of a PBPK model for rats, the model was extrapolated and then tested using human pharmacokinetic data. Testing and verification of the models included comparisons of predictions to experimental data in several rat tissues and time course RPT and dRPT plasma concentrations in humans from several single- and repeated-dosing studies. Finally, the model was used to predict RPT concentrations in the lung during the intensive and continuation phases of a current recommended TB treatment regimen. Based on these results, it is anticipated that the PBPK model developed in this study will be useful in evaluating dosing regimens for RPT and for characterizing tissue-level doses that could be predictors of problems related to efficacy or safety.

scholarly journals Intracellular Concentrations of Posaconazole in Different Compartments of Peripheral Blood

2010 ◽  
Vol 54 (7) ◽  
pp. 2928-2931 ◽  
Author(s):  
Fedja Farowski ◽  
Oliver A. Cornely ◽  
Jörg J. Vehreschild ◽  
Pia Hartmann ◽  
Tim Bauer ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Fungal Infections ◽  
Gradient Centrifugation ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Peripheral Blood Mononuclear ◽  
Liquid Chromatography Tandem Mass ◽  
Intracellular Concentrations ◽  
High Concentrations

ABSTRACT Therapeutic drug monitoring (TDM) of antifungal plasma concentrations is increasingly recommended. However, data on antifungal concentrations in the other compartments of the peripheral blood are limited. Hence, we collected 23 blood samples from 14 patients receiving posaconazole for prophylaxis of fungal infections. These samples were separated by double-discontinuous Ficoll-Hypaque density gradient centrifugation. The intracellular posaconazole concentrations of the obtained cells, i.e., the peripheral blood mononuclear cells (PBMCs), polymorphonuclear leukocytes (PMNs), and red blood cells (RBCs), were determined by liquid chromatography-tandem mass spectrometry. The intracellular concentrations of the PBMCs and PMNs were significantly higher than those of surrounding media (P < 0.001). The ratios between the intracellular and extracellular concentrations (C/E) were 22.5 ± 21.2, 7.66 ± 6.50, and 0.09 ± 0.05 for the PBMCs, PMNs, and RBCs, respectively. Posaconazole reaches high concentrations within human PBMCs and PMNs and is, to a lesser extent, present in RBCs. The high intracellular concentrations might contribute to posaconazole efficacy and distribution.

scholarly journals Validation of a UHPLC-MS/MS Method to Quantify Twelve Antiretroviral Drugs within Peripheral Blood Mononuclear Cells from People Living with HIV

2020 ◽  
Vol 14 (1) ◽  
pp. 12
Author(s):  
Amedeo De Nicolò ◽  
Alice Ianniello ◽  
Micol Ferrara ◽  
Valeria Avataneo ◽  
Jessica Cusato ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Multiple Reaction Monitoring ◽  
Antiretroviral Drugs ◽  
Hiv Treatment ◽  
People Living With Hiv ◽  
Peripheral Blood Mononuclear ◽  
Monitoring Method ◽  
Blood Mononuclear Cells

Recently, anti-HIV treatment has achieved high efficacy and tolerability. Nevertheless, few data are available about the intracellular penetration of antiretrovirals, partly due to the technical challenges related to intracellular quantification. This work aimed to validate an ultra-high performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS) method for the simultaneous quantification of maraviroc, nevirapine, rilpivirine, dolutegravir, raltegravir, cobicistat, darunavir, ritonavir, atazanavir, efavirenz, elvitegravir, and etravirine within peripheral blood mononuclear cells (PBMCs) and apply it to samples from patients. PBMCs were isolated by density gradient on cell preparation tubes (CPT). Samples were prepared by addition of internal standards (IS), sonication, centrifugation, and drying. Reconstituted extracts underwent chromatographic separation by reversed phase UHPLC and detection was performed by electrospray ionization and multiple reaction monitoring. Method validation followed FDA and EMA guidelines, showing acceptable accuracy, precision, recovery and IS-normalized matrix effect. The application to 56 samples from patients undergoing antiretroviral treatment provided description of intracellular penetration, showing method eligibility for future studies.

Prediction of dolutegravir pharmacokinetics and dose optimization in neonates via physiologically based pharmacokinetic (PBPK) modelling

2019 ◽  
Vol 75 (3) ◽  
pp. 640-647 ◽  
Author(s):  
Fazila Bunglawala ◽  
Rajith K R Rajoli ◽  
Mark Mirochnick ◽  
Andrew Owen ◽  
Marco Siccardi
Keyword(s):  
Clinical Data ◽  
Pbpk Model ◽  
Simulated Data ◽  
Integrase Inhibitor ◽  
Antiretroviral Drugs ◽  
Pbpk Modelling ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Optimal Dosing ◽  
Physiologically Based

Abstract Background Only a few antiretroviral drugs (ARVs) are recommended for use during the neonatal period and there is a need for more to be approved to increase treatment and prophylaxis strategies. Dolutegravir, a selective integrase inhibitor, has potential for treatment of HIV infection and prophylaxis of transmission in neonates. Objectives To model the pharmacokinetics of dolutegravir in neonates and to simulate a theoretical optimal dosing regimen. Methods The physiologically based pharmacokinetic (PBPK) model was built incorporating the age-related changes observed in neonates. Virtual neonates between 0 and 28 days were simulated. The model was validated against observed clinical data for raltegravir and midazolam in neonates, prior to the prediction of dolutegravir pharmacokinetics. Results Both raltegravir and midazolam passed the criteria for model qualification, with simulated data within 1.8-fold of clinical data. The qualified model predicted the pharmacokinetics for several multidose regimens of dolutegravir. Regimen 6 involved 5 mg doses with a 48 h interval from Day 1–20, increasing to 5 mg once daily on Week 3, yielding AUC and Ctrough values of 37.2 mg·h/L and 1.3 mg/L, respectively. These exposures are consistent with those observed in paediatric patients receiving dolutegravir. Conclusions Dolutegravir pharmacokinetics were successfully simulated in the neonatal PBPK model. The predictions suggest that during the first 3 weeks of life a 5 mg dose administered every 48 h may achieve plasma exposures needed for therapy and prophylaxis.

scholarly journals Antioxidant and Inflammatory Gene Expression Profiles of Bovine Peripheral Blood Mononuclear Cells in Response to Arthrospira platensis before and after LPS Challenge

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 814
Author(s):  
Magdalena Keller ◽  
Elisa Manzocchi ◽  
Deborah Rentsch ◽  
Rosamaria Lugarà ◽  
Katrin Giller
Keyword(s):  
Gene Expression ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Expression Profiles ◽  
Plasma Concentrations ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Anti Inflammatory ◽  
Β Carotene

Oxidative stress and inflammatory diseases are closely related processes that need to be controlled to ensure the desirable high performance of livestock. The microalga spirulina has shown antioxidant and anti-inflammatory properties in monogastric species. To investigate potential beneficial effects in ruminants, we replaced soybean meal (SOY) in the diets of dairy cows and fattening bulls by spirulina (SPI) and analyzed plasma concentrations of antioxidants (β-carotene, α-tocopherol, polyphenols) and serum total antioxidant capacity. Following in vitro stimulation with lipopolysaccharide (LPS), peripheral blood mononuclear cells (PBMCs) were isolated for expression analysis of inflammation- and antioxidant-defense-related genes. Plasma β-carotene concentration was higher in SPI, compared to SOY cows, but did not differ in bulls. Plasma total phenol concentration was significantly higher in SPI, compared to SOY bulls, but not in cows. Stimulation of bovine PBMCs with LPS increased the expression of most cytokines and some antioxidant enzymes. Gene expression of PBMCs derived from SPI animals, compared to SOY animals, hardly differed. Our results indicate that in ruminants, spirulina might not have potent antioxidant and anti-inflammatory properties. Future studies should evaluate the microbial degradation of spirulina and its bioactive compounds in the rumen to provide further data on potential beneficial health effects in ruminants.

scholarly journals Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 908
Author(s):  
Lukas Kovar ◽  
Andreas Weber ◽  
Michael Zemlin ◽  
Yvonne Kohl ◽  
Robert Bals ◽  
...  
Keyword(s):  
Pbpk Model ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Pbpk Modeling ◽  
Pharmacokinetic Studies ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Physiologically Based ◽  
Pediatric Populations

Fentanyl is widely used for analgesia, sedation, and anesthesia both in adult and pediatric populations. Yet, only few pharmacokinetic studies of fentanyl in pediatrics exist as conducting clinical trials in this population is especially challenging. Physiologically-based pharmacokinetic (PBPK) modeling is a mechanistic approach to explore drug pharmacokinetics and allows extrapolation from adult to pediatric populations based on age-related physiological differences. The aim of this study was to develop a PBPK model of fentanyl and norfentanyl for both adult and pediatric populations. The adult PBPK model was established in PK-Sim® using data from 16 clinical studies and was scaled to several pediatric subpopulations. ~93% of the predicted AUClast values in adults and ~88% in pediatrics were within 2-fold of the corresponding value observed. The adult PBPK model predicted a fraction of fentanyl dose metabolized to norfentanyl of ~33% and a fraction excreted in urine of ~7%. In addition, the pediatric PBPK model was used to simulate differences in peak plasma concentrations after bolus injections and short infusions. The novel PBPK models could be helpful to further investigate fentanyl pharmacokinetics in both adult and pediatric populations.

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