ORCID Profile
0000-0001-8225-145X
Current Organisation
University of South Australia
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Publisher: Frontiers Media SA
Date: 20-09-2021
Abstract: Pregnancy-induced changes in plasma pharmacokinetics of many antiretrovirals (ARV) are well-established. Current knowledge about the extent of ARV exposure in lymphoid tissues of pregnant women and within the fetal compartment is limited due to their inaccessibility. Subtherapeutic ARV concentrations in HIV reservoirs like lymphoid tissues during pregnancy may constitute a barrier to adequate virological suppression and increase the risk of mother-to-child transmission (MTCT). The present study describes the pharmacokinetics of three ARVs (efavirenz, dolutegravir, and rilpivirine) in lymphoid tissues and fetal plasma during pregnancy using materno-fetal physiologically-based pharmacokinetic models (m-f-PBPK). Lymphatic and fetal compartments were integrated into our previously validated adult PBPK model. Physiological and drug disposition processes were described using ordinary differential equations. For each drug, virtual pregnant women ( n = 50 per simulation) received the standard dose during the third trimester. Essential pharmacokinetic parameters, including Cmax, Cmin, and AUC (0–24), were computed from the concentration-time data at steady state for lymph and fetal plasma. Models were qualified by comparison of predictions with published clinical data, the acceptance threshold being an absolute average fold-error (AAFE) within 2.0. AAFE for all model predictions was within 1.08–1.99 for all three drugs. Maternal lymph concentration 24 h after dose exceeded the reported minimum effective concentration (MEC) for efavirenz (11,514 vs. 800 ng/ml) and rilpivirine (118.8 vs. 50 ng/ml), but was substantially lower for dolutegravir (16.96 vs. 300 ng/ml). In addition, predicted maternal lymph-to-plasma AUC ratios vary considerably (6.431—efavirenz, 0.016—dolutegravir, 1.717—rilpivirine). Furthermore, fetal plasma-to-maternal plasma AUC ratios were 0.59 for efavirenz, 0.78 for dolutegravir, and 0.57 for rilpivirine. Compared with rilpivirine (0 h), longer dose forgiveness was observed for dolutegravir in fetal plasma (42 h), and for efavirenz in maternal lymph (12 h). The predicted low lymphoid tissue penetration of dolutegravir appears to be significantly offset by its extended dose forgiveness and adequate fetal compartment exposure. Hence, it is unlikely to be a predictor of maternal virological failure or MTCT risks. Predictions from our m-f-PBPK models align with recommendations of no dose adjustment despite moderate changes in exposure during pregnancy for these drugs. This is an important new application of PBPK modeling to evaluate the adequacy of drug exposure in otherwise inaccessible compartments.
Publisher: Frontiers Media SA
Date: 08-09-2022
Abstract: The nitazoxanide plus atazanavir/ritonavir for COVID-19 (NACOVID) trial investigated the efficacy and safety of repurposed nitazoxanide combined with atazanavir/ritonavir for COVID-19. This is a pilot, randomized, open-label multicenter trial conducted in Nigeria. Mild to moderate COVID-19 patients were randomly assigned to receive standard of care (SoC) or SoC plus a 14-day course of nitazoxanide (1,000 mg b.i.d.) and atazanavir/ritonavir (300/100 mg od) and followed through day 28. Study endpoints included time to clinical improvement, SARS-CoV-2 viral load change, and time to complete symptom resolution. Safety and pharmacokinetics were also evaluated ( ClinicalTrials.gov ID: NCT04459286). There was no difference in time to clinical improvement between the SoC ( n = 26) and SoC plus intervention arms ( n = 31 Cox proportional hazards regression analysis adjusted hazard ratio, aHR = 0.898, 95% CI: 0.492–1.638, p = 0.725). No difference was observed in the pattern of saliva SARS-CoV-2 viral load changes from days 2–28 in the 35% of patients with detectable virus at baseline (20/57) (aHR = 0.948, 95% CI: 0.341–2.636, p = 0.919). There was no significant difference in time to complete symptom resolution (aHR = 0.535, 95% CI: 0.251–1.140, p = 0.105). Atazanavir/ritonavir increased tizoxanide plasma exposure by 68% and median trough plasma concentration was 1,546 ng/ml (95% CI: 797–2,557), above its putative EC 90 in 54% of patients. Tizoxanide was undetectable in saliva. Nitazoxanide co-administered with atazanavir/ritonavir was safe but not better than standard of care in treating COVID-19. These findings should be interpreted in the context of incomplete enrollment (64%) and the limited number of patients with detectable SARS-CoV-2 in saliva at baseline in this trial. [ t2/show/NCT04459286 ], identifier [NCT04459286].
Publisher: Public Library of Science (PLoS)
Date: 25-09-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2022
DOI: 10.1097/FTD.0000000000000929
Abstract: Dolutegravir is currently the preferred component of first-line antiretroviral therapy. To facilitate clinical pharmacology studies in key populations, quantitative analytical methods compatible with micros ling and adaptable to resource-limited settings are desirable. The authors developed and validated a liquid chromatography–ultraviolet detection method to quantify dolutegravir in dried blood spots (DBS). Calibration standards and quality control s les were prepared by spotting 50 μL of dolutegravir-spiked whole blood on each circle of DBS cards. Three spots (two 6-mm punches/spot) were extracted with methanol. Chromatographic separation was achieved with gradient elution of acetonitrile otassium phosphate monobasic buffer (pH 5) on a reverse-phase C18 column (flow rate, 1 mL/min) using pioglitazone as the internal standard. UV detection was performed at 260 nm. In the clinical pharmacokinetic study, DBS from finger prick was collected from participants (n = 10) at 8 time points over 12 hours postdosing, with paired plasma at 1 and 12 hours. The method was used to quantify dolutegravir, estimating pharmacokinetic parameters. Agreement between DBS and plasma concentrations was evaluated using linearity and Bland–Altman plots. The method was validated over the concentration range of 0.4–10 mcg/mL, accuracy was 102.4%–114.8%, and precision was 3.4%–14.7%. The mean recovery was 42.3% (%CV: 8.3). The mean (±SD) dolutegravir concentration in DBS was 37.5% (±3.8%) lower than that in the plasma. DBS-derived and measured plasma concentrations showed strong correlation with linearity (R 2 = 0.9804) and Bland–Altman plots. Means (%CV) of area under curve, C max , and C 24 from the DBS-derived plasma concentration were 37.8 (23.2) mcg·h/mL, 2.7 (24.7) mcg/mL, and 1.34 (31.6) mcg/mL, respectively. The application of this simple, accurate, and precise method will expand opportunities for clinical assessment of dolutegravir in resource-limited settings.
Publisher: AIP Publishing
Date: 2021
DOI: 10.1063/5.0019152
Abstract: The present study scrutinizes premixed flame dynamics in micro-channels, thereby shedding light on advanced miniature micro-combustion technologies. While equidiffusive burning (when the Lewis number Le = 1) is a conventional approach adopted in numerous theoretical studies, real premixed flames are typically non-equidiffusive (Le ≠ 1), which leads to intriguing effects, such as diffusional-thermal instability. An equidiffusive computational study [V. Akkerman et al., Combust. Flame 145, 675–687 (2006)] reported regular oscillations of premixed flames spreading in channels having nonslip walls and open extremes. Here, this investigation is extended to non-equidiffusive combustion in order to systematically study the impact of the Lewis number on the flame in this geometry. The analysis is performed by means of computational simulations of the reacting flow equations with fully-compressible hydrodynamics and one-step Arrhenius chemical kinetics in channels with adiabatic and isothermal walls. In the adiabatic channels, which are the main case of study, it is found that the flames oscillate at low Lewis numbers, with the oscillation frequency decreasing with Le, while for the Le & 1 flames, a tendency to steady flame propagation is observed. The oscillation parameters also depend on the thermal expansion ratio and the channel width, although the impacts are rather quantitative than qualitative. The analysis is subsequently extended to the isothermal channels. It is shown that the role of heat losses to the walls is important and may potentially dominate over that of the Lewis number. At the same time, the impact of Le on burning in the isothermal channels is qualitatively weaker than that in the adiabatic channels.
Publisher: Elsevier BV
Date: 06-2009
Publisher: California Digital Library (CDL)
Date: 22-01-2021
DOI: 10.21426/B636050688
No related grants have been discovered for Abdulafeez Akinloye.