Purpose
Non-adherence to the antiretroviral (ARV) regimen is a critical factor in determining efficacy of ARV drugs for pre-exposure prophylaxis (PrEP). A long-acting parenteral formulation may be an effective alternative to daily oral dosing. A pharmacokinetic and tissue distribution study of drug-loaded nanoparticle (NP) was performed in female humanized CD34+-NSG mice.
Methods
Mice received 200 mg/kg each of tenofovir alafenamide (TAF) and elvitegravir (EVG) as free drugs (TAF+EVG solution) or as drug loaded NP (TAF+EVG NP) formulation by subcutaneous (SubQ) administration. Plasma and tissue were collected to determine tenofovir (TFV) and EVG concentrations using LC-MS/MS. Non-compartmental analysis was performed using WinNonlin.
Results
SubQ administration of TAF+EVG NP formulation resulted in long residence time and exposure for both drugs. The AUC(0–72h) of TFV and EVG was 14.1±2.0, 7.2±1.8 μg×hr/mL from drugs in solution (free) and the AUC(0–14day) for the same drugs was 23.1±4.4, 39.7±6.7 μg×hr/mL from NPs. The observed elimination half-life (t1/2) for TFV of free and NPs were 14.2 h, 5.1 days and for EVG 10.8 h, 3.3 days, respectively.
Conclusion
This study documents that a TAF+EVG NP provides sustained release, which can overcome patient non-adherence to dosing and may facilitate prediction of appropriate protective drug concentration for HIV prophylaxis.
There are errors in the published article (Volume 34, Number 12, pp. 2749-2755.The errors occurred in pharmacokinetic study design of materials and methods section on page 2750-51.
Introduction:
Four Factor Prothrombin Complex Concentrate (4F-PCC) is indicated for reversal of warfarin-induced coagulopathy. In small cohort studies, 4F-PCC has similar hemostatic efficacy rates reversing non-vitamin K anticoagulants (NOACs). There are no comparison studies evaluating 4F-PCC for the reversal of warfarin versus NOACs in the setting of intracerebral hemorrhage (ICH).
Methods:
A multicenter retrospective cohort study was conducted between 2013-2020 at a comprehensive stroke system in ICH patients who received 4F-PCC for the reversal of warfarin or a NOAC. Patients were included if they were adults with an acute ICH, anticoagulant regimen of warfarin (INR 1.3 or greater) or NOAC, and 2 head CT scans within 24 hours to determine hemostatic efficacy. Hemostatic efficacy was evaluated by the Sarode scale. The chi square and t-test were used as appropriate for demographic and clinical data, with multivariable regression analysis conducted in a forward stepwise manner, retaining variables with significance less than 0.05.
Results:
One hundred fifty-seven patients were included (baseline characteristics in Table 1). There was no statistically significant difference in effective hemostasis observed between warfarin and NOAC patients (83% vs 75%, p=0.33). Similarly, multivariable analysis did not demonstrate a significant difference in effective hemostasis (OR 0.55, 95% CI: 0.2-1.3, p=0.2). However, due to wide 95% confidence intervals, we cannot exclude a key treatment effect from PCC. After controlling for baseline characteristics, patients treated with NOACs had 53% lower odds of a good clinical outcome compared to those treated with warfarin (Figure 1; OR 0.47, 95% CI: 0.2-1.3, p=0.13).
Conclusions:
In conclusion, there was no statistically significant difference in hemostatic efficacy or clinical outcomes between warfarin and NOAC patients following reversal with 4F-PCC.
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