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Molecular Pharmaceutics Jan 2020Antiretroviral therapy (ART) has improved the quality of life in patients infected with HIV-1. However, complete viral suppression within anatomical compartments remains...
Antiretroviral therapy (ART) has improved the quality of life in patients infected with HIV-1. However, complete viral suppression within anatomical compartments remains unattainable. This is complicated by adverse side effects and poor adherence to lifelong therapy leading to the emergence of viral drug resistance. Thus, there is an immediate need for cellular and tissue-targeted long-acting (LA) ART formulations. Herein, we describe two LA prodrug formulations of darunavir (DRV), a potent antiretroviral protease inhibitor. Two classes of DRV prodrugs, M1DRV and M2DRV, were synthesized as lipophilic and hydrophobic prodrugs and stabilized into aqueous suspensions designated NM1DRV and NM2DRV. The formulations demonstrated enhanced intracellular prodrug levels with sustained drug retention and antiretroviral activities for 15 and 30 days compared to native DRV formulation in human monocyte-derived macrophages. Pharmacokinetics tests of NM1DRV and NM2DRV administered to mice demonstrated sustained drug levels in blood and tissues for 30 days. These data, taken together, support the idea that LA DRV with sustained antiretroviral responses through prodrug nanoformulations is achievable.
Topics: Animals; CD4-Positive T-Lymphocytes; Cell Survival; Chromatography, Liquid; Darunavir; Drug Resistance, Viral; HIV Protease Inhibitors; HIV-1; Humans; Macrophages; Male; Mice; Mice, Inbred BALB C; Microscopy, Electron; Prodrugs; Rats; Tandem Mass Spectrometry
PubMed: 31742407
DOI: 10.1021/acs.molpharmaceut.9b00871 -
Chemical Communications (Cambridge,... Oct 2022We report our recent development of a conceptually new generation of exceptionally potent non-peptidic HIV-1 protease inhibitors that displayed excellent pharmacological... (Review)
Review
We report our recent development of a conceptually new generation of exceptionally potent non-peptidic HIV-1 protease inhibitors that displayed excellent pharmacological and drug-resistance profiles. Our X-ray structural studies of darunavir and other designed inhibitors from our laboratories led us to create a variety of inhibitors incorporating fused ring polycyclic ethers and aromatic heterocycles to promote hydrogen bonding interactions with the backbone atoms of HIV-1 protease as well as van der Waals interactions with residues in the S2 and S2' subsites. We have also incorporated specific functionalities to enhance van der Waals interactions in the S1 and S1' subsites. The combined effects of these structural templates are critical to the inhibitors' exceptional potency and drug-like properties. We highlight here our molecular design strategies to promote backbone hydrogen bonding interactions to combat drug-resistance and specific design of polycyclic ether templates to mimic peptide-like bonds in the HIV-1 protease active site. Our medicinal chemistry and drug development efforts led to the development of new generation inhibitors significantly improved over darunavir and displaying unprecedented antiviral activity against multidrug-resistant HIV-1 variants.
Topics: Darunavir; HIV-1; HIV Protease Inhibitors; Ether; Drug Design; HIV Protease; Drug Resistance; Peptides; Crystallography, X-Ray; Drug Resistance, Viral
PubMed: 36200462
DOI: 10.1039/d2cc04541a -
Acta Pharmaceutica (Zagreb, Croatia) Mar 2022The epidemic of the novel coronavirus disease (COVID-19) that started in 2019 has evoked an urgent demand for finding new potential therapeutic agents. In this study, we...
The epidemic of the novel coronavirus disease (COVID-19) that started in 2019 has evoked an urgent demand for finding new potential therapeutic agents. In this study, we performed a molecular docking of anti-HIV drugs to refine HIV protease inhibitors and nucleotide analogues to target COVID-19. The evaluation was based on docking scores calculated by AutoDock Vina and top binding poses were analyzed. Our results suggested that lopinavir, darunavir, atazanavir, remdesivir, and tipranavir have the best binding affinity for the 3-chymotrypsin-like protease of COVID-19. The comparison of the binding sites of three drugs, namely, darunavir, atazanavir and remdesivir, showed an overlap region of the protein pocket. Our study showed a strong affinity between lopinavir, darunavir, atazanavir, tipranavir and COVID-19 protease. However, their efficacy should be confirmed by studies since there are concerns related to interference with their active sites.
Topics: Humans; Lopinavir; Darunavir; Atazanavir Sulfate; Molecular Docking Simulation; Peptide Hydrolases; COVID-19; Protease Inhibitors; Antiviral Agents
PubMed: 36651526
DOI: 10.2478/acph-2022-0010 -
The Journal of Antimicrobial... Aug 2021HIV exposure to penile tissues provides a risk of acquisition among men, yet studies evaluating penile antiretroviral (ARV) drug distribution have been lacking. We...
BACKGROUND
HIV exposure to penile tissues provides a risk of acquisition among men, yet studies evaluating penile antiretroviral (ARV) drug distribution have been lacking. We measured ARVs on urethral and glans surface swabs collected following a dose of tenofovir alafenamide, emtricitabine, elvitegravir, darunavir and cobicistat.
METHODS
Thirty-five HIV-negative male participants provided urethral swabs, glans swabs, rectal swabs, blood and urine up to 96 h following a single dose of tenofovir alafenamide/emtricitabine/elvitegravir/cobicistat and darunavir. ARVs were measured by liquid chromatography-mass spectrometry with a lower limit of detection (LOD) of 1 ng/swab for swabs and 10 ng/mL for plasma and urine. Concentrations are reported as median and range.
RESULTS
Urethral swab emtricitabine and darunavir concentrations peaked at 4 h for emtricitabine (36 ng/swab; 3-307 ng/swab) and 8 h for darunavir (25 ng/swab; 2-52 ng/swab). Glans swab emtricitabine and darunavir concentrations peaked 24 h after dosing (emtricitabine 14 ng/swab,
darunavir 6 ng/swab, darunavir concentrations are between 10 and 20 μg/mL, similar to rectal secretions, 4-fold greater than in plasma, but 2-fold lower than in urine. Tenofovir and elvitegravir were detected on less than 20% of urethral or glans swabs collected within 24 h of dosing. CONCLUSIONS
We document ARV dosing in the urethra and on the glans surface with high drug concentrations noted for emtricitabine and darunavir and lower tenofovir and elvitegravir concentrations. Data suggest a potential protective role of urethral emtricitabine or darunavir against penile HIV acquisition.
Topics: Anti-HIV Agents; Cobicistat; Emtricitabine; HIV Infections; HIV-1; Humans; Male; Pharmaceutical Preparations; Urethra
PubMed: 34007982
DOI: 10.1093/jac/dkab155 -
Drug Design, Development and Therapy 2018A fixed-dose combination consisting of darunavir (Drv), cobicistat (Cobi), emtricitabine (2',3'-dideoxy-5-fluoro-3'-thiacytidine [FTC]), and tenofovir alafenamide (Taf)... (Review)
Review
A fixed-dose combination consisting of darunavir (Drv), cobicistat (Cobi), emtricitabine (2',3'-dideoxy-5-fluoro-3'-thiacytidine [FTC]), and tenofovir alafenamide (Taf) has been recently approved by the European Medicines Agency for the treatment of HIV infection, and is the first ever protease-inhibitor-based single-tablet regimen. This article provides a detailed description of its pharmacokinetic, efficacy, and safety profile. The pharmacokinetics of single compounds were analyzed, with a special focus on contrasts between Drv/Cobi and Drv/ritonavir (Rtv). When comparing Cobi and Rtv, multiple interactions must be taken into account: in comparison to Rtv, Cobi is a more selective CYP3A4 inhibitor and has no clinical effect on other isoenzymes inhibited by Rtv (eg, 2C8 and 2C9). Moreover, unlike Cobi, Rtv shows in vivo induction activity on some CYP isoenzymes (eg, 1A2, 2C19, 2C8, 2C9, and 2B6), glucuronyltransferases (eg, UGT1A4), and Pgp. Drv-Cobi-FTC-Taf has recently been demonstrated to be of equal efficacy to Drv-Rtv and other protease inhibitors in both experienced (EMERALD study) and naïve (AMBER study) patients. Moreover, kidney and bone safety profiles have been shown to be good, as has central nervous system tolerance. Total cholesterol:low-density-lipoprotein cholesterol and total cholesterol:high-density-lipoprotein cholesterol ratios are generally high in Drv-Cobi-FTC-Taf vs Rtv-Drv-FTC + tenofovir disoproxil fumarate. An unlikely role of Drv in influencing cardiovascular risk in HIV infection has also been reported. Kidney safety profile is influenced by Cobi, with an increase in creatinine plasma concentration of 0.05-0.1 mg/dL and a parallel glomerular filtration-rate reduction of 10 mL/min within the first 4 weeks after Cobi introduction, which remains stable during treatment. Bone and central nervous system safety profiles were found to be good in randomized clinical trials of both experienced and naïve patients. The efficacy and safety of Drv/Cobi/FTC/Taf are comparable to other drug regimens recommended for HIV treatment.
Topics: Adenine; Alanine; Anti-HIV Agents; Cobicistat; Darunavir; Drug Combinations; Emtricitabine; HIV; HIV Infections; Humans; Protease Inhibitors; Randomized Controlled Trials as Topic; Tenofovir
PubMed: 30464395
DOI: 10.2147/DDDT.S147493 -
Rationale and clinical utility of the darunavir-cobicistat combination in the treatment of HIV/AIDS.Drug Design, Development and Therapy 2015This article is to provide an update overview of cobicistat (COBI)-boosted darunavir in response to its recent approval by the US Food and Drug Administration, and... (Review)
Review
This article is to provide an update overview of cobicistat (COBI)-boosted darunavir in response to its recent approval by the US Food and Drug Administration, and inclusion as an alternative first-line regime in the 2015 treatment guidelines in the US. COBI is a relatively new non-antiretroviral cytochrome P450 3A inhibitor or pharmacoenhancer. The rationale behind COBI development was to provide an alternative to ritonavir (RTV) as a protease inhibitor pharmacoenhancer, due to associated adverse events with short- and long-term RTV use, such as gastrointestinal intolerability, drug-drug interactions, insulin resistance, lipodystrophy, and hyperlipidemia. Although in vitro studies suggest that COBI may result in a lower incidence of undesired drug-drug interactions and lipid-associated disorders than RTV, not all Phase III studies have well addressed these issues, and the data are limited. However, Phase III studies have demonstrated tolerability, noninferiority, and bioequivalence of COBI compared to RTV. Two main advantages of COBI over RTV-containing regimes have been noted as follows: 1) COBI has no anti-HIV activity; therefore, resistance to COBI as a booster in addition to protease inhibitor resistance is of little concern, allowing for COBI-containing regimes in future. 2) COBI's solubility and dissolution rate allow for co-formulated/fixed-dose combination products. Nonetheless, prior to initiating COBI-containing treatment regimens, the following should be considered: 1) COBI may increase serum creatinine levels and reduce estimated glomerular filtration rate (GFR) without affecting actual GFR; 2) potential drug-drug interaction data are insufficient, warranting caution when initiating COBI in conjunction with concomitant medication or in individuals with multiple comorbidities; 3) food plays a pivotal role in boosting darunavir exposure, warranting caution and patient education on the importance of taking COBI-containing regimens with appropriate amounts of food; and 4) data on the success of COBI-containing regimens in treatment-experienced patients are limited.
Topics: Cobicistat; Cytochrome P-450 CYP3A Inhibitors; Darunavir; Drug Combinations; Drug Interactions; Food-Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Risk Factors; Treatment Outcome
PubMed: 26566368
DOI: 10.2147/DDDT.S63989 -
Drug Discoveries & Therapeutics May 2020The virus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is currently affecting more than 200 countries and territories worldwide. It has been declared as... (Review)
Review
The virus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is currently affecting more than 200 countries and territories worldwide. It has been declared as pandemic by World Health Organization (WHO) and the whole world is suffering from corona virus disease 2019 (COVID-19). Currently, no treatment for SARS-CoV-2 are approved because of lack of evidence, but a number of clinical trials are in process and we are expecting fruitful results very soon. This review focuses on various approaches of treatment and few of the most recent clinical trials carried out in this field.
Topics: Adenosine Monophosphate; Alanine; Amides; Antibodies, Monoclonal, Humanized; Antiviral Agents; Betacoronavirus; COVID-19; Chloroquine; Clinical Trials as Topic; Coronavirus Infections; Darunavir; Drug Combinations; Humans; Hydroxychloroquine; Immunization, Passive; Indoles; Interferon-alpha; Interferon-beta; Lopinavir; Pandemics; Pneumonia, Viral; Pyrazines; Ritonavir; SARS-CoV-2; COVID-19 Drug Treatment; COVID-19 Serotherapy
PubMed: 32336723
DOI: 10.5582/ddt.2020.03008 -
AIDS (London, England) Jan 2021To evaluate changes in weight and BMI in adults with HIV-1 at 1 and 2 years after starting an antiretroviral regimen that included doravirine, ritonavir-boosted...
OBJECTIVE
To evaluate changes in weight and BMI in adults with HIV-1 at 1 and 2 years after starting an antiretroviral regimen that included doravirine, ritonavir-boosted darunavir, or efavirenz.
DESIGN
Post-hoc analysis of pooled data from three randomized controlled trials.
METHODS
We evaluated weight change from baseline, weight gain at least 10%, and increase in BMI after 48 and 96 weeks of treatment with doravirine, ritonavir-boosted darunavir, or efavirenz-based regimens. Risk factors for weight gain and metabolic outcomes associated with weight gain were also examined.
RESULTS
Mean (and median) weight changes were similar for doravirine [1.7 (1.0) kg] and ritonavir-boosted darunavir [1.4 (0.6) kg] and were lower for efavirenz [0.6 (0.0) kg] at week 48 but were similar across all treatment groups at week 96 [2.4 (1.5), 1.8 (0.7), and 1.6 (1.0) kg, respectively]. No significant differences between treatment groups were found in the proportion of participants with at least 10% weight gain or the proportion with BMI class increase at either time point. Low CD4 T-cell count and high HIV-1 RNA at baseline were associated with at least 10% weight gain and BMI class increase at both timepoints, but treatment group, age, sex, and race were not.
CONCLUSION
Weight gains over 96 weeks were low in all treatment groups and were similar to the average yearly change in adults without HIV-1. Significant weight gain and BMI class increase were similar across the treatment groups and were predicted by low baseline CD4 T-cell count and high baseline HIV-1 RNA.
Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Mass Index; CD4 Lymphocyte Count; Darunavir; HIV Infections; Humans; Pyridones; Ritonavir; Treatment Outcome; Triazoles; Viral Load
PubMed: 33048879
DOI: 10.1097/QAD.0000000000002725 -
Clinical Pharmacokinetics Feb 2021Protease inhibitors such as darunavir are an important therapeutic option in the anti-human immunodeficiency virus arsenal. Current dosage guidelines recommend using...
BACKGROUND AND OBJECTIVES
Protease inhibitors such as darunavir are an important therapeutic option in the anti-human immunodeficiency virus arsenal. Current dosage guidelines recommend using cobicistat- or ritonavir-boosted darunavir 800 mg every 24 h (q24h) in protease inhibitor-naïve patients, or ritonavir-boosted darunavir 600 mg q12h in experienced patients. However, darunavir displays a large, poorly characterized, inter-individual pharmacokinetic variability. The objectives of this study were to investigate the pharmacokinetics of darunavir and to elucidate the sources of its inter-individual variability using population pharmacokinetic modeling. Then, to determine the appropriateness of current treatment guidelines and the feasibility of alternative dosing regimens in a representative cohort of adult patients using simulations.
METHODS
Sparse pharmacokinetic samples were collected in 127 patients with human immunodeficiency virus type 1 infection, then supplemented with rich sampling data from a subset of 12 individuals. Data were analyzed using the nonlinear mixed-effects modeling software NONMEM. The effect of reduced doses (600 mg q24h and 400 mg q24h) or reduced frequency of administration (800 mg q24h for 5 days followed by 2 days of treatment interruption) was simulated.
RESULTS
Our model adequately described the pharmacokinetics of darunavir. Predictors of individual exposure were CYP3A5*3 and SLCO3A1 rs8027174 genotypes, sex, and alpha-1 acid glycoprotein level. No relationship was apparent between darunavir area under the curve and treatment efficacy or safety. For reduced dose regimens, darunavir concentrations remained above the protein binding-corrected EC in the majority of subjects. More stringent pharmacokinetic targets were not reached in a significant proportion of patients.
CONCLUSIONS
These results add to the growing body of evidence that darunavir-based therapy could be simplified to reduce costs and toxicity, as well as to improve patient compliance. However, the heterogeneity in pharmacokinetic response should be considered when assessing whether individual patients could benefit from a particular regimen, for instance through the use of population pharmacokinetic models.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT03101644, date of registration: 5 April, 2017.
Topics: Cobicistat; Darunavir; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Ritonavir
PubMed: 32696441
DOI: 10.1007/s40262-020-00920-z -
European Journal of Clinical... Apr 2021A variety of diagnostic methods are available to validate the performance of population pharmacokinetic models. Internal validation, which applies these methods to the...
PURPOSE
A variety of diagnostic methods are available to validate the performance of population pharmacokinetic models. Internal validation, which applies these methods to the model building dataset and to additional data generated through Monte Carlo simulations, is often sufficient, but external validation, which requires a new dataset, is considered a more rigorous approach, especially if the model is to be used for predictive purposes. Our first objective was to validate a previously published population pharmacokinetic model of darunavir, an HIV protease inhibitor boosted with ritonavir or cobicistat. Our second objective was to use this model to derive optimal sampling strategies that maximize the amount of information collected with as few pharmacokinetic samples as possible.
METHODS
A validation dataset comprising 164 sparsely sampled individuals using ritonavir-boosted darunavir was used for validation. Standard plots of predictions and residuals, NPDE, visual predictive check, and bootstrapping were applied to both the validation set and the combined learning/validation set in NONMEM to assess model performance. D-optimal designs for darunavir were then calculated in PopED and further evaluated in NONMEM through simulations.
RESULTS
External validation confirmed model robustness and accuracy in most scenarios but also highlighted several limitations. The best one-, two-, and three-point sampling strategies were determined to be pre-dose (0 h); 0 and 4 h; and 1, 4, and 19 h, respectively. A combination of samples at 0, 1, and 4 h was comparable to the optimal three-point strategy. These could be used to reliably estimate individual pharmacokinetic parameters, although with fewer samples, precision decreased and the number of outliers increased significantly.
CONCLUSIONS
Optimal sampling strategies derived from this model could be used in clinical practice to enhance therapeutic drug monitoring or to conduct additional pharmacokinetic studies.
Topics: Adult; Aged; Darunavir; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Models, Biological; Reproducibility of Results
PubMed: 33175180
DOI: 10.1007/s00228-020-03036-2