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Antimicrobial Agents and Chemotherapy Mar 2020The purpose of this study was to evaluate the pharmacokinetics of ritonavir-boosted fosamprenavir during pregnancy and postpartum. Amprenavir (the active moiety of... (Clinical Trial)
Clinical Trial
The purpose of this study was to evaluate the pharmacokinetics of ritonavir-boosted fosamprenavir during pregnancy and postpartum. Amprenavir (the active moiety of fosamprenavir) and ritonavir intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy and postpartum. Plasma concentrations of amprenavir and ritonavir were measured using high-performance liquid chromatography. The target amprenavir area under the concentration-versus-time curve (AUC) was higher than the 10th percentile (27.7 μg · h/ml) of the median area under the curve for ritonavir-boosted fosamprenavir in adults receiving twice-daily fosamprenavir-ritonavir at 700 mg/100 mg. Twenty-nine women were included in the analysis. The amprenavir AUC from time zero to 12 h (AUC) was lower (geometric mean ratio [GMR], 0.60 [confidence interval {CI}, 0.49 to 0.72] [ < 0.001]) while its apparent oral clearance was higher (GMR, 1.68 [CI, 1.38 to 2.03] [ < 0.001]) in the third trimester than postpartum. Similarly, the ritonavir AUC was lower in the second (GMR, 0.51 [CI, 0.28 to 0.91] [ = 0.09]) and third (GMR, 0.72 [CI, 0.55 to 0.95] [ = 0.005]) trimesters than postpartum, while its apparent oral clearance was higher in the second (GMR, 1.98 [CI, 1.10 to 3.56] [ = 0.06]) and third (GMR, 1.38 [CI, 1.05 to 1.82] [ = 0.009]) trimesters than postpartum. The amprenavir area under the curve exceeded the target for 6/8 (75%) women in the 2nd trimester, 18/28 (64%) in the 3rd trimester, and 19/22 (86.4%) postpartum, and the trough concentrations () of amprenavir were 4- to 16-fold above the mean amprenavir-protein-adjusted 50% inhibitory concentration (IC) of 0.146 μg/ml. Although amprenavir plasma concentrations in women receiving ritonavir-boosted fosamprenavir were lower during pregnancy than postpartum, the reduced amprenavir concentrations were still above the exposures needed for viral suppression.
Topics: Adult; Area Under Curve; Carbamates; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Maternal Age; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimesters; RNA, Viral; Ritonavir; Sulfonamides; Viral Load
PubMed: 32015036
DOI: 10.1128/AAC.02260-19 -
International Journal of Molecular... Apr 2023Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett's esophagus (BE) and...
Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Proton pump inhibitors (PPIs) are the standard-of-care for GERD and are among the most prescribed drugs in the world, but do not protect against nonacid components of reflux such as pepsin, or prevent reflux-associated carcinogenesis. We recently identified an HIV protease inhibitor amprenavir that inhibits pepsin and demonstrated the antireflux therapeutic potential of its prodrug fosamprenavir in a mouse model of laryngopharyngeal reflux. In this study, we assessed the capacity of amprenavir to protect against esophageal epithelial barrier disruption in vitro and related molecular events, E-cadherin cleavage, and matrix metalloproteinase induction, which are associated with GERD severity and esophageal cancer. Herein, weakly acidified pepsin (though not acid alone) caused cell dissociation accompanied by regulated intramembrane proteolysis of E-cadherin. Soluble E-cadherin responsive matrix metalloproteinases (MMPs) were transcriptionally upregulated 24 h post-treatment. Amprenavir, at serum concentrations achievable given the manufacturer-recommended dose of fosamprenavir, protected against pepsin-induced cell dissociation, E-cadherin cleavage, and MMP induction. These results support a potential therapeutic role for amprenavir in GERD recalcitrant to PPI therapy and for preventing GERD-associated neoplastic changes.
Topics: Animals; Mice; Pepsin A; Protease Inhibitors; Quality of Life; Esophageal Neoplasms; Enzyme Inhibitors; Laryngopharyngeal Reflux; Proton Pump Inhibitors
PubMed: 37047737
DOI: 10.3390/ijms24076765 -
Laryngoscope Investigative... Aug 2023Laryngopharyngeal reflux (LPR) causes chronic cough, throat clearing, hoarseness, and dysphagia and can promote laryngeal carcinogenesis. More than 20% of the US...
BACKGROUND
Laryngopharyngeal reflux (LPR) causes chronic cough, throat clearing, hoarseness, and dysphagia and can promote laryngeal carcinogenesis. More than 20% of the US population suffers from LPR and there is no effective medical therapy. Pepsin is a predominant source of damage during LPR which disrupts laryngeal barrier function potentially via E-cadherin cleavage proteolysis and downstream matrix metalloproteinase (MMP) dysregulation. Fosamprenavir (FDA-approved HIV therapeutic and prodrug of amprenavir) is a pepsin-inhibiting LPR therapeutic candidate shown to rescue damage in an LPR mouse model. This study aimed to examine amprenavir protection against laryngeal monolayer disruption and related E-cadherin proteolysis and MMP dysregulation in vitro.
METHODS
Laryngeal (TVC HPV) cells were exposed to buffered saline, pH 7.4 or pH 4 ± 1 mg/mL pepsin ± amprenavir (10-60 min). Analysis was performed by microscopy, Western blot, and real time polymerase chain reaction (qPCR).
RESULTS
Amprenavir (1 μM) rescued pepsin acid-mediated cell dissociation ( < .05). Pepsin acid caused E-cadherin cleavage indicative of regulated intramembrane proteolysis (RIP) and increased 24-h postexposure ( < .05). Acid alone did not cause cell dissociation or E-cadherin cleavage. Amprenavir (10 μM) protected against E-cadherin cleavage and induction ( < .05).
CONCLUSIONS
Amprenavir, at serum concentrations achievable provided the manufacturer's recommended dose of fosamprenavir for HIV, protects against pepsin-mediated cell dissociation, E-cadherin cleavage, and MMP dysregulation thought to contribute to barrier dysfunction and related symptoms during LPR. Fosamprenavir to amprenavir conversion by laryngeal epithelia, serum and saliva, and relative drug efficacies in an LPR mouse model are under investigation to inform development of inhaled formulations for LPR.
PubMed: 37621274
DOI: 10.1002/lio2.1102 -
Journal of Molecular Graphics &... Nov 2021Drug resistance is a serious problem for controlling the HIV/AIDS pandemic. Current antiviral drugs show several orders of magnitude worse inhibition of highly resistant...
Drug resistance is a serious problem for controlling the HIV/AIDS pandemic. Current antiviral drugs show several orders of magnitude worse inhibition of highly resistant clinical variant PRS17 of HIV-1 protease compared with wild-type protease. We have analyzed the effects of a common resistance mutation G48V in the flexible flaps of the protease by assessing the revertant PRS17 for changes in enzyme kinetics, inhibition, structure, and dynamics. Both PRS17 and the revertant showed about 10-fold poorer catalytic efficiency than wild-type enzyme (0.55 and 0.39 μMmin compared to 6.3 μMmin). Clinical inhibitors, amprenavir and darunavir, showed 2-fold and 8-fold better inhibition, respectively, of the revertant than of PRS17, although the inhibition constants for PRS17 were still 25 to 1,200-fold worse than for wild-type protease. Crystal structures of inhibitor-free revertant and amprenavir complexes with revertant and PRS17 were solved at 1.3-1.5 Å resolution. The amprenavir complexes of PRS17 and PRS17 showed no significant differences in the interactions with inhibitor, although changes were observed in the conformation of Phe53 and the interactions of the flaps. The inhibitor-free structure of the revertant showed flaps in an open conformation, however, the flap tips do not have the unusual curled conformation seen in inhibitor-free PRS17. Molecular dynamics simulations were run for 1 μs on the two inhibitor-free mutants and wild-type protease. PRS17 exhibited higher conformational fluctuations than the revertant, while the wild-type protease adopted the closed conformation and showed the least variation. The second half of the simulations captured the transition of the flaps of PRS17 from a closed to a semi-open state, whereas the flaps of PRS17 tucked into the active site and the wild-type protease retained the closed conformation. These results suggest that mutation G48V contributes to drug resistance by altering the conformational dynamics of the flaps.
Topics: Catalytic Domain; Drug Resistance, Viral; HIV Protease; HIV Protease Inhibitors; Mutation; Pharmaceutical Preparations; Protein Conformation
PubMed: 34419931
DOI: 10.1016/j.jmgm.2021.108005 -
Topics in HIV Medicine : a Publication... 2005Knowledge of drug-drug interactions is crucial to HIV therapeutics. Recent reports in this area include reduced atazanavir exposure with coadministration of omeprazole... (Review)
Review
Knowledge of drug-drug interactions is crucial to HIV therapeutics. Recent reports in this area include reduced atazanavir exposure with coadministration of omeprazole or rifampin; increased hepatic toxicity with coadministration of saquinavir and rifampin; reduced buprenorphine exposure with concurrent efavirenz administration; absence of clinically significant interactions of depomedroxyprogesterone with nevirapine, efavirenz, or nelfinavir; increased atazanavir and saquinavir exposure with the double-boosted regimen of atazanavir/saquinavir/ritonavir; reduced amprenavir, lopinavir, and saquinavir exposure with the addition of tipranavir/ritonavir therapy; and reduced lopinavir and amprenavir exposure with the addition of fosamprenavir or fosamprenavir/ritonavir to lopinavir/ritonavir. This article summarizes a presentation on drug-drug interactions in HIV therapeutics by Angela D. M. Kashuba, PharmD, at the International AIDS Society-USA course in Los Angeles in April 2005.
Topics: Anti-HIV Agents; Drug Interactions; HIV Infections; Humans
PubMed: 16082056
DOI: No ID Found -
Biochimica Et Biophysica Acta Jul 2002Virtually all the compounds that are currently used, or are subject of advanced clinical trials, for the treatment of human immunodeficiency virus (HIV) infections,... (Review)
Review
Virtually all the compounds that are currently used, or are subject of advanced clinical trials, for the treatment of human immunodeficiency virus (HIV) infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): i.e. zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine [(-)FTC], tenofovir disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e. nevirapine, delavirdine, efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e. saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and lopinavir. In addition to the reverse transcriptase (RT) and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 [bicyclam (AMD3100) derivatives] and CCR5 (TAK-779 derivatives); (iii) virus-cell fusion, through binding to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs and PIs have been developed that possess, respectively: (i) improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased activity ["second" or "third" generation NNRTIs (i.e. TMC-125, DPC-083)] against those HIV strains that are resistant to the "first" generation NNRTIs, or (iii) as in the case of PIs, a different, nonpeptidic scaffold [i.e. cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)]. Nonpeptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating the mode of action of these agents from cell-free enzymatic assays to intact cells. Two examples in point are L-chicoric acid and the nonapeptoid CGP64222, which were initially described as an integrase inhibitor or Tat antagonist, respectively, but later shown to primarily act as virus adsorption/entry inhibitors, the latter through blockade of CXCR4.
Topics: Anti-HIV Agents; Binding Sites; Capsid; Capsid Proteins; Drug Design; Gene Products, gag; HIV; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Molecular Structure; Receptors, HIV; Reverse Transcriptase Inhibitors; Transcriptional Activation; Viral Proteins; gag Gene Products, Human Immunodeficiency Virus
PubMed: 12084468
DOI: 10.1016/s0925-4439(02)00089-3 -
Current Medicinal Chemistry Nov 2001Virtually all the compounds that are currently used, or under advanced clinical trial, for the treatment of HIV infections, belong to one of the following classes: (i)... (Review)
Review
Virtually all the compounds that are currently used, or under advanced clinical trial, for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): i.e., zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine [(-)FTC], tenofovir (PMPA) disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine (MKC-442); and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease step, various other events in the HIV replicative cycle are potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polyoxometalates, zintevir, negatively charged albumins, cosalane analogues); (ii) viral entry, through blockade of the viral coreceptors CXCR4 and CCR5 [bicyclams (i.e. AMD3100), polyphemusins (T22), TAK-779, MIP-1 alpha LD78 beta isoform]; (iii) virus-cell fusion, through binding to the viral glycoprotein gp41 [T-20 (DP-178), T-1249 (DP-107), siamycins, betulinic acid derivatives]; (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA) and NCp7 peptide mimics]; (v) proviral DNA integration, through integrase inhibitors such as L-chicoric acid and diketo acids (i.e. L-731,988); (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (fluoroquinolone K-12, Streptomyces product EM2487, temacrazine, CGP64222). Also, in recent years new NRTIs, NNRTIs and PIs have been developed that possess respectively improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides of d4T), or increased activity against NNRTI-resistant HIV strains [second generation NNRTIs, such as capravirine and the novel quinoxaline, quinazolinone, phenylethylthiazolylthiourea (PETT) and emivirine (MKC-442) analogues], or, as in the case of PIs, a different, non-peptidic scaffold [i.e. cyclic urea (DMP 450), 4-hydroxy-2-pyrone (tipranavir)]. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating from cell-free enzymatic assays to the mode of action of these agents in intact cells. A number of compounds (i.e. zintevir and L-chicoric acid, on the one hand; and CGP64222 on the other hand) have recently been found to interact with virus-cell binding and viral entry in contrast to their proposed modes of action targeted at the integrase and transactivation process, respectively.
Topics: Amino Acid Sequence; Animals; Anti-HIV Agents; Binding Sites; Capsid; Capsid Proteins; Drug Design; Enfuvirtide; Enzyme Inhibitors; Gene Products, gag; HIV; HIV Envelope Protein gp41; HIV Integrase; HIV Reverse Transcriptase; Humans; Molecular Sequence Data; Peptide Fragments; Reverse Transcriptase Inhibitors; Transcription, Genetic; Viral Proteins; gag Gene Products, Human Immunodeficiency Virus
PubMed: 11562282
DOI: 10.2174/0929867013371842 -
Antimicrobial Agents and Chemotherapy Mar 2002Data from three pharmacokinetic drug interaction studies of amprenavir and ritonavir were used to develop a pharmacokinetic interaction model using NONMEM (nonlinear... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Data from three pharmacokinetic drug interaction studies of amprenavir and ritonavir were used to develop a pharmacokinetic interaction model using NONMEM (nonlinear mixed-effect model). A two-compartment linear model with first-order absorption best fit the amprenavir data, while a one-compartment model was used to describe the ritonavir data. The inhibition of elimination of amprenavir by ritonavir was modeled with a maximum effect (Emax) inhibition model and the observed ritonavir concentration. Monte Carlo simulation was then used to predict amprenavir concentrations for various combinations of amprenavir and ritonavir in twice-daily and once-daily dosing regimens. Simulated minimum amprenavir concentrations in plasma (Cmin) in twice-daily and once-daily dosing regimens were compared with protein binding-adjusted 50% inhibitory concentrations (IC50s) for clinical human immunodeficiency virus isolates with different susceptibilities to protease inhibitors (central tendency ratios). The model based on the first two studies predicted the results of the third study. Data from all three studies were then combined to refine the final model. The observed and simulated noncompartmental pharmacokinetic parameters agreed well. From this model, several candidate drug regimens were simulated. These simulations suggest that, in patients who have clinically failed a traditional amprenavir regimen, a regimen of 600 mg of amprenavir with 100 mg of ritonavir twice daily would result in Cmin-to-IC50 ratios similar to that of 1,200 mg of amprenavir twice daily alone for wild-type viruses. In addition, once-daily regimens that result in C(min)s above the protein binding-corrected IC50s for wild-type virus are clearly feasible.
Topics: Adolescent; Adult; Algorithms; Anti-HIV Agents; Carbamates; Computer Simulation; Drug Interactions; Female; Furans; Humans; Male; Middle Aged; Models, Biological; Monte Carlo Method; Reproducibility of Results; Ritonavir; Sulfonamides
PubMed: 11850257
DOI: 10.1128/AAC.46.3.746-754.2002