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Profiles of Drug Substances,... 2021Darunavir: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl] (isobutyl)amino}-3-hydroxy-1-phenyl-2-butanyl]carbamate is a synthetic... (Review)
Review
Darunavir: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl] (isobutyl)amino}-3-hydroxy-1-phenyl-2-butanyl]carbamate is a synthetic non-peptide protease inhibitor. On June 2006, it was first approved by the Food and Drug administration (FDA) for treatment of resistant type-1 of the human immunodeficiency virus (HIV). In July 2016, the FDA expanded the approval for use of darunavir in pregnant women with HIV infection. Darunavir prevents the replication of HIV virus by inhibiting the catalytic activity of the HIV-1 protease enzyme, and selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, which prevents the formation of mature infectious virus particles. Darunavir is unique among currently available protease inhibitors because it maintains antiretroviral activity against a variety of multidrug-resistant HIV strains. This article discusses, by a critical extensive review of the literature, the description of darunavir in terms of its names, formulae, elemental composition, appearance, and use in the treatment of HIV-infected patients. The article also discusses the methods for preparation of darunavir, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.
Topics: Darunavir; Drug Resistance, Viral; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Pregnancy; United States
PubMed: 33461696
DOI: 10.1016/bs.podrm.2020.07.001 -
Drugs Jul 2018Darunavir/cobicistat/emtricitabine/tenofovir AF (Symtuza) is the first protease inhibitor (PI)-based single-tablet regimen (STR) available for the treatment of adults... (Review)
Review
Darunavir/cobicistat/emtricitabine/tenofovir AF (Symtuza) is the first protease inhibitor (PI)-based single-tablet regimen (STR) available for the treatment of adults and adolescents (aged ≥ 12 years) with HIV-1 infection. It combines the PI darunavir (which has a high genetic barrier to resistance) with the pharmacokinetic booster cobicistat and the nucleos(t)ide reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide (tenofovir AF), the latter being associated with less off-target tenofovir exposure than its predecessor tenofovir disoproxil fumarate (tenofovir DF). Over 48 weeks in phase 3 trials, darunavir/cobicistat/emtricitabine/tenofovir AF was noninferior to darunavir/cobicistat plus emtricitabine/tenofovir DF in establishing virological suppression in antiretroviral therapy (ART)-naïve adults and, likewise, was noninferior to an ongoing boosted PI, emtricitabine plus tenofovir DF regimen in preventing virological rebound in virologically-suppressed, ART-experienced adults. Resistance did not emerge to the STR components, with the exception being an emtricitabine resistance-associated mutation (RAM) [M184I/V] in one of seven recipients who experienced virological failure (although M184V was a minority variant at screening in this patient). Darunavir/cobicistat/emtricitabine/tenofovir AF was generally well tolerated, with renal and bone profile improvements but less favourable effects on some lipids versus tenofovir DF-based regimens. Thus, although longer-term and cost-effectiveness data would be beneficial, darunavir/cobicistat/emtricitabine/tenofovir AF is a welcome addition to the STRs available for the treatment of adults and adolescents with HIV-1 infection, being the first to combine the high genetic resistance barrier of darunavir with the renal/bone profile of tenofovir AF, thus expanding the patient population for whom an STR may be suitable.
Topics: Adenine; Alanine; Anti-HIV Agents; Bone Density; Cobicistat; Darunavir; Dose-Response Relationship, Drug; Drug Therapy, Combination; Emtricitabine; Genes, MDR; HIV Infections; HIV-1; Humans; Renal Reabsorption; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome
PubMed: 29915897
DOI: 10.1007/s40265-018-0934-2 -
Expert Review of Clinical Pharmacology Dec 2017Combination antiretroviral therapy is recommended during pregnancy to decrease the rate of HIV transmission to the baby and reduce morbidity in the mother. More than 50%... (Review)
Review
Combination antiretroviral therapy is recommended during pregnancy to decrease the rate of HIV transmission to the baby and reduce morbidity in the mother. More than 50% of women are prescribed a protease inhibitor-based regimen during pregnancy. Darunavir was recently reclassified as a first-line protease inhibitor for use in pregnancy in the US Department of Health and Human Services Perinatal Guidelines. Areas covered: This is a brief review of the use of protease inhibitor therapy during pregnancy, and a discussion of darunavir's utility in this area. Clinical pharmacology and trial data are reviewed, and the safety, efficacy and dosing of darunavir during pregnancy is discussed. Expert commentary: Darunavir has become an important option in the management of HIV during pregnancy. Both once-daily dosing and twice-daily dosing regimens have shown efficacy in clinical studies. Although a significant reduction in total (protein bound and unbound) plasma concentrations of darunavir has been noted during pregnancy, antiviral activity appears to be maintained with standard dosing. This is likely due to diminished changes in unbound drug concentrations. Preterm delivery and low birth weight have been noted for pregnancies of women on darunavir-containg regimens, but a causal relationship has not yet been demonstrated.
Topics: Animals; Darunavir; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Infectious Disease Transmission, Vertical; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Infectious
PubMed: 28988509
DOI: 10.1080/17512433.2017.1390428 -
Expert Opinion on Pharmacotherapy Jul 2018Darunavir (DRV) was the last approved protease inhibitor (PI) and has been extensively used for the treatment of HIV in both naïve and experienced subjects due to its... (Review)
Review
Darunavir (DRV) was the last approved protease inhibitor (PI) and has been extensively used for the treatment of HIV in both naïve and experienced subjects due to its high genetic barrier and efficacy. The introduction in clinical practice of integrase strand transfer inhibitors limited its role in the management of naïve subjects and in antiretroviral treatment simplification strategies. However, recent data from trials that have investigated the new DRV/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) combination showed an excellent efficacy and tolerability of this coformulation both in naïve patients and in those with viral suppression, making D/C/F/TAF a new option for the treatment of HIV infection. Areas covered: The authors present and discuss the efficacy and safety data of DRV when used in antiretroviral-naïve, multiexperienced subjects and in the setting of treatment deintensification in subjects with viral suppression. Moreover, the authors evaluate the recent data from two different Phase III trials on D/C/F/TAF both in treatment-naïve and virologically suppressed subjects. Expert opinion: Although novel antiretroviral drugs may become available over time, DRV continues to represent a valuable option for multiexperienced subjects and has a role in simplification regimens. In addition, the convenience of D/C/F/TAF coformulation may be useful for the future management of HIV-infected subjects.
Topics: Adenine; Clinical Trials as Topic; Cobicistat; Darunavir; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV Protease Inhibitors; Half-Life; Humans; Tenofovir; Treatment Outcome
PubMed: 29913082
DOI: 10.1080/14656566.2018.1484901 -
Expert Review of Anti-infective Therapy Jun 2015A current focus in HIV management is improving adherence by minimizing pill burden with convenient formulations, including fixed-dose combinations (FDCs). Darunavir, a... (Review)
Review
A current focus in HIV management is improving adherence by minimizing pill burden with convenient formulations, including fixed-dose combinations (FDCs). Darunavir, a HIV protease inhibitor, co-administered with low-dose ritonavir (800/100 mg once daily), is recommended in guidelines in combination with other antiretrovirals for HIV patients with no darunavir resistance-associated mutations. Cobicistat is an alternative agent to ritonavir for boosting plasma drug levels of darunavir among other antiretrovirals. Cobicistat is a more specific cytochrome P450 3A inhibitor than ritonavir without enzyme-inducing properties. This review describes the differing effects of cobicistat and ritonavir on metabolic enzymes, which explains their differing drug-drug interactions, and summarizes some of the studied drug-drug interactions for cobicistat. It also outlines the clinical development and data for a once-daily darunavir/cobicistat FDC. This FDC thus allows for a once-daily treatment regimen (including background antiretrovirals) with reduced pill burden.
Topics: Clinical Trials as Topic; Cobicistat; Cytochrome P-450 CYP3A Inhibitors; Darunavir; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Ritonavir; Treatment Outcome
PubMed: 25962100
DOI: 10.1586/14787210.2015.1033400 -
AIDS Reviews 2017Current antiretroviral therapy reaches and maintains viral suppression over the years in more than 90% of treated HIV-infected individuals. Although integrase inhibitors... (Review)
Review
Current antiretroviral therapy reaches and maintains viral suppression over the years in more than 90% of treated HIV-infected individuals. Although integrase inhibitors are the preferred third agent in antiretroviral therapy in the current guidelines, rilpivirine, a non-nucleoside reverse transcrip- tase inhibitor, and darunavir (DRV), a second-generation protease inhibitor, are the preferred third companion to be used along with a backbone of two nucleos(t)ide reverse transcriptase inhibitors as first-line triple HIV combination treatment. However, rilpivirine is not recommended in patients with plasma HIV-RNA above 100,000 copies/mL. Raltegravir requires uncomfortably twice daily dosing, whereas dolutegravir is often given as coformulation with abacavir, a drug that requires prior HLA-B5701 testing. Antiretroviral combinations based on DRV provide a unique robustness in terms of antiviral potency and resistance barrier, rendering this drug pivotal as part of rescue regimens for the treatment failures. Furthermore, dual antiretroviral therapy with DRV plus lami- vudine has been tested with success as maintenance therapy. Finally, DRV has demonstrated its safety and efficacy in special patient populations, including pregnant women, pediatrics, HIV-2 infection, and individuals coinfected with viral hepatitis. Single-tablet regimens containing DRV coformulated with cobicistat alone or with other antiretrovirals should improve drug adherence. These fixed-dose combinations represent a step forward universal antiretroviral regimen, ensuring maximal efficacy, tolerability, and convenience.
Topics: Darunavir; HIV Infections; HIV Protease Inhibitors; Humans
PubMed: 28664942
DOI: No ID Found -
AIDS Reviews 2017The dosage of darunavir/ritonavir is 800/100 mg once daily for treatment-naive patients or treatment-experienced patients with no prior darunavir resistance associated... (Review)
Review
The dosage of darunavir/ritonavir is 800/100 mg once daily for treatment-naive patients or treatment-experienced patients with no prior darunavir resistance associated mutations, and 600/100 mg twice daily for treatment-experienced patients with one or more darunavir resistance associated mutations. Results from the five available pharmacokinetic studies show reductions in total darunavir plasma concentrations of between 20-50% during the third trimester of pregnancy. The unbound darunavir concentrations have been measured only in subsets of patients in two of the five pharmacokinetic studies. The unbound concentrations were 11% higher during pregnancy in one study of the 600/100 mg twice-daily dosage, and 13-38% lower during pregnancy for the 800/100 mg once-daily dosage. Ratios of darunavir concentration in cord blood compared to maternal plasma are in the range of 0.11-0.18, suggesting that darunavir does not have high trans-placental penetration. Despite the decrease in exposure, the darunavir/ritonavir 800/100 mg once-daily regimen in HIV-positive pregnant women in combination with background antiretroviral therapy has been effective in preventing mother-to-child transmission in the studies included in this review. Among the 137 infants born across the five studies, there was one case of mother-to-child transmission, which was in a mother taking the 600/100 mg twice-daily dose but who had documented poor adherence to treatment.
Topics: Abnormalities, Drug-Induced; Animals; Anti-HIV Agents; Darunavir; Drug Therapy, Combination; Female; HIV Infections; Humans; Placenta; Pregnancy; Pregnancy Complications, Infectious; Ritonavir
PubMed: 28182610
DOI: No ID Found -
Paediatric Drugs Oct 2015Darunavir (Prezista®), administered in combination with ritonavir and background antiretroviral therapy, is approved in the USA and the EU for the treatment of HIV-1... (Review)
Review
Darunavir (Prezista®), administered in combination with ritonavir and background antiretroviral therapy, is approved in the USA and the EU for the treatment of HIV-1 infection in pediatric patients aged ≥3 years. Ritonavir-boosted darunavir provided effective virologic suppression in treatment-naïve adolescents with HIV-1 infection, according to the results of the noncomparative, phase II DIONE trial. Ritonavir-boosted darunavir also had sustained efficacy in treatment-experienced children and/or adolescents with HIV-1 infection, according to the results of the noncomparative, phase II DELPHI and ARIEL trials. Ritonavir-boosted darunavir was generally well tolerated in pediatric patients with HIV-1 infection. Although more data are needed in pediatric populations (particularly data comparing darunavir with other antiretroviral agents), ritonavir-boosted darunavir is an important option for the treatment of pediatric patients with HIV-1 infection.
Topics: Anti-Retroviral Agents; Child; Darunavir; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans
PubMed: 26323490
DOI: 10.1007/s40272-015-0146-0 -
Enfermedades Infecciosas Y... Dec 2018Darunavir is the gold standard protease inhibitor in antiretroviral treatment. It has undergone complete development through randomised clinical trials throughout the... (Review)
Review
Darunavir is the gold standard protease inhibitor in antiretroviral treatment. It has undergone complete development through randomised clinical trials throughout the entire spectrum of HIV infection, with 2 different dosages and clear indications of when to use each one of them. It has been studied in mono, dual and triple therapy. It can also be administered boosted with either ritonavir or cobicistat. The data indicate that it is the antiretroviral with the greatest barrier against resistance development and that it is the drug with the longest residence time bound to its receptor (protease), thus having the longest dissociation time. Its limited impact on selected mutations in the protease by other inhibitors and its high barrier against resistance have resulted in its widespread commercial use being associated with a steady decrease in the mutations circulating in the protease having an impact on its activity. Supplement information: This article is part of a supplement entitled "Co-formulated cobicistat-boosted darunavir, emtricitabine, and tenofovir alafenamide for the treatment of HIV infection", which is sponsored by Janssen.
Topics: Darunavir; Drug Resistance, Viral; HIV Infections; HIV Protease Inhibitors; Humans
PubMed: 30545469
DOI: 10.1016/S0213-005X(18)30391-4 -
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