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Introduction: Drug-drug cocrystals of Lopinavir and Ritonavir were designed and characterized. In view of literature, Ritonavir increases the oral bioavailability of Lopinavir in low dosage. Aim: The present research aimed to improve the solubility, dissolution, and oral bioavailability of Lopinavir through a cocrystallization approach using Ritonavir as a coformer. Materials and Methods: Cocrystallization was carried out using wet grinding and solvent evaporation methods. Prepared Cocrystals were examined and evaluated using characterization methods such as DSC, PXRD, FTIR, Polarized light microscopy, % Drug content, FE-SEM, Micromeritics properties, Solubility, Dissolution, and Stability studies as per ICH guidelines. Results: Developed cocrystals were showed superior solubility and dissolution as compared to pure drug. After 48 hr, aqueous solubility of Lopinavir and Ritonavir co-amorphous formulation (LRCWG) was increased 3.7-fold in the wet grinding method, while Lopinavir and Ritonavir Cocrystals Prepared by Solvent Evaporation Method (LRCSE) indicated 5.9-fold increase compared to pure drug. The co-amorphous formulation was developed using wet grinding showed 86% drug release at 60 min, and cocrystals synthesized through solvent evaporation method showed 94% of drug release. Conclusion: Cocrystals produced using solvent evaporation approach were stable and showed excellent physico-chemical characteristics. The study concluded that the cocrystallization approach would prove to be a successful method to improve physico-chemical and mechanical properties. [ABSTRACT FROM AUTHOR]

• Randomized, placebo-controlled trial of lopinavir/ritonavir against COVID-19. • Enrolled outpatient participants within 6 days of positive SARS-CoV-2 antigen test. • Prioritized remote data collection via daily surveys. • Lopinavir/ritonavir did not improve outcomes relative to placebo for COVID-19. Effective and widely available therapies are still needed for outpatients with COVID-19. We aimed to evaluate the efficacy and safety of lopinavir/ritonavir (LPV/r) for early treatment of non-hospitalized individuals diagnosed with COVID-19. This randomized, placebo (Plb)-controlled, double-blind, multi-site decentralized clinical trial enrolled non-hospitalized adults with confirmed SARS-CoV-2 infection and six or fewer days of acute respiratory infection symptoms who were randomized to either twice-daily oral LPV/r (400 mg/100 mg) or Plb for 14 days. Daily surveys on study days 1 through 16 and again on study day 28 evaluated symptoms, daily activities, and hospitalization status. The primary outcome was longitudinal change in an ordinal scale based on a combination of symptoms, activity, and hospitalization status through day 15 and was analyzed by use of a Bayesian longitudinal proportional odds logistic regression model for estimating the probability of a superior recovery for LPV/r over Plb (odds ratio >1). Between June 2020 and December 2021, 448 participants were randomized to receive either LPV/r (n = 216) or Plb (n = 221). The mean symptom duration before randomization was 4.3 days (SD 1.3). There were no differences between treatment groups through the first 15 days for the ordinal primary outcome (odds ratio 0.96; 95% credible interval: 0.66 to 1.41). There were 3.2% (n = 7) of LPV/r and 2.7% (n = 6) of Plb participants hospitalized by day 28. Serious adverse events did not differ between groups. LPV/r did not significantly improve symptom resolution or reduce hospitalization in non-hospitalized participants with COVID-19. ClinicalTrials.gov Identifier: NCT04372628 [ABSTRACT FROM AUTHOR]

Lopinavir/ritonavir (LPV/r) is recommended by the World Health Organization as first-line treatment for HIV-infected infants and young children. We performed a composite population pharmacokinetic (PK) analysis on LPV plasma concentration data from 6 pediatric and adult studies to determine maturation and formulation effects from infancy to adulthood. Intensive PK data were available for infants, children, adolescents, and adults (297 intensive profiles/1662 LPV concentrations). LPV PK data included 1 adult, 1 combined pediatric-adult, and 4 pediatric studies (age 6 weeks to 63 years) with 3 formulations (gel-capsule, liquid, melt-extrusion tablets). LPV concentrations were modeled using nonlinear mixed effects modeling (NONMEM v. 7.3; GloboMax, Hanover, Maryland) with a one compartment semiphysiologic model. LPV clearance was described by hepatic plasma flow (QHP ) times hepatic extraction (EH ), with EH estimated from the PK data. Volume was scaled by linear weight (WT/70)1.0 . Bioavailability was assessed separately as a function of hepatic extraction and the fraction absorbed from the gastrointestinal tract. The absorption component of bioavailability increased with age and tablet formulation. Monte Carlo simulations of the final model using current World Health Organization weight-band dosing recommendations demonstrated that participants younger than 6 months of age had a lower area under the drug concentration-time curve (94.8 vs >107.4 μg hr/mL) and minimum observed concentration of drug in blood plasma (5.0 vs > 7.1 μg/mL) values compared to older children and adults. Although World Health Organization dosing recommendations include a larger dosage (mg/m2 ) in infants to account for higher apparent clearance, they still result in low LPV concentrations in many infants younger than 6 months of age receiving the liquid formulation.

Enzyme inhibitors are frequently used to treat viral illnesses. Protease inhibitors are a promising class for combating novel and life-threatening viral infections. This research aimed to evaluate the efficacy and safety of lopinavir/ritonavir monotherapy or lopinavir/ritonavir plus interferon for the treatment of COVID-19. The PubMed, Scopus, Web of Science, and Cochrane Library databases were searched for English articles with full texts available online. ReviewManager software was used to conduct a meta-analysis, subgroup analysis, and sensitivity analysis. Following the creation of the protocol, the collected sources were sorted into categories and evaluated for quality. Risk and hazard ratios and the random effects model were implemented, with statistical heterogeneity assigned using the Higgins I2 statistic. Lopinavir/ritonavir, with or without interferon, was associated with a nonsignificant higher mortality rate (odds ratio [OR] 1.29; 95% confidence interval [CI] 0.95 to 1.761; p = 0.1), as was clinical improvement (OR 1.2; 95% CI 0.8 to 1.84; p = 0.36). The difference in the length of hospital stay was in favor of the control group but statistically insignificant (standardized mean difference [SMD] 0.07; 95% CI −0.44 to 0.57; p = 0.79). The pooled data showed that lopinavir/ritonavir, with or without interferon, was associated with a significantly higher number of adverse events than placebo (OR 1.2; 95% CI 1.09 to 2.34; p = 0.02). Serious adverse events were insignificantly increased in the treated group over the control group (OR 1.2; 95% CI 0.96 to 2.12; p = 0.08). In the subgroup analysis, it was found that interferon used with lopinavir/ritonavir did not have a statistically significant effect on mortality rates (OR 1.75; 95% CI 0.87 to 3.55; p = 0.37), adverse effects (OR 1.20; 95% CI 0.75 to 1.91; p = 0.27), or serious adverse effects (OR 1.86; 95% CI 1.17 to 2.96; p = 0.33). Treatment with lopinavir/ritonavir alone or in combination with interferon for COVID-19 did not significantly outperform placebo in this study. Large randomized clinical trials are required to evaluate lopinavir/ritonavir in conjunction with interferon for the treatment of COVID-19. Such studies would benefit greatly from being conducted in a double-blind fashion at multiple locations. [ABSTRACT FROM AUTHOR]

A current clinical challenge in cancer is multidrug resistance (MDR) mediated by ABC transporters. Breast cancer resistance protein (BCRP) or ABCG2 transporter is one of the most important ABC transporters implicated in MDR and the use of inhibitors is a promising approach to overcome the resistance in cancer. This study aimed to characterize the molecular mechanism of ABCG2 inhibitors identified by a repurposing drug strategy using antiviral, anti-inflammatory and antiparasitic agents. Lopinavir and ivermectin can be considered as pan-inhibitors of ABC transporters, since both compounds inhibited ABCG2, P-glycoprotein and MRP1. They inhibited ABCG2 activity showing IC50 values of 25.5 and 23.4 µM, respectively. These drugs were highly cytotoxic and not transported by ABCG2. Additionally, these drugs increased the 5D3 antibody binding and did not affect the mRNA and protein expression levels. Cell-based analysis of the type of inhibition suggested a non-competitive inhibition, which was further corroborated by in silico approaches of molecular docking and molecular dynamics simulations. These results showed an overlap of the lopinavir and ivermectin binding sites on ABCG2, mainly interacting with E446 residue. However, the substrate mitoxantrone occupies a different site, binding to the F436 region, closer to the L554/L555 plug. In conclusion, these results revealed the mechanistic basis of lopinavir and ivermectin interaction with ABCG2. [ABSTRACT FROM AUTHOR]

Lopinavir and ritonavir (LPV/r) are the primary anti-human immunodeficiency virus (HIV) drugs recommended by the World Health Organization for treating children aged 3 years and above who are infected with the HIV. These drugs are typically available in liquid formulations to aid in dosing for children who cannot swallow tablets. However, the strong bitter taste associated with these medications can be a significant obstacle to adherence, particularly in young children, and can jeopardize the effectiveness of the treatment. Studies have shown that poor palatability can affect the survival rate of HIV-infected children. Therefore, developing more child-friendly protease inhibitor formulations, particularly those with improved taste, is critical for children with HIV. The molecular mechanism by which lopinavir and ritonavir activate bitter taste receptors, TAS2Rs, is not yet clear. In this study, we utilized a calcium mobilization assay to characterize the activation of bitter taste receptors by lopinavir and ritonavir. We discovered that lopinavir activates TAS2R1 and TAS2R13, while ritonavir activates TAS2R1, TAS2R8, TAS2R13, and TAS2R14. The development of bitter taste blockers that target these receptors with a safe profile would be highly desirable in eliminating the unpleasant bitter taste of these anti-HIV drugs. [ABSTRACT FROM AUTHOR]

Lopinavir/ritonavir is a potent coformulation of protease inhibitors used against HIV infection. Lopinavir is the main responsible for viral load suppression, whereas ritonavir is a pharmacokinetic enhancer. Both of them have recently gained relevance as candidate drugs against severe coronavirus disease (COVID-19). However, significant beneficial effects were not observed in randomized clinical trials. This review summarizes the main physical-chemical, pharmacodynamic, and pharmacokinetic properties of ritonavir and lopinavir, along with the analytical methodologies applied for biological matrices, pharmaceutical formulations, and stability studies. The work also aimed to provide a comprehensive impurity profile for the combined formulation. Several analytical methods in four different pharmacopeias and 37 articles in literature were evaluated and summarized. Chromatographic methods for these drugs frequently use C8 or C18 stationary phases with acetonitrile and phosphate buffer (with ultraviolet detection) or acetate buffer (with tandem mass spectrometry detection) as the mobile phase. Official compendia methods show disadvantages as extended total run time and complex mobile phases. HPLC tandem-mass spectrometry provided high sensitivity in methodologies applied for human plasma and serum samples, supporting the therapeutic drug monitoring in HIV patients. Ritonavir and lopinavir major degradation products arise in alkaline and acidic environments, respectively. Other non-chromatographic methods were also summarized. Establishing the impurity profile for the combined formulation is challenging due to a large number of impurities reported. Easier and faster analytical methods for impurity assessment are still needed. [ABSTRACT FROM AUTHOR]

A liquid chromatography tandem mass spectrometry (LC–MS/MS) method has been validated for quantification of three antiretroviral drugs (efavirenz [EFV], lopinavir [LPV], and ritonavir [RTV]) from human breast milk. The samples were extracted employing protein precipitation method using methanol as precipitating agent. The supernatant was evaporated and reconstituted before injecting into the chromatograph and separated on a biphenyl column. Calibration curves for the three tested antiretroviral drugs were linear (r ≥ 0.999) over the range examined. The inter‐ and intra‐day coefficients of variation (CV) were ≤15% for efavirenz, lopinavir, and ritonavir. Mean recovery ranged from 96% to 105% and no major matrix effects were observed. This validated LC–MS/MS method was efficiently applied to determine EFV, LPV, and RTV concentrations in breast milk from Human Immunodeficiency Virus (HIV)‐positive breastfeeding mothers. This assay requires a simple sample processing method with a short run time, making it well suited for high‐throughput routine clinical or research purposes. [ABSTRACT FROM AUTHOR]

The environment has rapidly looked at proven specialist task forces in the aftermath of the COVID-19 pandemic to build public health policies and measures to mitigate the effects of emerging coronaviruses. According to the researchers, taking 10 μg of 25-hydroxy vitamin D daily is recommended to keep us safe. There have been several studies recently indicating that there is a reduced risk of contracting Coronavirus by 25-hydroxy vitamin D consumption, even though there is no scientific data to prove that one would not affect the COVID-19 viral infection by 25-hydroxy vitamin D consumption. In this regard, the present study investigates the important literature and the role of 25-hydroxy vitamin D to prevent COVID-19 infection by conducting an in-silico study with SARS-CoV-2 spike protein as a target. Lopinavir, a previously reported drug candidate, served as a reference standard for the study. MD simulations were carried out to improve predictions of receptor-ligand complexes which offer novelty and strength to the current study. MD simulation protocols were explored and subjected to 25-hydroxy vitamin D and a known drug, Lopinavir. Comparison of ligands at refined models to the crystal structure led to promising results. Appropriate timescale simulations have been used to understand the activation mechanism, the role of water networks for receptor function, and the ligand binding process. Furthermore, MD simulations in combination with free energy calculations have also been carried out for lead optimization, evaluation of ligand binding modes, and assessment of ligand selectivity. From the results, 25-hydroxy vitamin D was discovered to have the vital interaction and highest potency in LBE, lower RMSD, and lower inhibition intensity similar to the standard. The findings from the current study suggested that 25-hydroxy vitamin D would be more effective in treating COVID-19. Compared with Lopinavir, 25-hydroxy vitamin D had the most potent interaction with the putative binding sites of the SARS-CoV-2 spike protein of COVID-19. [ABSTRACT FROM AUTHOR]

According to a number of studies, medicinal plants and drugs based on them can be used as inhibitors of various viral infections, including the SARS-CoV-2 virus at different stages of their manifestation and development. In a number of countries, official recommendations have been developed for independent and auxiliary therapy of COVID-19 with medicinal plants and drugs based on them. However, in combination with drugs developed for the treatment of COVID-19, various interactions, including adverse ones, may occur.Purpose: to systematize and analyze data on possible interactions of medicinal plants and natural biologically active substances, which are major active substances in plant raw materials, with medicinal products recommended for the treatment of COVID-19.Materials and methods. The study selected drugs recommended for the treatment of COVID-19 at various stages and severity with different mechanisms of action. We used open information on confirmed drug interactions on the website of the international database https://go.drugbank.com/. Results and discussion. The results of possible interactions with the following medicinal plants were revealed: St. John’s wort, Digitalis, Periwinkle, Colchicum, Cinchona, Strophant, Ergot, Pepper, Lemon, Coffee, Tea, Yohimbe tree, Garlic, Evening primrose, Poppy opium, Rauwolfia serpentine.Conclusion. The drugs used for the treatment of COVID-19 of different anatomical and therapeutic groups are considered, possible changes in their therapeutic efficacy are identified when taken simultaneously with medicinal plants or biologically active substances of plant origin contained in food and nutritional supplements. It is shown that not all interactions may be undesirable. The effect of medicinal plants on the pharmacokinetics of drugs has not been studied enough and seems to be an important and promising aspect of pharmacovigilance activities. Interesting interactions have been identified: St. John’s wort and drugs based on it can cause the induction of CYP3A and reduce the therapeutic effect when used together with drugs: lopinavir, remdesivir, umifenovir, nirmatrelvir; the cardiotoxic effect of interferon can be reduced through the use of medicinal plant materials containing cardiac glycosides; the combination of ferulic acid with peginterferon alfa-2a increases the risk and severity of bleeding. It was found that the Drugbank database does not contain information on drug-drug interactions of medicinal plants with molnupiravir.