On 11 March 2020, the World Health Organization (WHO) classified the Coronavirus Disease 2019 (COVID-19) as a global pandemic, which tested healthcare systems, administrations, and treatment ingenuity across the world. COVID-19 is caused by the novel beta coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Since the inception of the pandemic, treatment options have been either limited or ineffective. Remdesivir, a drug originally designed to be used for Ebola virus, has antiviral activity against SARS-CoV-2 and has been included in the COVID-19 treatment regimens. Remdesivir is an adenosine nucleotide analog prodrug that is metabolically activated to a nucleoside triphosphate metabolite (GS-443902). The active nucleoside triphosphate metabolite is incorporated into the SARS-CoV-2 RNA viral chains, preventing its replication. The lack of reported drug development and characterization studies with remdesivir in public domain has created a void where information on the absorption, distribution, metabolism, elimination (ADME) properties, pharmacokinetics (PK), or drug-drug interaction (DDI) is limited. By understanding these properties, clinicians can prevent subtherapeutic and supratherapeutic levels of remdesivir and thus avoid further complications in COVID-19 patients. Remdesivir is metabolized by both cytochrome P450 (CYP) and non-CYP enzymes such as carboxylesterases. In this narrative review, we have evaluated the currently available ADME, PK, and DDI information about remdesivir and have discussed the potential of DDIs between remdesivir and different COVID-19 drug regimens and agents used for comorbidities. Considering the nascent status of remdesivir in the therapeutic domain, extensive future work is needed to formulate safer COVID-19 treatment guidelines involving this medication.

Vitamin D3 is an endogenous fat-soluble secosteroid, either biosynthesized in human skin or absorbed from diet and health supplements. Multiple hydroxylation reactions in several tissues including liver and small intestine produce different forms of vitamin D3. Low serum vitamin D levels is a global problem which may origin from differential absorption following supplementation. The objective of the present study was to estimate the physicochemical properties, metabolism, transport and pharmacokinetic behavior of vitamin D3 derivatives following oral ingestion. GastroPlus software, which is an in silico mechanistically-constructed simulation tool, was used to simulate the physicochemical and pharmacokinetic behavior for twelve vitamin D3 derivatives. The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules were employed to derive the relevant parameters from the structural features of the compounds. The majority of the vitamin D3 derivatives are lipophilic (log P values >5) with poor water solubility which are reflected in the poor predicted bioavailability. The fraction absorbed values for the vitamin D3 derivatives were low except for calcitroic acid, 1,23S,25-trihydroxy-24-oxo-vitamin D3, and (23S,25R)-1,25-dihydroxyvitamin D3-26,23-lactone each being greater than 90% fraction absorbed. Cytochrome P450 3A4 (CYP3A4) is the primary hepatic enzyme along with P-glycoprotein involved in the disposition of the vitamin D derivatives. Lipophilicity and solubility appear to be strongly associated with the oral absorption of the vitamin D3 derivatives. Understanding the ADME properties of vitamin D3 derivatives with the knowledge of pharmacological potency could influence the identification of pharmacokinetically most acceptable vitamin D3 derivative for routine supplementation.

ObjectiveTo assess the risk of neuropsychiatric adverse effects (ie, depression, anxiety, insomnia, dizziness, suicidal behaviour) among patients treated with rilpivirine, dolutegravir and dolutegravir/rilpivirine.DesignThis is a systematic review and meta-analysis of randomised controlled trials. Quality of evidence was assessed using Jadad scoring system.Data sourcesThree electronic databases were searched for available publications up to 1 May 2020. Searches included relevant studies, trial registers, conference proceeding abstracts and grey literature.Inclusion criteriaRandomised controlled trials with data focused on adult participants (ie, 18 years of age or older) receiving dolutegravir 50 mg, rilpivirine 25 mg or combination of dolutegravir 50 mg/rilpivirine 25 mg once daily.ResultsTwenty studies with a minimum duration of 48 weeks and average Jadad score of 4 were included (n=10 998). Primary objective demonstrated a relative risk (RR) synergistic effect on depressive symptoms for dolutegravir/rilpivirine (RR=2.82; 95% CI (1.12 to 7.10)) when compared with dolutegravir (RR=1.10; 95% CI (0.88 to 1.38)) and rilpivirine (RR=1.08; 95% CI (0.80 to 1.48)). Secondary objectives showed no difference between dolutegravir, rilpivirine and dolutegravir/rilpivirine to efavirenz. Additionally, excluding efavirenz studies, dolutegravir and dolutegravir/rilpivirine yielded increased depression (RR=1.34; 95% CI (1.04 to 1.74)).ConclusionThe combination of dolutegravir/rilpivirine appears to increase the risk of depressive symptoms. Despite the increase, the clinical significance is unknown and needs further study. Additionally, neurotoxicity risk appears similar between dolutegravir, rilpivirine and dolutegravir/rilpivirine antiretroviral therapy when compared with efavirenz-based antiretroviral therapy.

Purpose: Remdesivir, a drug originally developed against Ebola virus, is currently recommended for patients hospitalized with coronavirus disease of 2019 (COVID-19). In spite of United States Food and Drug Administration’s recent assent of remdesivir as the only approved agent for COVID-19, there is limited information available about the physicochemical, metabolism, transport, pharmacokinetic (PK), and drug-drug interaction (DDI) properties of this drug. The objective of this in silico simulation work was to simulate the biopharmaceutical and DDI behavior of remdesivir and characterize remdesivir PK properties in special populations which are highly affected by COVID-19. Methods: The Spatial Data File format structures of remdesivir prodrug (GS-5734) and nucleoside core (GS-441524) were obtained from the PubChem database to upload into the GastroPlus software 9.8 version (Simulations Plus Inc., USA). The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules of GastroPlus were used to simulate physicochemical and PK properties, respectively, in healthy and predisposed patients. Physiologically based pharmacokinetic (PBPK) modeling of GastroPlus was used to simulate different patient populations based on age, weight, liver function, and renal function status. Subsequently, these data were used in the Drug-Drug Interaction module to simulate drug interaction potential of remdesivir with other COVID-19 drug regimens and with agents used for comorbidities. Results: Remdesivir nucleoside core (GS-441524) is more hydrophilic than the inactive prodrug (GS-5734) with nucleoside core demonstrating better water solubility. GS-5734, but not GS-441524, is predicted to be metabolized by CYP3A4. Remdesivir is bioavailable and its clearance is achieved through hepatic and renal routes. Differential effects of renal function, liver function, weight, or age were observed on the PK profile of remdesivir. DDI simulation study of remdesivir with perpetrator drugs for comorbidities indicate that carbamazepine, phenytoin, amiodarone, voriconazole, diltiazem, and verapamil have the potential for strong interactions with victim remdesivir, whereas agents used for COVID-19 treatment such as chloroquine and ritonavir can cause weak and strong interactions, respectively, with remdesivir. Conclusions: GS-5734 (inactive prodrug) appears to be a superior remdesivir derivative due to its hepatic stability, optimum hydrophilic/lipophilic balance, and disposition properties. Remdesivir disposition can potentially be affected by different physiological and pathological conditions, and by drug interactions from COVID-19 drug regimens and agents used for comorbidities. Methods: The Spatial Data File format structures of remdesivir prodrug and nucleoside core were obtained from the PubChem database to upload into the GastroPlus software 9.8 version. The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) PredictorTM and PKPlusTM modules were used to simulate physicochemical and PK properties, respectively, in healthy and predisposed patients. Physiologically based pharmacokinetic (PBPK) modeling of GastroPlus was used to simulate different patient populations based on age, weight, liver function, and renal function status. Subsequently, these data were used in the Drug-Drug InteractionTM module to simulate drug interaction potential of remdesivir with other COVID-19 drug regimens and with agents used for commodities. Results: Remdesivir nucleoside core (GS-441524) is more hydrophilic than the inactive prodrug (GS-5734) with nucleoside core demonstrating better water solubility. GS-5734, but not GS-441524, is predicted to be metabolized by CYP3A4. Remdesivir is bioavailable and its clearance is achieved through hepatic and renal routes. Differential effects of renal function, liver function, weight, or age were observed on the PK profile of remdesivir. DDI simulation study of remdesivir with perpetrator drugs for comorbidities indicate that carbamazepine, phenytoin, amiodarone, voriconazole, diltiazem, and verapamil have the potential for strong interactions with victim remdesivir, whereas chloroquine and ritonavir can cause weak and strong interactions, respectively, with remdesivir. Conclusions: GS-5734 (inactive prodrug) appears to be a superior remdesivir derivative due to its hepatic stability, optimum hydrophilic/lipophilic balance, and disposition properties. Remdesivir disposition can potential be affected by different physiological and pathological conditions, and by drug interactions from COVID-19 drug regimens and agents used for comorbidities.

BackgroundVitamin D3 is an endogenous substance either biosynthesized in humans or absorbed from diet and health supplements. Although calcitriol, the most active form of vitamin D3, is primarily responsible for the health benefits of vitamin D3 including bone and anticancer functions, there are several derivatives in the metabolic pathways of vitamin D3. Calcitriol has largely been the focus of the disposition experimental studies but not the other vitamin D3 derivatives. The objective of this study was to identify the physicochemical and pharmacokinetic properties of vitamin D3 derivatives in silico.MethodsThirteen chemical structures of vitamin D3 derivatives were obtained from the PubChem and PubMed databases. The structures were imported to the GastroPlus software and simulations were run using the Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor module. The ADMET Predictor data were used to simulate the pharmacokinetic properties using physiologically‐based pharmacokinetic (PBPKPlus) modeling. The ADMET Predictor module provided the structure‐based physicochemical properties, cytochrome P450‐based metabolism and the ability to cross blood‐brain barrier by vitamin D3 derivatives. In comparison, the PBPKPlus module predicted the pharmacokinetic properties (e.g., bioavailability, half‐life, clearance) based on the physicochemical parameters. It also developed pharmacokinetic curves for the vitamin D3 derivatives and simulated concentration versus time plots. Microsoft Excel module was used to compile the data obtained and run lipophilicity (Log P) versus fraction absorbed (Fa) correlation analyses.ResultsThe predicted hydrogen ion (pH) values ranged from 3.0 to 9.0 with calcitriol having a lipophilicity of 5.5 units. The structures with more hydroxyl groups have better solubility values than the structures with fewer hydroxyl groups. The fraction absorbed values for the vitamin D3 derivatives were low except for calcitroic acid, 1,23,25‐trihydroxy‐24‐oxo‐vitamin D3, and 1,25‐dihydroxyvitamin D3‐26,23‐lactone each being greater than 90% fraction absorbed. The half‐lives ranged from 1.2 to 8.0 hours with 1,23,25‐trihydroxyvitamin D3 having the lowest half‐life of 1.2 hours. Most of the vitamin D3 derivatives have high blood‐brain barrier penetration ability except for calcitetrol, 1,23,25 trihydroxyvitamin D3, and 1,23,25‐trihydroxy‐24‐oxo‐vitamin D3. The lipophilicity (Log P) versus fraction absorbed (Fa) of all the vitamin D3 derivatives studied yielded a correlation (r2) of 0.66.ConclusionSimulation data from GastroPlus indicate that vitamin D3 pathway has several structurally‐related compounds with differential physicochemical and pharmacokinetic properties that ranged from being hydrophilic to lipophilic and thus influencing their plasma concentration. The hydrophilic derivatives of vitamin D3 have higher fraction absorbed over the lipophilic ones. Understanding the ADME properties of vitamin D3 derivatives with the knowledge of pharmacological potency could influence the identification of pharmacokinetically most acceptable vitamin D3 derivative for routine supplementation.Support or Funding InformationGastroPlus software was provided by Simulations Plus, Inc. (Lancaster, CA).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.