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PURPOSE: Dysregulations of key signaling pathways in metabolic syndrome are multifactorial, eventually leading to cardiovascular events. Hyperglycemia in conjunction with dyslipidemia induces insulin resistance and provokes release of proinflammatory cytokines resulting in chronic inflammation, accelerated lipid peroxidation with further development of atherosclerotic alterations and diabetes. We have proposed a novel combinatorial approach using FDA approved compounds targeting IL-17a and DPP4 to ameliorate a significant portion of the clustered clinical risks in patients with metabolic syndrome. In our current research we have modeled the outcomes of metabolic syndrome treatment using two distinct drug classes. METHODS: Targets were chosen based on the clustered clinical risks in metabolic syndrome: dyslipidemia, insulin resistance, impaired glucose control, and chronic inflammation. Drug development platform, BIOiSIM™, was used to narrow down two different drug classes with distinct modes of action and modalities. Pharmacokinetic and pharmacodynamic profiles of the most promising drugs were modeling showing predicted outcomes of combinatorial therapeutic interventions. RESULTS: Preliminary studies demonstrated that the most promising drugs belong to DPP-4 inhibitors and IL-17A inhibitors. Evogliptin was chosen to be a candidate for regulating glucose control with long term collateral benefit of weight loss and improved lipid profiles. Secukinumab, an IL-17A sequestering agent used in treating psoriasis, was selected as a repurposed candidate to address the sequential inflammatory disorders that follow the first metabolic insult. CONCLUSIONS: Our analysis suggests this novel combinatorial therapeutic approach inducing DPP4 and Il-17a suppression has a high likelihood of ameliorating a significant portion of the clustered clinical risk in metabolic syndrome.
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Resistencia a la Insulina , Síndrome Metabólico , Humanos , Síndrome Metabólico/tratamiento farmacológico , Interleucina-17 , Glucemia/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Transducción de Señal , InflamaciónRESUMEN
The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca2+-mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors and calcium channel blockers (CCBs), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCBs and ACEi compounds to tissues implicated in COVID-19 pathogenesis.
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Antivirales/farmacocinética , Tratamiento Farmacológico de COVID-19 , Reposicionamiento de Medicamentos/métodos , Hipertensión Pulmonar/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacocinética , Antivirales/sangre , Biosimilares Farmacéuticos , COVID-19/complicaciones , Bloqueadores de los Canales de Calcio/farmacocinética , Simulación por Computador , Bases de Datos Farmacéuticas , Desarrollo de Medicamentos/métodos , Humanos , Hipertensión Pulmonar/virología , Distribución TisularRESUMEN
Fluoroquinolones (FQs) are a widespread class of broad-spectrum antibiotics prescribed as a first line of defense, and, in some cases, as the only treatment against bacterial infection. However, when administered orally, reduced absorption and bioavailability can occur due to chelation in the gastrointestinal tract (GIT) with multivalent metal cations acquired from diet, coadministered compounds (sucralfate, didanosine), or drug formulation. Predicting the extent to which this interaction reduces in vivo antibiotic absorption and systemic exposure remains desirable yet challenging. In this study, we focus on quinolone interactions with magnesium, calcium and aluminum as found in dietary supplements, antacids (Maalox) orally administered therapies (sucralfate, didanosine). The effect of FQ-metal complexation on absorption rate was investigated through a combined molecular and pharmacokinetic (PK) modeling study. Quantum mechanical calculations elucidated FQ-metal binding energies, which were leveraged to predict the magnitude of reduced bioavailability via a quantitative structure-property relationship (QSPR). This work will help inform clinical FQ formulation design, alert to possible dietary effects, and shed light on drug-drug interactions resulting from coadministration at an earlier stage in the drug development pipeline.
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The use of opioid analgesics in treating severe pain is frequently associated with putative adverse effects in humans. Topical agents that are shown to have high efficacy with a favorable safety profile in clinical settings are great alternatives for pain management of multimodal analgesia. However, the risk of side effects induced by transdermal absorption and systemic exposure is of great concern as they are challenging to predict. The present study aimed to use "BIOiSIM" an artificial intelligence-integrated biosimulation platform to predict the transdermal disposition of opioid analgesics. The model successfully predicted their exposure following the topical application of central opioid agonist buprenorphine and peripheral agonist oxycodone in healthy human subjects with simulation of intra-skin exposure in subjects with burns and pressure wounds. The predicted plasma levels of analgesics were used to evaluate the safety of the therapeutic pain control in patients with the dermal structural impairments caused by acute (burns) or chronic cutaneous lesions (pressure wounds) with topical opioid analgesics.
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Prediction of the first-in-human dosing regimens is a critical step in drug development and requires accurate quantitation of drug distribution. Traditional in vivo studies used to characterize clinical candidate's volume of distribution are error-prone, time- and cost-intensive and lack reproducibility in clinical settings. The paper demonstrates how a computational platform integrating machine learning optimization with mechanistic modeling can be used to simulate compound plasma concentration profile and predict tissue-plasma partition coefficients with high accuracy by varying the lipophilicity descriptor logP. The approach applied to chemically diverse small molecules resulted in comparable geometric mean fold-errors of 1.50 and 1.63 in pharmacokinetic outputs for direct tissue:plasma partition and hybrid logP optimization, with the latter enabling prediction of tissue permeation that can be used to guide toxicity and efficacy dosing in human subjects. The optimization simulations required to achieve these results were parallelized on the AWS cloud and generated outputs in under 5 h. Accuracy, speed, and scalability of the framework indicate that it can be used to assess the relevance of other mechanistic relationships implicated in pharmacokinetic-pharmacodynamic phenomena with a lower risk of overfitting datasets and generate large database of physiologically-relevant drug disposition for further integration with machine learning models.
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INTRODUCTION: Transdermal drug delivery is gaining popularity as an alternative to traditional routes of administration. It can increase patient compliance because of its painless and noninvasive nature, aid compounds in bypassing presystemic metabolic effects, and reduce the likelihood of adverse effects through decreased systemic exposure. In silico physiological modeling is critical to predicting dermal exposure for a therapeutic and assessing the impact of different formulations on transdermal disposition. METHODS: The present study aimed at developing a physiologically based transdermal platform, "BIOiSIM", that could be globally applied to a wide variety of compounds to predict their transdermal disposition. The platform integrates a 16-compartment model of compound pharmacokinetics and was used to simulate and predict drug exposure of three chemically and biologically distinct drug-like compounds. Machine learning optimization was composed of two components: exhaustive search algorithm (coarse-tuning) and descent (fine-tuning) integrated with the platform used to quantitatively determine parameters influencing pharmacokinetics (eg permeability, kperm) of test compounds. RESULTS: The model successfully predicted drug exposure (AUC, Cmax and Tmax) following transdermal application of morphine, buprenorphine and nicotine in human subjects, mostly with less than two-fold absolute average fold error (AAFE). The model was further able to successfully characterize the relationship between observed systemic exposure and intended pharmacological effect. The predicted systemic concentration of morphine and plasma levels of endogenous pain biomarkers were used to estimate the effectiveness of a given therapeutic regimen. CONCLUSION: BIOiSIM marks a novel approach to in silico prediction that will enable leveraging of machine learning technology in the pharmaceutical space. The approach to model development outlined results in scalable, accurate models and enables the generation of large parameter/coefficient datasets from in vivo clinical data that can be used in future work to train quantitative structure activity relationship (QSAR) models for predicting likelihood of compound utility as a transdermally administered therapeutic.