In Silico Prediction of Andrographolide Dosage Regimens for COVID-19 Treatment
Teerachat Saeheng, Juntra Karbwang, Kesara Na-Bangchang
The American Journal of Chinese Medicine, doi:10.1142/s0192415x22500732
Andrographolide (APE) has been used for COVID-19 treatment in various clinical settings in South-East Asia due to its benefits on reduction of viral clearance and prevention of disease progression. However, the limitation of APE clinical use is the high incidence of adverse events. The objective of this study was to find the optimal dosage regimens of APE for COVID-19 treatment. The whole-body physiologically-based pharmacokinetic (PBPK) models were constructed using data from the published articles and validated against clinical observations. The inhibitory effect of APE was determined for the potency of drug efficacy. For prevention of pneumonia, multiple oral doses such as 120 mg for three doses, followed by 60 mg three times daily for 4 consecutive days, or 200 mg intravenous infusion at the rate of 20 mg/h once daily is advised in patients with mild COVID-19. For prevention of pneumonia and reduction of viral clearance time, the recommended dosage regimen is 500 mg intravenous infusion at the rate of 25 mg/h once daily in patients with mild-tomoderate COVID-19. One hundred virtual populations (50 males and 50 females) were simulated for oral and intravenous infusion formulations of APE. The eligible PBPK/PD models successfully predicted optimal dosage regimens and formulations of APE for prevention of disease progression and/or reduction of viral clearance time. Additionally, APE should be co-administered with other antiviral drugs to enhance therapeutic efficacy for COVID-19 treatment.
Cholangiocarcinoma (No. 1/2556 , dated 12 October 2013 ), and the National Research Council of Thailand (No. 45/2561 , dated 10 September 2018) . K.N. was supported by the National Research Council of Thailand under the Research Team Promotion grant (grant number NRCT 820/2563, dated 12 November 2020).
Supplementary Information
References
Atzori, Villani, Regazzi, Cargnel, Detection of intrapulmonary concentration of lopinavir in an HIV-infected patient, AIDS
Baneyx, Parrott, Meille, Iliadis, Lavé, Physiologically-based pharmacokinetic modeling of CYP3A4 induction by rifampicin in human: Influence of time between substrate and inducer administration, Eur. J. Pharm. Sci
Benjapolpitak, Visitanon, Sawangthum, Thanirat, Vannarat, Short report on the use of Andrographis paniculata as treatment of COVID-19 patients, J. Thai. Trad. Alt. Med
Camon, Alonso, Munoz, Cardozo, Bernal-Maurandi et al., Hospital Clinic of Barcelona COVID-19 Research Group. C-reactive protein cut-off for early tocilizumab and dexamethasone prescription in hospitalized patients with COVID-19, Sci. Rep
Cui, Merritt, Assa, Mustehsan, Chung et al., Early and significant reduction in C-reactive protein levels after corticosteroid therapy is associated with reduced mortality in patients with COVID-19, J. Hosp. Med
Ernest, Hall, Jones, Mechanism-based inactivation of CYP3A by HIV protease inhibitors, J. Pharm. Exp. Ther
Eron, Feinberg, Kressler, Horowitz, Witt et al., Once-daily dose versus twice-daily lopinavir-ritonavir in antiretroviral-naïve HIV-positive patients: A 48week randomized clinical trial, J. Infect. Dis
Gao, Su, Wang, Xiong, Sun et al., Integrated computer-aided formulation design: A case study of andrographolide/cyclodextrin ternary formulation, Asian. J. Pharm
Hsu, Granneman, Witt, Locke, Denissen et al., Re-use and distribution is strictly not permitted, except for Open Access articles. pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects, Am. J. Chin. Med.
Kigen, Edwards, Drug-transporter mediated interactions between anthelminthic and antiretroviral drugs across the Caco-2 cell monolayers, BMC Pharmacol. Toxicol
Kirby, Collier, Kharasch, Whittington, Thummel et al., Complex drug interactions of HIV protease inhibitors 1: Inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir, Drug Metab. Dispos
Koudriakova, Iatsimirskaia, Utkin, Vouros, Storozhuk et al., Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochrome P4503A by ritonavir, Drug Metab. Dispos
Li, He, Tang, Ding, Chu et al., Andrographolide inhibits inflammatory cytokines secretion in LPSstimulated RAW264.7 cells through suppression of NF-κB/MAPK signaling pathway, Evid.-Based Complement. Altern. Med
Lim, Chan, Tan, The, Razak et al., Andrographis paniculata (Burm.F.) Wall. Ex Nees, andrographolide, and andrographolide analogues as SARs-CoV-2 antivirals? A rapid review, Nat. Prod. Commun
Pandey, Rao, Andrographolide: Its pharmacology, natural bioavailability and current approaches to increase its content in Andrographis paniculata, Int. J. Complement. Alternat. Med
Panossian, Hovhannisyan, Mamikonyan, Abrahamian, Hambardzumyan et al., Pharmacokinetic and oral bioavailability of APE from Andrographis paniculata fixed combination Kan Jang in rats and human, Phytomedicine
Perazzolo, Zhu, Lin, Nguyen, Ho, Systems and clinical pharmacology of COVID-19 therapeutic candidates: A clinical and translational medicine perspective, J. Pharm. Sci
Pholphana, Panomvana, Rangkadilok, Suriyo, Puranajoti et al., Andrographis paniculata: Dissolution investigation and pharmacokinetic studies of four major active diterpenoids after multiple oral dose administration in healthy Thai volunteers, J. Ethnopharmacol
Rafiq, Iqbal, Jamil, Khan, Pharmacokinetic studies of rifampicin in healthy volunteers and tuberculosis patients, Int. J. Agric. Biol
Rasool, Khalid, Majeed, Saeed, Imran et al., Development and evaluation of physiologically-based pharmacokinetic drug-disease models for predicting rifampicin exposure in tuberculosis and cirrhosis populations, Pharmaceutics
Rattanaraksa, Poolwiwatchaikool, Nimitvilai, Loatrakul, Srimanee, The efficacy and safety of Andrographis paniculata Extract for treatment of COVID-19 patients with mild symptoms in Nakhonpathom hospital, Reg. 4-5 Med. J
Sa-Ngiamsuntorn, Suksatu, Pewkliang, Thongsri, Kanjanasirirat et al., Anti-SARs-CoV-2 activity of Andrographolis paniculata Extract and its major component Andrographolide in human lung epithelial cells and cytotoxicity evaluation in major organ cell representatives, J. Nat. Prod
Saeheng, Karbwang, Na-Bangchang, None, Am. J. Chin. Med.
Saeheng, Na-Bangchang, Karbwang, Utility of physiologically-based pharmacokinetic (PBPK) modeling in oncology drug development and its accuracy: A systematic review, Eur. J. Clin. Pharmacol
Saeheng, Na-Bangchang, Siccardi, Rajoli, Karbwang, Physiologically-based pharmacokinetic modeling for optimal dosage prediction of quinine coadministered with ritonavir-boosted lopinavir, Clin. Pharmacol. Ther
Siccardi, Rajoli, Dickinson, Khoo, Owen et al., In silico simulation of interaction between rifampicin and boosted darunavir
Stigliani, Haghi, Russo, Young, Traini, Antibiotic transport across bronchial epithelial Effects of molecular weight, LogP and apparent permeability, Eur. J. Pharm. Sci
Stoeckle, Witting, Kapadia, An, Marks, Elevated inflammatory markers are associated with poor outcomes in COVID-19 patients treated with remdesivir, J. Med. Virol
Tanwettiyanont, Piriyachananusorn, Sangsoi, Boonsong, Sunpapoa et al., The efficacy of Andrographis paniculata (Burm. F.) Wall. Ex Nees crude extract in hospitalized mild COVID-19 patients: A retrospective cohort study,
doi:10.1101/2022.01.01.22268609Vannarat, Andrographis paniculata in COVID-19 patients
Varma, Lai, Feng, Litchfield, Goosen et al., Physiologically based modeling of pravastatin transporter-mediated hepatobiliary disposition and drug-drug interactions, Pharm. Res
Wagner, Zhao, Arya, Mullick, Struble et al., Physiologically based pharmacokinetic modeling for predicting the effect of intrinsic and extrinsic factors on darunavir or lopinavir exposure co-administered with ritonavir, Jr. Clin. Pharm
Wannaratna, Leethong, Inchai, Chueawiang, Sriraksa et al., Efficacy and safety of Andrographis paniculata extract in patients with mild COVID-19: A randomized controlled trial, medRXiv,
doi:10.1101/2021.07.08.21259912Ye, Wang, Tang, Liu, Yang et al., Poor oral bioavailability of a promising anticancer agent andrographolide is due to extensive metabolism and efflux by P-glycoprotein, J. Pharm. Sci
Zhang, Lv, Zhou, Xie, Xu et al., Efficacy and safety of Xiyanping injection in the treatment of COVID-19: A multicenter, prospective, open-label and randomized controlled trial, Phytother. Res
Zhang, Mcilleron, Ren, Van Der Walt, Karlsson et al., Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children, Antivir. Ther
Zhao, Hu, Wang, Comparative metabolism and stability of andrographolide in liver microsomes from humans, dogs and rats using ultra-performance liquid chromatography coupled with triple-quadrupole and Fourier transform ion cyclotron resonance mass spectrometry, Rapid Commun. Mass Spectrom
Ziglam, Baldwin, Daniels, Andrew, Finch, Rifampicin concentrations in bronchial mucosa, epithelial lining fluid, alveolar macrophages, and serum following a single 600 mg oral dose in patients undergoing fibre-optic bronchoscopy, J. Antimicrob. Chemother
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'abstract': '<jats:p> Andrographolide (APE) has been used for COVID-19 treatment in various clinical '
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'regimens of APE for COVID-19 treatment. The whole-body physiologically-based pharmacokinetic '
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'clinical observations. The inhibitory effect of APE was determined for the potency of drug '
'efficacy. For prevention of pneumonia, multiple oral doses such as 120[Formula: see text]mg '
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'advised in patients with mild COVID-19. For prevention of pneumonia and reduction of viral '
'clearance time, the recommended dosage regimen is 500[Formula: see text]mg intravenous '
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