The Transfer of Molnupiravir and Nirmatrelvir Across the Human Placenta and Prediction of Drug Safety in Pregnancy
Zabek, Magdalene
;
Western University,2024.
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Abstract: Molnupiravir and nirmatrelvir are effective COVID-19 therapeutics, however there is limited data on their safety during pregnancy. The objective is to quantify the placental transfer of nirmatrelvir and β-D-N4-hydroxycytidine (NHC), the metabolite of molnupiravir found in plasma. A systematic review on the pharmacokinetics of nirmatrelvir found no data in pregnant subjects, though several studies reported parameters in non-pregnant individuals such as CL, VD, and fu. Using the ex vivo human placental perfusion model, nirmatrelvir showed a fetal-maternal concentration ratio (F:M) of 0.34 at therapeutic doses (2.21 μg/mL) and 0.46 (22.1 μg/mL) at supratherapeutic doses. Adjusted F:M for non-placental physiological factors ranged from 0.26-0.35 (2.21 μg/mL) and 0.38-0.51 (22.1 μg/mL). For NHC, the F:M was (2.97μg/mL) and (29.7 μg/mL). Results suggest that therapeutic and supratherapeutic doses of nirmatrelvir and NHC can passively cross the placental barrier. This data can be considered to create better safety recommendations regarding their use in pregnancy.
Keywords:
COVID-19 ;
placental perfusion ;
pregnancy ;
nirmatrelvir ;
molnupiravir ;
pharmacokinetics ;
placental transfer ;
drug safety ;
nucleoside analogue ;
main protease inhibitor
Purchased from AmBeed:
3258-02-4 ;
155213-67-5
Need for a Standardized Translational Drug Development Platform: Lessons Learned from the Repurposing of Drugs for COVID-19
Frauke Assmus
;
Jean-Sélim Driouich
;
Rana Abdelnabi
, et al.
Microorganisms,2022,10(8):1639.
DOI:
10.3390/microorganisms10081639
PubMed ID:
36014057
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Abstract: In the absence of drugs to treat or prevent COVID-19, drug repurposing can be a valuable strategy. Despite a substantial number of clinical trials, drug repurposing did not deliver on its promise. While success was observed with some repurposed drugs (e.g., remdesivir, dexamethasone, tocilizumab, baricitinib), others failed to show clinical efficacy. One reason is the lack of clear translational processes based on adequate preclinical profiling before clinical evaluation. Combined with limitations of existing in vitro and in vivo models, there is a need for a systematic approach to urgent antiviral drug development in the context of a global pandemic. We implemented a methodology to test repurposed and experimental drugs to generate robust preclinical evidence for further clinical development. This translational drug development platform comprises in vitro, ex vivo, and in vivo models of SARS-CoV-2, along with pharmacokinetic modeling and simulation approaches to evaluate exposure levels in plasma and target organs. Here, we provide examples of identified repurposed antiviral drugs tested within our multidisciplinary collaboration to highlight lessons learned in urgent antiviral drug development during the COVID-19 pandemic. Our data confirm the importance of assessing in vitro and in vivo potency in multiple assays to boost the translatability of pre-clinical data. The value of pharmacokinetic modeling and simulations for compound prioritization is also discussed. We advocate the need for a standardized translational drug development platform for mild-to-moderate COVID-19 to generate preclinical evidence in support of clinical trials. We propose clear prerequisites for progression of drug candidates for repurposing into clinical trials. Further research is needed to gain a deeper understanding of the scope and limitations of the presented translational drug development platform.
Keywords:
COVID-19 ;
drug repurposing ;
translational medicine ;
pandemics ;
clinical trials
Purchased from AmBeed:
55981-09-4 ;
23828-92-4 ;
198904-31-3 ;
59721-29-8 ;
259793-96-9 ;
1190307-88-0 ;
481-49-2 ;
155213-67-5 ;
61718-82-9
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