September 11, 2020
We are delighted to announce the second webinar in the SOLVO Biotechnology Meet the Experts Transporter Webinar Series:
Titel: Vitamin Transport in Clinical Toxicities: Folate and Neural Tube Birth Defects
Date: 29 September, 2020
Presenter: Maciej J. Zamek-Gliszczynski. PhD, Senior Fellow and Director, DMPK, GlaxoSmithKline
Time: 8 am (PDT), 11 am (EDT), 4 pm (GMT), 5 pm (CET)
Summary of the presentation: Preliminary analysis of ongoing birth surveillance study identified evidence of potential increased risk for neural-tube defects (NTDs) in newborns associated with exposure to dolutegravir at time of conception (Zash et al. 2008). Folate deficiency is a common cause of NTDs. Folate’s hydrophilic nature results in negligible passive membrane permeability and transport-mediated disposition. Dolutegravir and other HIV integrase inhibitor drugs were evaluated for inhibition of folate transport pathways: proton-coupled folate transporter (PCFT), reduced folate carrier (RFC), and folate receptor α (FRα)-mediated endocytosis (Zamek-Gliszczynski et al., 2019). Inhibition of folate transport was extrapolated to clinic using established approaches for transporters in intestine, distribution tissues, basolateral and apical membranes of renal proximal tubules (2017 FDA Guidance). The present studies showed that dolutegravir is not a clinical inhibitor of folate transport pathways, and it is not predicted to elicit clinical decreases in maternal and fetal folate levels. Furthermore, clinically-relevant HIV integrase inhibitor drug class effect on folate transport pathways was not observed. Consistent with these findings, upon more complete enrollment of the birth surveillance study, dolutegravir no longer exhibited increased risk for NTDs (Zash et al., 2020).
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