Vitamin Transport in Clinical Toxicities:  Folate and Neural Tube Birth Defects

Date: September 29 2020
Presenter(s): Maciej Zamek-Gliszczynski, PhD

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).

About the presenter:


Senior Fellow and Director, DMPK, GlaxoSmithKline, Collegeville, PA, USA


Maciej Zamek-Gliszczynski has 15 years of industry (Eli Lilly and GSK) experience in leading DMPK and PK/PD/clinical pharmacology aspects of oncology, endocrine/metabolic, and infectious disease programs at all stages between discovery, clinical development, and post-marketing (6 clinical candidate selections & INDs, 2 NDAs).  He is an experienced global manager, having led the Quantitative Drug Disposition group responsible for understanding victim and perpetrator DDIs for the entire GSK portfolio.  Dr. Zamek-Gliszczynski’s research is focused on PK/PD and DDI implications of drug and metabolite transport.  He is the author of >100 manuscripts and presentations on this subject (>5,000 cites, -index = 35).  He serves on the editorial boards of Pharmaceutical Research and Drug Metabolism and Disposition.  Dr. Zamek-Gliszczynski is a member of the International Transport Consortium (ITC) steering committee, was past chair of AAPS PK/PD/Drug Metabolism (PPDM) section, and he served as GSK management representative on IQ Translational ADME Leadership Group (TALG).  He has been active in organizing DMPK/clinical pharmacology meetings with ITC, ASCPT and AAPS.  Dr. Zamek-Gliszczynski lectures in graduate-level PK/PD courses and serves as external committee advisor (including as adjunct prof at UNC).  He enjoys developing scientists and has an established mentorship record at the associate scientist, junior and peer Ph.D., as well as graduate student and post-doc levels.