Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Hutson, Janine R.

Affiliation

Children’s Health Research Institute, London, ON, Canada; Lawson Research Institute, London, ON, Canada

2nd Supervisor

Garcia-Bournissen, Facundo

Affiliation

Children’s Health Research Institute, London, ON, Canada; Lawson Research Institute, London, ON, Canada

Co-Supervisor

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 b-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.

Summary for Lay Audience

COVID-19 is a disease from a virus that can make pregnant individuals very sick, as pregnant people are more likely to be admitted to hospital or have worse health after being sick with COVID-19. New medications that fight this virus such as nirmatrelvir and molnupiravir have been shown to reduce the risk of being in hospital or getting very sick. We need to understand if these medications are passed to the baby when a person is pregnant in order to decide if this medication is safe for the pregnancy. This project aims to determine whether these new medications cross the human placenta, the organ that separates the parent from the baby. If we know that these medications cross the placenta and go to the baby and how much, we can predict whether these medications may be safe in the pregnancy. Human placentas are collected after cesarean sections and put it into a plastic chamber, then tubing that represents both the parent’s blood and the unborn baby’s blood is set up. Medication is then introduced at therapeutic or 10x therapeutic concentrations into parent’s blood and see if it transfers across the placenta. We then measured the amount of drug that goes across the placenta and into the unborn baby’s blood. Based on the experiments, for both drugs, it was discovered they do indeed pass through the placenta and is exposed to the baby. We can use this information to know what doses might be safe or what other drugs may cause problems if given at the same time. By decreasing the impact of COVID-19 in pregnancy, which can result in admission to the intensive care unit (ICU) or preterm delivery, we hope to maintain good health of parent and the baby.

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