The Transfer of Molnupiravir and Nirmatrelvir Across the Human Placenta and Prediction of Drug Safety in Pregnancy

Zabek, M., Electronic Thesis and Dissertation Repository, 10427

Sep 2024

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Ex Vivo study showing placental transfer of molnupiravir (NHC) and nirmatrelvir in human placentas. Author used a placental perfusion model to assess drug transfer across the human placental barrier. Both compounds readily crossed the placental barrier at therapeutic and supratherapeutic concentrations, and were detectable on the fetal side within 10-20 minutes. The study suggests passive transfer as the main mechanism for both drugs, though efflux transporters may play a role for nirmatrelvir at therapeutic concentrations.

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Study covers paxlovid and molnupiravir.

Zabek et al., 27 Sep 2024, preprint, 1 author.

Ex Vivo studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Paxlovid All

The Transfer of Molnupiravir and Nirmatrelvir Across the Human The Transfer of Molnupiravir and Nirmatrelvir Across the Human Placenta and Prediction of Drug Safety in Pregnancy Placenta and Prediction of Drug Safety in Pregnancy

Supervisor: Hutson Magdalene Zabek

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 -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.

List of Appendices 3 The placental transfer of nirmatrelvir using the ex vivo human placental perfusion model Magdalene Zabek 1, 4, 5 , Eddie Chan 4, 5 , Facundo Garcia-Bournissen 1, 3, 4, 5 and Janine Viability calculations were completed for all perfusions and presented in Table 3 -2. Fetal arterial pressure was under 80mmHg and was constant throughout the experiment, as well as the fetal volume loss for all experiments was < 4 mL/hr. The mean maternal and fetal flow rate was 12 mL/min and 3 mL/min, respectively. pH levels in maternal and fetal perfusates were maintained within physiological ranges. Calculated viability parameters indicated preserved placental viability, reflecting normal physiological processes. Chapter 4 4 Molnupiravir use in pregnancy: a transplacental study Magdalene Zabek 1,4,5 , Eddie Chan 4, 5 , Facundo Garcia-Bournissen 1,3,4,5 and Janine Appendices Appendix A. Viability and integrity assessment of placental perfusions Throughout the experiment, several parameters are measured to ensure the viability and integrity of the placenta. Fetal volume loss (>4ml/hr) and fetal arterial inflow pressure (>80mmHg) were monitored. A volume loss or pressure any greater indicates trauma in the placental tissue and the perfusion will seize. In addition, samples were taken from maternal and fetal circuits (1.6ml) at specific timepoints to measure perfusate pH, glucose consumption, lactate production, oxygen transfer, net oxygen..

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