Physiologically‐based pharmacokinetic modeling of remdesivir and its metabolites in pregnant women with COVID‐19

Abstract

Pregnant individuals are at high risk for severe illness from COVID‐19, and there is an urgent need to identify safe and effective therapeutics for this population. Remdesivir (RDV) is a SARS‐CoV‐2 nucleotide analog RNA polymerase inhibitor. Limited RDV pharmacokinetic (PK) and safety data are available for pregnant women receiving RDV. The aims of this study were to translate a previously published nonpregnant adult physiologically based PK (PBPK) model for RDV to pregnancy and evaluate model performance with emerging clinical PK data in pregnant women with COVID‐19. The pregnancy model was built in the Open Systems Pharmacology software suite (Version 10) including PK‐Sim® and MoBi® with pregnancy‐related changes of relevant enzymes applied. PK were predicted in a virtual population of 1000 pregnant subjects, and prediction results were compared with in vivo PK data from the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network 2032 study. The developed PBPK model successfully captured RDV and its metabolites' plasma concentrations during pregnancy. The ratios of prediction versus observation for RDV area under the curve from time 0 to infinity (AUC 0–∞ ) and maximum concentration (C max ) were 1.61 and 1.17, respectively. For GS‐704277, the ratios of predicted versus observed were 0.94 for AUC 0–∞ and 1.20 for C max . For GS‐441524, the ratios of predicted versus observed were 1.03 for AUC 0–24 , 1.05 for C max , and 1.07 for concentrations at 24 h. All predictions of AUC and C max for RDV and its metabolites were within a twofold error range, and about 60% of predictions were within a 10% error range. These findings demonstrate the feasibility of translating PBPK models to pregnant women to potentially guide trial design, clinical decision making, and drug development.

Physiologically Based Pharmacokinetic (PBPK) Modeling of small molecules: How Much Progress Have We Made?

“…described the application of PBPK modeling to pregnant populations to either predict drug disposition in the pregnant mother or to evaluate the fetal exposure and potential toxicokinetics of the therapeutic agents in the fetus (Table 2). The majority (n=5) of the pregnancy PBPK models were constructed using Simcyp simulator Bukkems et al, 2022;Peng et al, 2022;Li and Xie, 2023), but other software packages such as R (n=2, (Chang et al, 2022;Kapraun et al, 2022)), PK-Sim (n=2, (Alsmadi, 2023;Liu et al, 2023))…”

“…Within the pregnancy applications a variety of model acceptance criteria were used within and between the studies and majority of the studies defined model acceptance criteria in model development workflow (Table 2). Four studies stated that model performance was evaluated based on visual comparison of predicted and observed data Chang et al, 2022;Alsmadi, 2023;Liu et al, 2023), while one study assessed the correlation between predicted and observed data (Kapraun et al, 2022). Two studies used the 90% predictive interval as the range that observed data needed to be within (Alsmadi, 2023;Li and Xie, 2023) and one specified a visual comparison of the observed mean plasma concentration-time curve and the predicted 5-95 th percentile (Coppola et al, 2022).…”

“…Similarly two papers (Bukkems et al, 2022;Peng et al, 2022) established a stringent criteria for predicted pharmacokinetics parameters with 0.8-1.25 fold (bioequivalence) or 0.7-1.3-fold (narrow therapeutic index), respectively. The 2-fold range of pharmacokinetics parameters was also used in two studies (Li and Xie, 2023;Liu et al, 2023).…”

Remdesivir Use in the Real-World Setting: An Overview of Available Evidence

“…Pregnant women when compared to similar age non-pregnant individuals are more likely to require hospitalization or even admission to the ICU and need invasive MV [ 71 ]. They have been historically excluded from drug development research protocols in fear of adverse pregnancy and maternal health outcomes [ 83 ]. RWE from the US showed that RDV was a potent and low-risk treatment option, promoting clinical improvement, lowering ICU and death rates, and resulting in a low incidence of serious adverse effects [ 71 , 72 , 73 , 74 ].…”

Transplacental transfer of Remdesivir and GS‐441524: An ex vivo perfusion study

“…Several reviews reported the use of Rmd in pregnant women, 4–7 but did not analyse Rmd or GS concentration neither in mothers nor in cord blood. A physiological based PK model has been done to predict mother concentrations but without fetal concentrations 8 . Gilead's report suggested some reproductive toxicity in rats, 3 but no data regarding Rmd and its metabolite transfer through the placental was available.…”