These observations suggest that the presence of selective mechanisms of regulation for individual CYP enzymes can be influenced by age and sex. However, we suggest that sex has a limited ability to explain intersubject variation of activity for these phenotypic measures of CYP enzyme activity.

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Background In a phase I/II study, a maternal respiratory syncytial virus vaccine candidate (RSVPreF3) demonstrated an acceptable safety profile and efficiently increased RSV-specific humoral immune responses in non-pregnant women. Methods In this phase II observer-blind, placebo-controlled, randomized clinical trial (NCT04126213), the safety of RSVPreF3 (60 or 120 µg), administered during late second or third trimester, was evaluated in 213 18-40-year-old healthy pregnant women through six months post-delivery and their offspring through infancy; immunogenicity was evaluated through day 43 post-delivery and day 181 post-birth, respectively. Results RSVPreF3 was well tolerated. No pregnancy-related or neonatal adverse events of special interest were considered vaccine/placebo-related. In the 60 and 120 µg RSVPreF3 groups: (i) neutralizing antibody (nAb) titers in mothers increased 12.7- and 14.9-fold against RSV-A and 10.6- and 13.2-fold against RSV-B, respectively, one month post-vaccination and remained 8.9–10.0-fold over pre-vaccination at day 43 post-delivery, (ii) nAb titers were consistently higher compared to placebo recipients, (iii) placental transfer ratios for anti-RSVPreF3 antibodies at birth were 1.62 and 1.90, respectively, and (iv) nAb levels in infants were highest at birth and declined through day 181 post-birth. Conclusions RSVPreF3 maternal vaccination had an acceptable safety risk profile and induced robust RSV-specific immune responses with successful antibody transfer to their newborns.

Cytochrome p450 (CYP) 2D6 activity exhibits wide intersubject variation even among individuals with similar genotypes in whom the active enzyme is expressed. There is, therefore, a need to understand the mechanisms involved in determining its activity. The relationship of messenger ribonucleic acid (mRNA) expression to CYP2D6 activity has been evaluated in hepatic and extrahepatic tissues to test the hypothesis of coordinated regulation. In human liver microsomes, there was a greater than 25-fold variation in both bufuralol hydroxylation and concentration of mRNA for CYP2D6, with a significant association between variables (n = 20; Spearman correlation coefficient [r(s)] = 0.85, P <.001). In normal subjects, there was a similar extent of interindividual variation in in vivo activity of CYP2D6, measured as the debrisoquin (INN, debrisoquine) recovery ratio, and in mRNA for CYP2D6 in peripheral blood mononuclear cells, with a significant association between variables (n = 78; r(s) = 0.56 [95% confidence interval, 0.35 to 0.73], P <.001), whereas no association was found between mRNA for CYP2D6 and CYP2E1 activity. Recipients of liver transplants, at a time of stable liver function, had a similar relationship between debrisoquin recovery ratio and concentration of mRNA for CYP2D6 in peripheral blood mononuclear cells (n = 27; r(s) = 0.74 [95% confidence interval, -0.16 to 0.44], P <.001). Three recipients, who had CYP2D6*4/*4 genotypes, remained phenotypically poor metabolizers for CYP2D6 after liver transplantation. Collectively, these results imply that transcriptional regulation of mRNA for CYP is a major determinant of in vivo activity and that regulation of intrahepatic and extrahepatic enzymes is coordinated, possibly through a mechanism that is predominantly extrahepatic.