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PurposeTo characterize prednisone use in pregnant women with rheumatoid arthritis using individual-level heat-maps and clustering individual trajectories of prednisone dose, and to evaluate the association between prednisone dose trajectory groups and gestational length.MethodsThis study included pregnant women with rheumatoid arthritis who enrolled in the MotherToBaby Autoimmune Diseases in Pregnancy Study (2003-2014) before gestational week 20 and reported prednisone use without another oral glucocorticoid during pregnancy (n = 254). Information on medication use and pregnancy outcomes was collected by telephone interview plus by medical record review. Prednisone daily dose and cumulative dose were plotted by gestational day using a heat map for each individual. K-means clustering was used to cluster individual trajectories of prednisone dose into groups. The associations between trajectory group and demographics, disease severity measured by the Health Assessment Questionnaire at enrollment, and gestational length were evaluated.ResultsWomen used prednisone 3 to 292 days during pregnancy, with daily doses ranging from

Complications throughout the peripartum period may be caused by preexisting conditions or pregnancy-induced conditions and may alter pharmacotherapy management. Pharmacotherapy management during late pregnancy and delivery requires careful consideration due to changing hormones, hemodynamic status, and pharmacokinetics, and concerns for potential maternal and/or fetal morbidity. Increased maternal and fetal monitoring are often required and may lead to therapy changes. Pharmacists, as key members of the interprofessional team, can contribute essential perspective to the management of postpartum pharmacotherapy through assessment and recommendation of appropriate and judicious use of medications. [ABSTRACT FROM AUTHOR]

Aims: Previously, retinoids have decreased CYP2D6 mRNA expression in vitro and induced CYP3A4 in vitro and in vivo. This study aimed to determine whether isotretinoin administration changes CYP2D6 and CYP3A activities in patients with severe acne. Methods: Thirty‐three patients (22 females and 11 males, 23.5 ± 6.0 years old) expected to receive isotretinoin treatment completed the study. All participants were genotyped for CYP2D6 and CYP3A5. Participants received dextromethorphan (DM) 30 mg orally as a dual‐probe substrate of CYP2D6 and CYP3A activity at two study timepoints: pre‐isotretinoin treatment and with isotretinoin for at least 1 week. The concentrations of isotretinoin, DM and their metabolites were measured in 2‐h postdose plasma samples and in cumulative 0‐4‐h urine collections using liquid chromatography‐mass spectrometry. Results: In CYP2D6 extensive metabolizers, the urinary dextrorphan (DX)/DM metabolic ratio (MR) (CYP2D6 activity marker) was numerically, but not significantly, lower with isotretinoin administration compared to pre‐isotretinoin (geometric mean ratio [GMR] [90% confidence interval (CI)] 0.78 [0.55, 1.11]). The urinary 3‐hydroxymorphinan (3HM)/DX MR (CYP3A activity marker) was increased (GMR 1.18 [1.03, 1.35]) and the urinary DX‐O‐glucuronide/DX MR (proposed UGT2B marker) was increased (GMR 1.22 [1.06, 1.39]) with isotretinoin administration compared to pre‐isotretinoin. Conclusions: Administration of isotretinoin did not significantly reduce CYP2D6 activity in extensive metabolizers, suggesting that the predicted downregulation of CYP2D6 based on in vitro data does not translate into humans. We observed a modest increase in CYP3A activity (predominantly CYP3A4) with isotretinoin treatment. The data also suggest that DX glucuronidation is increased following isotretinoin administration. [ABSTRACT FROM AUTHOR]

Changes in the maternal metabolome, and specifically the maternal lipidome, that occur during pregnancy are relatively unknown. The objective of this investigation was to evaluate the effects of pregnancy on sphingolipid levels using metabolomics analysis followed by confirmational, targeted quantitative analysis. We focused on three subclasses of sphingolipids: ceramides, sphingomyelins, and sphingosines. Forty-seven pregnant women aged 18 to 50 years old participated in this study. Blood samples were collected on two study days for metabolomics analysis. The pregnancy samples were collected between 25 and 28 weeks of gestation and the postpartum study day samples were collected ≥3 months postpartum. Each participant served as their own control. These samples were analyzed using a Ultra-performance liquid chromatography/mass spectroscopy/mass spectroscopy (UPLC/MS/MS) assay that yielded semi-quantitative peak area values that were used to compare sphingolipid levels between pregnancy and postpartum. Following this lipidomic analysis, quantitative LC/MS/MS targeted/confirmatory analysis was performed on the same study samples. In the metabolomic analysis, 43 sphingolipid metabolites were identified and their levels were assessed using relative peak area values. These profiled sphingolipids fell into three categories: ceramides, sphingomyelins, and sphingosines. Of the 43 analytes measured, 35 were significantly different during pregnancy (p < 0.05) (including seven ceramides, 26 sphingomyelins, and two sphingosines) and 32 were significantly higher during pregnancy compared to postpartum. Following metabolomics, a separate quantitative analysis was performed and yielded quantified concentration values for 23 different sphingolipids, four of which were also detected in the metabolomics study. Quantitative analysis supported the metabolomics results with 17 of the 23 analytes measured found to be significantly different during pregnancy including 11 ceramides, four sphingomyelins, and two sphingosines. Fourteen of these were significantly higher during pregnancy. Our data suggest an overall increase in plasma sphingolipid concentrations with possible implications in endothelial function, gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy, and fetal development. This study provides evidence for alterations in maternal sphingolipid metabolism during pregnancy. [ABSTRACT FROM AUTHOR]

Most of the interventions performed by obstetric providers involve the administration of drugs. Pregnant patients are pharmacologically and physiologically different from nonpregnant young adults. Therefore, dosages that are effective and safe for the general public may be inadequate or unsafe for the pregnant patient and her fetus. Establishing dosing regimens appropriate for pregnancy requires evidence generated from pharmacokinetic studies performed in pregnant people. However, performing these studies during pregnancy often requires special design considerations, evaluations of both maternal and fetal exposures, and recognition that pregnancy is a dynamic process that changes as gestational age advances. In this article, we address design challenges unique to pregnancy and discuss options for investigators, including timing of drug sampling during pregnancy, appropriate selection of control groups, pros and cons of dedicated and nested pharmacokinetic studies, single‐dose and multiple‐dose analyses, dose selection strategies, and the importance of integrating pharmacodynamic changes into these protocols. Examples of completed pharmacokinetic studies in pregnancy are provided for illustration. [ABSTRACT FROM AUTHOR]

The mechanism of cytochrome P450 2D6 (CYP2D6) induction during pregnancy has not been evaluated in humans. This study assessed the changes in CYP2D6 and CYP3A activities during pregnancy and postpartum, and the effect of vitamin A administration on CYP2D6 activity. Forty‐seven pregnant CYP2D6 extensive metabolizers (with CYP2D6 activity scores of 1 to 2) received dextromethorphan (DM) 30 mg orally as a single dose during 3 study windows (at 25 to 28 weeks of gestation, study day 1; at 28 to 32 weeks of gestation, study day 2; and at ≥3 months postpartum, study day 3). Participants were randomly assigned to groups with no supplemental vitamin A (control) or with supplemental vitamin A (10 000 IU/day orally for 3 to 4 weeks) after study day 1. Concentrations of DM and its metabolites, dextrorphan (DX) and 3‐hydroxymorphinan (3HM), were determined from a 2‐hour post‐dose plasma sample and cumulative 4‐hour urine sample using liquid chromatography–mass spectrometry. Change in CYP2D6 activity was assessed using DX/DM plasma and urine metabolic ratios. The activity change in CYP3A was also assessed using the 3HM/DM urine metabolic ratio. The DX/DM urine ratio was significantly higher (43%) in pregnancy compared with postpartum (P =.03), indicating increased CYP2D6 activity. The DX/DM plasma ratio was substantially higher in the participants, with an activity score of 1.0 during pregnancy (P =.04) compared with postpartum. The 3HM/DM urinary ratio was significantly higher (92%) during pregnancy, reflecting increased CYP3A activity (P =.02). Vitamin A supplementation did not change CYP2D6 activity during pregnancy; however, plasma all‐trans retinoic acid (atRA) concentrations were positively correlated with increased CYP2D6 activity during pregnancy and postpartum. Further research is needed to elucidate the mechanisms of increased CYP2D6 activity during pregnancy. [ABSTRACT FROM AUTHOR]

Tacrolimus is an approved immunosuppressive agent and a known substrate for CYP3A. Micafungin is an echinocandin antifungal agent and a mild inhibitor of CYP3A metabolism in vitro. The objectives of [...]

Cyclosporine is a marketed immunosuppressive agent and a known substrate for CYP3A. Micafungin is an antifungal agent and a mild inhibitor of C YP3A-mediated metabolism in vitro. The objectives of [...]

Preexisting hypertension complicates 5% of all pregnancies. The objective of this study was to evaluate steady-state atenolol pharmacokinetics and pharmacodynamics (n = 17) during the second trimester (2nd T), third [...]