Application of a physiologically based pharmacokinetic model to predict isoniazid disposition during pregnancy.

Pregnancy can increase the risk of latent tuberculosis infection (LTBI) progression to tuberculosis (TB) disease. Isoniazid (INH) is the preferred preventative treatment for LTBI in pregnancy. INH is mainly cleared by N-acetyltransferase 2 (NAT2) but the pharmacokinetics (PK) of INH in different NAT2 phenotypes during pregnancy is not well characterized. To address this knowledge gap, we used physiologically based pharmacokinetic (PBPK) modeling to evaluate NAT2 phenotype-specific effects of pregnancy on INH disposition. A whole-body PBPK model for INH was developed and verified for non-pregnant NAT2 fast (FA), intermediate (IA), and slow (SA) acetylators. Model predictive performance was assessed using a drug-specific model acceptance criterion for mean plasma area under the curve (AUC) and peak plasma concentration (Cmax ), and the absolute average fold error (AAFE) for individual plasma concentrations. The verified model was extended to simulate INH disposition during pregnancy in NAT2 SA, IA, and FA populations. A sensitivity analysis was conducted using the verified PBPK model and known changes in INH disposition during pregnancy to determine whether NAT2 activity changes during pregnancy or other INH clearance pathways are altered. This analysis suggested that NAT2 activity is unchanged while other INH clearance pathways increase by ~80% during pregnancy. The model was applied to explore the effect of pregnancy on INH disposition in two ethnic populations with different NAT2 phenotype distributions and with high TB burden. Our PBPK model can be used to predict INH disposition during pregnancy in diverse populations and expanded to other drugs cleared by NAT2 during pregnancy.

Impact of Pregnancy and Vitamin A Supplementation on CYP2D6 Activity.

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.

Community Pharmacists' Services during the COVID-19 Pandemic: A Case Study of Lagos State, Nigeria.

Objective: To explore the services community pharmacists in Lagos state provided to their communities during the COVID-19 pandemic. Methods: A cross-sectional survey of community pharmacists drawn from all the Association of Community Pharmacists' zones in Lagos state was done from April to June 2021. Data were collected using a structured, self-reported online questionnaire via Google Forms and were analyzed using descriptive and inferential statistical analysis. Findings: Two hundred and forty community pharmacists participated in the study; the response rate was 80.5%. Patient counseling (99.6%), assessment and treatment of common acute ailments (99.6%), and patient education on hygiene (99.6%) were the most reported services provided by community pharmacists. The COVID-19 infection prevention and control measures most frequently practiced by the pharmacists include cleaning of floors with soap and water (98.4%), provision of hand sanitizers for staff use (97.1%), and taking precautions when handling prescriptions and dispensing drugs (96.7%). Significant barriers to the provision of the services were reduced workforce in the pharmacy, time constraints, and extended working hours. Zinc (98.3%), Vitamin C (97.5%), and ivermectin (95.0%) tablets were the most reported medications for the prevention and treatment of COVID-19 infection. Conclusion: Community pharmacists in Lagos state actively provide pharmacy services and practice various recommended infection prevention and control measures to mitigate the spread of COVID-19 infection in their communities.

Use of Herbal Medicine by Pregnant Women: What Physicians Need to Know.

About 80% of the consumers worldwide use herbal medicine (HMs) or other natural products. The percentage may vary significantly (7%-55%) among pregnant women, depending upon social status, ethnicity, and cultural traditions. This manuscript discusses the most common HMs used by pregnant women, and the potential interactions of HMs with conventional drugs in some medical conditions that occur during pregnancy (e.g., hypertension, asthma, epilepsy). It also includes an examination of the characteristics of pregnant HM consumers, the primary conditions for which HMs are taken, and a discussion related to the potential toxicity of HMs taken during pregnancy. Many cultures have used HMs in pregnancy to improve wellbeing of the mother and/or baby, or to help decrease nausea and vomiting, treat infection, ease gastrointestinal problems, prepare for labor, induce labor, or ease labor pains. One of the reasons why pregnant women use HMs is an assumption that HMs are safer than conventional medicine. However, for pregnant women with pre-existing conditions like epilepsy and asthma, supplementation of conventional treatment with HMs may further complicate their care. The use of HMs is frequently not reported to healthcare professionals. Providers are often not questioning HM use, despite little being known about the HM safety and HM-drug interactions during pregnancy. This lack of knowledge on potential toxicity and the ability to interact with conventional treatments may impact both mother and fetus. There is a need for education of women and their healthcare professionals to move away from the idea of HMs not being harmful. Healthcare professionals need to question women on whether they use any HMs or natural products during pregnancy, especially when conventional treatment is less efficient and/or adverse events have occurred as herbal-drug interactions could be the reason for these observations. Additionally, more preclinical and clinical studies are needed to evaluate HM efficacy and toxicity.