Quantification of sertraline maternal/fetal ratio and amniotic fluid concentration using a pregnancy physiologically based pharmacokinetic model.

AIMS: Selective serotonin reuptake inhibitors (SSRIs) are indicated for a variety of psychiatric conditions which may require treatment during pregnancy. Knowledge of appropriate SSRI dosages that maintain maternal therapeutic benefit and minimize fetal risk are needed. Assessment of fetal exposure to drugs is challenging since sampling is often limited to a single concentration from the umbilical cord at delivery. Physiologically based pharmacokinetic (PBPK) modelling provides a non-invasive approach to quantify exposure in pregnancy. METHODS: We incorporated sertraline clearances mediated by passive diffusion, placental efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) into our previously published pregnancy PBPK model for sertraline. Simulations were performed for various sertraline doses (25-200 mg) at 40 weeks gestational age to predict the minimum (Cmin ), maximum (Cmax ) and average (Cavg ) sertraline maternal and fetal plasma concentrations and evaluated them against observed maternal and cord concentrations obtained at delivery from five clinical studies. RESULTS: The accuracy of the PBPK predictions as indicated by the average fold error (AFE) value for Cmax , Cmin and Cavg for maternal plasma sertraline concentrations at delivery was 1.7, 1.2 and 1.4, respectively. The AFE for the Cmax , Cmin and Cavg for cord blood sertraline concentration at delivery was 1.2, 1 and 1.1, respectively. The AFE for cord-maternal sertraline concentration ratio at delivery for Cmax , Cmin and Cavg was 0.7, 0.9 and 0.8, respectively. CONCLUSIONS: The PBPK model we developed may serve as a guide for maternal sertraline dose adjustment during pregnancy considering changes in exposures for both mother and fetus.

Reconsideration of 2008 decision: Food and Drug Administration approval of etanercept for systemic treatment of moderate to severe pediatric psoriasis.

Although systemic etanercept was approved in 2004 for adults, the Food and Drug Administration (FDA) denied approval for use in children with psoriasis in 2008. Revision of the FDA's risk-benefit assessment in response to understanding of disease burden, unmet medical need, and the effect of off-label use in children with psoriasis led to the 2016 approval as the first systemic biologic product for the treatment of children aged 4-17 with moderate to severe psoriasis. This article delineates the thinking that led to this reconsideration. The underlying thinking paved the way to inform current pediatric drug development as the FDA continues to bring needed medical products to children.

Application of physiologically based pharmacokinetic modeling for sertraline dosing recommendations in pregnancy.

Pregnancy is a period of significant change that impacts physiological and metabolic status leading to alterations in the disposition of drugs. Uncertainty in drug dosing in pregnancy can lead to suboptimal therapy, which can contribute to disease exacerbation. A few studies show there are increased dosing requirements for antidepressants in late pregnancy; however, the quantitative data to guide dose adjustments are sparse. We aimed to develop a physiologically based pharmacokinetic (PBPK) model that allows gestational-age dependent prediction of sertraline dosing in pregnancy. A minimal physiological model with defined gut, liver, plasma, and lumped placental-fetal compartments was constructed using the ordinary differential equation solver package, 'mrgsolve', in R. We extracted data from the literature to parameterize the model, including sertraline physicochemical properties, in vitro metabolism studies, disposition in nonpregnant women, and physiological changes during pregnancy. The model predicted the pharmacokinetic parameters from a clinical study with eight subjects for the second trimester and six subjects for the third trimester. Based on the model, gestational-dependent changes in physiology and metabolism account for increased clearance of sertraline (up to 143% at 40 weeks gestational age), potentially leading to under-dosing of pregnant women when nonpregnancy doses are used. The PBPK model was converted to a prototype web-based interactive dosing tool to demonstrate how the output of a PBPK model may translate into optimal sertraline dosing in pregnancy. Quantitative prediction of drug exposure using PBPK modeling in pregnancy will support clinically appropriate dosing and increase the therapeutic benefit for pregnant women.

The Food and Drug Administration Office of Women's Health: Impact of Science on Regulatory Policy: An Update.

The U.S. Food and Drug Administration Office of Women's Health (FDA OWH) has supported women's health research for ∼20 years, funding more than 300 studies on women's health issues, including research on diseases/conditions that disproportionately affect women in addition to the evaluation of sex differences in the performance of and response to medical products. These important women's health issues are studied from a regulatory perspective, with a focus on improving and optimizing medical product development and the evaluation of product safety and efficacy in women. These findings have influenced industry direction, labeling, product discontinuation, safety notices, and clinical practice. In addition, OWH-funded research has addressed gaps in the knowledge about diseases and medical conditions that impact women across the life span such as cardiovascular disease, pregnancy, menopause, osteoporosis, and the safe use of numerous medical products.

Aseptic meningitis associated with rofecoxib.

Rofecoxib is a nonsteroidal anti-inflammatory drug that is reported to act by selectively inhibiting cyclooxygenase-2. A review and analysis of reports sent to the Spontaneous Reporting System of the Food and Drug Administration, Rockville, Md, suggest that aseptic meningitis is associated with rofecoxib use. To our knowledge, there have been no published reports of aseptic meningitis occurring in association with rofecoxib use to date. We report 5 serious cases of aseptic meningitis associated with rofecoxib use.

Use of a spontaneous adverse drug events database for identification of unanticipated drug benefits.

We describe an examination of a spontaneous adverse events database in an effort to identify agents with possible hitherto unknown antiangiogenic properties. The surrogate end point was abnormal wound healing. This analysis represents use of this database for identification of a possibly useful in vivo side effect. Through thoughtful choice of end points, we believe spontaneous adverse events databases have the capacity for hypothesis generation in a search for unanticipated beneficial drug properties.

Renal failure associated with the use of celecoxib and rofecoxib.

OBJECTIVE: Celecoxib and rofecoxib are two relatively new nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit the cyclo-oxygenase-2 (COX-2) isoenzyme at therapeutic concentrations. The nephrotoxic potential of selective COX-2 inhibitors has not been clearly established. This study was conducted in order to understand the association between acute renal failure and the two COX-2 inhibitors celecoxib and rofecoxib. METHODS: A search was performed in the US Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS) to identify cases of renal failure submitted to the FDA. A MEDLINE search of the English language literature was also performed to identify published cases of renal failure associated with celecoxib and rofecoxib. RESULTS: One hundred twenty-two and 142 domestic US cases of celecoxib and rofecoxib-associated renal failure, respectively, were identified in the AERS database. The literature search identified 19 cases of acute renal impairment in association with celecoxib and rofecoxib. In addition, drug regulatory authorities in the UK, Canada, and Australia have received about 50 reports of renal failure with celecoxib and rofecoxib. Descriptive statistics of the AERS cases have been summarised in this report. CONCLUSIONS: Data from AERS and published case reports suggest that use of both these drugs is associated with renal effects similar to that of conventional nonselective NSAIDs. Physicians should be aware that serious or life-threatening renal failure has been reported in patients with normal or impaired renal function after short-term therapy with celecoxib and rofecoxib. Patients at greatest risk for renal injury are those with pre-existing renal impairment, heart failure, liver dysfunction, those taking diuretics and/or ACE inhibitors, and the elderly. Kidney function should be monitored closely for any signs of potential renal injuries soon after initiating treatment with these agents, especially in high-risk populations. In addition, healthcare practitioners should adequately warn patients of the signs and symptoms of serious renal toxicity, and of the need for them to see their physician promptly if they occur. Celecoxib and rofecoxib are not recommended for use in patients with advanced renal disease.

Spontaneous reports of hypertension leading to hospitalisation in association with rofecoxib, celecoxib, nabumetone and oxaprozin.

BACKGROUND AND OBJECTIVE: Data on file with the US FDA, and other published studies, suggest that the selective cyclo-oxygenase (COX)-2 inhibitor NSAID rofecoxib has a greater hypertensive adverse effect than other NSAIDs, including celecoxib. In this study we describe a pharmacoepidemiologic analysis of spontaneous adverse event reports of acute, clinically serious hypertension (as defined by hospitalisation) reported in association with rofecoxib, celecoxib, nabumetone and oxaprozin. The objective of this analysis is to assess whether postmarketing data are consistent with results of clinical trials. We also collapse cases into series for the identification of possible risk factors for clinically severe, NSAID-associated hypertension. METHODS: Domestic (US) cases of apparently unconfounded, acute hypertension leading to hospitalisation were collected and reviewed from the spontaneous adverse events database of the FDA for rofecoxib, celecoxib, nabumetone and oxaprozin for the initial 3 years of marketing. Drug use data for the same intervals enabled calculation of reporting rates. RESULTS: In an analysis of reporting rates, hospitalisation for acute blood pressure (BP) elevation was reported more frequently (3.8-fold) for rofecoxib compared with celecoxib. A total of 34 cases are collapsed into case series. No cases were identified for either nabumetone or oxaprozin. Inspection of reviewed cases for celecoxib and rofecoxib suggest that these patients (average age 72 years) were potentially high-risk candidates for NSAID therapy. DISCUSSION AND CONCLUSION: During early marketing, hospitalisation for acute BP elevation appears to have been reported more frequently for rofecoxib compared with celecoxib. This is consistent with clinical trial data on file with the FDA, and other published studies that found rofecoxib to have a greater effect on BP than other NSAIDs, including celecoxib. This finding may be particularly relevant in older patients given the prevalence of hypertension and cardiovascular disease in this age group.

Deaths associated with inappropriate intravenous colchicine administration.

Intravenous (IV) colchicine is occasionally prescribed for the treatment of acute gouty arthritis. The Food and Drug Administration (FDA) recently received a report of death in a patient that was associated with inappropriate IV dosing of colchicine. This report prompted further investigation of other deaths associated with IV colchicine use in the FDA Adverse Event Reporting System (AERS) and the medical literature. A total of 20 deaths were identified. Eight patients were females, 11 were males, and the gender was unknown in 1. In all cases, the recommended maximum cumulative dose of 2 to 4 mg during a course of therapy was exceeded. Dose reductions are recommended in patients with renal or hepatic disease and in the elderly. All reported adverse events were associated with colchicine toxicity, including thrombocytopenia, leukopenia, pancytopenia, agranulocytosis, aplastic anemia, acute renal failure, and disseminated intravascular coagulopathy. Death occurred within 1 to 40 days after drug administration. Therapeutic guidelines exist for use of IV colchicine and these guidelines should be followed to prevent serious toxicities and death.

Changes in ciprofloxacin utilization as shown in a large pharmacy claims database: effects of proximity to criminal anthrax exposure in October 2001.

OBJECTIVE: Identify, during the period of criminal anthrax exposures in October 2001, changes in utilization of ciprofloxacin and geographic patterns of any identified variations. DESIGN: Observational. SETTING: United States. PATIENTS: Individuals making prescription claims through a pharmacy benefits management company. INTERVENTIONS: Analysis of AdvancePCS pharmacy claims database. MAIN OUTCOME MEASURES: Percentage change in ciprofloxacin utilization for 2000 and 2001 and, by locale, for September and October 2001. RESULTS: Utilization of ciprofloxacin tablets was significantly lower in calendar year 2001 than in calendar year 2000 (median decline, 10.3%) for all months except October, when utilization of ciprofloxacin increased 9.8%. During the period of anthrax exposures (October 2001 versus September 2001), affected geographic areas, including New York (an increase of 62.5%), some other Mid-Atlantic states, and Florida (28.5%), had some of the highest percentage increases in the rate of ciprofloxacin utilization. CONCLUSION: Many Americans actively sought prophylaxis with ciprofloxacin during the course of the October 2001 anthrax attack and that utilization was higher in, but not limited to, locales with publicized cases of disease. Pharmacists, clinicians, and public health officials should note that such behavior may be expected in the event of a similar attack and should be familiar with current recommendations for the assessment and management of anthrax exposure.

Spontaneous reports of thrombocytopenia in association with quinine: clinical attributes and timing related to regulatory action.

Quinine has been marketed in the United States (U.S.) both over-the-counter (OTC) and by prescription for numerous purposes, including malaria and muscle spasms. In 1994 and 1995, the U.S. Food and Drug Administration (FDA) acted to limit the marketing of quinine based on the conclusion that no data supported its safe and efficacious use in these settings. This report includes clinical attributes from the largest case series to date of apparently isolated thrombocytopenia in association with quinine and trends in the receipt of spontaneous adverse event reports to FDA's Center for Drug Evaluation and Research (CDER) for this drug-event combination in relation to regulatory action. In this study, we reviewed reports of spontaneous adverse drug events received by CDER. From 1974 through December 2000, CDER received 397 adverse event reports for quinine. Based on crude, unreviewed counts, 141 (35.5%) of these reports described apparently isolated thrombocytopenia. Reporting for this event peaked in 1995, coincident with regulatory action, and has subsequently declined. After elimination of cases confounded by acute or chronic disease or concomitant drug therapy, 64 reports of quinine-associated thrombocytopenia were used to form a case series. This case series, including 11 cases since January 1996, supports the potential for rapid time-to-onset (median 7 days) and clinical severity (hospitalization reported in 55 of the 64 cases). Although the number of reports since regulatory action is limited, CDER continues to receive reports of thrombocytopenia in association with quinine in use for nocturnal leg cramps. Extrapolation of spontaneous adverse event reports for a product with substantial OTC use precludes estimates of rates/incidence. Therefore, the effect of regulatory actions in 1994/1995 is difficult to measure using this approach. Although reports have decreased since regulatory actions on quinine, quinine remains available in the U.S. by prescription and in food products/dietary supplements. This case series confirms previous smaller series that suggest quinine-associated thrombocytopenia may present rapidly with symptoms of profound thrombocytopenia. Clinicians evaluating patients with new-onset and apparently idiopathic thrombocytopenia should maintain clinical vigilance for ingestion of quinine and elicit a detailed food/dietary supplement history from the patient.