Metformin serum concentrations during pregnancy and post partum - A clinical study in patients with polycystic ovary syndrome.

BACKGROUND AND OBJECTIVES: Metformin is used to treat gestational diabetes. It is also used to treat women with polycystic ovary syndrome and has been shown to prevent late miscarriage and preterm birth. However, increased renal clearance during pregnancy causes a decline in serum concentrations of metformin. The aim of this study was to explore the time course of the pregnancy-related changes in metformin pharmacokinetics and the return to the non-pregnant state. METHOD: A subgroup of women in the PregMet2 study (n = 73) agreed to provide serum samples at three time-points in pregnancy (gestational weeks 19, 28 and 32) and once in post partum, (either 2, 4 or 8 weeks after delivery). Serum metformin concentrations were compared using a four-parameter logistic model. FINDINGS: The mean steady-state serum concentration of metformin during pregnancy was 9.39 µmoL/L, whereas the post partum concentration was 12.36 µmoL/L, an increase of 32% (p = 0,019). This change took place already during the first 2 weeks post partum. CONCLUSION: Clinicians who treat pregnant women with metformin should be aware of the significant decrease in metformin concentration mediated by pregnancy, and the rapid increase after delivery, as it may impact both the therapeutic efficacy and the risk of adverse drug reactions.

Antidepressant transfer into amniotic fluid, umbilical cord blood & breast milk: A systematic review & combined analysis.

OBJECTIVE: Data regarding the ability of antidepressants to enter fetal, newborn and infant fluids have become gradually available, but mechanisms of antidepressant transfer remain poorly understood. Here we calculated penetration ratios in an array of matrices from combined samples of pregnant/breastfeeding women taking antidepressants. METHOD: We performed a systematic literature search of PubMed and EMBASE to identify studies with concentrations of antidepressants from maternal blood, amniotic fluid, umbilical cord blood and/or breast milk. Penetration ratios were calculated by dividing the concentrations in amniotic fluid, umbilical cord plasma or breast milk by the maternal plasma concentration. When data from multiple studies were available, we calculated combined penetration ratios, weighting the study mean by study size. RESULTS: Eighty-five eligible studies were identified. For amniotic fluid, the highest penetration ratios were estimated for venlafaxine (mean 2.77, range 0.43-4.70 for the active moiety) and citalopram (mean 2.03, range 0.35-6.97), while the lowest ratios were for fluvoxamine (mean 0.10) and fluoxetine (mean 0.11, range 0.02-0.20 for the active moiety). For umbilical cord plasma, nortriptyline had the highest ratio (mean 2.97, range 0.25-26.43) followed by bupropion (mean 1.14, range 0.3-5.08). For breast milk, the highest ratios were observed for venlafaxine (mean 2.59, range 0.85-4.85), mianserin (mean 2.22, range 0.80-3.64) and escitalopram (mean 2.19, range 1.68-3.00). CONCLUSION: We observed considerable variability across antidepressants regarding their ability to enter fetal, newborn and infant fluids. Measuring antidepressant concentrations in a maternal blood sample can provide a reliable estimate of fetal/infant exposure, although further evidence for concentration-dependent effects is required.

The impact of pregnancy on the pharmacokinetics of antidepressants: a systematic critical review and meta-analysis.

Introduction: Pregnancy-related physiological changes exert a crucial impact on the pharmacokinetics of antidepressants; however, the current evidence presents inconsistencies. A clearer understanding of pregnancy-related effects on antidepressant disposition may facilitate the development of guidelines for appropriate dose adjustments during the course of pregnancy based on therapeutic drug monitoring.Areas covered: We systematically reviewed studies comparing antidepressant levels in the same individuals during pregnant and non-pregnant states. Using dose-adjusted plasma concentration measurements, we estimated alteration ratios between the 3rd trimester and baseline (before or after pregnancy). Additionally, we performed a meta-analysis for changes in dose-adjusted concentrations to estimate mean differences.Expert opinion: Data for several antidepressants display clear alteration patterns during pregnancy. On the basis of the alteration ratios trimipramine, fluvoxamine, and nortriptyline show a prominent decrease in dose-adjusted levels, especially in the 3rd trimester. Clomipramine, imipramine, citalopram, and paroxetine show smaller decreases in dose-adjusted concentrations in the third trimester. For escitalopram, venlafaxine and fluoxetine, changes are considered negligible. For sertraline, there was a tendency toward increased dose-adjusted concentrations in pregnancy. Available evidence suffers from major limitations and factors affecting pharmacokinetics have been insufficiently addressed. Further research is required to promote knowledge on pregnancy effects on antidepressant pharmacokinetics.

Excretion of Antipsychotics Into the Amniotic Fluid, Umbilical Cord Blood, and Breast Milk: A Systematic Critical Review and Combined Analysis.

BACKGROUND: Antipsychotics are being increasingly prescribed during pregnancy and in the postpartum period. However, knowledge regarding the ability of antipsychotics to enter the fetal, newborn, and infant circulation presents inconsistencies. Evidence for penetration ratios in an array of matrices will contribute to further studies examining the mechanistic pathway from antipsychotic use to adverse events. METHODS: A systematic literature search of PubMed and EMBASE was performed to identify studies assessing the concentrations of antipsychotics in maternal blood (serum or plasma), amniotic fluid, umbilical cord blood, and/or breast milk. The penetration ratios were estimated by dividing the antipsychotic concentrations in the target matrix (ie, amniotic fluid, umbilical cord blood or breast milk) by the maternal concentration. Data are provided in means with ranges or SD depending on data availability. RESULTS: Forty-nine eligible studies were identified. For amniotic fluid, the penetration ratios were estimated for quetiapine, clozapine, and flupentixol, with quetiapine displaying the highest ratio (mean 0.59, range 0.09-1.70 versus 0.56, range 0.31-0.82 for clozapine and 0.24, range 0.23-0.24 for flupentixol). For umbilical cord blood, olanzapine had the highest ratio (mean 0.71 ± 0.42) followed by haloperidol (mean 0.66 ± 0.40) and paliperidone (mean 0.53, range 0.50-0.58). In case of breast milk, the highest ratio was observed for amisulpride (mean 14.42, range 11.86-19.50) followed by clozapine (mean 3.19, range 2.79-4.32) and haloperidol (mean 3.11, range 0.59-6.67). CONCLUSIONS: The ability of antipsychotics to enter the fetal, newborn, and infant circulation varies considerably among antipsychotics. Given sampling constraints of other matrices, measuring antipsychotic concentrations in maternal blood may represent the least expensive, most readily available, and reliable estimate of fetal/infant exposure.

Methadone serum concentrations and influencing factors: A naturalistic observational study.

RATIONALE: Although methadone maintenance treatment (MMT) has long been used for opioid addiction, our knowledge on its pharmacokinetics is still limited. OBJECTIVES: We aimed to investigate effects of age, gender, and various co-medications on methadone serum concentration-to-dose ratio (CDR) in a naturalistic setting. METHODS: In total, 4425 routine serum methadone concentrations obtained from 1691 MMT patients in the period October 1999 to July 2017 were included. Information about doses, age, gender, and concurrent medications was available in the laboratory database at the Department of Clinical Pharmacology at St. Olav University Hospital in Trondheim, Norway. A log-linear mixed model was used when analyzing the data. RESULTS: Mean age was 38.4 (range, 21-78) years and 70% were men. Mean CDR was 332 (range, 7-1776) (ng/mL)/(100 mg/d). Concomitant medication with at least one out of totally 170 drugs was recorded in 26% of the samples. CDRs were significantly lower in women (- 9%; confidence interval (CI), - 13%, - 4%; p = 0.001) and with concurrent use of CYP inducers (- 36%; CI, - 44%, - 28%; p < 0.001), but higher using CYP3A4 inhibitors as co-medications (+ 36%; CI, + 10%, + 68%; p = 0.005). CONCLUSIONS: Our results warrant taking into consideration gender differences in methadone metabolism as well as the impact of potential drug-drug interactions to obtain an optimal therapeutic effect and avoid adverse effects in MMT. Although the clinical implications of the altered drug levels require further study, our results call for close clinical monitoring of all patients undergoing MMT, preferably along with laboratory measurements of methadone serum concentrations.

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition.

Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we retrospectively assessed 201 routine serum antipsychotic therapeutic drug monitoring concentration measurements obtained from a total of 110 pregnancies in 103 women, and 512 measurements from the same women before and after pregnancy. Serum concentrations in the third trimester were significantly lower than baseline for quetiapine (-76%; confidence interval (CI), -83%, -66%; P < 0.001) and aripiprazole (-52%; CI, -62%, -39%; P < 0.001), but not for olanzapine (-9%; CI, -28%, +14%; P = 0.40). For the remaining antipsychotics (perphenazine, haloperidol, ziprasidone, risperidone, and clozapine), our dataset was limited, but it indicates that concentrations may decline at least for perphenazine and possibly also for haloperidol. Even though the clinical consequence of the serum concentrations decline remains to be elucidated, our results warrant close clinical monitoring throughout pregnancy, preferentially supported by therapeutic drug monitoring.

Detection Times of Carboxylic Acid Metabolites of the Synthetic Cannabinoids JWH-018 and JWH-073 in Human Urine.

Over the past years, use of synthetic cannabinoids has become increasingly popular. To draw the right conclusions regarding new intake of these substances in situations of repeated urinary drug testing, knowledge of their elimination rate in urine is essential. We report data from consecutive urine specimens from five subjects after ingestion of synthetic cannabinoids. Urinary concentrations of the carboxylic acid metabolites JWH-018-COOH and JWH-073-COOH were measured by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) with a limit of quantification of 0.1 ng/mL. In these subjects, specimens remained positive over a period of 20-43 (mean 27) days for JWH-018-COOH and over a period of 11-25 (mean 19) days for JWH-073-COOH. Detection times were shorter for subjects that appeared to have ingested only one, or a few, doses prior to urine collection in the study. Creatinine-normalized concentrations (CN-concentrations) slowly declined throughout the follow-up period in all subjects, suggesting that no new intake had taken place during this period. Mean elimination half-lives in urine were 14.0 (range 4.4-23.8) days for CN-JWH-018-COOH and 9.3 (range 3.6-16.8) days for CN-JWH-073-COOH. These data show that urine specimens could be positive for JWH-018-COOH for more than 6 weeks and JWH-073-COOH for more than 3 weeks after ingestion. However, such long detection periods require a low limit of quantification.

Effect of proton pump inhibitors on the serum concentrations of the selective serotonin reuptake inhibitors citalopram, escitalopram, and sertraline.

BACKGROUND: The selective serotonin reuptake inhibitors (SSRIs) citalopram, escitalopram, and sertraline are all metabolized by the cytochrome P-450 isoenzyme CYP2C19, which is inhibited by the proton pump inhibitors (PPIs) omeprazole, esomeprazole, lansoprazole, and pantoprazole. The aim of the present study was to evaluate the effect of these PPIs on the serum concentrations of citalopram, escitalopram, and sertraline. METHODS: Serum concentrations from patients treated with citalopram, escitalopram, or sertraline were obtained from a routine therapeutic drug monitoring database, and samples from subjects concomitantly using PPIs were identified. Dose-adjusted SSRI serum concentrations were calculated to compare data from those treated and those not treated with PPIs. RESULTS: Citalopram concentrations were significantly higher in patients treated with omeprazole (+35.3%; P < 0.001), esomeprazole (+32.8%; P < 0.001), and lansoprazole (+14.7%; P = 0.043). Escitalopram concentrations were significantly higher in patients treated with omeprazole (+93.9%; P < 0.001), esomeprazole (+81.8%; P < 0.001), lansoprazole (+20.1%; P = 0.008), and pantoprazole (+21.6%; P = 0.002). Sertraline concentrations were significantly higher in patients treated with esomeprazole (+38.5%; P = 0.0014). CONCLUSIONS: The effect of comedication with PPIs on the serum concentration of SSRIs is more pronounced for omeprazole and esomeprazole than for lansoprazole and pantoprazole, and escitalopram is affected to a greater extent than are citalopram and sertraline. When omeprazole or esomeprazole are used in combination with escitalopram, a 50% dose reduction of the latter should be considered.

Detection times of pregabalin in urine after illicit use: when should a positive specimen be considered a new intake?

BACKGROUND: Pregabalin has an abuse potential and is occasionally used as a recreational drug. To draw the right conclusions regarding new intake of pregabalin in situations of repeated urinary drug testing, the knowledge of its disappearance rate in urine is essential. METHODS: One healthy male volunteer took a single oral dose of pregabalin at 2 occasions, first 75 mg and thereafter 150 mg. All urine was collected in 8-hour portions for 5 days and analyzed for pregabalin. A systematic search for literature describing concentrations of pregabalin in urine was performed, and the results from these studies were interpreted on the basis of the findings from the healthy volunteer. RESULTS: In the healthy volunteer, specimens remained positive for 56 hours after intake of 75 mg and for 64 hours after intake of 150 mg. Urinary elimination half-lives based upon creatinine-normalized concentrations were 5.7-5.9 hours. The systematic literature search revealed only 1 article describing urinary concentrations of pregabalin. In that study, including 4799 urinary samples, the median concentration was not higher than the initial concentration found in the healthy volunteer. By applying a urinary elimination half-life of 6 hours on that material, at least 50% would be expected to have negative urine specimens within 3 days and a total of 5 days would be needed to achieve negative urine specimens in the subject with the maximum urinary concentration measured. CONCLUSION: In subjects with normal renal function, it seems highly unlikely that a urine specimen should remain positive for pregabalin for more than 5-6 days after intake.

Short communication: Urinary excretion of 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol in a pregnant woman following heavy, chronic cannabis use.

Differentiating new intake of drugs-of-abuse from residual drug excretion may be difficult, especially following chronic drug usage and for drugs with long elimination half-lives such as cannabis. In the present case, cannabis was found in the urine of a young pregnant woman following heavy and chronic cannabis use. She was warned that if she continued using cannabis while pregnant she would be forced to be hospitalized. She was subjected to serial urine testing with 2-7-day intervals. Urinary 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THCCOOH) concentrations, measured by liquid chromatography-mass spectrometry, declined from 348 to 3.9 ng/mL over a surprisingly long period of 12 weeks (84 days). Several algorithms for detecting new drug intake were applied during this time course; most indicated that the woman continued to smoke cannabis following the first urine test. The woman denied any use after the first specimen collection. In retrospect, her THCCOOH excretion profile supports her story. Algorithms for detecting new drug intake have been validated for occasional cannabis users only. We advise caution when interpreting urine test results from heavy, chronic cannabis users, especially when serious consequences are involved.

Outcome of whole-brain irradiation for breast cancer patients.

PURPOSE: To determine the overall survival (OS) of breast cancer patients treated by Whole Brain Radiation Therapy (WBRT) and possible important prognostic factors for OS. MATERIAL AND METHODS: The study population comprised 99 patients with brain metastases (BM) treated with WBRT in the period 1988 to 2004 at St. Olavs University Hospital, Trondheim, Norway. Prognostic factors as age, performance status, axillary lymph node involvement and extent of BM were evaluated. RESULTS: Median survival (range) of the total population from start of irradiation was 5.3 (0.3-157) months. For patients >60 years, 40-60 years and <40 years median survival (range) were 4.5 (0.3-92), 6.8 (0.3-157) and 8.5 (0.8-11) months, respectively (NS, p=0.5), and for Karnofsky performance status (KPS) < or >70, were 3.7 (0.3-92) and 6.8 (1.0-157) months, respectively (NS, p=0.17). One,three, 12 and 24 month survival rate were 90, 64, 29 and 11%, respectively. Grouping patients according to Recursive Partitioning Analyses (RPA) classes, the median survival (range) were 8.0 (1.0-157), 6.5 (1.3-92) and 3.5 (0.3-92) months for RPA class 1, 2 and 3, respectively (NS, p=0.6). CONCLUSION: KPS and in particular the extent of BM were the most important prognostic factors. Grouping patients into RPA classes may be important when deciding whether breast cancer patients should be aggressively treated for their BM.