Andreas Austgulen Westin

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.

Therapeutic drug monitoring (TDM) repertoire in Norway.

BACKGROUND In many clinical situations it is useful to measure drug levels in patient samples. The purpose of this survey is to obtain an overview of the therapeutic drug monitoring analyses offered by Norwegian laboratories. MATERIAL AND METHOD At the end of 2011, the authors of this article phoned all the public and private hospitals in Norway, and located their laboratories. All clinical chemical and pharmacological laboratories were contacted and asked to state which drug analyses (including drugs-of-abuse and toxic alcohols, but excluding metabolites) they performed in blood/serum at the time in question. The overview thus obtained was updated and quality assured by means of further telephone contact with the laboratories in August 2012. RESULTS Around 80 laboratories were contacted. In August 2012, 49 of them performed analyses of drugs in blood/serum. Altogether, these laboratories offered 151 different analyses. This article provides an overview of the analyses that were carried out, and where. INTERPRETATION The overview of analyses provided here can be used as a tool in everyday practice. However, the user must be aware that the analytical repertoire of the laboratories is constantly changing. A web-based, dynamic version is currently being planned.

Does Level of Care, Sex, Age, or Choice of Drug Influence Adherence to Treatment With Antipsychotics?

Abstract Rates of nonadherence during treatment with antipsychotics have been found to vary in a wide range from 20% to 90%. The aim of the present study was to investigate the influence of inpatient versus outpatient status on the adherence to treatment with olanzapine and clozapine. In the period from 1999 to 2007, olanzapine and clozapine were the 2 most frequently analyzed antipsychotics at the Department of Clinical Pharmacology at St. Olavs University Hospital, Trondheim, Norway, with more than 24,000 and more than 18,000 samples, respectively. In total, 111 patients on olanzapine and 95 patients on clozapine had provided samples in both the inpatient and outpatient settings and were included in the study. The primary outcome variable was the serum concentration-to-dose ratio (C/D ratio), that is, the serum drug concentration per milligram of drug given. For olanzapine, the C/D ratio in the outpatient setting was 10.7% lower than in the inpatient setting (P = 0.013). No such difference was found for clozapine. The difference in the olanzapine group was exclusively attributed to a lower outpatient ratio in females. For clozapine, no sex influence was found. No effect of age on the C/D ratios was found either for olanzapine or for clozapine. The lower C/D ratio in females using olanzapine in the outpatient setting might imply that they, in contrast to males, are less adherent to their medication when outside hospital. For clozapine, there were no indications of differences in adherence between inpatients and outpatients.

Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies

Davies SJC, Westin AA, Castberg I, Lewis G, Lennard MS, Taylor S, Spigset O. Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies.

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.

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.

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.

Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: Changes in drug disposition

Background Pregnancy may cause changes in drug disposition. The clinical consequences may be profound and even counterintuitive; in some cases pregnant women may need more than twice their usual drug dose in order to maintain therapeutic drug levels. For antidepressants, evidence on drug disposition in pregnancy is scarce. The aim of this study was to determine the effects of pregnancy on serum levels of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine in a large and naturalistic patient material, in order to provide tentative dose recommendations for pregnant women. Methods Using patient data from two routine therapeutic drug monitoring (TDM) services in Norway with linkage to the national birth registry, dose-adjusted serum drug concentrations of SSRIs and venlafaxine during pregnancy were compared to the women’s own baseline (non-pregnant) values, using a linear mixed model. Findings Overall, the TDM databases contained 196,726 serum concentration measurements from 54,393 women. After data linkage and drug selection (SSRIs or venlafaxine only), we identified 367 analyses obtained from a total of 290 pregnancies in 281 women, and 420 baseline observations from the same women. Serum concentrations in the third trimester were significantly lower than baseline for paroxetine (–51%; 95% confidence interval [CI], –66%, –30%; p<0.001), fluvoxamine (–56%; CI, –75%, –23%; p = 0.004) and citalopram (–24%; CI, –38%, –7%; p = 0,007), and higher than baseline for sertraline (+68%; CI, +37%, +106%; p<0.001). For escitalopram, fluoxetine and venlafaxine concentrations did not change significantly. Conclusions For paroxetine and fluvoxamine the pronounced decline in maternal drug serum concentrations in pregnancy may necessitate a dose increase of about 100% during the third trimester in order to maintain stable concentrations. For fluoxetine, venlafaxine, citalopram, escitalopram and sertraline, the present study indicates that dose adjustments are generally not necessary during pregnancy.

Effects of age and gender on the serum levels of clozapine, olanzapine, risperidone, and quetiapine

To investigate serum concentrations of second‐generation antipsychotics in relation to age and gender in a population ranging from 18 to 100 years.

Can Physical Exercise or Food Deprivation Cause Release of Fat‐Stored Cannabinoids?

The aim of this study was to evaluate whether physical exercise or food deprivation may increase cannabinoid levels in serum or urine in abstinent chronic cannabis users. The study took place in a drug detoxification ward parallel to study participants receiving treatment. Six chronic, daily cannabis users (one female, five males, average age 30.0 years; BMI 20.8) were exposed to a 45-min. moderate-intensity workout and a 24-hr period of food deprivation. Serum samples were drawn prior to and after interventions and analysed for Δ9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) by liquid chromatography–tandem mass spectrometry (LCMSMS), and all voided urine was tested for THCCOOH by LCMSMS and normalized to the creatinine levels, yielding ng/mg ratios. There were no major differences in the measured cannabinoid levels in serum or urine before and after physical exercise or food deprivation. We conclude that exercise and/or food deprivation are unlikely to cause sufficient cannabinoid concentration changes to hamper correct interpretations in drug testing programmes.