Target-Site Pharmacokinetics of the Echinocandin Antifungal Anidulafungin in Ascites and Pleural Effusion During Critical Illness

Target-Site Pharmacokinetics of the Echinocandin Antifungal Anidulafungin in Ascites and Pleural Effusion During Critical Illness

Oral Communications Fluindione was the main VKA prescribed followed by warfarin. However we observed a progressive report to warfarine prescriptions (...

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Oral Communications Fluindione was the main VKA prescribed followed by warfarin. However we observed a progressive report to warfarine prescriptions (1st period (fluindione/ warfarin), 9; 2nd, 6; 3rd: 4). We identified 2 patients (1%) exposed to DOAs (dabigatran) during the 1st period, 24 patients (9%) during the 2nd period (dabigatran, (42%); rivaroxaban, (58%)), and 47 (19%) during the 3rd period (dabigatran, (21%); rivaroxaban, (51%); apixaban, (28%)). Reasons for admission, divided in three categories (hemorrhagic disease, thrombotic disease, and all other causes of admission) were quantitatively comparable during the three periods in patients exposed to VKAs. This comparison was not possible with DOAs in view of the limited number of patients. Conclusions:  This study performed over a period of 5 years confirmed, through hospitalization data, a progressive increased in DOA prescriptions, a report of fluindione prescriptions to warfarine, and of dabigatran to factor Xa-inhibitors.

Risk of Major Congenital Malformations after First Trimester Exposure to Topical Azoles R. Rotem1; B. Fishman1; G. Koren1,2; S. Daniel1,3; E. Lunenfeld3; and A. Levy1 1 Ben-Gurion University of the Negev; 2Maccabi Health Services; and 3Soroka Medical Center, Beer-Sheva, Israel Background:  Azole anti-fungals are used by pregnant women with vaginal candidiasis. Few studies have examined the association between first trimester exposure to topical azoles (clotrimazole and miconazole in particular) and birth defects. All were case-control, and were subjected to recall bias. Methods:  A retrospective cohort study was conducted, including all women who gave birth at Soroka Medical Center in Beer-Sheva, Israel, and registered with the Clalit health maintenance organization from January 1999 to December 2009. A computerized database of dispensed medications was linked to two computerized databases containing information on maternal and infant hospitalizations. A database that recorded pregnancy terminations due to fetal illness or malformation was analyzed. Potential confounders were assessed and controlled for. Crude and adjusted risks of major congenital malformations and for specific malformations were calculated. Results:  During the study period, a total of 101,615 pregnancies were registered, 100,520 were admitted for birth and 1,095 for pregnancy termination. A total of 1,993 women were exposed to clotrimazole vaginal tablets and 313 to miconazole vaginal tablets during the first trimester of pregnancy. No association was found between exposure to clotrimazole and major malformations in general (adjusted OR 1.09, 95% confidence interval 0.91-1.30) or specific malformations. A weak association was found between exposure to miconazole and major malformations (adjusted OR 1.48, 95% confidence interval 1.002- 2.18). Specifically, between miconazole exposure and musculoskeletal malformation in general (adjusted OR 2.11, 95% confidence interval 1.12- 3.97) and other congenital musculoskeletal anomalies (ICD 756) (adjusted OR 3.43, 95% confidence interval 1.52- 7.73), in particular, and cleft lip and palate (adjusted OR4.59, 95% confidence interval 1.13- 18.65). Conclusions:  In contrast to previous studies, our study demonstrated that intrauterine exposure to miconazole during the first trimester of pregnancy was associated with major and specific malformations. Further studies are needed to clarify these findings.

Bioequivalence Studies of Highly Variable Drugs - An Example of Itraconazole V. Dragojevic-Simic1; A. Kovacevic1; N. Rancic1; V. Jacevic2; S. Djordjevic2; V. Kilibarda2; Z. Segrt3; and M. Mikov4

August 2017

1 Centre for Clinical Pharmacology & Medical Faculty, Military Medical Academy, Belgrade, Serbia; 2Poison Control Centre, Medical Faculty & Military Medical Academy, Belgrade, Serbia; 3 Treatment Sector & Medical Faculty, Military Medical Academy, Belgrade, Serbia; and 4Institute for Pharmacology, Clinical Pharmacology and Toxicology, Medical Faculty, Novi Sad, Serbia Background:  Highly variable drugs (HVDs) are those whose withinsubject variability (WSV) for a parameter is larger than 30.00%. Itraconazole, a broad-spectrum triazole antifungal agent, is HVD with low bioavailability (55.00%). The aim of the study was the bioequivalence (BE) evaluation of two itraconazole products by using reference-scaling approach, since its reference formulation was HVD product. Methods:  Randomized, 3-sequence, 3-period, 2-treatment, partially replicated crossover design was used. During three periods, each of the 38 healthy subjects, in random order, was given a single 100 mg dose of the test (T) and reference (R) capsules of itraconazole under fed conditions. Subjects were randomized to receive R product twice and T product once. Each dose was separated by 14-days washout period. Blood samples for the pharmacokinetic (PK) assessment were collected before dosing and during 72h post dose. Plasma concentrations of itraconazole and hydroxy itraconazole were analysed by using Liquid Chromatography Mass Spectrometry (LC/MS) technique. Calculated relevant PK parameters of itraconazole and hydroxy itraconazole were AUC0-72h, AUC0-∝ , Cmax, Tmax, T1/2 and Kel. Results:  The 90% CI for the geometric mean test-to-reference ratio of AUC0-t was fully contained within the interval of 80.00% to 125.00%, both for itraconazole and hydroxy itraconazole. As far as Cmax was concerned, this ratio was fully contained within the anticipated interval from 72.15% to 138.59%, both for drug and metabolite, since obtained WSV was 44.95%. During the study three subjects encountered a total of four adverse events. They were mild in intensity, lasted few hours and completely resolved. Conclusions:  The two commercially available itraconazole products (100 mg capsules) have met predetermined criteria for BE and may be prescribed interchangeably. Therefore, the use of the reference-scaling approach for HVD itraconazole with the recommended 3-period design (TRR, RTR and RRT) is very efficient way to obtain this information.

Target-Site Pharmacokinetics of the Echinocandin Antifungal Anidulafungin in Ascites and Pleural Effusion During Critical Illness R. Welte1; I. Lorenz1; P. Eller2; M. Joannidis1; and R. Bellmann1⁎ Medical University of Innsbruck, Innsbruck, Austria; and 2 Medical University of Graz, Graz, Austria Background:  Echinocandins are recommended for treatment of invasive candidiasis in moderately or severely compromised patients as they has shown efficacy in candidaemia. Data on target-site penetration are limited so far. Therefore, we assessed anidulafungin pharmacokinetics in ascites and pleural effusion of critically ill patients treated with standard dose for proven or suspected invasive candidiasis. Methods: Adult critically ill patients were enrolled. Samples of ascites pleural and effusion were drawn from drainages inserted for therapeutic purpose before as well as 1, 4, 8, 12, 18, and 24 hours after start of anidulafungin infusion. Blood samples were taken simultaneously. From patients undergoing paracenteses single ascites and blood samples were taken. Anidulafungin quantification was performed with high pressure liquid chromatography (HPLC) and UV detection at 306 nm after precipitation of proteins by acetonitrile. Results:  Anidulafungin pharmacokinetics has been determined in ascites of four and in pleural effusion of two critically ill patients so



Clinical Therapeutics far. Ascites penetration was also assessed in a single sample obtained at paracentesis. Anidulafungin peak concentrations in ascites amounted to 0.34-0.98 mg/L. The plasma peak levels were 3.827.70 mg/L. The penetration ratio (AUC in ascites/AUC in plasma) amounted to 0.07-0.37. In pleural effusion, anidulafungin peak concentrations of 1.02 and 2.02 mg/L were measured. Conclusions:  Anidulafungin concentrations in ascites and in pleural effusion were lower than the simultaneous plasma levels. During treatment with standard dose, concentrations in ascites and pleural effusion were above or within the range of minimal inhibitory concentrations (MICs) reported for relevant Candida isolates.

Psychological Insuline Resistance. Descriptive Observational Study in 123 Patients with Type 2 Diabetes Mellitus Not Taking Insulin in Paris Area, France S. Mouly; J.-F. Bergmann; and P.-J. Guillausseau Département de Médecine Interne, APHP, Groupe Hospitalier Lariboisière Saint-Louis Fernand Widal, Paris, France Background:  General practicioners (GP) usually deal with psychological insulin reluctance from patients with Type 2 diabetes mellitus (T2DM) to whom insulin need to be prescribed in addition to oral antidiabetic drugs. Reasons to explain this reluctance to insulin is usually psychological and patient-driven. We have assessed the clinical importance and relevance of these negative ideas regarding insulin treatment. Methods:  This prospective, descriptive observational study enrolled 131 ambulatory patients with proven T2DM who had never been treated with insulin prior to study enrollment and who were asked to answer a 24 items questionnaire based on all the factors negatively associated to insulin treatment, according to literature search. Results:  Eight patients provided incomplete data or did yet receive insulin during the management of diabetes mellitus and were removed from the final analysis. Based on the 124 questionnaires analyzed, the most frequent negative ideas regarding insulin treatment were feeling that the disease worsens upon insulin start (84.5%), that starting insulin is then irreversible (65%), fear of this unknown treatment (56.9%), of changes in the daily schedule and organization of meals (55.3%), of scheduling constraints (47.1%), of hypoglycemia (45.5%), of complicated supplies required for injection (43.1%), feeling that insulin treatment is due to a previous bad self-management of their disease (37.4%) and fear of the negative experience of insulin therapy as reported by other patients or relatives with diabetes mellitus (30.9%). Most of these negative ideas were reported by women, young patients, patients with low level of education or those with recently diagnosed T2DM. Interestingly, the effectiveness of T2DM control did not influence the current results. Conclusions:  The current study emphasizes the need to improve patient-physician relationship by providing the most relevant information regarding insulin treatment and increase treatment adherence.

Sex Differences in Spontaneous Reports on Adverse Drug Events for Antihypertensive Drugs D.M. Rydberg1,2⁎; S. Mejyr1; D. Loikas2,3; K. Schenck-Gustafsson1,2; M. von Euler1,2; and R.E. Malmström1,2 1 Karolinska University Hospital, Stockholm, Sweden; 2Karolinska Institutet, Stockholm, Sweden; and 3Public Healthcare Services Committee, Stockholm County Council, Stockholm, Sweden Background:  In general, few data exist regarding sex differences in spontaneous adverse drug event (ADE) reporting. We wanted to explore if sex differences are found in spontaneously reported adverse drug events for antihypertensive drug treatment in routine care.


Methods:  A cross sectional analysis combining number of reports for ten groups of antihypertensive drugs; ACE inhibitors (ACE-I), with or without thiazide combinations, angiotensin receptor blockers (ARB), with or without thiazide combinations, diuretics (thiazides, potassium-sparing agents, sulfonamides, aldosterone antagonists), selective betablockers and dihydropyridine calcium channel blockers (DHPs), from the national pharmacovigilance database with data from the Swedish Prescribed Drug Register, from 2005 to 2012. The total number of reports was adjusted to the number of exposed patients and the number of dispensed DDDs, respectively, among women and men (ORs with 95% CI). The most frequently reported ADEs were collected and co-medication and co-prescription were analysed. Results:  In women, a higher prevalence of ADE reports was seen in six of the ten groups of antihypertensive drugs: ACE-I (OR 1.21; 1.09-1.35) ACE-I with combinations (OR 1.61; 1.44-1.79), ARB with combinations (OR 2.12; 1.47-3.06), thiazides (OR 1.78; 1.332.39), diuretics and potassium sparing agents (OR 1.62; 1.22-2.17) and DHPs (OR 1.40; 1.17-1.67). For aldosterone antagonists, we observed a higher prevalence of ADE reports in men (OR 0.75; 0.590.97). One of the most frequently reported events found in several subgroups were hyponatremia. This diagnosis also had a very high overrepresentation in women. Conclusions:  This ecological study of reported ADEs due to antihypertensive treatment showed a higher prevalence of reports in women in six out of ten groups of antihypertensive drugs. The only group of antihypertensive agents with a higher prevalence of ADE reports in men was aldosterone antagonists.

Investigating Real-World Clopidogrel Pharmacogenetics in Stroke Using a Bioresource Linked to Electronic Medical Records A. Tornio⁎; R. Flynn; S. Morant; E. Velten; C.N.A. Palmer; T.M. MacDonald; and A.S.F. Doney University of Dundee, Dundee, United Kingdom Background: Increased risk of arterial thrombo-occlusive events (ATEs) in clopidogrel-treated individuals due to CYP2C19 loss-offunction variants is established in the context of acute ischaemic heart disease where dual antiplatelet therapy is the norm. Few studies have considered the ischaemic stroke population where guidelines usually indicate clopidogrel monotherapy. We used the GoDARTS bioresource linked to longitudinal electronic medical records to examine the real-world impact of the CYP2C19*2 loss-of-function variant in all patients prescribed clopidogrel following an acute ATE. We then employed this model to investigate specifically the ischaemic stroke sub-population. Methods: Patients hospitalized for ATEs (myocardial infarction, ischaemic stroke or peripheral artery disease) who subsequently redeemed prescriptions for clopidogrel in the community within 21 days of hospital admission were entered into the study. An additive Cox proportional hazards model adjusted for age at study entry, sex, exposure to aspirin and/or proton pump inhibitors was used to compare the rate of primary end point of re-hospitalisation for an ATE or death from any cause between individuals carrying one or two CYP2C19*2 alleles and non-carriers. Results:  15,317 subjects had been genotyped for the CYP2C19*2 allele with 25.9% carrying at least one loss-of-function allele. Overall 651 patients qualified for entry into the study. During 24 months follow-up the primary endpoint occurred in 299 patients (46%). CYP2C19*2 carriers had an increased risk (HR 1.29; 95% confidence interval 1.04-1.59, P= 0.019) compared to non-carriers. In the subgroup whose qualifying event was an ischaemic stroke (n= 94)

Volume 39 Number 8S