Victoria C. Ziesenitz

Frequency of the SLCO1B1 388A>G and the 521T>C polymorphism in Tanzania genotyped by a new LightCycler®-based method

PurposeThe 388A>G and the 521T>C polymorphism of the SLCO1B1 gene affect the activity of the uptake transporter OATP1B1, thus influencing kinetics, safety, and efficacy of substrate drugs. To evaluate the impact of these polymorphisms in populations of different ethnic origins, it is important to know their frequencies and to develop fast and reliable methods for genotyping. We therefore established a new, high-throughput method and determined the genotype and allelic frequencies of these polymorphisms in Tanzanians, for which the frequencies were unknown thus far.MethodsNew LightCycler® 480-based methods with hybridization probes were established and used to genotype 366 Tanzanian and 236 European individuals for 388A>G (rs2306283) and 521T>C (rs4149056) in the SLCO1B1 gene. The methods were validated by direct sequencing of the polymerase chain reaction (PCR) products of heterozygous individuals and checked for intrarun precision repeatability, interrun precision reproducibility, robustness, and deviations from the Hardy–Weinberg equilibrium.ResultsThe new methods allow unambiguous identification of the corresponding genotypes. There was a clear difference in allelic distribution between Tanzanians and Europeans, with the 388A>G (rs2306283) being much more prevalent in Tanzanians (87% vs 41%) and the 521T>C (rs4149056) being very rare in this African population (6% vs 17%).ConclusionsWe developed robust and high-throughput methods to genotype common SLCO1B1 allelic variants with the LightCycler® 480. In Tanzanians, we identified the highest frequency of the 388A>G and 521T>C polymorphisms ever reported from black populations. The clinical relevance of SLCO1B1 genetic variation in the African population remains to be investigated.

Clinical Pharmacology of Frequently Used Intravenous Drugs During Bariatric Surgery in Adolescents

Obesity represents one of the most important public health issues according to the World Health Organization. Additionally, in a recent National Health and Nutrition Survey of 2011-2012, approximately 17 % of children and adolescents in the United States were considered obese. The obesity rate is higher within the adolescent age group as compared to preschool children. Childhood obesity is particularly problematic, because the co-morbid disease states which accompany obesity may require frequent pharmacotherapy and/ or surgical intervention. Despite the potential for increased pharmacotherapy among obese patients, there is a paucity of dosing guidelines for this special population. Optimal drug dosing in obese pediatric patients has not been sufficiently explored as the present data available are mostly specific for obese adults. In this review, we present an overview concerning what is currently known about the pharmacokinetics and pharmacogenetics of frequently used drugs including midazolam, fentanyl and its newer derivatives, morphine, ketamine, acetaminophen, dexmedetomidine and enoxaparin in obese adolescents undergoing bariatric surgery. We will also summarize the current dosing recommendations of anesthetic drugs in bariatric anesthesia.

Pharmacokinetic interaction of intravenous fentanyl with ketoconazole.

Fentanyl is primarily metabolized by CYP3A, but has also been suggested to act as a weak inhibitor of CYP3A. We investigated the influence of CYP3A inhibition by ketoconazole on the pharmacokinetics of intravenously administered fentanyl and the effect of fentanyl on CYP3A activity. A prospective, open‐label, randomized, monocentre, crossover study was conducted in 16 healthy volunteers. They received fentanyl alone (5 microgram per kilogram) or fentanyl plus ketoconazole (200 milligram orally B.I.D. over 2 days). Naloxone (2 × 0.2 milligram i.v.) was given simultaneously with fentanyl to mitigate any opioid effect. Midazolam was administered as a CYP3A probe drug. Fentanyl and its metabolites were quantified by LC/MS/MS in blood and urine samples obtained over 24 hour. Exposure of fentanyl (AUC0‐∞) was significantly increased to 133% and systemic clearance was reduced to 78% by ketoconazole, norfentanyl formation was significantly delayed and partial metabolic clearance decreased to 18%. Fentanyl had no influence on midazolam exposure and CYP3A activity whereas ketoconazole decreased CYP3A activity to 13%. Although fentanyl N‐dealkylation is substantially inhibited by ketoconazole, exposure of fentanyl itself increased by one third only. Clinically fentanyl dosage adjustments may become necessary when ketoconazole or other strong CYP3A inhibitors are given simultaneously. Fentanyl itself does not influence CYP3A activity.

Fentanyl pharmacokinetics is not dependent on hepatic uptake by organic anion-transporting polypeptide 1B1 in human beings.

A recent study investigating the pharmacokinetics of fentanyl in Sprague–Dawley rats suggested fentanyl to be a substrate of rat organic anion‐transporting polypeptide Oatp. In human beings, the most important OATP for the pharmacokinetics of many drugs is OATP1B1. Therefore, genetic variants of OATP1B1 (SLCO1B1) might modulate fentanyl pharmacokinetics and efficacy in human beings. Sixteen healthy male and female volunteers, homozygous for SLCO1B1*1a (genetic wild‐type) (n = 11) or *15 (deficient haplotype carrying the single‐nucleotide polymorphisms rs2306283 and rs4149056 and exhibiting altered transport activity; n = 5), were included in this randomized crossover study. The participants received fentanyl (5 μg/kg) intravenously alone or with the OATP inhibitor rifampicin (600 mg single oral dose). The pharmacokinetics of fentanyl and norfentanyl were determined by liquid chromatography coupled to tandem mass spectrometry (LC‐MS/MS). In addition, fentanyl uptake in vitro was evaluated in OATP1B1 overexpressing HEK293 cells and compared to a mock‐transfected cell line. In the clinical trial, fentanyl clearance was 18.8 ± 8.2 mL/min. kg in SLCO1B1*1a and 19.5 ± 1.8 mL/min/kg in SLCO1B1*15 carriers and not significantly different between the genotypes. During rifampicin, fentanyl clearance was 15.0 ± 4.4 mL/min/kg in SLCO1B1*1a and 16.7 ± 5.9 mL/min/kg in SLCO1B1*15 carriers (p > 0.5). In addition, in vitro data also indicate that fentanyl is not transported by OATP1B1. In conclusion, our data indicate that OATP1B1 has no impact on fentanyl pharmacokinetics in human beings.

Repair of an aorto-right ventricular tunnel in a newborn.

A newborn presented with an aorto-right ventricular tunnel, a defect connecting the left aortic sinus to the right ventricle. The patient underwent repair on 4th day of life.

Cytochrome P450‐3A Phenotyping Using Midazolam Is Not Altered by OATP1B1 Polymorphisms

To the Editor: In their recent article, “OATP1B1 Polymorphism as a Determinant of Erythromycin Disposition,” Lancaster et al.1 state that SLCO1B1 polymorphisms coding for organic anion–transporting polypeptide (OATP) 1B1 significantly affect the metabolism of erythromycin. Hence, when used for cytochrome P450-3A phenotyping, this will limit the validity of erythromycin as a probe drug.2 Midazolam is probably the most frequently used cytochrome P450-3A probe drug. In vitro evidence suggests that it is not transported by OATP1A2, OATP1B1, or OATP1B3 in vitro,3 but this has never been confirmed in vivo. We therefore investigated the effect of SLCO1B1 polymorphisms on midazolam metabolism in humans in a retrospective analysis of previously determined oral midazolam concentration–time profiles. All clinical trials were approved by the Competent Authority in Germany and the Ethics Committee of the Medical Faculty of the University of Heidelberg (EudraCT: 2009-013060-39, 2010-018962-22, 2010-019171-29, 2011-000516-25, 2010-022328-64, and 2010-02286813), and all participants gave written informed consent before the study. Thirty-two individuals (31 Caucasians and 1 Hispanic; 20 males) were homozygous for the wild-type OATP1B1 (SLCO1B1 c.388AA-c.521TT, SLCO1B1*1A), and eight individuals (seven Caucasians, one Hispanic; six males) were homozygous for a variant of OATP1B1 haplotype with reduced transport activity (SLCO1B1 c.388GG–c.521CC, SLCO1B1*15). Anthropometric data were not statistically different between the two genotypes (SLCO1B1*1A vs. SLCO1B1*15: age 31.0 vs. 31.6 years; weight 70.6 vs. 73.3 kg; body mass index: 22.6 vs. 23.4 kg/m2). All study participants received 3 mg midazolam solution orally (Dormicum; Roche Pharma, Grenzach-Wyhlen, Germany) to determine the partial metabolic clearance of midazolam to 1′-hydroxymidazolam using a validated limited sampling strategy.4 The partial metabolic oral clearance of midazolam to 1′-hydroxymidazolam was 714 ml/min (geometric mean; 90% confidence interval 626–814) in the SLCO1B1*1A group and not significantly altered in the SLCO1B1*15 group (645 ml/min; 90% confidence interval 529–787; Mann– Whitney U-test: P = 0.47; Figure 1). A post hoc sample-size calculation using the variance of our data with α = 0.05 and a power of 80% revealed that we had a power to detect a clearance difference of 46%. To detect a 20% difference with a power of 80%, data for 162 subjects in the SLCO1B1*1A group and 41 subjects in the SLCO1B1*15 group would be necessary. Hence, although we were able to exclude a clinically relevant midazolam clearance difference between SLCO1B1*1A and SLCO1B1*15, the sample was not sufficiently large to exclude a contribution of OATP1B1 to midazolam clearance. In contrast to that of erythromycin, midazolam pharmacokinetics is not critically modulated by SLCO1B1 polymorphisms, indicating that it more closely reflects cytochrome P450-3A activity than erythromycin.

No, we are not—we keep forgetting the right ventricle

Dear Editor, With interest, we read the review of Goenka and coworkers in the Journal concerning the most commonly used endpoints of recent randomized clinical phase III trials evaluating the effects of therapeutic drugs on acute or chronic heart failure [1]. These endpoints vary between acute and chronic heart failure trials based on the different pathophysiology of these conditions. Endpoints used in chronic heart failure trials are more heterogeneous compared to acute heart failure studies. However, from the perspective of physicians treating adult and pediatric patients with right heart failure, we would like to highlight the absence of any consideration of clinical trials in patients with right heart failure in the methodology of this review [1]. As a consequence, we need to respond to the question Bare we doing it right?^ raised by the authors in the title of their review: Bno, we are not—because we keep forgetting the right ventricle!^ [2]. Upon screening the supplementary material provided by Goenka and co-workers, we identified four studies (three protocols NCT 01156636, NCT 01726049, NCT 00820352, and one publication [3]) aiming at patients with right heart failure and several studies also considering patients with right ventricular dysfunction (e.g., NCT 01584557), but numerous relevant trials in patients with pulmonary hypertension and heart failure are currently ignored [4–12]. Regarding right heart failure, there is an even more controversial discussion on suitable endpoints than Goenka and coworkers have described in their review focusing on left heart failure, because signs and symptoms of left heart failure cannot be simply transferred to conditions with right ventricular dysfunction. In recent Cochrane analyses on diseases leading to right heart failure, such as pulmonary arterial hypertension (PAH) and Eisenmenger syndrome, the most commonly used end points were (functional) exercise capacity (6-min walking test (6MWT), VO2max), functional class (NYHA/WHO), dyspnea score, pulmonary function tests, cardiopulmonary hemodynamics, time to clinical worsening, biomarkers (NT-proBNP, arterial blood gases), serious adverse events, healthrelated quality of life, hospitalization, and mortality [13–17]. While the 6MWT as a measure of exercise capacity has been commonly used due to its simplicity and validity (regarding mortality) in patients with PAH [18], it has been shown not to reflect short-term morbidity and mortality in a metaanalysis [19]. Therefore, it may not be a sufficient surrogate endpoint [20]. Also, hemodynamic parameters seemed to underestimate the benefits in survival of long-term targeted therapy [21]. This had led to a paradigm shift from using single endpoints to composite, yet heterogeneous, endpoints in recent trials [22]. Time-to-clinical-worsening (TTCW) may be an alternative endpoint to the 6MWT, but has experienced relevant modification over time. From simply being defined as first occurrence or deterioration of clinical symptoms such as arterial hypotension, right ventricular, hepatic, or renal failure Regarding the review article BEnd points in heart failure—are we doing it right?^ By L. Goenka, M. George, and S. Selvarajan, Eur J Clin Pharmacol 2017; 73 (6): 651–659

Management of anaphylaxis and allergies in patients with long QT syndrome - review of current evidence

OBJECTIVE To develop a treatment algorithm for patients with long QT syndrome (LQTS) in case they need antiallergic medications for allergic reactions, including asthma and anaphylaxis. DATA SOURCES A literature review was performed to assess safety and to develop antiallergic treatment strategies for patients with LQTS. STUDY SELECTIONS LQTS is a heterogeneous group of myocardial repolarization disorders characterized by prolongation of the QT interval that potentially results in life-threatening torsades de pointes tachycardia. Data on pharmacologic treatment in case of anaphylaxis in LQTS are sparse. For this narrative review, all currently available articles on the use of antiallergic drugs for allergic reactions, anaphylaxis, and asthma in patients with LQTS were used. RESULTS Local allergic symptoms can be safely treated primarily with fexofenadine, levocetirizine, desloratadine, or cetirizine and, if needed, a short course of corticosteroids. In case of systemic symptoms, epinephrine should be administered. It may be less effective in patients with LQTS treated with β-blockers, necessitating the use of glucagon as add-on treatment. In case of lower airway obstruction, ipratropium bromide should be used, but if not effective, inhaled β2-adrenergic agents may be used. Continuous cardiac monitoring is indicated with the use of epinephrine and inhaled β2-adrenergic agents. The use of the latter also warrants intense monitoring of serum potassium levels. Clemastine and dimetindene should be avoided in patients with LQTS. CONCLUSION Patients with LQTS have a higher risk of life-threatening complications during the treatment of their allergic reactions because of the underlying disease and concomitant treatment with β-blockers. Treatment algorithms will certainly decrease these complications.

Variable expression of Alagille syndrome in a family with a new JAG1 gene mutation

We report the case of a patient with tetralogy of Fallot with absent pulmonary valve and familial Alagille syndrome who successfully underwent cardiac repair. The patients sister had liver and congenital heart disease. The father had undergone liver transplantation but showed no significant cardiac abnormalities. A yet-unknown mutation of the JAG1 gene was discovered in this family with variable expression of Alagille syndrome.

PO-0049 Coronary Artery Anomalies In Patients Undergoing Arterial Switch Operation

Background and aims The arterial switch operation (ASO) is the surgical standard of care for repair of transposition of the great arteries (D-TGA). Until recently, anatomical variations of the coronary arteries, especially the intramural course of a single coronary artery, were considered contraindications for ASO. Transfer of the coronary arteries may be a surgical challenge in these cases increasing the risk of (sub-)acute coronary artery occlusions. Methods We report our management of two exemplary cases of D-TGA with coronary artery anomalies: (1) Single coronary ostium of RCA, Cx and LAD originating from aortic sinus II and an intramural course of the proximal LAD. (2) Side-by-side position of the great arteries, RCA and LAD originating from sinus I and Cx from sinus II. Results Both neonates successfully underwent ASO with transfer of the coronary arteries. During the post-operative period, patient 1 was diagnosed with a subacute anteroseptal ischemia and was then managed conservatively. Follow-up echocardiogram at 12 months demonstrated satisfactory left and good right ventricular function. The postsurgical course of patient 2 was uneventful with good biventricular function at follow-up. Conclusions Anatomical variations of the coronary arteries require adaptions of the surgical technique of coronary artery transfer. Nowadays, ASO is even possible in patients with D-TGA and complex coronary anomalies. The long-term management, however, has to be evaluated, e.g. regarding the need for coronary artery re-surgery.