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Rationale: Spironolactone is a steroidal drug prescribed for a variety of medical conditions and is extensively metabolized quickly after administration. Measurement of spironolactone and its metabolites remains challenging using mass spectrometry (MS) due to in-source fragmentation and relatively poor ionization using electrospray ionization. Therefore, improved methods of measurements are needed, particularly in the case of small sample volumes. Methods: Girard's reagent P (GP) derivatization of spironolactone was employed to improve response and provide an MS-based solution to the measurement of spironolactone and its metabolites. We performed ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESIMS/MS) and ion mobility spectrometry (IMS)-high-resolution mass spectrometry (HRMS) to fully characterize the GP derivatization products. Analytes were studied in positive ionization mode, and MS/MS was performed using nonresonance and resonance excitation collision-induced dissociation. Results: We observed the successful GP derivatization of spironolactone and its metabolites using authentic chemical standards. A signal enhancement of 1-2 orders of magnitude was observed for GP-derivatized versions of spironolactone and its metabolites. Further, GP derivatization eliminated in-source fragmentation. Finally, we performed GP derivatization and ultra-high-performance liquid chromatography- high-resolution mass spectrometry (UHPLC-HRMS) in a small volume of murine serum (20 µL) from spironolactone-treated and control animals and observed multiple spironolactone metabolites only in the spironolactone-treated group. Conclusions: GP derivatization was proven to have advantageous mass spectral performance (e.g., limiting in-source fragmentation, enhancing signals, and eliminating isobaric analytes) for spironolactone and its metabolites. This work and the detailed characterization using ultra-high-performance liquid chromatography- high-resolution tandem mass spectrometry (UHPLC-HRMS/MS) and IMS serve as the foundation for future developments in reaction optimization and/or quantitative assay development. [ABSTRACT FROM AUTHOR]

Mineralocorticoid receptor antagonists (MRAs) are one of the renin–angiotensin–aldosterone system inhibitors widely used in clinical practice. While spironolactone and eplerenone have a long-standing profile in clinical medicine, finerenone is a novel agent within the MRA class. It has a higher specificity for mineralocorticoid receptors, eliciting less pronounced adverse effects. Although approved for clinical use in patients with chronic kidney disease and heart failure, intensive non-clinical research aims to further elucidate its mechanism of action, including dose-related selectivity. Within the field, animal models remain the gold standard for non-clinical testing of drug pharmacological and toxicological properties. Their role, however, has been challenged by recent advances in in vitro models, mainly through sophisticated analytical tools and developments in data analysis. Currently, in vitro models are gaining momentum as possible platforms for advanced pharmacological and pathophysiological studies. This article focuses on past, current, and possibly future in vitro cell models research with clinically relevant MRAs. [ABSTRACT FROM AUTHOR]

Spironolactone, a potassium-sparing diuretic, is used to treat hypertension, heart failure, and certain hyperandrogenic disorders. Its use during pregnancy is not recommended due to the risk of feminizing male fetuses, primarily because of its antiandrogenic activity. However, human data remain scarce and largely inconclusive. Here, we present the first case of a 25-year-old pregnant woman, at 16 weeks of gestation, who was inadvertently exposed to spironolactone (240 mg/day) for 1 week due to a pharmacy dispensing error. The patient subsequently delivered a healthy male infant with normal genitalia at 38 weeks of gestation following vaginal delivery. Current follow-up shows that the infant is healthy and developing normally. This article summarizes the potential causes of spironolactone-induced anomalous genital development and explores the safety of new-generation mineralocorticoid receptor antagonists (MRAs) during pregnancy. The mechanisms behind spironolactone-induced anomalous genital development in male fetuses have not been fully elucidated. Spironolactone competes with dihydrotestosterone for binding to androgen receptors and inhibits enzymes involved in androgen biosynthesis, which may partly explain its antiandrogenic effects. Recent advancements in MRAs have led to the development of compounds with higher selectivity for the mineralocorticoid receptor, thereby reducing the incidence of antiandrogen side effects. These new-generation MRAs may be effective alternatives during pregnancy, but more data are needed to establish their safety in pregnant women. This case contributes to the limited but growing body of literature on the safety profile of spironolactone in pregnancy, providing insights into its effects during a critical period of fetal development. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the association between spironolactone use and controlled ovarian hyperstimulation (COH) outcomes. Methods: Retrospective study, including patients who underwent COH. Oocyte yield and maturation rates were compared by categories of spironolactone use at the start of their cycle. Results: 402 patients were included. 83 patients continued spironolactone, 44 patients discontinued spironolactone, and 275 matched control patients were spironolactone-naïve. No difference was observed in the number of oocytes retrieved (17 ± 14 vs. 15 ± 13, p = 0.4) or mature oocytes vitrified (15 ± 9.5 vs. 12 ± 11, p = 0.4) in patients who continued spironolactone use and spironolactone naïve patients, respectively. When comparing patients who continued spironolactone use and patients who discontinued spironolactone use, no difference was seen in the number of oocytes retrieved (17 ± 14 vs. 17.5 ± 7.8, p = 0.9) or mature oocytes vitrified (15 ± 9.5 vs. 13.5 ± 6.5, p = 0.5), respectively. There was no observed relationship between total daily spironolactone dose (< 100mg/day, 100mg/day, 150mg/day and > 200 mg/day) and the total number of mature oocytes vitrified (respectively, 14.0 ± 13.0, 16.0 ± 7.8, 14.0 ± 4.5, 11.0 ± 7.0 oocytes, p = 0.4). Conclusions: This is the first study to evaluate the association between spironolactone and oocyte yield and maturation rates during COH cycles. These findings can assist in counseling patients on the implications of continuing spironolactone during COH cycle. [ABSTRACT FROM AUTHOR]

Quantitative systems pharmacology (QSP) models are rarely applied prospectively for decision-making in clinical practice. We therefore aimed to operationalize a QSP model for potas-sium homeostasis to predict potassium trajectories based on spironolactone administrations. For this purpose, we proposed a general workflow that was applied to electronic health records (EHR) from patients treated in a German tertiary care hospital. The workflow steps included model exploration, local and global sensitivity analyses (SA), identifiability analysis (IA) of model parameters, and specification of their inter-individual variability (IIV). Patient covariates, selected parameters, and IIV then defined prior information for the Bayesian a posteriori prediction of individual potassium trajectories of the following day. Following these steps, the successfully operationalized QSP model was interactively explored via a Shiny app. SA and IA yielded five influential and estimable parameters (extracellular fluid volume, hyperaldosteronism, mineral corticoid receptor abundance, potassium intake, sodium intake) for Bayesian prediction. The operationalized model was validated in nine pilot patients and showed satisfactory performance based on the (absolute) average fold error. This provides proof-of-principle for a Prescribing Monitoring of potassium concentrations in a hospital system, which could suggest preemptive clinical measures and therefore potentially avoid dangerous hyperkalemia or hypokalemia. [ABSTRACT FROM AUTHOR]

Approximately 0.6% of the United States population identifies as transgender or gender nonbinary. The term transgender refers to a person who experiences incongruence between their sex at birth and their gender identity. The care of the transgender patient is complex, often requiring the expertise of various medical and surgical specialties. The prevalence of gender-affirming surgery is increasing as societal acceptance and cultural norms are shifting. While gender-affirming procedures include a variety of body systems, airway and facial procedures are of particular importance to anesthesia providers. Anesthetic concerns for masculinization and feminization procedures of the airway and face include bleeding, injury to the airway, and other perioperative challenges. Transgender procedures of the airway and face often require advanced airway techniques. Following airway surgery, patients are at an increased risk for tracheal stenosis or perforation, glottic stenosis, vocal cord damage or dysfunction, and/or dysphagia. Additionally, transgender patients may undergo hormone therapy to achieve their gender goals. Providers should be aware of the implications associated with administration of hormones such as thromboembolic events, cardiovascular effects, and changes in various laboratory values. A knowledge of novel surgical procedures, medical therapies, and the psychosocial implications associated with transition is essential for the safe, comprehensive, and holistic care of the transgender patient. [ABSTRACT FROM AUTHOR]

Purpose of Review: Diuretics are the cornerstone therapy for acute heart failure (HF) and congestion. Patients chronically exposed to loop diuretics may develop diuretic resistance as a consequence of nephron remodelling, and the combination of diuretics will be necessary to improve diuretic response and achieve decongestion. This review integrates data from recent research and offers a practical approach to current pharmacologic therapies to manage congestion in HF with a focus on combinational therapy. Recent Findings: Until recently, combined diuretic treatment was based on observational studies and expert opinion. Recent evidence from clinical trials has shown that combined diuretic treatment can be started earlier without escalating the doses of loop diuretics with an adequate safety profile. Summary: Diuretic combination is a promising strategy for overcoming diuretic resistance in HF. Further studies aiming to get more insights into the pathophysiology of diuretic resistance and large clinical trials confirming the safety and efficacy over standard diuretics regimens are warranted. [ABSTRACT FROM AUTHOR]

Background A goal of gender-affirming hormone therapy (GAHT) for transgender women is to use estradiol to suppress endogenous production of testosterone. However, the effects of different estradiol regimens and route of administration on testosterone suppression is unknown. This is the first open-label randomized trial comparing different GAHT regimens for optimal estradiol route and dosing. Objective To evaluate 1 month and 6 months testosterone suppression <50 ng/dL with pulsed (once- or twice-daily sublingual 17-beta estradiol) and continuous (transdermal 17-beta estradiol) GAHT. Methods This study was conducted at an outpatient adult transgender clinic. Thirty-nine transgender women undergoing initiation of GAHT were randomly assigned to receive either once-daily sublingual, twice-daily sublingual, or transdermal 17-beta estradiol. All participants received spironolactone as an antiandrogen. Doses were titrated at monthly intervals to achieve total testosterone suppression <50 ng/dL. Results Transdermal 17-beta estradiol resulted in more rapid suppression of total testosterone, lower estrone levels, with no differences in estradiol levels when compared to once-daily and twice-daily sublingual estradiol. Moreover, there was no difference in the mean estradiol dose between the once-daily and twice-daily sublingual 17-beta estradiol group. Conclusion Continuous exposure with transdermal 17-beta estradiol suppressed testosterone production more effectively and with lower overall estradiol doses relative to once or twice daily sublingual estradiol. Most transgender women achieved cisgender women testosterone levels within 2 months on 1 or 2 0.1 mg/24 hours estradiol patches. Given no difference between once- or twice-daily sublingual estradiol, pulsed 17-beta estradiol likely provides no benefit for testosterone suppression. [ABSTRACT FROM AUTHOR]

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension and is associated with a higher cardiometabolic risk than essential hypertension. The aim of this consensus is to provide practical clinical recommendations for its surgical and medical treatment, pathology study and biochemical and clinical follow-up, as well as for the approach in special situations like advanced age, pregnancy and chronic kidney disease, from a multidisciplinary perspective, in a nominal group consensus approach of experts from the Spanish Society of Endocrinology and Nutrition (SEEN), Spanish Society of Cardiology (SEC), Spanish Society of Nephrology (SEN), Spanish Society of Internal Medicine (SEMI), Spanish Radiology Society (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Society of Laboratory Medicine (SEQC(ML)), Spanish Society of Anatomic-Pathology and Spanish Association of Surgeons (AEC). Keypoints: The treatment of choice for PA is medical therapy with mineralocorticoid receptor blockade for bilateral cases and unilateral adrenalectomy for unilateral PA. The goals of PA treatment are to normalize blood pressure (BP) and excessive aldosterone production, with the final aim of improving associated comorbidities and reducing mortality. Spironolactone is usually the mineralocorticoid receptor antagonist (MRA) of choice for medical treatment of PA. However, eplerenone has a similar efficacy to that of spironolactone when used in doses 2–3 times higher than the latter and administered 2–3 times a day. Eplerenone has the advantage of not inducing the anti-androgenic side effects commonly seen with spironolactone. Adrenalectomy is the gold standard procedure used to remove the aldosterone-hypersecreting adrenal tissue. The Primary Aldosteronism Outcome (PASO) group criteria are recommended for defining the control objectives of biochemical and clinical response to treatment. [ABSTRACT FROM AUTHOR]

Background: The management in primary care (PC) of the patients with Heart Failure (HF) is different from the management hospital, in a special way compared to cardiology departments. Objective: To define the characteristics in both phenotypes of HF in prevalent and incident cases of HF in patients recruited in a large PC sample. Methods: We proposed a and longitudinal analyses, in patients of the IBERICAN cohort, that recruited 8,066 patients in the Spanish primary care system, with 15,488 patients-years of follow-up. Of them, 252 patients (3.1%) had diagnoses of HF. HF was classified according to the 2014 guidelines in two groups: HF with a reduced eject fraction or HFrEF (LVEF < 50%) and HF with preserved eject fraction or HFpEF (LVEF ≥ 50%). Recommended treatment was defined as the patient receiving drug treatment with Renin-Angiotensin-System (RAS) blockers with beta-blockers and, optionally, spironolactone. The incidence of new cases of HF was calculated in the 7,814 patients without HF in the inclusion visit. Finally, we analysed which variables associated the onset new cases and get the hazard ratio (HR) with the confidence interval at 95% ([95%CI]). Clinical trials register: NCT02261441 (02/05/2017). Results: The HFpEF was the most frequent phenotype in prevalent cases (61.1%) and incident cases (73.9%). Patients with HFrEF had a higher prevalence of coronary heart disease (p = 0.008) and PAD (p = 0.028), and no statistically significant differences was observed in the therapeutic groups used between both groups. The incidence of HF was 12.8 cases/1000 inhabitants/year, 35.6% of them was diagnosed in PC. The renin-angiotensin system blockers were more used in PC (60%) and beta-blockers (100%) and spironolactone (60%) in hospital. The female sex showed a protective effect for incident cases (0.51 [0.28–0.92]); and AF (HR [95%CI]: 2.90 [1.51–5.54]), coronary heart disease (HR [95%CI]: 2.18 [1.19-4.00]) and hypertension (HR [95%CI]: 1.91 [1.00-3.64]) increased the risk of developing HF. Conclusions: HF phenotype more frequent and incident in PC was the HFpEF, but only one third of them are diagnosed in PC level. The female sex showed a protective effect and atrial fibrillation, ischaemic heart disease and hypertension increased the risk of develop HF. [ABSTRACT FROM AUTHOR]

Multivariate regression models, including classical least square, principal component regression, and partial least square, combined with UV-Vis absorbance spectra, have been developed and validated to simultaneously determine furosemide and spironolactone in tablets. The central composite design method is used to design calibration and validation concentration sets for the models. The method was applied in the concentration ranges of 4.4–15.6 mg/L for spironolactone and 2.4–13.6 mg/L for furosemide. The method exhibited good correlation coefficients (R2) with low root mean square error of calibration values of 0.22, 0.16, and 0.17 mg/L for spironolactone and 0.20, 0.17, and 0.18 mg/L for furosemide, respectively. The root mean square error of prediction values for spironolactone and furosemide are less than 10% of the average concentration values, corresponding to 1 mg/L for spironolactone and 0.8 mg/L for furosemide. Precision assessment encompassed repeatability and intermediate precision, while comparison with the HPLC method revealed no statistically significant disparity (α = 0.05). Notably, classical least square, principal component regression, and partial least square methods exhibited successful simultaneous quantification of spironolactone and furosemide within the Spiromide-40 combination tablet. Additionally, the functions and code for the analytical methods implemented in R are provided, facilitating easy usage for the readers. [ABSTRACT FROM AUTHOR]

Kidney disease frequently coexists with cardiovascular (CV) diseases, and this dual presence significantly amplifies the risk of adverse clinical outcomes. Shared pathophysiological mechanisms and common CV risk factors contribute to the increased expression of mineralocorticoid receptors, which in turn can drive the progression of chronic CV–kidney disorders. The steroidal mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone have demonstrated efficacy in improving patient outcomes in cases of heart failure with reduced ejection fraction or after a myocardial infarction, but have limited value in patients with chronic kidney disease. The non-steroidal MRA finerenone has now established itself as a foundational guideline-recommended therapy in patients with diabetic kidney disease. To date, these pharmacological agents have been developed in distinct patient populations. The consequences of their distinct pharmacological profiles necessitate further consideration. They have not undergone testing across the entire spectrum of cardiorenal scenarios, and the evidence base is currently being complemented with ongoing trials. In this review, we aim to synthesize the existing body of evidence and chart the future trajectory for the use of spironolactone, eplerenone and finerenone in improving clinical outcomes across the diverse spectrum of cardiorenal diseases. By consolidating the current state of knowledge, we seek to provide valuable insights for informed decision making in the management of patients with these complex and interconnected conditions. [ABSTRACT FROM AUTHOR]

Cyproterone acetate (CPA) and spironolactone (SPL) are different antiandrogens in gender-affirming hormone therapy (GAHT) for transgender women. Few studies have evaluated their efficacy and user satisfaction, especially among East Asians. This study aimed to evaluate these aspects in Chinese transgender women. Data were collected retrospectively from transgender women visiting the Peking University Third Hospital from 2012 to 2021. From 639 people identified as transgender women, 151 of them (80 using CPA and 71 using SPL, 16 to 40-year-old) under stable GAHT ≥6 months were enrolled. Total testosterone levels and visual analogue scale (VAS)-based satisfaction scores were evaluated. No difference was observed in age between the CPA and SPL groups (median [IQR], 22 [20–24] years and 23 [20–26] years, respectively). The duration of GAHT was longer in CPA group than in SPL group (18 [10–32] months vs. 12 [8–21] months, p = 0.009). Total testosterone levels were significantly lower with CPA treatment (25 mg/d) than with SPL treatment (100 mg/d) (median [IQR]: 0.7 [0.7–2.1] nmol/L vs. 13.0 [6.0–17.8] nmol/L, p < 0.001). The proportion of total testosterone levels reaching the recommended range was significantly higher in CPA group than in SPL group (75.0% vs. 11.3%, p < 0.001). VAS-based satisfaction scores for erection decreased and figure feminization were higher in CPA group than in SPL group, which remained unchanged after adjusting for age, treatment duration, estradiol dose, and comorbid mental disorders (p < 0.05). The prolactin levels were higher in CPA group than in SPL group (18.9 [11.8–28.1] ng/ml vs. 11.8 [7.9–18.4] ng/ml, p < 0.001). No severe safety events were reported in both groups. In Chinese transgender women, CPA was more effective than SPL in lowering testosterone levels. Additionally, VAS scores indicated greater satisfaction with erection decreased and figure feminization using CPA compared to SPL. [ABSTRACT FROM AUTHOR]

Androgenetic alopecia is the most common type of hair loss. Although the exact cause of this condition is not fully understood, it is known to involve excessive amounts of dihydrotestosterone. There are various treatment options available for androgenetic alopecia that aim to target these mechanisms. The FDA-approved therapies for this condition include topical minoxidil, oral finasteride, and low-level light therapy. This review will discuss the potential benefits of using spironolactone, dutasteride, and bicalutamide as alternative treatment options for androgenetic alopecia. [ABSTRACT FROM AUTHOR]

Co-trimoxazole is a combination of two antimicrobial drugs, (trimethoprim and sulfamethoxazole), that are used to treat a wide variety of infections such as urinary tract infection, pneumocystis pneumonia and traveler's diarrhea. Hyperkalemia is a life-threatening electrolyte disturbance. Objectives: This study aimed to determine the incidence of hyperkalemia and its risk factors among hospitalized patients receiving intravenous co-trimoxazole at Sultan Qaboos University Hospital (SQUH) in Muscat, Oman. Methods: This retrospective observational study included patients that were prescribed intravenous co-trimoxazole and identified using a computerized pharmacy system between January 2010 and December 2020. Patients' demographic and clinical characteristics were retrieved from their electronic medical records. The data were analyzed using descriptive and inferential statistical tests. Results: A total of 420 patients participated in this study. The median age of the patients was 51 (35-65) years and 55.5% were male. Hyperkalemia associated with co-trimoxazole was observed in (40.2%) of the patients. Around (44.2%) of patients who experienced hyperkalemia received a high dose of co-trimoxazole (15-20 mg/kg). Hyperkalemia occurred after the 5th day of co-trimoxazole treatment. Logistic regression analysis showed no relationship between hyperkalemia and age (adjusted odds ratio (AOR) 1.054, p=0.84), sex (AOR 1.167; p=0.471), dose (AOR 0.779; p=0.251), or use of concomitant medications (angiotensin-converting inhibitors, AOR 1.054, p=0.84; angiotensin receptor blockers, AOR 0.564; p=0.734; β-blockers, AOR 0.986; p=0.963; potassium supplements, AOR 0.59; p=0.175; nonsteroidal anti-inflammatory drugs, AOR 0.842, p=0.684; spironolactone AOR 0.748, p=0.629; heparin AOR 0.822, p=0.382; calcineurin inhibitor, AOR 1.537, p=0.406). Conclusion: Co-trimoxazole use was associated with a high incidence of hyperkalemia in this group of patients. No association between hyperkalemia and risk factors was observed. Serum potassium levels should be closely monitored, especially in the first week of co-trimoxazole treatment, to prevent the incidence of hyperkalemia, and clinical staff should adhere to serum monitoring guidelines. [ABSTRACT FROM AUTHOR]

Background: The compounding of extemporaneous preparations has historically been an essential part of the pharmacist's role, and, even today, its importance is recognized in all regulatory frameworks worldwide. The paediatric age group is known to be a therapeutic orphan, due to the low availability of formulations adapted to this population. There are potential dangers involved in treating paediatric patients with drugs approved for adults, or, more generally, off-label prescription medicines, since the excipients may be not suitable for children. As a result, the prescription of extemporaneous preparations is a common practice among paediatricians. Objective: Knowing cardiovascular diseases are currently the main cause of mortality in Haiti, the objective of this study was to develop a suitable paediatric oral liquid formulation of spironolactone with simple and low-cost excipients, and with an easy set-up method. This is in order to make the preparation suitable for the preparation in hospital or community pharmacies in those countries - even with limited resources- where it is necessary to administer spironolactone to paediatric patients. Methods: For the formulation being studied, in addition to the quality according to the directives set out in the European Pharmacopoeia, the stability was evaluated to assure adequate validity for therapeutic uses. For the evaluation of the uniformity of the suspension content, a standard procedure was developed through a HPLC method. The suspension samples were also analysed with a spectrophotometric assay. Results: The uniformity of content results confirmed that the concentration of the active molecule in each suspension was consistent. In addition, no variation in the expected concentration greater than 10% was detected after 90 days. Concerning pH, from the data, it can be observed that no sample underwent a significant variation in pH over time. Conclusion: We chose to focus our research on the development of a suspension with a very simple composition and a simple preparation procedure, while bearing in mind the quality of the finished product must be guaranteed. The preparation procedures should always be congruous with the equipment usually available in a community or hospital pharmacy's compounding laboratory, in whatever part of the world it is located. [ABSTRACT FROM AUTHOR]

Introduction: It is crucial to utilize combination therapy for immunoglobulin A nephropathy (IgAN) patients to reduce proteinuria and maintain stable kidney function. We demonstrate the safety and efficacy of low-dose spironolactone in the management of IgAN patients. Methods: Adult IgAN patients treated with spironolactone were evaluated. Patients were separated into two categories according to whether 24-h proteinuria was reduced by more than 20% after 2 months of spironolactone treatment compared to baseline levels. Results: Eighty-eight patients were analyzed and 24-h proteinuria decreased from 0.93 g to 0.70 g (p < 0.001) after 2 months of treatment with spironolactone, accompanied by a slight decrease in eGFR from 75.7 to 73.9 mL/min/1.73 m2 (p = 0.033). Intriguingly, 47 patients in the effective mineralocorticoid receptor antagonist (MRA) group showed less endocapillary hypercellularity (p = 0.040). In the ineffective group, 18 patients discontinued MRA treatment because 24-h proteinuria increased from 0.83 g to 1.04 g, while the other 23 patients continued with spironolactone and proteinuria decreased to 0.57 g in the sixth month (p = 0.001). Furthermore, 12 patients with persistent high proteinuria during prednisone therapy were added with spironolactone. 24-proteinuria was dropped from 0.95 g to 0.73 g at the second month and to 0.50 g at the sixth month. Conclusions: In our study, we confirmed spironolactone’s efficacy in reducing urine protein excretion in IgA nephropathy patients within 2 months of treatment. However, response varied among patients, with those showing endocapillary proliferation (E1) in renal biopsies having poor spironolactone responsiveness. Administering MRAs to patients with eGFR over 30 mL/min did not result in hyperkalemia, indicating the treatment’s safety.

Background and objectiveAn important barrier to HIV prevention among transgender women (TGW) is the concern that oral pre-exposure prophylaxis (PrEP) negatively affects the efficacy of feminizing hormone therapy (FHT). We aimed to assess the impact of PrEP on FHT pharmacokinetics (PK) among TGW from Brazil.MethodsWe performed a drug-drug interaction sub-study among TGW enrolled in a daily oral PrEP demonstration study (PrEParadas, NCT03220152). Participants had a first PK assessment (PK1) 15 days after FHT (estradiol valerate 2-6 mg plus spironolactone 100-200 mg) initiation and then started PrEP (tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg). A second PK evaluation was performed 12 weeks later (PK2). Blood samples were collected prior and after the directly observed dosing (0, 0.5, 1, 2, 4, 6, 8, and 24 hours). Pharmacokinetic parameters of estradiol, spironolactone, and metabolites were estimated by non-compartmental analysis (Monolix 2021R2, Lixoft®) and compared as geometric mean ratios (GMRs, 90% confidence interval [CI]).ResultsAmong 19 TGW who completed the substudy, median age was 26 years (interquartile range: 23-27.5). Estradiol area under the plasma concentration-time curve (AUCτ) and trough concentrations did not differ between PK1 and PK2 evaluations (GMR [90% CI]: 0.89 [0.76-1.04] and 1.06 [0.94-1.20], respectively). Spironolactone and canrenone AUCτ were statistically lower at PK2 than PK1 (0.76 [0.65-0.89] and 0.85 [0.78-0.94], respectively). Canrenone maximum concentration was also lower at PK2 than PK1 (0.82 [0.74-0.91]).ConclusionEstradiol PK was not influenced by PrEP concomitant use. The small differences observed in some spironolactone and canrenone PK parameters should not prevent the concomitant use of estradiol-based FHT and PrEP.Trial registrationThis trial (NCT03220152) was registered on July 18, 2017.