Santos et al. BMC Nephrology (2020) 21:24 https://doi.org/10.1186/s12882-019-1659-5 CASE REPORT Open Access Ambrisentan use in a HIV-1 infected patient with end-stage renal disease and pulmonary hypertension: minimal removal by hemodialysis - a case report José Ramón Santos1,2* , Ana Merino3,4, Walter E. Haefeli5, Cristina Miranda1, Marisol Prats6, Ioana Bancu3,4, Lucía Bailón1 and José Moltó1,2 Abstract Background: Ambrisentan is a selective endothelin receptor antagonist used for the treatment of pulmonary arterial hypertension (PAH). Little is known about ambrisentan removal by hemodialysis in patients with end-stage renal disease (ESRD). Case presentation: A 53-year-old woman with HIV/hepatitis C virus (HCV) co-infection, PAH and ESRD on regular hemodialyis was admitted in our hospital due to refractory heart failure while on treatment with bosentan (125 mg twice daily) and tadalafil (20 mg once daily) for PAH and antiretroviral treatment (cART) including darunavir/ cobicistat (800/150 mg once daily). Excessive exposure to bosentan due to drug interactions between bosentan and darunavir/cobicistat was suspected. Bosentan was replaced by ambrisentan, with progressive improvement in her clinical condition. Pre- and postdialyzer cocentrations of ambrisentan in plasma were determined and hemodialysis extraction ratio for ambrisentan was 2%. Conclusions: Our results suggest that hemodialysis results in minimal ambrisentan removal, and therefore no specific ambrisentan dosage adjustment seems to be required in ESRD patients undergoing hemodialysis. Keywords: Ambrisentan, Hemodialysis, Pulmonary arterial hypertension, HIV-infection, Drug interactions Background Defining optimal dosing of many drugs in patients on The life expectancy of people living with HIV has shown hemodialysis may be difficult. Drug removal by significant improvement in recent decades, largely due to hemodialysis is an essential factor in determining differ- the widespread use of combined antiretroviral therapy ent dosing regimens. However, the pharmacokinetics of (cART). However, this has been followed by an increase in many drugs in patients on hemodialysis has been poorly the prevalence of non-AIDS-defining co-morbidities, in- studied, and information about their hemodialyzability cluding pulmonary arterial hypertension (PAH) and remains scant [3–5]. In addition, HIV patients with PAH chronic kidney disease [1, 2]. The prevalence of PAH in or ESRD are frequently affected by other co-morbidities the HIV population is approximately 0.5%, with a little that require specific therapies. These patients often variation since the introduction of cART. Nevertheless, receive many different drugs (polypharmacy), with a the number of HIV-infected patients with end-stage renal potential risk for drug-drug interactions among them [6, disease (ESRD) requiring renal replacement therapy has 7]. Here we report a clinical case involving an HIV-1- increased. infected patient with severe PAH and ESRD on hemodialysis who was treated with ambrisentan with the * Correspondence: jrsantos@flsida.org intention to avoid drug interactions between bosentan 1 Fundacio Lluita contra la SIDA, Barcelona, Spain 2 Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, and cART. Ambrisentan is a selective endothelin-A re- Ctra de Canyet, s/n, 08916 Badalona, Barcelona, Spain ceptor antagonist, which is approved for the treatment Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Santos et al. BMC Nephrology (2020) 21:24 Page 2 of 4 of PAH [8, 9]. However, despite its better pharmacoki- regimen was changed to darunavir/ritonavir (800/100 netic profile in comparison to bosentan, no data on mg once daily) plus etravirine (200 mg twice daily) and ambrisentan pharmacokinetics in hemodialysis patients dolutegravir (50 mg twice daily). Thereafter, the patient were available, so we evaluated the effect of hemodialysis experienced progressive improvement in her clinical on ambrisentan concentrations. condition, HIV RNA in plasma was re-suppressed (< 40 copies/ml), and she was finally discharged to resume her Case presentation usual hemodialysis program (3 sessions per week). The patient in this clinical case was a 53-year-old To evaluate the effect of hemodialysis on ambrisentan woman who was admitted to our hospital with severe plasma concentrations, paired samples of blood entering respiratory failure. She had been diagnosed with HIV/ (‘in’) and leaving (‘out’) the dialyzer and of the resulting hepatitis C virus (HCV) co-infection in 2000 as well as dialysate were collected during one dialysis session. with PAH in 2002. In addition, she had ESRD and had Blood samples were collected into heparin-lithium- been undergoing high-flux hemodialysis sessions since containing 4-ml tubes 12.2 h after last ambrisentan dose. 2014 (vascular access: venous-arterial fistula; dialyzer: Plasma was isolated by centrifugation (3200 g for 15 Revaclear® 400, capillary 101 dialyzer, membrane area min), and stored at − 80 °C until analysis. Dialysate (20 1.8 m2; Bicart® Gambro bicarbonate cartridge; blood ml) was directly collected from the dialysate port of the flow: 350 mL/min; dialysate flow: 500 mL/min). The pa- dialyzer. Ambrisentan concentrations in both plasma tient was undergoing 3 dialysis sessions per week and and dialysate were determined using high-performance each session lasted approximately 4 h. liquid chromatography coupled with tandem mass spec- In January 2018, the patient was receiving cART with trometry (LC-MS/MS) using a validated method [10], lopinavir/ritonavir (400/100 mg twice daily) plus ralte- and the hemodialysis extraction ratio (ER) for ambrisen- gravir (400 mg twice daily), as well as bosentan (125 mg tan was calculated following standard procedures [5]. twice daily) plus tadalafil (20 mg once daily) for PAH. At The patient gave and signed an informed consent before that time, treatment with glecaprevir/pibrentasvir was sampling took place. indicated for HCV. To avoid drug interactions with The effect of hemodialysis on ambrisentan concentra- HCV drugs, cART was switched to raltegravir (400 mg tions was evaluated during one hemodialysis session. twice daily) plus rilpivirine (25 mg once daily), and Pre- and postdialyzer total ambrisentan concentrations bosentan and tadalafil were temporarily discontinued. In were 42.8 ng/mL and 42.5 ng/mL, respectively, with neg- April 2018, after completing 8 weeks of HCV treatment, ligible ambrisentan concentrations in dialysate (3.92 ng/ bosentan and tadalafil were reintroduced at the same mL). The hemodialysis extraction ratio was only 2.0%. doses as before HCV treatment, and rilpivirine was re- At the end of the dialysis session (26.3 h after dosing), placed by darunavir/cobicistat (800/150 mg once daily). total ambrisentan concentrations in plasma were 35.6 From April 2018 to September 2018 the patient had ng/ml. several episodes of congestive heart failure, which were satisfactory managed with medical treatment. Neverthe- Discussion and conclusions less, in September 2018 the patient presented with se- The small differences between plasma ambrisentan concen- vere respiratory failure and clinical signs compatible trations going in and coming out of the dialyzer, together with decompensated heart failure, and she had to be with barely noticeable ambrisentan concentrations in di- hospitalized. On her admission, the patient underwent alysate in this patient, suggest a minimal removal of ambri- daily hemodialysis sessions, and the negative fluid bal- sentan by hemodialysis in patients with ESRD. This finding ance in each session was increased. However, the re- is consistent with the physiochemical characteristics of sponse to hemodialysis was poorer than expected, ambrisentan, which is 99% bound to plasma proteins, and suggesting additional determinants of her clinical situ- is minimally eliminated by the kidneys, with only 3% of its ation. In addition, during the admission, virologic failure dose being excreted unchanged into urine [8]. was evidenced by an HIV-1 RNA load in plasma of 5424 Besides the effect of hemodialysis on ambrisentan con- copies/mL, with HIV evolution and development of new centrations, the clinical case presented here highlights drug resistance mutations in the integrase gene (N155H) the complexity of drug-drug interactions affecting HIV- not present in previous genotypes. After ruling out other infected patients. In this case, mutual interactions be- conditions, bosentan toxicity—probably because exces- tween bosentan and cART were suspected. The patient sive exposure to bosentan due to drug interactions be- had clinical signs of fluid retention associated with tween bosentan and darunavir/cobicistat was considered. bosentan toxicity, which was presumably the result of Bosentan was therefore replaced by ambrisentan with excessive bosentan concentrations due to potent cyto- the intention of avoiding drug-drug interactions with chrome P450 3A4 (CYP3A4) inhibition by cobicistat. Al- cART. Additionally, cART was optimized, and the though no specific studies have evaluated the effect of Santos et al. BMC Nephrology (2020) 21:24 Page 3 of 4 cobicistat on bosentan pharmacokinetics, data with lopi- Authors’ contributions navir/ritonavir have shown a rather substantial > 5-fold J.R.S., J.M., I.B. conceived and contributed to the study design; J.R.S, A.M., I.B., M.P., L.B. contributed to the patient inclusion and clinical management; J.M., increase in bosentan exposure [11]. In the other direc- W.E.H. contributed to evaluate ambrisentan plasma concentrations and to tion, bosentan induces CYP3A4 activity [12], which is calculate the extraction ratio; C.M., A.M. contributed to sampling and data the main metabolic pathway for both darunavir and collection; J.R.S, A. M, W.E.H., M.P., I.B., L.B., J.M. contributed to the drafting of the manuscript and provided critical revisions of the manuscript. The authors cobicistat. Previous studies have shown a decline in cobici- had full access to the data, and the corresponding author had the final stat exposure, and consequently inappropriately low responsibility for submitting the manuscript for publication. darunavir concentrations, when darunavir/cobicistat is combined with the CYP3A4 inducers [13]. Consequently, Funding This work was supported by the Fundació Lluita contra la SIDA. The funder combining bosentan with darunavir/cobicistat plus raltegra- had no role in study design, data collection and analysis, interpretation of vir could have resulted in functional monotherapy with ral- data, decision to publish, or preparation of the manuscript. tegravir, leading to the virological failure and the Availability of data and materials development of new resistance mutations observed in this The datasets used and/or analysed during the current study are available patient. Unfortunately, although it seems the most plausible from the corresponding author on reasonable request. hypothesis, no plasma samples to determine bosentan and antiretrovirals concentrations were available. Nevertheless, Ethics approval and consent to participate Not Applicable. progressive improvement in the clinical condition of the pa- tient along with re-suppression of HIV RNA after switching Consent for publication to ambrisentan and ART adjustment is concordant with Written informed consent was obtained from the patient for publication of our theory. this Case Report and any accompanying images and videos. A copy of the written consent is available for review by the Editor of this journal. Ambrisentan is a selective endothelin-A receptor antagonist with proven efficacy and safety in the treatment of PAH [8]. Competing of interests In contrast to bosentan, ambrisentan is only a minor sub- WEH reports having received personal fees, non-financial support, or other strate of CYP3A4 and its elimination is mainly mediated by support such as research grants from Actelion GmbH, Aspen Europe GmbH, AstraZenica GmbH, BayerPharma AG, Berlin-Chemie AG, Boehringer GmbH, glucuronidation via several uridine-glucuronosyltransferase GSK, Bristol-Myers Squibb GmbH, Chiesi GmbH, Daiichi Sankyo GmbH, MSD (UGT) isozymes [8]. Thus, the effect of potent CYP3A4 in- Sharp & Dohme GmbH, Roche, Grünenthal GmbH, Novartis, Pfizer GmbH, hibitors on ambrisentan pharmacokinetics is much less com- and personal fees and other from Roche GmbH, Smooth ClinicalTrials Ltd., Sumaya Biotec GmbH & Co. KG, and Vaximm GmbH. JRS and JM have re- pared to bosentan, and ambrisentan may be safely used in ceived research funding, consultancy fees, and lecture sponsorships from this scenario, as observed in our patient. Moreover, ambrisen- and have served on advisory boards for various laboratories (MSD, Abbvie, tan does not have any significant effect on the activity of Boehringer Ingelheim, Gilead Sciences, Viiv Healthcare, Janssen Cilag, and Bristol-Myers-Squibb). UGT or cytochrome P450 isozymes or drug transporters, lim- AM, CM, MP, LB, and IB have no conflicts of interest to declare. iting the possibility of drug-drug interactions. It is noteworthy that ambrisentan concentrations at the end of the dialysis ses- Author details 1 Fundacio Lluita contra la SIDA, Barcelona, Spain. 2Infectious Diseases sion were in the same range as those described in healthy vol- Department, Hospital Universitari Germans Trias i Pujol, Ctra de Canyet, s/n, unteers receiving regular doses [14, 15], suggesting the 08916 Badalona, Barcelona, Spain. 3Universitat Autònoma de Barcelona, absence of a need for dose adjustment in patients with ESRD. Barcelona, Spain. 4Nephrology Department, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain. 5Department of Clinical Pharmacology and Based on the minimal extraction ratio of ambrisentan Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, by hemodialysis observed in our patient, no ambrisentan Germany. 6Pulmonology Department, Hospital Universitari Germans Trias i dose adjustment seems to be necessary in patients with Pujol, Barcelona, Spain. PAH and ESRD undergoing hemodialysis. However, fur- Received: 1 August 2019 Accepted: 5 December 2019 ther investigations in this topic are recommendable. HIV- infected patients receiving polypharmacy may be affected by complex drug-drug interactions that require appropri- References 1. Ando M, Yanagisawa N. 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