Drug–Drug Interactions Between Sucroferric Oxyhydroxide and Losartan, Furosemide, Omeprazole, Digoxin and Warfarin in Healthy Subjects
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J Nephrol DOI 10.1007/s40620-014-0080-1 ORIGINAL ARTICLE Drug–drug interactions between sucroferric oxyhydroxide and losartan, furosemide, omeprazole, digoxin and warfarin in healthy subjects Edward Chong • Veena Kalia • Sandra Willsie • Peter Winkle Received: 1 November 2013 / Accepted: 8 March 2014 Ó The Author(s) 2014. This article is published with open access at Springerlink.com Abstract which AUC 0–8 h was measured), was unaffected to a Background The novel iron-based phosphate binder su- clinically significant extent by the presence of sucroferric croferric oxyhydroxide is being investigated for the treatment oxyhydroxide, irrespective of whether sucroferric oxyhy- of hyperphosphatemia. Patients with chronic kidney disease droxide was administered with the drug or 2 h earlier. often have multiple comorbidities that may necessitate the Conclusions There is a low risk of drug–drug interactions daily use of several types of medication. Therefore, the between sucroferric oxyhydroxide and losartan, furose- potential pharmacokinetic drug–drug interactions between mide, digoxin and warfarin. There is also a low risk of sucroferric oxyhydroxide and selected drugs commonly taken drug–drug interaction with omeprazole (based on AUC0–? by dialysis patients were investigated. values). Therefore, sucroferric oxyhydroxide may be Methods Five Phase I, single-center, open-label, random- administered concomitantly without the need to adjust the ized, three-period crossover studies in healthy volunteers dosage regimens of these drugs. investigated the effect of a single dose of sucroferric oxyhy- droxide 1 g (based on iron content) on the pharmacokinetics Keywords Chronic kidney disease Á of losartan 100 mg, furosemide 40 mg, omeprazole 40 mg, Hyperphosphatemia Á Sucroferric oxyhydroxide Á digoxin 0.5 mg and warfarin 10 mg. Pharmacokinetic Pharmacokinetics Á Phase I parameters [including area under the plasma concentration– time curve (AUC) from time 0 extrapolated to infinite time (AUC0–?) and from 0 to 24 h (AUC0–24)] for these drugs were Introduction determined: alone in the presence of food; with sucroferric oxyhydroxide in the presence of food; 2 h after food and su- One of the serious and common clinical consequences of croferric oxyhydroxide administration. chronic kidney disease (CKD) is hyperphosphatemia, which Results Systemic exposure based on AUC0–? for all is associated with CKD-mineral bone disorder [1], and drugs, and AUC0–24 for all drugs except omeprazole (for increased risk of cardiovascular events [2] and mortality [3– 6]. As a result, patients on dialysis often require phosphate Clinical trial registration numbers: NCT01477411, NCT01324752, binding agents to control serum phosphorus concentrations. NCT01438359, NCT01452906, NCT01477424. The novel polynuclear iron (III)-oxyhydroxide phos- phate binder sucroferric oxyhydroxide is being investigated E. Chong (&) Á V. Kalia for the treatment of hyperphosphatemia. It is formulated as Vifor Pharma, Clinical Development, Aspreva International Ltd., a chewable tablet that may be taken without water. In 1203, 4464 Markham Street, Victoria, BC V8Z 7X8, Canada e-mail: [email protected] Phase I clinical studies, sucroferric oxyhydroxide was shown to be associated with minimal iron absorption S. Willsie through the gastrointestinal (GI) tract, and to be well tol- PRA International, Lenexa, KS, USA erated [7, 8]. A Phase II dose-finding study demonstrated P. Winkle that sucroferric oxyhydroxide doses of 1.0–2.5 g/day Anaheim Clinical Trials, Anaheim, CA, USA (based on iron content) significantly lowered serum 123 J Nephrol phosphorus concentrations [9]. A Phase III study in 0–24 h (AUC0–24); AUC from time 0 extrapolated to infinite patients with hyperphosphatemia undergoing hemo- or time (AUC0–?); peak serum concentration (Cmax); time to peritoneal dialysis was recently undertaken [10]. In this Cmax (Tmax) and terminal half-life (t1/2)]. Adverse event study, patients (n = 1,059) were randomized to receive profiles and routine biochemical/hematological laboratory sucroferric oxyhydroxide 1.0–3.0 g/day or sevelamer tests were also assessed. 4.8–14.4 g/day. It was shown that sucroferric oxyhydrox- ide was non-inferior to sevelamer in terms of serum phosphorus control over the first 12 weeks of treatment, Subjects and methods maintained its phosphorus-lowering effect over 52 weeks with a lesser pill burden than sevelamer, and was associ- Study design and interventions ated with reduced non-adherence to treatment [10, 11]. Patients with CKD often have multiple comorbidities, Five Phase I, single-center, open-label, randomized, three- including cardiovascular disease, hypertension and diabetes, period crossover studies investigated the PK effect of su- which may necessitate the use of several different types of croferric oxyhydroxide (single dose of 1 g, based on iron daily medications [12, 13]. In vitro studies have identified a content) on the following medications: losartan potassium few potential interactions between sucroferric oxyhydroxide (CozaarÒ 100 mg), furosemide (LasixÒ 40 mg), omepra- and some common medications (unpublished data) pre- zole (PrilosecÒ 40 mg), digoxin (LanoxinÒ 0.5 mg) and scribed to patients with CKD. Therefore, a program of warfarin (CoumadinÒ 10 mg). The doses of these drugs are human in vivo pharmacokinetic (PK) drug–drug interaction based on the approved doses and those that are commonly (DDI) studies between sucroferric oxyhydroxide and several used in clinical practice and/or have been used in PK common medications was undertaken. Here we report data interaction studies. The dose of sucroferric oxyhydroxide is from five separate Phase I clinical DDI studies undertaken in the maximum single dose proposed for clinical use. Each healthy adults of sucroferric oxyhydroxide administered study comprised a screening visit, 12 safety and PK visits, with medications selected based on adsorption of these two washout periods (7 days each) and one follow-up visit medications onto sucroferric oxyhydroxide from in vitro 2 weeks after the last administration of study medication. investigations. Digoxin and warfarin did not show interac- Subjects were randomized (1:1:1) to one of three treat- tions in the in vitro investigations, but were chosen due to ment groups by sequentially following a randomization their narrow therapeutic window. The primary objective of code list. Treatment Group 1 began with ‘Schedule 1’ these studies was to assess whether there was any effect of dosing, Treatment Group 2 began with ‘Schedule 2’ dos- sucroferric oxyhydroxide on medication exposure [area ing, and Treatment Group 3 began with ‘Schedule 3’ under the plasma concentration–time curve from time dosing (Table 1). After a 7-day washout period, subjects Table 1 Study drug administration Dosing Day -1 Day 1 Day 8a/11 Day 9a/12 Day 16a/22 Day 17a/23 schedule 1 Sucroferric Sucroferric oxyhydroxide Test drugd Sucroferric Sucroferric oxyhydroxide TIDb single dosec oxyhydroxide TIDb oxyhydroxide c Test drugd single dose Test druge 2 Test drugd Sucroferric Sucroferric Sucroferric Sucroferric oxyhydroxide TIDb oxyhydroxide oxyhydroxide TIDb oxyhydroxide single dosec single dosec Test druge Test drugd 3 Sucroferric Sucroferric oxyhydroxide Sucroferric Sucroferric Test drugd oxyhydroxide TIDb single dosec oxyhydroxide TIDb oxyhydroxide c Test druge single dose Test drugd a Warfarin interaction study only b Sucroferric oxyhydroxide 1 g (based on iron content) three times daily (TID; 6 tablets/day; total daily dose of 3 g/day, based on iron content) given with meals c Sucroferric oxyhydroxide 1 g (based on iron content) given as a single dose of two tablets with breakfast d Test drug single dose given with breakfast e Test drug single dose given 2 h after breakfast/sucroferric oxyhydroxide administration but C1 h before the next meal 123 J Nephrol from Treatment Group 1 crossed over to receive ‘Schedule the difference of 0.43 (in the log scale), a 1-sided a of 0.05, 2’ dosing, Treatment Group 2 crossed over to receive an expected ratio of 1, and the bioequivalence limits of ‘Schedule 3’ dosing, and Treatment Group 3 crossed over 80–125 %. to receive ‘Schedule 1’ dosing. After a further 7-day For the warfarin study, at least 36 evaluable subjects washout period, subjects from Treatment Group 1 crossed were considered sufficient to demonstrate the bioequiva- over to receive ‘Schedule 3’ dosing, Treatment Group 2 lence in a crossover design with a power of more than crossed over to receive ‘Schedule 1’ dosing, and Treatment 95 %, considering a SD of the difference of 0.35 (in the log Group 3 crossed over to receive ‘Schedule 2’ dosing. scale), a 1-sided a of 0.05, an expected ratio of 1, and the bioequivalence limits of 80–125 %. Participants Statistical methods Subjects eligible for these studies were healthy male or female volunteers aged 20–50 years, and with a body mass PK parameters were calculated using non-compartmental index of 18–32 kg/m2. The subjects had to provide written methods with WinNonlinÒ Professional Version 5.1.1 or informed consent before the commencement of any study- higher (Pharsight Corp., Mountain View, CA, USA). PK specific procedures. All protocols were approved by an computations were performed in SASÒ Version 9.1 or independent Review Board. Subjects were ineligible for the higher. The plasma PK parameters were estimated from the studies if they had participated in a clinical trial with an concentration–time profiles for all PK population subjects. investigational