Original Manuscript Clinical Pharmacology in Drug Development 2020, 00(0) 1–8 C  2020, The American College of Clinical Pharmacology DOI: 10.1002/cpdd.787 Safety of Candesartan, Amlodipine, and Atorvastatin in Combination: Interaction Study in Healthy Subjects Kristina Gundlach 1 , Katharina Wolf 1 , Isam Salem 2 , Olaf Randerath 3 , and Dan Seiler 1 Abstract For effcient cardiovascular risk protection antihypertensive treatment is often combined with cholesterol-lowering treatment, although solid data of interaction and side effects are missing. This is a prospective, single-center interac- tion study conducted in a fxed sequence design at steady state of candesartan, amlodipine, and atorvastatin. Five-day monotherapy of candesartan 8 mg was followed by 5-day atorvastatin 40 mg monotherapy and subsequently 9-day am- lodipine 5 mg monotherapy; each treatment separated by washout phases. Immediately after amlodipine monotherapy, all 3 drugs were administered concomitantly for 5 days. Pharmacokinetic parameters as well as safety were assessed. Eigh- teen healthy subjects enrolled and completed the study.No signifcant difference in the maximum concentration (C max ) and the area the under plasma concentration–time curve (AUC) for amlodipine and AUC of atorvastatin was detected following combination versus monotherapy.C max of atorvastatin decreased slightly but clinically not relevantly when given in combination. A statistically signifcant but not below 0.80-fold decrease between candesartan following combination vs monotherapy was detected for C max and AUC. In general, all treatments were well tolerated. Concluding, systemic exposure of candesartan, amlodipine, and atorvastatin is not clinically signifcantly changed upon coadministration. These data support a fxed-dose combination of the 3 components for dual cardiovascular risk prevention. Keywords comedication, drug-drug interaction, dyslipidemia, hypertension, pharmacokinetics According to the World Health Organization, more people die annually from cardiovascular diseases (CVDs) than from any other cause. 1 An estimated 17.7 million people died from CVDs in 2015, representing 31% of all global deaths. Of these deaths, an estimated 7.4 million were due to coronary heart disease, and 6.7 million were due to stroke. Hypertension and dyslipidemia belong to the risk factors for CVD, and they frequently coexist in the adult population. 2 The presence of >1 risk factor for CVD, however, indicates a high cardiovascular risk, and consequently, in clinical practice, it is necessary to treat both conditions if they coexist. Such a dual-risk intervention can be achieved by combining blood pressure (BP)-lowering treatment with cholesterol-lowering treatment. Regarding BP- lowering treatment, drug classes recommended by current guidelines for initial treatment are renin- angiotensin system (RAS) blocker, diuretics, and calcium-channel blocker (CCB). 3–5 β -Blockers, which had regularly been used as initial treatment in the past, are nowadays used only in patients with additional indications like clinical coronary artery disease, heart failure, angina, or post myocardial infarction. 3,5 Often, 1 single hypertensive treatment does not reach BP targets; in this case, current American guide- lines recommend the combination of 2 drugs. 3,4 The current European guidelines for the management of arterial hypertension even emphasize an initial combi- nation therapy, ideally as a single-pill concept, for all patients. 5 As the combination of medications targeting multiple mechanisms reduces the heterogeneity of the BP response to initial treatment, the frst comedication should include a RAS blocker with either a diuretic or a CCB. 3–5 1 Midas Pharma GmbH, Ingelheim, Germany 2 International Pharmaceutical Research Center, Amman, Jordan 3 Apontis Pharma GmbH & Co. KG, Monheim, Germany Submitted for publication 22 January 2020; accepted 6 February 2020. Corresponding Author: Kristina Gundlach, PhD, Midas Pharma GmbH, Rheinstr. 49, 55218 Ingel- heim, Germany (e-mail: kristina.gundlach@midas-pharma.com)