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An Overview of Satavaptan: a Selective V2 Receptor Antagonist

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An Overview of Satavaptan: a Selective V2 Receptor Antagonist DRUG EVALUATION An overview of satavaptan: a selective V2 receptor antagonist Satavaptan is a new selective V2 receptor antagonist that shares the aquaretic effect of the other arginine vasopressin antagonists. Its usefulness has been demonstrated in the correction of hyponatremia as well as in fluid removal in patients with cirrhosis. In addition, animal studies have suggested promising effects in the treatment of several other conditions, such as polycystic kidney disease, renal cell carcinoma, glaucoma, diabetic nephropathy and urinary tract infections. This article reviews the various animal and human studies that have outlined its potential clinical role and provided direction for further research with this drug. 1 KEYWORDS: arginine vasopressin antagonist n cirrhosis n hyponatremia n satavaptan Jareer Farah , Suleiman Daifallah2, Hammam Zmily1 The increasing recognition of the risk of hypona- AVP stimulation results in vasoconstriction & Jalal K Ghali†1 tremia and its public health impact [1–4] has been [11,12]. V1B receptors are expressed on the cells ¹Detroit Medical Center, matched by increasing interest in the new class of of the anterior pituitary gland and throughout Wayne State University, Detroit, drugs, proven to correct hyponatremia, the argi- the brain [13] and, when stimulated, they medi- MI, USA 2Wayne State University/John D Dingell [14,15] nine vasopressin (AVP) V2 receptor antagonists ate acetylcholine (ACTH) release . V2 VA Medical Center, Detroit, MI, USA (so-called vaptans). receptors are located mainly on the principal †Author for correspondence: Two vaptans have already been approved for cells of the collecting ducts of the kidneys and, Tel.: +1 313 745 7061 Fax: +1 313 745 9021 the management of hyponatremia in the USA, by binding to it, AVP allows water reabsorp- [email protected] and considerable research efforts have been tion [11,16]. AVP stimulation of V2 receptors devoted to develop other vaptans. that are located in the basolateral membrane This article details the basic, animal and of the renal tubular cells activates adenylate human studies of the AVP antagonist satavaptan. cyclase, leading to increased concentration of cyclic–3´–5´–adenosine monophosphate Arginine vasopressin (cAMP), as well as activation of protein kinase Arginine vasopressin plays a major role in A (PKA). PKA triggers the water channel aqua- + plasma Na regulation [5]. It is a hormone that porin 2 (AQP2)-containing vesicles to fuse with is mainly synthesized in the hypothalamic para- the luminal plasma membrane of the collect- ventricular and supraoptic nuclei and stored in ing duct, thereby allowing water to enter the the posterior pituitary gland [2]. AVP release cell [17]. Passive resorption of water through the is normally controlled by serum osmolality. basolateral membrane (AQP3 and AQP4) along Changes in serum osmolality are sensed by spe- osmotic gradients by way of other water chan- cial osmoreceptors [6] and an increase in serum nels into the vasa recta completes the process of osmolality by as little as 1% triggers the release reabsorption [17]. of AVP [7]. In addition, a drop in blood volume is sensed by baroreceptors, resulting in stimu- Pharmacology of satavaptan lation of AVP secretion through a cascade of The chemical structure of satavaptan mechanisms [8]. Moreover, angiotensin II that (SR121463) is 1-[4-(N-tert-butylcarbamoyl)- is synthesized through the rennin–angiotensin– 2-methoxybenzene sulfonyl]-5-ethoxy-3-spiro- aldosterone system directly stimulates the [4-(2-morpholinoethoxy)cyclohexane]indol- release of AVP [9,10]. 2-one. It was synthesized in Sanofi Recherche, Toulouse, France [18]. AVP receptors SR121463 is an orally active, nonpeptide The actions of AVP are mediated by bind- antagonist of AVP V2 receptors. It has been ing to a group of different receptor isoforms. studied in different animal species (mice, These receptors are classified into three differ- rats, dogs, rabbits, bovines, monkeys and ent subtypes. V1A receptors are found mainly pigs) and humans. SR121463 displayed a high on the vascular smooth muscle cells, where competitive affinity for AVP V2 receptors 10.2217/THY.10.36 © 2010 Future Medicine Ltd Therapy (2010) 7(4), 409–422 ISSN 1475-0708 409 DRUG EVALUATION Farah, Daifallah, Zmily & Ghali An overview of satavaptan: a selective V2 receptor antagonist DRUG EVALUATION (0.6 ≤ Ki ≤ 4.1 nM); it inhibits, in a dose- species. Effects attributable to the pharmaco- dependent manner, the AVP-specific binding logical V2R action of SR121463 (i.e., dehydra- to kidney medullo–papillary membranes of tion due to exaggerated pharmacological activity rat, bovine and human origin with nanomolar at AVP V2 receptors) were reported. Intravenous and even subnanomolar potency (Ki values of and oral safety margins, based on pharmaco- 1.42, 0.64 and 4.1 nM, respectively). SR121463 logically active dosages and no observed effect exhibits only weak affinities for other AVP dosages for target organ toxicity, are over and oxytocin (OT) receptors; it interacts with 100-fold for rats. at least a 100-fold lower potency with V1A, No genotoxicity or mutagenicity was V1B and OT receptors than with V2 recep- observed in the Ames and DNA repair tests tors, explaining its highly specific and selective in vitro [20]. V2 receptor antagonist activity [18–21]. The aquaretic effect of satavaptan was noted Effects of satavaptan in multiple animal and human studies following in hyponatremia oral and intravenous administration. It induces Antagonism of the V2 receptor increases free a dose-dependent increase in the urine flow rate water excretion causing hypoosmolar urine, (water clearance) and a decrease in urine osmo- enhanced diuresis and increased serum Na+ levels. lality (Uosm) without major changes in uri- nary Na+ and K+ excretion over a 24-h period n Animal studies following the drug administration. Several animal studies on satavaptan were con- In an experiment in normally hydrated sistent with the aforementioned effects and conscious rats by Serradeil Le Gal, SR121463 have demonstrated the aquaretic effect of sat- was administered intravenously at doses rang- avaptan (TABLE 1) [23–28]. In an experiment by ing from 0.003 to 0.3 mg/kg, and orally at Lacour et al. [26], acute oral administration of doses ranging from 0.03 to 10 mg/kg. Both SR121463 to rats induced a dose-dependent routes of administration induced a dose- aquaresis accompanied by an increase in AVP dependent increase in the urine flow rate and and aldosterone excretion. This early hormonal decrease in Uosm. The intravenous dose was increase was a compensatory mechanism for the five-times more potent than the oral dose, an increase in plasma osmolality. This is consis- effect consistent with good bioavailability for tent with the earlier observation: a 1% change SR121463 [18]. in plasma osmolality could change plasma The maximum effect was reached in a AVP concentration by 1 pg/ml in healthy sub- 2-h period after oral administration of dif- jects [29]. However, with chronic treatment, ferent doses of SR121463. The higher doses urine volume and aldosterone excretion fell (3–10 mg/kg) had an effect lasting 6–24 h after by 40% while urine AVP remained constant. administration in normally hydrated conscious In another experiment by Perucca et al. [30], rats [18]. intraperitoneal injection of satavaptan in rats In a clinical trial in humans, satavaptan was induced natriuretic effect within the first 4–6 h reported to have a long half-life of 14–17 h, with of treatment. This natriuretic effect remained maximum plasma concentrations 3 h after dos- far smaller than its diuretic effect and sevenfold ing. The mean plasma concentration increased less than that induced by furosemide. Moreover, with dosage and duration of drug administra- the natriuretic effect was not apparent in the + tion and stabilized on day 5 [22]. SR121463 24-h urine sample as compensatory Na reten- was 94.5–96% bound to plasma proteins and tion occurred after initial Na+ loss. This small its major route of excretion in animals was natriuretic effect of V2 receptor antagonists dur- via feces. ing the first 4–6 h was also observed in other studies [26,31]. Safety of satavaptan Safety pharmacology studies demonstrated that n Human studies SR121463 was well tolerated in mice, rats and In a multicenter, randomized, double-blind, dogs with no major effects on cardiovascular placebo-controlled study, Soupart et al. studied and respiratory function, central and autonomic the effect of satavaptan in patients with the syn- nervous systems, hydro-electrolytic balance and drome of inappropriate antidiuretic hormone gastrointestinal function. SR121463 was evalu- secretion (SIADH) [22]. This study had a short- ated for general toxicity in single and repeated and long-term part; the short-term had two administration studies in rodents and nonrodent phases. In the 5-day double-blind phase, nine 410 Therapy (2010) 7(4) future science group D RUG E VALUATION Farah, Daifallah, Zmily &Ghali Table 1. Animal studies showing the aquaretic effect of satavaptan. future sciencegroup Study Species Condition Intervention Results Ref. of species Serradeil-Le Rats (male Normal, • 0.003–0.3 mg/kg iv. (n = 6) • Oral SR121463A and OPC-31260 caused a dose-dependent [19] Gal et al. Sprague-Dawley) conscious • 0.03–10 mg/kg oral SR121463A (n = 7) or 10 mg/kg increase in Uv and reduction in Uosm OPC-31260 (n = 8) or 30 mg/kg furosemide (n = 8) • iv. SR121463A increased Uv or 30 mg/kg hydrochlorothiazide (n = 8) or vehicle • Both hydrochlorothiazide and furosemide increased Uv, but An satavaptan: overview of a (n = 20) also increased urine Na+ and K+ excretion Serradeil-Le Rats (male BB) Central • 10 mg/kg ip. • SR121463A increased Uv and decreased Uosm [19] Gal et al. hereditary DI • SR121463A is a V2 antagonist without intrinsic agonistic activity Shen et al. Rats (Sprague- 16 normal rats • Twice-daily dose of 0.3 mg/kg ip.
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