Adding amino acid residues to the amino terminus can prolong the duration of biological activity of vasopressin (Forsling et al. Further, the clinical use of terlipressin lies in its ability to generate L-VP over a prolonged period. The prolonged pharmacologic effect following injection of terlipressin at 7.5 μg/kg was from the conversion of terlipressin to L-VP in humans. Terlipressin is almost completely metabolized in the tissues by ubiquitous peptidases and L-VP is released gradually from tissues into the circulation, which likely contributes to the longer duration of action of terlipressin than that of vasopressin. 2008).Īfter intravenous (IV) administration of terlipressin, the glycyl residues of terlipressin are cleaved by endogenous tissue proteases resulting in a rapid decrease of terlipressin levels in blood circulation. In patients with HRS, the potent agonist activity of terlipressin and L-VP at V 1 receptors leads to splanchnic vasoconstriction that results in increased mean arterial pressure (MAP) and effective intravascular volume, as well as decreased heart rate (HR), which improves renal function (European Association for the Study of the Liver 2018 Jamil et al. It is believed that the in vivo response to terlipressin administration is likely due to partial V 1a agonist activity of terlipressin and full V 1 agonist activity of L-VP (Jamil et al. Cellular activity indicates that terlipressin is a partial agonist at V 1a, and a full agonist at V 2 while L-VP is a full agonist at both V 1 and V 2 receptors. Results from the binding of terlipressin and L-VP investigation suggest that the binding affinity of L-VP to the V 1 or V 2 receptor is 600–700-fold greater than that of terlipressin. Terlipressin acts as a systemic vasoconstrictor via the vascular vasopressin V 1 receptors, primarily due to its metabolite lysine-vasopressin (L-VP), albeit of its own low potency. It differs from endogenous human vasopressin by the substitution of lysine for arginine at the eighth position of the endogenous molecule (lys 8) and the addition of 3 glycyl residues at the amino terminus (Jamil et al. 1980) with an average molecular mass of 1227.4 Da (as a free base). Terlipressin, a synthetic vasopressin analog, is a 12-amino-acid peptide with the chemical name N-8- l-lysinevasopressin (Jamil et al. 2007 European Association for the Study of the Liver 2018). An increasing body of knowledge of the pathophysiology of HRS has demonstrated that vasoconstrictive drug therapy may improve renal function in patients with HRS (Salerno et al. At present, there are no approved therapies available in the United States or Canada for the treatment of HRS. If left untreated, patients with HRS have a poor prognosis (Gines et al. Hepatorenal syndrome (HRS), a potentially reversible renal failure, is a serious, rapidly progressing disease complicating decompensated chronic liver disease associated with cirrhosis (Arroyo et al. PD response, change in MAP, and HR were well correlated to L-VP concentrations compared with baseline values, the estimated maximum decrease in HR would be 10.6 bpm and the estimated maximum increase in MAP would be 16.2 mm Hg. Therefore, no weight-based dose is needed for terlipressin to treat HRS patients. However, simulation suggested that body weight had no clinically meaningful effects on the exposure of L-VP through terlipressin. Body weight was identified as the only covariate for the clearance of terlipressin. The population PK modeling results showed that the estimated clearances for terlipressin and L-VP are 27.4 L/h and 318 L/h, respectively, for a typical patient with a body weight of 86 kg. L-VP was well characterized as the active metabolite of terlipressin by a one-compartment model with first-order elimination. A two-compartment model with first-order elimination adequately described the PK of terlipressin. In addition, mean arterial pressure (MAP) and heart rate (HR) from 40 patients with HRS were available to explore the relationship between terlipressin and L-VP plasma concentrations and pharmacodynamic (PD) response. Sparse PK samples from 69 patients with HRS who participated in terlipressin phase 3 clinical studies were used for model development. The objective of this population pharmacokinetics (PK) analysis was to characterize the PK of terlipressin and its active metabolite, lysine-vasopressin (L-VP), in patients with hepatorenal syndrome (HRS), following intravenous administration of terlipressin 1 mg to 2 mg every 6 h.
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