Daniël M. Jonker, Nis Agerlin Windeløv
Ferring Pharmaceuticals A/S, Denmark
Introduction:
In critically ill patients, marked changes in pharmacokinetics and pharmacodynamics occur due to, for example, increased distribution volume and decreased renal clearance [1]. Further, in septic shock marked vasodilation is accompanied by increases in vasoactive mediators including vasopressin and catecholamines, which may affect the PD effects of vasopressors but not much data are available. Selepressin is a selective V1a receptor agonist that is effective in maintaining blood pressure in septic shock [2]. The PK and blood pressure effects of selepressin have been studied in a first-in-man trial in healthy subjects as well as in two phase 2 trials in patients with sepsis requiring vasopressor treatment [3], offering the opportunity to assess the impact of septic shock on the PK and PD of selepressin.
Objectives:
To compare the PK and PD of selepressin in healthy subjects and in subjects with sepsis requiring vasopressor treatment and to identify covariates that affect selepressin exposure.
Methods:
In the first-in-man trial (A), healthy subjects were administered an IV infusion of selepressin (n = 30, 4 groups) or placebo (n = 12) for 6 hours. The two patient trials (B and C) included subjects with sepsis requiring vasopressor support, who received selepressin (or placebo) add-on to norepinephrine until shock resolution for up to 7 days. In trial B, patients received IV selepressin at a fixed infusion rate (n = 31, 3 groups), or placebo (n = 21). Trial C was an open-label feasibility trial in 30 patients in which selepressin infusion rate could be increased from the initial rate.
A population PK model was developed using the data from the three trials. The covariates of interest were pre-defined and included baseline values of body weight and creatinine clearance (CrCL), and age, sex, fluid balance, renal replacement therapy (yes/no) and acute kidney injury class. Fluid balance was assessed in 24 h collection periods by subtracting the volume of fluids administered from the volume excreted. For the trial in healthy subjects, an exposure-response model was developed relating selepressin concentrations to changes in mean arterial pressure (MAP). In patients, such a model could not be developed as infusion rates of norepinephrine were adjusted to maintain MAP at the intended target of 65-80 mmHg. Instead, the selepressin exposure-response relationship for norepinephrine infusion rate was explored.
Results:
A two compartment PK model described selepressin plasma concentrations adequately in all trials. In the patient trials, the median duration of selepressin infusion ranged from 33 to 76 hours across groups in trial B and from 21 to 53 hours in trial C. During the first 24 hours of treatment, on average 7.5 L of fluids were administered in trial B, and a similar volume in trial C. The peripheral and central volumes of distribution were estimated to be respectively 2.8 [90% CI: 1.5 – 5.2] and 1.7 [90% CI: 1.4-2.0] times higher in patients than in healthy subjects. Selepressin clearance was 1.4 times lower in patients than in healthy subjects. The main covariate identified for selepressin clearance was body weight, with selepressin exposure estimated to be 1.3 [90% CI: 1.2 – 1.4] times higher in a subject weighing 45 kg compared to a subject weighing 77 kg. The effects of age and CrCL on clearance were of similar magnitude but could not be estimated independently from each other due to CrCL decreasing with age.
In healthy subjects, an increase in the placebo-corrected change from baseline in MAP was described using a linear exposure-response model without effect delay. The increase in MAP amounted to 9 mmHg at a plasma concentration of 0.8 ng/mL. In patients, selepressin could substitute for norepinephrine to maintain MAP at 65-80 mmHg, in the presence of an exposure-dependent reduction in norepinephrine infusion rate without sign of an effect delay. At a plasma concentration of 0.8 ng/mL selepressin, the norepinephrine requirement was decreased by 0.1 µg/kg/min. In comparison, a MAP increase by 10 mmHg requires an increase in norepinephrine infusion rate of 0.1-0.2 µg/kg/min [4-6].
Conclusion:
The PK of selepressin differ between healthy subjects and patients with septic shock, the main difference being a marked increase in distribution volume. Judging from the decrease in norepinephrine requirement, the blood pressure response to selepressin is qualitatively similar in patients and healthy subjects.
References:
[1] Smith BS et al. Chest (2012) 141(5), 1327 – 1336.
[2] Russel JA et al. Crit Care (2017) 21(1), 213.
[3] https://www.clinicaltrials.gov, NCT01000649 and NCT01612676
[4] Dubin A et al. Crit Care (2009) 13(3), R92.
[5] Jhanji S et al. Crit Care Med (2009) 37(6), 1961-1966.
[6] Deruddre S et al. Intensive Care Med (2007) 33, 1557 – 1562.
Reference: PAGE 28 (2019) Abstr 8939 [www.page-meeting.org/?abstract=8939]
Poster: Drug/Disease Modelling - Endocrine