Homoarginine population kinetics
Christine J. Kleist (1), Chi-Un Choe (2), Dorothee Atzler (3,4,5,6), Mirjam Schönhoff (6), Rainer Böger (6,7), Edzard Schwedhelm (6,7), Sebastian G. Wicha (1)
(1) Dept. of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Germany, (2) Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, (3) Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität, Munich, Germany, (4) German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany, (5) Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität, Munich, Germany, (6) Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, (7) German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
Objectives: Homoarginine is an endogenous amino acid. Besides its endogenous synthesis it is a constituent of the human diet. Reduced concentrations were found in patients with renal, cardio- and cerebrovascular disease [1]. Low homoarginine independently predicted morbidity and mortality in these patients, as well as in the general population [2]–[7]. The aim of this pharmacometric analyses was to describe the typical kinetic parameters of homoarginine and the detection of covariates thereof. Further, new dosing regimens for the homoarginine supplementation were evaluated based on clinical trial simulations with the developed population kinetic model with the objective to optimally mimic the endogenous homoarginine concentration range of 2.0 µmol/L to 4.1 µmol/L.
Methods: The population kinetic analyses were based on a run-in phase and a double-blind, placebo-controlled crossover study in healthy volunteers for oral homoarginine supplementation with a dosing regimen of 125 mg daily[8]. NONMEM 7.4 was used for the population kinetic modelling. Different kinetic models with or without baseline were evaluated and inter-individual variability (IIV) was assessed on all structural parameters. Different graphical, as well as statistical model diagnostic criteria were used for model selection. A nonparametric bootstrap analysis with n = 1000 samples was performed to diagnose parameter uncertainty.
Two simulation datasets with virtual individuals were build. One dataset comprised younger and the other older patients, as the clinical dataset was comprising two different age groups (21 to 34 years, n = 14 and 43 to 61 years, n = 6). The baseline value of the final population kinetic model was adjusted for low endogenous homoarginine concentrations (1.29 ± 0.37 µmol/L) as observed in a diseased population [3]. The simulations of different daily dosing regimens and a reference regimen of 125 mg once weekly, currently used in a clinical study [9], were evaluated. The time in the target concentration range and the impact of patient covariates on the target concentrations and the time in the target concentration range were inspected.
Results: The final population kinetic model was a two-compartment model with baseline and first order absorption. A combined residual error model was implemented for baseline and for the dose related concentrations a sole proportional error model was superior. IIV was supported on clearance (Cl), central volume of distribution (V2) and peripheral volume of distribution (V3). Ideal body weight was found as covariate on Cl and V3, and age was found as covariate on V2. After covariate inclusion the IIV on V3 tended to zero and was not considered any more. The typical kinetic parameters found for a patient with an ideal body weight of 75 kg and an age of 29 years were Cl=3.67 L/h, V2=69.5 L, V3=235 L, Q=28.5 L/h, ka=0.924 h^-1 and baseline=2.77 µmol/L.
Simulations with the regimens of 20 mg and 25 mg q 24 h resulted in the highest fraction of the population reaching >90 % time in the target concentration range from 2.0 µmol/L to 4.1 µmol/L. The impact of age as covariate was detected in the concentrations achieved 1 h after dosing: The concentration achieved by the younger age group was higher compared to the older group (c1h, median, old = 3.77 µmol/L, c1h, median, young = 3.11 µmol/L). The impact of weight on time in the target range was minor.
Conclusions: The dosing regimen of 20 mg to 25 mg once daily led to the highest time in target attainment, and for this dosing regimen the impact of covariates was minor. Hence, no advantage of covariate-based stratified dosing regimens was found. The dosing regimen of 25 mg led to fewer patients being below the target concentration compared to 20 mg and therefore underexposure would be avoided. In contrast, 125mg once weekly led to supra-physiological peak concentrations as well as too low trough concentrations. Overall the time in target was lower with the weekly interval. Therefore, the dosing regimen of 25 mg once daily should be further evaluated in clinical trials, as it best mimics physiological homoarginine concentrations and thus might be best suited in supplementation therapy to reduce the cardiovascular risk.
References:
[1] C. U. Choe et al., “Homoarginine levels are regulated by l-arginine: Glycine amidinotransferase and affect stroke outcome: Results from human and murine studies,” Circulation, vol. 128, no. 13, pp. 1451–1461, 2013, doi: 10.1161/CIRCULATIONAHA.112.000580.
[2] A. A. Kayacelebi et al., “Low plasma homoarginine concentration is associated with high rates of all-cause mortality in renal transplant recipients.,” Amino Acids, vol. 49, no. 7, pp. 1193–1202, 2017, doi: 10.1007/s00726-017-2420-7.
[3] D. Atzler, J.-L. Cracowski, K. Cordts, R. H. Böger, M. Humbert, and E. Schwedhelm, “Homoarginine predicts mortality in treatment-naive patients with pulmonary arterial hypertension.,” Int. J. Cardiol., vol. 217, pp. 12–5, Aug. 2016, doi: 10.1016/j.ijcard.2016.04.161.
[4] P. Ravani et al., “Homoarginine and mortality in pre-dialysis chronic kidney disease (CKD) patients.,” PLoS One, vol. 8, no. 9, p. e72694, 2013, doi: 10.1371/journal.pone.0072694.
[5] D. Atzler et al., “Homoarginine--an independent marker of mortality in heart failure.,” Int. J. Cardiol., vol. 168, no. 5, pp. 4907–9, Oct. 2013, doi: 10.1016/j.ijcard.2013.07.099.
[6] D. Atzler et al., “Low Homoarginine Levels in the Prognosis of Patients With Acute Chest Pain.,” J. Am. Heart Assoc., vol. 5, no. 4, p. e002565, Apr. 2016, doi: 10.1161/JAHA.115.002565.
[7] D. Atzler et al., “Homoarginine and cardiovascular outcome in the population-based Dallas Heart Study.,” Arterioscler. Thromb. Vasc. Biol., vol. 34, no. 11, pp. 2501–7, Nov. 2014, doi: 10.1161/ATVBAHA.114.304398.
[8] D. Atzler et al., “Oral supplementation with L-homoarginine in young volunteers,” Br. J. Clin. Pharmacol., vol. 82, no. 6, pp. 1477–1485, 2016, doi: 10.1111/bcp.13068.
[9] Homoarginine Supplementation in Patients After Stroke (HiS); clinicaltrials.gov NCT03692234