Effect of peritoneal dialysis in end-stage renal disease on apixaban pharmacokinetics

1CHU de Caen Normandie, Department of Clinical Research and Biostatistics, Caen, France, 2Department of Nephrology, Normandie University, UNICAEN, CHU de Caen Normandie, Caen, France, 3ANTICIPE, U1086 INSERM-UCN, Centre François Baclesse, Caen, France, 4CHU de Caen Normandie, Pharmacologie, Caen, France, 5CHU de Caen Normandie, Hématologie Biologique, Caen, France, 6CHU de Caen Normandie, Centre de Recherche Clinique, Caen, France, 7CHU Rouen, Nephrology, Dialysis and Kidney Transplantation, Rouen, France, 8Univ Rouen Normandie, INSERM EnVI U1096, “Endothelium, Valvulopathy and Heart Failure”, 9CHU Rouen, CIC-CRB 1404, Department of Pharmacology, Rouen, France, 10Department of Clinical Research and Biostatistics, CHU de Caen Normandie and Caen Normandy University, Caen, France, 11INSERM U1311 DYNAMICURE, Caen Normandy University, Caen, France and 12CHU de Caen Normandie, Néphrologie, Caen, France

Limited pharmacokinetics data are guiding the use of apixaban in end-stage renal disease (ESRD) patients on hemodialysis but none on peritoneal dialysis. Apixaban could be an alternative to harmful warfarin anticoagulation [1,2]. Before conducting studies to explore the efficacy and safety of apixaban in this patient population, a pharmacokinetic study was required which is essential to determine the appropriate dosage [3]. The objective of the ApiDP (' APIxaban et Dialyse Péritonéale') study was then to assess the effect of peritoneal dialysis in ESRD patients on the pharmacokinetic parameters of apixaban. ApiDP was a prospective, controlled pharmacokinetics trial (NCT04006093) which included participants in two French University hospitals. Each ESRD patient on peritoneal dialysis was matched to a volunteer with normal renal function based on age, weight and sex to act as control. A single oral 5 mg dose of apixaban was administered and adequate blood and urine ± dialysate samples were collected for determination of pharmacokinetic parameters during 72 h. ESRD patients were undergoing continuous ambulatory peritoneal dialysis at enrollment and the peritoneal dialysis scheme was standardized at the time of apixaban administration: patients received four exchanges per day with dialysate volumes of 2 L per exchange: Dianeal R (6 h), Nutrineal R (6 h), Physioneal 40: 1.36% R (4 h) and Extraneal R (8 h) solutions. The pharmacokinetic parameters of apixaban were derived from plasma concentration-time curve using a 1-compartment open model. The apparent first-order rate constant (ke) was determined by least squares regression analysis of the terminal phase of the plasma concentration-time curves. The resulting parameters were calculated as follows: apparent halflife (T 1/2 ) from the relation T 1/2 = Ln2/ke; apparent volume of distribution (V/F) from D/C 0 where D is the administered dose and C 0 the plasma concentration extrapolated at time 0; AUC 0-inf , the area under the concentration-time curve extended to infinity from AUC 0-inf = AUC 0-24 h + (C 24 h/ke), AUC 0-24 h being calculated using the linear trapezoidal rule over the interval of 0 to 24 h; apparent total plasma clearance, ratio of total plasma clearance on bioavailability (Cl/F) from the equation Cl/F = D/AUC 0-inf . The maximum plasma concentration (C max ) and the time required to reach C max (T max ) were observed from the concentration-time profile for each participant. The peritoneal dialysis extraction ratio (PDER) (fraction of apixaban in the dialysis solution) was estimated for the first 24 h period using the following equation: PDER(%) = (Dd/D) × 100, where Dd is the total amount of drug recovered in the peritoneal dialysis fluid at the end of the 24 h period following apixaban administration. The total amount of apixaban recovered in urine (Du) and the renal extraction ratio (RER) were so determined for the first 24 h period. Renal and peritoneal clearances (Cl r and Cl p , respectively) were calculated during the 24 h period that followed apixaban administration using the following relations: Cl r = Q 24h urine/AUC 0-24 h and Cl p = Q 24h dialysate/AUC 0-24 h .
Twenty-four subjects were included: 12 subjects with ESRD on peritoneal dialysis and 12 matched control volunteers. The mean [± standard deviation (SD)] age was 63 (±9) years old. Sixteen subjects were men, eight were women. Their mean body weight was 74 (±13) kg. Among peritoneal  Figure 1 illustrates the kinetics of apixaban plasma concentrations in 12 patients and 12 healthy volunteers administered with a single oral dose of apixaban (5 mg). Concentrations peaked and then declined in a mono-exponential manner until 48 h, as demonstrated by the correlation coefficient of the linear regression data, Ln C = f(t), which obtained 0.983 ± 0.022 (mean ± SD) and 0.987 ± 0.008 in ESRD patients and controls, respectively. Table 1 describes pharmacokinetic parameters. In patients, the geometric mean C max , T max and V/F values did not significantly differ from those of healthy group. However, compared with controls, apixaban AUC 0-inf and T 1/2 from ESRD patients on peritoneal dialysis were significantly higher: +73% (17-156) Effect of PD in ESRD on apixaban pharmacokinetics (P = .011) and +40% (24-58) (P < .001), respectively. Apparent Cl/F varied in line and was 40% lower (P = .016). Renal and peritoneal clearances, 1.0 ± 0.1 mL/min and 0.2 ± 0.1 mL/min, respectively, were negligible compared with the 12.4 ± 0.7 mL/min renal clearance determined in volunteers. In this first pharmacokinetics study of apixaban in patients with ESRD on peritoneal dialysis, we demonstrated differences in pharmacokinetic parameters in comparison with a normal renal function population. The AUC 0-inf and T 1/2 were significantly higher in subjects with ESRD undergoing peritoneal dialysis compared with healthy subjects. Clearance was reduced due to limited renal elimination and the passage in the dialysis peritoneal solution was very low. The robustness of the results of our study was further demonstrated by the consistency of the pharmacokinetic parameters in the group of healthy volunteers in comparison with other reports in healthy subjects [4]. In comparison with the data from the four pharmacokinetics studies on hemodialysis, apixaban is demonstrated to be less dialyzable by the peritoneal rather than the hemodialysis technique [5][6][7][8]. One might argue that the greater residual kidney function of peritoneal dialysis patients as well as the continuous purification provided by peritoneal dialysis may favor the renal elimination of apixaban; however, this is not the case. Our study supports the cautious reduction of apixaban dose from 5 to 2.5 mg twice daily for ESRD patients on peritoneal dialysis, subject to further pharmacokinetics/pharmacodynamics studies and clinical trials.

ACKNOWLED GEMENT S
We would like to thank those who made the research possible. First the participants, with normal or impaired renal function, gave of their time for a collective improvement of medical knowledge. François Fournel was the head of project of the ApiDP study. Blandine Lecrux helped with organization and monitoring of data. The peritoneal dialysis nurses and their head nurse collaborated with the nurses of the research center. Jean-Baptiste Woillard, Guillaume Duthoit and Cécile Courivaud were experts on the independent safety committee of the ApiDP study. Céleste Zerger helped with reviewing and revising the manuscript for grammar and syntax.

FUNDING
The ApiDP study was funded by the French Health Ministry, PHRC 2018.

C ONFLICT OF INTEREST STATEMENT
None declared.