Intravenous and subcutaneous administration of trastuzumab in a patient on peritoneal dialysis

Abstract

Trastuzumab is a monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). By analogy to endogenous IgG1, trastuzumab is probably catabolized in small peptides or amino acids by vascular endothelial cells. A second elimination route is degradation in lysosomes within the target cell after internalization. After subcutaneous (SC) administration, a significant role of the lymphatic system in maintaining the long plasma exposure of trastuzumab was demonstrated. Protein loss via peritoneal dialysis depends on the molecular weight and the relative amounts of the protein. Approximately 3% of IgG are lost in peritoneal dialysis per day. Only four patients on haemodialysis treated with intravenous (IV) trastuzumab have been reported. Two received single-agent trastuzumab every 3 weeks, for metastatic HER2-positive breast cancer (BC), with a good clinical response and no adverse event. The third patient received it for extramammary Paget s disease of scrotum. Lastly, pharmacokinetic (PK) assessment was carried out on a HER2-positive BC patient treated with weekly trastuzumab, showing comparable parameters to patients with no renal impairment. Cardiac toxicity seems to be more frequent in patients with renal failure, suggesting a closer monitoring. In this study, which was approved by the Ethics Committee of Strasbourg University Hospital, we gathered PK data in a patient under peritoneal dialysis, treated with adjuvant trastuzumab. A 56-year-old woman with end-stage renal disease, due to solitary functioning kidney, underwent surgery for a T2N0M0, HER2-positive, hormone receptor-negative BC. She received adjuvant chemotherapy (docetaxel cyclophosphamide) in combination with IV trastuzumab 8 mg/kg, as loading dose, followed by 6 mg/kg every 3 weeks. She dialyzed four times a day, using Bicavera bicompartmental bags of solution 1.5% glucose. After completing chemotherapy, she received single-agent trastuzumab, for 18 cycles in total, without any toxicity. Cardiac monitoring was performed every 3 months. She was last seen 3 years post-diagnosis and remains cancer-free. Our patient received four cycles of chemotherapy combined with IV trastuzumab, followed by two cycles of SC trastuzumab alone. During the next SC cycle (seventh cycle of trastuzumab), blood samples were drawn at different time points. The patient then switched to IV trastuzumab 6 mg/kg. During the third IV cycle (10th cycle in total), blood samples were drawn again. The obtained T0 plasma concentrations between the sixth and 10th cycle varied between 44.02 and 46.49 mg/L, suggesting a steady state was reached. Samples were sent to the laboratory of Pharmacology-Toxicology in François-Rabelais University. Serum trastuzumab concentrations were measured using a validated in-house ELISA test. The limit of detection was 0.072 mg/L; lower and upper limits of quantitation were 0.24 and 15 mg/L, respectively. We adopted a noncompartmental analysis. Figure 1 and Table 1 show trastuzumab concentrations over time. The maximum serum concentration was 136.21 μg/ml for SC route at 24 h and 307.66 μg/ml for IV route at 5 h. Due to technical problems, we did not collect samples at weeks 2 and 3 during the third IV cycle. The AUC% extrapolation was inferior to 20% of AUCinf (for IV route, calculated AUC = 30 588 and AUCinf = 35 433 h * mg/L). Global clearance, calculated as dose/AUC, was 0.33 L/day and 0.264 L/day at 3 weeks for SC and at 1 week for IV route, respectively. The volume of distribution (Vd) at 0 was around 13 L for IV and 8.5 L for SC route. However, Vd 1 week after SC administration was more than two-fold higher compared with IV administration due to the SC depots. We also sought for trastuzumab passage to peritoneal dialysate, by collecting dialysate samples during the third SC and IV cycle (Table 2). The concentration of the drug varied between 0.21 and 2.51 mg/L. To the best of our knowledge, this is the first PK study of trastuzumab in a patient on peritoneal dialysis. Serum concentration was constantly higher than 20 mg/L, which is considered the minimum concentration for anti-tumour activity in BC. The total body clearance was comparable with other studies. AUC of the two routes is difficult to compare, as it was calculated over a 3-week period for SC administration and a 1-week period for IV administration (43 548 versus 35 433 h * mg/L). In addition, our data concern a single patient and therefore cannot be used to construct reliable PK model. Quartino et al. described trastuzumab PK as a twocompartmental model with parallel linear and nonlinear elimination and first-order SC absorption. The slower absorption after SC administration (Figure 1) also indicates a series of processes or compartments, which strongly suggests a flip-flop PK for SC administration. In all dialysates, concentration was very low, with slightly higher concentrations following IV infusion. As expected from its high molecular weight, it is nearly unremoved from blood through peritoneal dialysis. Renal excretion of therapeutic monoclonal antibodies in general is not well documented. In conclusion, our patient had adequate exposure to trastuzumab and did not experience any toxicity. PK parameters were comparable with patients with normal renal function. Received: 20 October 2019 Revised: 30 November 2020 Accepted: 22 December 2020