Marie Lambert (1), Lawrence O. Dierickx (2), Séverine Brillouet (3), Frédéric Courbon (2), Etienne Chatelut (1)
(1) Institut Claudius-Regaud, Institut Universitaire du Cancer Toulouse – Oncopole; CRCT, Cancer Research Center of Toulouse, Inserm U1037, Université Paul Sabatier, Toulouse, France, (2) Department of Medical Imaging, Institut Universitaire du Cancer Toulouse – Oncopole, Toulouse, France , (3) Department of Radiopharmacy, Institut Universitaire du Cancer Toulouse – Oncopole, Toulouse, France
Introduction: Lutathera® (177Lu-Dotatate) is a peptide receptor radionuclide therapy indicated in the treatment of gastroenteropancreatic neuroendocrine tumors overexpressing somatostatin receptors. It is composed of a vector linking 177Lu, a β-emitter with a tumoricidal effect, to a somatostatin analog making it possible to preferentially target tumor cells. Co-administration of an amino acid solution is necessary to avoid dose limiting nephrotoxicity from renal tubular 177Lu-Dotatate reabsorption [1], [2]. Due to the emetic side effect, Primene®, composed of twenty amino acids, was recently replaced by Lysakare®, consisting of only Lysine and Arginine. However, to our knowledge, no clinical study has compared the impact of these two amino acid solutions on 177Lu-Dotatate pharmacokinetics. Moreover, dosimetric analyses, allowing in vivo quantification of absorbed doses in both healthy and tumor tissues —and currently used to monitor the efficiency and toxicity of sensitive organs (i.e., kidney and bone marrow)—, remain controversial [3], [4].
Objectives:
- To compare the impact of two types of amino acid solutions on 177Lu-Dotatate pharmacokinetics
- To evaluate the relation between pharmacokinetics and pharmacodynamics for 177Lu-Dotatate
Methods: Based on recommendations [5], [6], 83 patients received four intravenous infusions of 7.4 GBq of 177Lu-Dotatate at 8-week intervals, as well as co-administration of amino acids: Primene® (n=45) or Lysakare® (n=36) or Primene®, then Lysakare® (n=2). The 1,678 plasma 177Lu-Dotatate concentrations were analyzed using NONMEM 7.4.1 software according to the FOCE-I estimation method. Based on Puszkiel et al. [7], the tricompartmental model was used to quantify the effects of Primene® and Lysakare® on 177Lu-Dotatate elimination, as well as their inter-individual (IIV) and intra-individual (IOV) variabilities. The impact of amino acid solutions on the elimination rate constant of 177Lu-Dotatate (K10) as a categorical covariate (AA=1 during concomitant amino acid infusion or AA = 0 thereafter) led a significant decrease in objective function (ΔOFV = -153). Effects of the following covariates were then tested on K10: type of amino acids (TAA = 1 if Primene® or TAA = 0 if Lysakare®), serum creatinine, creatinine clearance, body weight, body surface area, age and sex. To evaluate the final model, bootstrap analysis with resampling (n=500) and a prediction-corrected visual predictive check (n=1000) were performed. The relationships between plasma 177Lu-Dotatate exposures and tumor response at six months, along with hematological and renal toxicity were assessed.
Results: Inclusion of the AA-type effect (with its specific IIV) on ƟAA significantly improved (OFV decrease of 26.5 p<0.001) adjustment: ƟAA, Primene® = 1.86 (IIV of 92.1%) versus ƟAA, Lysakare® = 0.597 (IIV 63.2%) with, respectively, Primene® or Lysakare® administration. Thus, in average, Primene® increased 177Lu-Dotatate K10, whereas Lysakare® decreased it, with a larger IIV for Primene®. Primene® caused a significant decrease in AUC (-34%, p<0.05) compared to Lysakare®. No nephrotoxicity was observed. A significant correlation (p=0.021) between plasma 177Lu-Dotatate exposure and the percentage of decrease in lymphocytes at Day15 in cycle 1 was observed. The mean AUC of patients experiencing hematotoxicity, leading to treatment discontinuation or dose concession, was 4,511 ± 2,669 MBq.h/L. The mean exposure of non-responders at six months (3,508 ± 977 MBq.h/L) was lower than that of responders (3,924 ± 1,541 MBq.h/L), but the difference was not significant.
Conclusion: As well as revealing different impact of each amino acid solution on 177Lu-Dotatate pharmacokinetics, these results open up a new avenue of research and offer the possibility of individually tailoring 177Lu-Dotatate administration for this indication, justified by the large pharmacokinetic IIV associated with a limited IOV for this radiolabeled compound.
References:
[1] Hennrich, U et Kopka, K Pharmaceuticals (Basel) 12 (3) : 114, 2019.
[2] Bodei, L. et al. Eur J Nucl Med Mol Imaging 38 (12) : 2125–2135, 2011.
[3] Eberlein U et al. Journal of Nuclear Medicine. 58 (Supplement 2) : 97S-103S, 2017.
[4] Huizing DMV et al. EJNMMI 8 : 89, 2018.
[5] Strosberg J. et al. N Engl J Med 376 (2), 125-135, 2017.
[6] Pavel M. et al. Annals of Oncology 31 (7), 844-860, 2020.
[7] Puszkiel, A et al. Clin Pharmacokinet, 58 (2) : 213–222, 2019.
Reference: PAGE 30 (2022) Abstr 9963 [www.page-meeting.org/?abstract=9963]
Poster: Drug/Disease Modelling - Oncology