Population pharmacokinetics of intraperitoneal irinotecan and SN-38 in patients with peritoneal metastases from colorectal origin
P. C. S. Rietveld (1,2), S.D.T. Sassen (1), N.A.D Guchelaar (2), J.W.A. Burger (3), R. H. J. Mathijssen (2), B. C. P. Koch (1), S. L. W. Koolen (1,2)
(1) Department of Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands, (2) Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands, (3) Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands.
Objectives:
Colorectal cancer (CRC) is a prevalent malignancy, accounting for approximately 10% of all cancer diagnoses worldwide [1]. At onset, peritoneal metastases (PM) are present in 5% of patients with CRC (synchronous PM), with up to 20% developing these in the disease course (metachronous PM) [2]. Patients with PM have poor prognosis, and for those who are not eligible for curative treatment with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with Cytoreductive Surgery (CRS), palliative chemotherapy is the only option, despite low survival rates [3, 4]. Recently, we conducted a phase I trial (INTERACT-I) in which irinotecan (IRI) was administered intraperitoneally (IP) to patients who were ineligible for CRS-HIPEC due to extensive peritoneal disease or an unresectable primary tumor [5, 6]. Irinotecan (IRI) is a widely used chemotherapeutic agent that is converted into active metabolite SN-38 in the blood, liver, and intestine. There is limited data about the pharmacokinetics (PK) of IRI and SN-38 following IP administration.
We aim to evaluate covariates that influence the PK profile of IRI and SN-38 after IP administration. Secondly, a population PK model was developed to support further development of IP IRI for patients with PM from colorectal origin. This could lead to a higher understanding of how PK affects the efficacy and/or adverse effects of IRI, thus providing the groundwork for Model Informed Precision Dosing.
Methods:
Data for the population PK study was obtained from the INTERACT-I study in which 18 patients were treated with IP IRI every two weeks in combination with systemic FOLFOX-bevacizumab. Patients aged >18y were diagnosed with PM of histologically proven colorectal origin and had extensive abdominal disease (i.e. Peritoneal Cancer Index score (PCI) > 20). Patient median age, BMI, and PCI were 64, 26.9, and 29 respectively, 6 were female (33%), and 12 had synchronous PM (66%). IRI and SN-38 were measured in plasma (588 samples) and SN-38 was measured in peritoneal fluid (267 samples). In total 855 blood and peritoneal fluid samples were available for analysis.
Concentration-Time data were log transformed and analyzed using NONMEM v7.5 using FOCE+I estimation. An additive residual error model was used. Inter-individual variability (IIV) of PK parameters was modeled exponentially. Numeric and visual validations were performed. Various candidate covariates were considered including age, sex, BMI, UGT genotype, performance score, smoking status, and hepatic function. Stepwise forward inclusion (p < 0.05) and backwards elimination (p < 0.01) were used for the covariate analysis.
Results:
IP conversion of IRI to SN-38 was observed and the IP exposure to SN-38 was high compared to systemic exposure. The final structural model consisted of an integral model combining a two compartments model for IRI (plasma and peripheral) with single compartments for SN-38 (plasma and IP). The IP IRI dose compartment was connected to IRI plasma and SN-38 IP compartments in one direction and the IRI plasma compartment was linked bidirectional to the IRI peripheral compartment. Additionally, the IRI in plasma compartment was connected to the SN-38 plasma compartment (one-way), that linked to the SN-38 IP compartment (one-way). The percentage of plasma IRI converted to SN-38 was fixed to 3%, based on literature. The final IRI population estimates were ka 0.695 h-1 (RSE14%), CL 32.5 L/h (9%) and V 183L (16%). For plasma SN-38, estimates were CL 44.5 L/h (14%) and V 15.1L (30%). The individual plots of the IP SN-38 compartment showed a poor fit probably due to high variability in IP concentrations. This might be due to sampling issues, uneven distribution or a metabolic rate limited clearance. Population estimates for this compartment were 4.43 L/h (19%), 481 L (38%) and 0.0845 (32%) for CL, V and metabolic rate respectively. The IRI IIV was 25.5% (57%) and 53.8% (12%) for CL and V, respectively, while SN-38 IIV was 41.9% (14%) and 63.4% (36%) for CL and V, respectively. All shrinkages were below 10%. A positive effect of BMI on SN-38 V of plasma (6.27, RSE 24%) was discovered as a predictive factor significantly improving the model.
Conclusions:
Our population PK model adequately described the IRI and SN-38 in plasma, with BMI as a predictive factor. In contrast, the observed SN-38 IP data could not be adequately described. This model will be used for the further clinical development of IP IRI.
References:
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