Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors

Abstract

IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes.

Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients

“…Furthermore, inter-patient variability in the PK and PD of NPs is greater in obese patients. Moreover, the efficacy of NPs of anticancer agents appears to be reduced in obese patients [13,16,21,31]. Our group has demonstrated in mouse-models that NPs preferentially distribute to adipose tissue versus muscle in a study that evaluated the exposures of small molecule CKD-602, a camptothecin analogue, and a PEGylated liposomal formulation of CKD-602 (S-CKD-602).…”

“…Associations between the PK variability of NPs and patient age, gender, type of cancer and the function of monocytes in patients with cancer have been previously reported [12–14]. In addition, the effects of body habitus, which is defined as the physical and constitutional characteristics of underweight, normal weight and overweight patients, on NP PK and PD have been evaluated [8,13–16]. In these studies, patients with a higher ratio of total to ideal body weight had increased clearance of PEGylated liposomal agents [15,16].…”

“…In addition, the effects of body habitus, which is defined as the physical and constitutional characteristics of underweight, normal weight and overweight patients, on NP PK and PD have been evaluated [8,13–16]. In these studies, patients with a higher ratio of total to ideal body weight had increased clearance of PEGylated liposomal agents [15,16]. In addition, the PK variability of NPs and other carrier-mediated agents (CMAs) is even greater in obese patients.…”

Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma

“…After treatment, the tumors were snap frozen, using liquid nitrogen, and stored at −80°C before drug extraction and quantification. Drug quantification by liquid chromatography (LC)-MS and inductively coupled plasma (ICP)-MS followed previously published methods (30)(31)(32).…”

Pharmacokinetics variability: Why nanoparticles are not just magic-bullets in oncology

“…Because nanoparticles, especially the stealth ones, are expected to bypass liver uptake and to avoid renal elimination, age which affects usually those organs should theoretically not be a factor of variation (Fig.5) and. al showed that clearance of pegylated liposomal irinotecan (IHL-305) was dependent on a composite marker between body mass and age [63]. The relationship between the ratio of total body weight to ideal body weight (TBW/IBW) and age with IHL-305 pharmacokinetics was evaluated, and showed that old patients plus TBW/IBW higher than the median displayed higher levels of free circulating irinotecan, thus suggesting a loss of stability of the nanoparticle in elderly patients with overweight.…”