Population Pharmacokinetics of Pegylated Liposomal CKD‐602 (S‐CKD602) in Patients With Advanced Malignancies

Abstract

S-CKD602 is a pegylated long-circulating liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. A population pharmacokinetic (PK) model for encapsulated and released CKD-602 following administration of S-CKD602 was developed to assess factors that may influence S-CKD602 PK. Plasma samples from 45 patients with solid tumors were collected in a phase 1 study. S-CKD602 was administered as a 1-hour intravenous infusion with doses ranging from 0.1 to 2.5 mg/m(2) . Plasma concentrations of encapsulated and released CKD-602 were used to develop a population PK model using NONMEM. PK of encapsulated CKD-602 was described by a 1-compartment model with nonlinear clearance, and PK of released CKD-602 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that tumor in the liver was a significant covariate for clearance of encapsulated CKD-602 and that age significantly influenced the release rate of CKD-602 from S-CKD602. Maximum elimination rate in patients with liver tumor is 1.5-fold higher compared with patients without liver tumor. Release rate of CKD-602 from S-CKD602 in patients less than 60 years old was 2.7-fold higher compared with patients 60 years old or older. These observations have potential implications in the optimal dosing of liposomal agents.

Translational Studies of Phenotypic Probes for the Mononuclear Phagocyte System and Liposomal Pharmacology

“…She was the only patient enrolled on our study with detectable tumors in her liver. Thus, the higher MPS activity and CL of PLD in this patient may be explained in part by the reported relationship between tumor metastases in liver and the CL of NP (Wu et al, 2011). Our group has previously reported that patients with primary or metastatic tumors in their liver (n 5 21) had a significantly (P 5 0.02) higher CL of the NP S-CKD602 compared with individuals without tumors in their liver (n 5 8) (22).…”

Formulation and physiologic factors affecting the pharmacology of carrier-mediated anticancer agents

“…Linear and nonlinear PK models were constructed for encapsulated CKD-602, and it was determined that liver tumor was a significant covariate for maximum velocity. Including liver tumor as a covariate in the model decreased the variation in Vmax by 29% [70]. The inter-patient variability in S-CKD602 PK disposition could possibly be explained by the presence of metastatic liver tumors, as the Vmax of patients with these tumors is 1.5-fold higher than those patients without liver tumors [70].…”

“…In a Phase I PK study evaluating encapsulated and released CKD-602, 45 patients were enrolled, of which 26 individuals had tumor(s) of all types in their liver [70]. Linear and nonlinear PK models were constructed for encapsulated CKD-602, and it was determined that liver tumor was a significant covariate for maximum velocity.…”

“…Including liver tumor as a covariate in the model decreased the variation in Vmax by 29% [70]. The inter-patient variability in S-CKD602 PK disposition could possibly be explained by the presence of metastatic liver tumors, as the Vmax of patients with these tumors is 1.5-fold higher than those patients without liver tumors [70]. This data suggests that patients with liver tumor may have 35% lower plasma exposure of encapsulated CKD-602, leaving them at risk for having a lower response potential.…”

Liposomes as nanomedical devices

“…102 PEG-bearing liposomes are not opsonized or affected by complement components, and consequently evade capture by mononuclear phagocytic system cells. 103,104 Finally, the presence of PEG in liposome formulations prevents aggregation, favors the formation of small, monodisperse particles, and increases the EPR effect, due to the extended circulation time and escape from the RES. 105 The practical consequences of these phenomena are evident when the biopharmaceutical profiles of Stealth liposomes and conventional liposomes are contemplated.…”