Search

Supplementary figure 1

Purpose:CPC634 is a novel nanoparticle entrapping docetaxel, developed to enhance the intratumoral chemotherapy exposure. This randomized cross-over study compared the intratumoral and plasma pharmacokinetics of CPC634 with conventional docetaxel.Patients and Methods:Adult patients with solid tumors were randomized to receive CPC634 (75 mg/m2) in cycle 1, and conventional docetaxel (75 mg/m2) in cycle 2 or vice versa. The study was powered to identify a 25% increase of intratumoral total docetaxel exposure after CPC634 infusion compared with conventional docetaxel. Four patients were allocated per tumor sampling time point, that is, 24, 48, 72, and 96 hours, 7 and 14 days after infusion during both cycles. Total docetaxel and released docetaxel from the nanoparticle were determined in tumor tissue derived from a metastatic lesion and in plasma. Pharmacokinetic data were analyzed using linear mixed modeling.Results:In total, 24 evaluable patients were included. In the tumor, CPC634 exhibited a 461% higher total docetaxel (P < 0.001) and a comparable released docetaxel concentration (P = 0.43). Plasma AUCinf was 27% higher (P = 0.001) and Cmax was 91% lower (P < 0.001) for CPC634 released docetaxel. The median observed neutrophil count nadir after conventional docetaxel treatment was lower (0.50 × 109/L) compared with CPC634 (4.30 × 109/L; P < 0.001).Conclusions:Here, we demonstrated that CPC634 enhanced the intratumoral total docetaxel exposure compared with conventional docetaxel. The lower incidence of neutropenia during CPC634 treatment is presumably related to lower plasma Cmax of released docetaxel. The unique pharmacokinetic profile of CPC634 nanoparticles has the potential to improve docetaxel treatment. A phase II efficacy trial of CPC634 is currently ongoing.

Supplementary Figure legend

Supplementary Table 1 tracked changes

Supplementary Table 1 clean version

Contains fulltext : 283013.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Sorafenib is a tyrosine-kinase inhibitor approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, thyroid carcinoma, and desmoid fibromatosis. As high inter-individual variability exists in exposure, there is a scientific rationale to pursue therapeutic drug monitoring (TDM). We investigated the feasibility of TDM in patients on sorafenib and tried to identify sub-groups in whom pharmacokinetically (PK) guided-dosing might be of added value. METHODS: We included patients who started on sorafenib (between October 2017 and June 2020) at the recommended dose of 400 mg BID or with a step-up dosing schedule. Plasma trough levels (C(trough)) were measured at pre-specified time-points. Increasing the dose was advised if C(trough) was below the target of 3750 ng/mL and toxicity was manageable. RESULTS: A total of 150 samples from 36 patients were collected. Thirty patients (83 %) had a C(trough) below the prespecified target concentration at a certain time point during treatment. Toxicity from sorafenib hampered dosing according to target C(trough) in almost half of the patients. In 11 patients, dosing was adjusted based on C(trough). In three patients, this resulted in an adequate C(trough) without additional toxicity four weeks after the dose increase. In the remaining eight patients, dose adjustment based on C(trough) did not result in a C(trough) above the target or caused excessive toxicity. CONCLUSIONS: TDM for sorafenib is not of added value in daily clinical practice. In most cases, toxicity restricts the possibility of dose escalations.