Differential effects of cyclo-oxygenase 1 and 2 inhibition on angiogenesis inhibitor-induced hypertension and kidney damage.

Vascular endothelial growth factor antagonism with angiogenesis inhibitors in cancer patients induces a 'preeclampsia-like' syndrome including hypertension, proteinuria and elevated endothelin (ET)-1. Cyclo-oxygenase (COX) inhibition with aspirin is known to prevent the onset of preeclampsia in high-risk patients. In the present study, we hypothesised that treatment with aspirin would prevent the development of angiogenesis inhibitor-induced hypertension and kidney damage. Our aims were to compare the effects of low-dose (COX-1 inhibition) and high-dose (dual COX-1 and COX-2 inhibition) aspirin on blood pressure, vascular function, oxidative stress, ET-1 and prostanoid levels and kidney damage during angiogenesis-inhibitor therapy in rodents. To this end, Wistar Kyoto rats were treated with vehicle, angiogenesis inhibitor (sunitinib) alone or in combination with low- or high-dose aspirin for 8 days (n=5-7/group). Our results demonstrated that prostacyclin (PGI2) and ET-1 were increased during angiogenesis-inhibitor therapy, while thromboxane (TXA2) was unchanged. Both low- and high-dose aspirin blunted angiogenesis inhibitor-induced hypertension and vascular superoxide production to a similar extent, whereas only high-dose aspirin prevented albuminuria. While circulating TXA2 and prostaglandin F2α levels were reduced by both low- and high-dose aspirin, circulating and urinary levels PGI2 were only reduced by high-dose aspirin. Lastly, treatment with aspirin did not significantly affect ET-1 or vascular function. Collectively our findings suggest that prostanoids contribute to the development of angiogenesis inhibitor-induced hypertension and renal damage and that targeting the prostanoid pathway could be an effective strategy to mitigate the unwanted cardiovascular and renal toxicities associated with angiogenesis inhibitors.

A Phase I study of the safety, pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors.

Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov).

Systemic exposure of floxuridine after hepatic arterial infusion pump chemotherapy with floxuridine in patients with resected colorectal liver metastases.

BACKGROUND: Floxuridine's high hepatic extraction ratio and short elimination half-life allows maximum liver exposure with minimal systemic side-effects. This study attempts to quantify the systemic exposure of floxuridine. METHODS: Patients undergoing continuous hepatic arterial infusion pump (HAIP) floxuridine after resection of colorectal liver metastases (CRLM) in two centres underwent six cycles of floxuridine at start dose 0.12 mg/kg/day. No concomitant systemic chemotherapy was administered. Peripheral venous blood samples were drawn during the first two cycles: pre-dose (only in the second cycle), 30 min, 1 h, 2 h, 7 h, and 15 days after floxuridine infusion. Foxuridine concentration in the residual pump reservoir was measured on day 15 of both cycles. A floxuridine assay with a lower boundary of detection of 0.250 ng/mL was developed. RESULTS: 265 blood samples were collected in the 25 patient included in this study. Floxuridine was mostly measurable at day 7 and day 15 (86 % and 88 % of patients respectively). The median dose corrected concentrations were 0.607 ng/mL [IQR: 0.472-0.747] for cycle 1 day 7, 0.579 ng/mL [IQR: 0.470-0.693] for cycle 1 day 15, 0.646 ng/mL [IQR: 0.463-0.8546] for cycle 2 day 7, and 0.534 ng/mL [IQR: 0.4257-0.7075] for cycle 2 day 15. One patient had remarkably high floxuridine concentrations reaching up to 44 ng/mL during the second cycle, without a clear explanation. The floxuridine concentration in the pump decreased by 14.7 % (range 0.5 %-37.8 %) over a period of 15 days (n = 18). CONCLUSION: Overall, negligible systemic concentrations of floxuridine were detected. However, remarkably increased levels were detected in one patient. Floxuridine concentration in the pump decreases over time.

Feasibility of therapeutic drug monitoring of sorafenib in patients with liver or thyroid cancer.

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 (Ctrough) were measured at pre-specified time-points. Increasing the dose was advised if Ctrough 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 Ctrough below the prespecified target concentration at a certain time point during treatment. Toxicity from sorafenib hampered dosing according to target Ctrough in almost half of the patients. In 11 patients, dosing was adjusted based on Ctrough. In three patients, this resulted in an adequate Ctrough without additional toxicity four weeks after the dose increase. In the remaining eight patients, dose adjustment based on Ctrough did not result in a Ctrough 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.