Doxorubicin concentrations in bone tumour-relevant tissues after bolus and continuous infusion: a randomized porcine microdialysis study

Cancer Chemotherapy and Pharmacology (2024) 93:555–564 https://doi.org/10.1007/s00280-023-04637-1 ORIGINAL ARTICLE Doxorubicin concentrations in bone tumour‑relevant tissues after bolus and continuous infusion: a randomized porcine microdialysis study Andrea René Jørgensen1,2 · Mats Bue1,2,3 · Pelle Hanberg1,2 · Elisabeth Krogsgaard Petersen1,2 · Christina Harlev1,2 · Jakob Hansen4 · Thomas Baad‑Hansen2,3 · Akmal Safwat2,5 · Maiken Stilling1,2,3 Received: 23 September 2023 / Accepted: 24 December 2023 / Published online: 8 February 2024 © The Author(s) 2024 Abstract Purpose Doxorubicin is a widely used chemotherapeutic drug that can be administered intravenously as both a bolus infusion and a continuous infusion. The latter is believed to lower the risk of cardiotoxicity, which is a critical long-term complication of doxorubicin treatment. The local tissue concentrations of doxorubicin will be reflected in both treatment efficacy and toxicity, but very limited information is available. The aim of this study was to measure the concentration of doxorubicin after continuous and bolus infusion in tissue compartments around a typical location of a bone tumour. Methods Sixteen pigs (female, Danish Landrace, mean weight 77 kg) were randomized into two groups of eight. Both groups received an intravenous infusion of 150 mg doxorubicin; Group 1 received a bolus infusion (10–15 min) and Group 2 received a continuous infusion (6 h). Before infusion, microdialysis catheters were placed intravenously and in four bone tumour-relevant tissue compartments (cancellous bone, subcutaneous tissue, synovial fluid of the knee joint and muscle tissue). Sampling was done (n = 15) over 24 h, and venous blood samples were collected as a reference. Results Area under the concentration–time curve (AUC0–24 h) for plasma (total concentration) was significantly different between the two groups, while peak drug concentration (Cmax) was significantly higher in two compartments (plasma and synovial fluid of the knee joint) in Group 1 compared to Group 2. Overall, the unbound tissue concentrations were extremely low with values below 0.20 µg/mL. Conclusion The pharmacokinetic profile for doxorubicin in the investigated tissues is very similar when comparing bolus and 6 h continuous infusion. Keywords Microdialysis · Doxorubicin · Doxorubicinol · Infusion · Bone Cancer Introduction * Andrea René Jørgensen 1 Aarhus Microdialysis Research Group, Orthopaedic Research Unit, Aarhus University Hospital, Palle JuulJensens Boulevard 99, J112, 8200 Aarhus N, Denmark 2 Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark 3 Department of Orthopaedic Surgery, Aarhus University Hospital, Aarhus N, Denmark 4 Department of Forensic Medicine, Aarhus University, Aarhus N, Denmark 5 Department of Oncology, Aarhus University Hospital, Aarhus N, Denmark Doxorubicin is a frequently used chemotherapeutic agent originating from the anthracycline family. Despite its clinical use for more than 50 years, the cytotoxic actions are still being debated, but are often ascribed to the inhibition of the topoisomerase enzyme II as well as the formation of reactive oxygen species [1–5]. Doxorubicin is used in both treatment and palliative therapy for a broad spectrum of cancers, e.g., osteosarcoma, breast cancer and leukaemia [1]. The use of doxorubicin can be both monotherapeutic and in combination with other chemotherapeutic drugs, radiation and/or surgery. When used as monotherapy or in combination with surgery, the recommended dosage is 60–75 mg/m2, based on the patient body surface area, and reduced in the case of compromised kidney and/or liver function [1]. Furthermore, Vol.:(0123456789) 556 it can be adjusted according to the level of effect as well as the development of side effects. The introduction of doxorubicin-based combination chemotherapy has, together with improved surgical interventions, contributed significantly to the survival of cancer patients, e.g., the 5-year survival for patients with osteosarcoma has since the 1960s increased from 30 to 80% [6]. Despite the long history of doxorubicin usage, only limited information regarding local target tissue concentrations of the drug exists. Until now, the current knowledge regarding tissue concentrations is merely based on analysis of tissue specimens, whose value is limited because of poor time resolution and not being able to distinguish between the bound and unbound fraction. Microdialysis is a promising pharmacokinetic tool that allows for continuous and simultaneous sampling of unbound molecules and can therefore circumvent these challenges. Intravenously administered doxorubicin can be given as either bolus or continuous infusion. Continuous infusion is believed to reduce the risk of cardiotoxicity, which is a devastating and dose-limiting side effect [7, 8]. Studies measuring the concentration of doxorubicin in plasma following systemic bolus administration have found great inter- and intraindividual differences [9–11]. These findings in combination with the potential risk of side effects, whereof the metabolite doxorubicinol is believed to contribute to the risk of cardiotoxicity [12–14], underline the need for also investigating local target tissue concentrations of doxorubicin and doxorubicinol to possibly correlate target concentrations with both effect and toxicity. The aim of this porcine study was to apply microdialysis for the assessment of doxorubicin concentrations in bone tumour-relevant tissues: cancellous bone, subcutaneous tissue, synovial fluid of the knee joint, muscle tissue and in the blood after bolus and continuous intravenous administration. We hypothesized heterogeneous distribution between the investigated tissue compartments, with lower concentrations in the bone tissue compared to soft tissue and higher peak drug concentrations in the bolus group compared to the continuous infusion group. Materials and methods Ethical approval The study was conducted at the Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark. Approval was obtained from the Danish Animal Experiments Inspectorate (license no. 2017/15–0201-01184) and carried out in accordance with existing laws and ARRIVE guidelines. All chemical analyses were performed at the Department of Forensic Medicine, Aarhus University, Aarhus, Denmark. Cancer Chemotherapy and Pharmacology (2024) 93:555–564 Microdialysis Microdialysis is a catheter-based method enabling dynamic collection of small samples, from any tissue of interest, called dialysates. This allows for concentration quantification of virtually any unbound drug in the extracellular matrix with a size below the membrane cut-off. The basic principle behind microdialysis is passive concentration-driven diffusion, which happens across a semipermeable membrane located at the tip of the microdialysis catheter. An equilibrium between the membrane and the surrounding tissue will never occur a (...truncated)