Porcine and Human In Vivo Simulations for Doxorubicin-Containing Formulations Used in Locoregional Hepatocellular Carcinoma Treatment

Abstract

It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. However, mathematical modeling can be used to predict doxorubicin release properties from these formulations and its in vivo pharmacokinetic (PK) profiles. A porcine semi-physiologically based pharmacokinetic (PBPK) model was scaled to a human physiologically based biopharmaceutical (PBBP) model that was altered to include HCC. DOX in vitro and in vivo release data from LIPDOX or DEBDOX were collected from the literature and combined with these in silico models. The simulated pharmacokinetic profiles were then compared with observed porcine and human HCC patient data. DOX pharmacokinetic profiles of LIPDOX-treated HCC patients were best predicted from release data sets acquired by in vitro methods that did not use a diffusion barrier. For the DEBDOX group, the best predictions were from the in vitro release method with a low ion concentration and a reduced loading dose. The in silico modeling combined with historical release data was effective in predicting in vivo plasma exposure. This can give useful insights into the release method properties necessary for correct in vivo predictions of pharmacokinetic profiles of HCC patients dosed with LIPDOX or DEBDOX.

Formulation, Characterization, and Evaluation of Doxorubicin-loaded Cubosome as a Cytotoxic Potentiator against HCT-116 Colorectal Cancer Cells

“…26 Different systems of DOX drug delivery has be developed in the past decade to overcome the adverse effects. 27 The major advantage offered by cubosome-based drug delivery is the controlled and targeted release of drugs. 28 Because of its advantages, it has been widely used for delivering many cancer drugs.…”

In Vitro Cell Toxicity and Intracellular Uptake of Doxorubicin Exposed as a Solution or Liposomes: Implications for Treatment of Hepatocellular Carcinoma

“…The in vitro exposure times in our study were selected based on their clinical relevance for the local pharmacokinetics of DOX and DOXol following TACE injections with an emulsion-based formulation (Lipiodol ® ) [ 24 ]. The DOX plasma concentrations in HCC patients have been reported to be approximately in the range 0.2–30 µM for several days in central and peripheral veins, with corresponding DOXol plasma concentrations between 0.01–0.03 µM [ 14 , 49 , 50 ]. The total intracellular concentrations of DOX in the cell lines used in our study, when exposed to DOX S or DOX PL at their IC 50 values, were several fold higher than their exposure concentrations ( Table 3 ).…”

“…Several modified-release parenteral drug delivery systems with DOX have been developed in an effort to prolong local tumor drug exposure and reduce off-target toxicity [ 13 , 14 ]. This includes therapeutic nanoparticles (TNPs) such as Doxil ® , a pegylated liposomal doxorubicin (DOX PL ) formulation for intravenous administration, where DOX is encapsulated in liposomes covered with a layer of polyethylene glycol coating.…”

“…In an effort to reduce the toxic side-effects of intravenous DOX therapy in HCC patients, several locoregional treatment strategies have been developed, including transarterial chemo-embolization (TACE) [ 1 , 20 , 22 ]. This technique uses high-precision image guidance to locally dose the drug delivery system through the tumor’s artery, thereby creating a high local concentration in the tumor tissue, while reducing the systemic exposure and subsequent side effects [ 14 , 23 , 24 ]. Recently, there has been an increasing interest in combining TACE with therapeutic nanoparticles (TNPs) [ 25 ].…”

A Prognostic Model Based on TMB-Related Lncrnas Predicts Outcome of Liver Cancer Patients

“…The occurrence, development and treatment of liver cancer has become a research hotspot [20][21][22][23]. Previously, the treatment and prognostic prediction of patients were established according to tumor size, pathological grading , and lymph node metastasis [24][25].…”