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| 2. |
- Ahnfelt, Emelie, et al.
(författare)
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Lipiodol-based emulsions used for transarterial chemoembolization and drug delivery : Effects of composition on stability and product quality
- 2019
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Ingår i: Journal of Drug Delivery Science and Technology. - : ELSEVIER. - 1773-2247. ; 53
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Tidskriftsartikel (refereegranskat)abstract
- Transarterial chemoembolization with emulsion-based formulations using doxorubicin hydrochloride (DOX) and Lipiodol (R) is the golden standard for the loco-regional treatment of unresectable hepatocellular carcinoma (HCC). However, from a pharmaceutical quality perspective these emulsions are poorly characterized. In this study, clinically relevant Lipiodol (R)-based emulsions were characterized in terms of emulsion stability, continuous phase classification and droplet-size distribution. Also, the solubility of DOX in the different emulsion components and the distribution of DOX to the lipid phase were investigated. These are key features to investigate due to the claimed tumor-seeking properties of Lipiodol (R). The in vitro release of DOX was studied in a miniaturized dialysis method and an empirical release model was applied to adjust for the passage of DOX across the dialysis membrane. The most stable emulsion ( > 72 h) was classified as water-in-oil (w/o), had the highest distribution of DOX to the lipid phase (20%) and an aqueous-to-lipid phase ratio of 1:4. The composition of the aqueous phase was a mixture (v/v) of iohexol (85%) and water (15%). Emulsions containing iohexol and a high aqueousto-lipid phase ratio (1:2-1:4) displayed prolonged in vitro release profiles of DOX. This study further emphasizes the medical need to standardize these emulsion-based drug delivery systems.
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| 3. |
- Borgå, Olof, et al.
(författare)
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Maximum Tolerated Dose and Pharmacokinetics of Paclitaxel Micellar in Patients with Recurrent Malignant Solid Tumours : A Dose-Escalation Study
- 2019
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Ingår i: Advances in Therapy. - : Springer. - 0741-238X .- 1865-8652. ; 36:5, s. 1150-1163
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: A water-soluble Cremophor EL-free formulation of paclitaxel, in which retinoic acid derivates solubilize paclitaxel by forming micelles (paclitaxel micellar), was studied for the first time in man to establish the maximum tolerated dose (MTD) and to characterize the pharmacokinetics (PK).Methods: This was an open-label, one-arm, dose-escalating study in patients with advanced solid malignant tumours, for which no standard therapy was available or had failed. Paclitaxel micellar was given as 1-h intravenous infusion every 21 days for 3 cycles, mainly without premedication. Plasma samples were collected during 24 h at the first cycle and paclitaxel concentrations were assayed by high-performance liquid chromatography. PK was evaluated using a two-compartment model.Results: Thirty-four patients received paclitaxel micellar at doses ranging between 90 and 275 mg/m2. MTD was established as 250 mg/m2. Fatigue and neuropathy were the most frequent dose-limiting toxicities. No hypersensitivity reactions were observed. PK of paclitaxel was evaluated in 25 data sets. Paclitaxel micellar had a rapid initial distribution phase, mean half-life 0.55 h, estimated to be completed 3 h after dosing and a mean terminal half-life of 8.8 h. Mean clearance was 13.4 L/h/m2 with fivefold interindividual variability. The residual areas after 10 h and 24 h were 15.7 ± 8.6% and 5.7 ± 3.9% of the area under the plasma concentration–time curve to infinite time (AUCinf), respectively.Conclusion: No new side effects unknown for paclitaxel were observed. Maximum plasma concentration (Cmax) and AUCinf showed a tendency to increase linearly with dose within the 150–275 mg/m2dose range. The possibility to administer paclitaxel micellar without steroid premedication makes it an attractive candidate for further studies in combination with immunotherapy.Trial Registration: EudraCT no: 2004-001821-54.
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| 4. |
- Dubbelboer, Ilse R., et al.
(författare)
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A Model -Based Approach To Assessing the Importance of Intracellular Binding Sites in Doxorubicin Disposition
- 2017
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Ingår i: Molecular Pharmaceutics. - : AMER CHEMICAL SOC. - 1543-8384 .- 1543-8392. ; 14:3, s. 686-698
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Tidskriftsartikel (refereegranskat)abstract
- Doxorubicin is an anticancer agent, which binds reversibly to topoisomerase I and II, intercalates to DNA base pairs, and generates free radicals. Doxorubicin has a high tissue:plasma partition coefficient and high intracellular binding to the nucleus and other subcellular compartments. The metabolite doxorubicinol has an extensive tissue distribution. This porcine study investigated whether the traditional implementation of tissue binding, described by the tissue:plasma partition coefficient (K-p,K-t),could be used to appropriately analyze and/or simulate tissue doxorubicin and doxorubicinol concentrations in healthy pigs, when applying a physiologically based pharmacokinetic (PBPK) model approach, or whether intracellular binding is required in the semi-PBPK model. Two semi-PBPK models were developed and evaluated using doxorubicin and doxorubicinol concentrations in healthy pig blood, bile, and urine and kidney and liver tissues. In the generic semi-PBPK model, tissue binding was described using the conventional K-p,K-t approach. In the binding-specific semi-PBPK model, tissue binding was described using intracellular binding sites. The best semi-PBPK model was validated against a second data set of healthy pig blood and bile concentrations. Both models could be used for analysis and simulations of biliary and urinary excretion of doxorubicin and doxorubicinol and plasma doxorubicinol concentrations in pigs, but the binding-specific model was better at describing plasma doxorubicin concentrations. Porcine tissue concentrations were 400- to 1250-fold better captured by the binding-specific model. This model adequately predicted plasma doxorubicin concentration time and biliary doxorubicin excretion profiles against the validation data set. The semi-PBPK models applied were similarly effective for analysis of plasma concentrations and biliary and urinary excretion of doxorubicin and doxorubicinol in healthy pigs. Inclusion of intracellular binding in the doxorubicin semi-PBPK models was important to accurately describe tissue concentrations during in vivo conditions.
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| 6. |
- Dubbelboer, Ilse R, et al.
(författare)
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The Effects of Lipiodol and Cyclosporin A on the Hepatobiliary Disposition of Doxorubicin in Pigs
- 2014
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 11:4, s. 1301-1313
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Tidskriftsartikel (refereegranskat)abstract
- Doxorubicin (DOX) emulsified in Lipiodol (LIP) is used as local palliative treatment for unresectable intermediate stage hepatocellular carcinoma. The objective of this study was to examine the poorly understood effects of the main excipient in the drug delivery system, LIP, alone or together with cyclosporin A (CsA), on the in vivo liver disposition of DOX. The advanced, multi-sampling-site, acute pig model was used; samples were collected from three blood vessels (v. portae, v. hepatica and v. femoralis), bile and urine. The four treatment groups (TI-TIV) all received two intravenous 5 min infusions of DOX into an ear vein: at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), LIP (TII), CsA (TIII) or LIP and CsA (TIV). Concentrations of DOX and its active metabolite doxorubicinol (DOXol) were analyzed using UPLC-MS/MS. A multi-compartment model was developed to describe the distribution of DOX and DOXol in plasma, bile and urine. LIP did not affect the pharmacokinetics of DOX or DOXol. CsA (TIII and TIV) had no effect on the plasma pharmacokinetics of DOX, but a 2-fold increase in exposure to DOXol and a significant decrease in hepatobiliary clearance of DOX and DOXol was observed. Model simulations supported that CsA inhibits 99% of canalicular biliary secretion of both DOX and DOXol, but does not affect the metabolism of DOX to DOXol. In conclusion, LIP did not interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX.
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| 7. |
- Dubbelboer, Ilse R, et al.
(författare)
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Treatment of intermediate stage hepatocellular carcinoma : a review of intrahepatic doxorubicin drug-delivery systems
- 2014
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Ingår i: Therapeutic delivery. - : Future Science Ltd. - 2041-5990 .- 2041-6008. ; 5:4, s. 447-466
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Tidskriftsartikel (refereegranskat)abstract
- The biopharmaceutical properties of doxorubicin delivered via two drug-delivery systems (DDSs) for the palliative treatment of unresectable hepatocellular carcinoma were reviewed with relation to the associated liver and tumor (patho)physiology. These two DDSs, doxorubicin emulsified with Lipiodol(®) and doxorubicin loaded into DC Bead(®) are different regarding tumor delivery, release rate, local bioavailability, if and how they can be given repeatedly, biodegradability, length of embolization and safety profile. There have been few direct head-to-head comparisons of these DDSs, and in-depth investigations into their in vitro and in vivo performance is warranted.
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| 8. |
- Lilienberg, Elsa, 1984-
(författare)
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Biopharmaceutical Evaluation of Intra-arterial Drug-Delivery Systems for Liver Cancer : Investigations in healthy pigs and liver cancer patients
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There are currently two types of intra-arterial drug-delivery system (DDS) in clinical use in the palliative treatment of primary liver cancer. The chemotherapeutic drug doxorubicin (DOX) can be formulated into a drug-in-lipiodol emulsion (LIPDOX) or a microparticulate drug-eluting bead system (DEBDOX). To facilitate development of future DDSs, we need to understand the release and local distribution of drug from these DDSs into the complex, in vivo, pathological environment.The overall aim of this project was to assess and improve understanding of the in vivo release of DOX from LIPDOX and DEBDOX and its local disposition in the liver. These processes were investigated in detail in a multisampling-site, healthy pig model and in human patients with liver cancer. The mechanisms involved in DOX disposition were studied by examining potential interactions between DOX and lipiodol and/or cyclosporine A (CsA) in pigs. In this project, the main elimination pathway for DOX and its primary metabolite doxorubicinol (DOXol) was via bile; their extensive canalicular carrier-mediated transport (e.g. ATP-binding cassette transporters ABCB1, ABCC1, ABCC2 and ABCG2) was inhibited by CsA. CsA had no effect on the carbonyl and aldo-keto reductases responsible for the metabolism of DOX into DOXol. LIPDOX released DOX more rapidly and to a greater extent into the circulation than DEBDOX, which had only released 15% of the dose in patients after 24 hrs. The systemic exposure to DOX was lower for DEBDOX than for LIPDOX. Greater fractions of DOXol were formed in blood and bile with LIPDOX than with DEBDOX. This may have been because DOX was more widely distributed into regions with increased metabolic capacity or because of increased intracellular uptake when DOX was delivered in LIPDOX. The excipient lipiodol in the LIPDOX formulation did not interact with transporters, enzymes or membranes that would explain the increased cellular uptake of DOX.In conclusion, the release of DOX from DEBDOX is more controlled in vivo than that from LIPDOX, indicating that DEBDOX is a more robust pharmaceutical product. The formulations for future optimized DDSs should therefore be more similar to DEBDOX than to LIPDOX.
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| 9. |
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| 10. |
- Lilienberg, Elsa, et al.
(författare)
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In vivo Drug Delivery Performance of Lipiodol-based Emulsion or Drug-eluting Beads in Patients with Hepatocellular Carcinoma
- 2017
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 14:2, s. 448-458
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Tidskriftsartikel (refereegranskat)abstract
- Doxorubicin (DOX) delivered in a lipiodol-based emulsion (LIPDOX) or in drug-eluting beads (DEBDOX) is used as palliative treatment in patients with intermediate-stage hepatocellular carcinoma (HCC). The primary objective of this study was to evaluate the in vivo delivery performance of DOX from LIPDOX or DEBDOX in HCC patients using the local and systemic pharmacokinetics of DOX and its main metabolite doxorubicinol (DOXol). Urinary excretion of DOX and DOXol, and their short-term safety and anti-tumor effects were also evaluated. In this open, prospective, non-randomized multi-center study, LIPDOX (n=13) or DEBDOX (n=12) were injected into the feeding arteries of the tumor. Local (vena cava/hepatic vein orifice) and systemic (peripheral vein) plasma concentrations of DOX and DOXol were determined in samples obtained up to 6 h and 7 days after treatment. Tumor response was assessed using computed tomography or magnetic resonance imaging. The Cmax and AUC0-24 h for DOX were 5.6-fold and 2.4-fold higher in LIPDOX vs DEBDOX recipients, respectively (p <0.001). After 6 h, the respective mean proportions of the dose remaining in the liver or drug-delivery system (DDS) were 49% for LIPDOX and 88% for DEBDOX. LIPDOX releases DOX faster than DEBDOX in HCC patients and provides more extensive local and systemic exposure (AUC) to DOX and DOXol initially (0-7 days). DEBDOX formulation has a release and distribution of DOX that is more restricted and rate controlled than LIPDOX.
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