Pharmacokinetics of Total and Unbound Paclitaxel After Administration of Paclitaxel Micellar or Nab-Paclitaxel: An Open, Randomized, Cross-Over, Explorative Study in Breast Cancer Patients.

INTRODUCTION: Paclitaxel micellar is a novel formulation of paclitaxel in which retinoic acid derivates solubilize paclitaxel. The aim of the present study was to compare the unbound and total plasma pharmacokinetics of the new formulation with those of nanoparticle albumin-bound (nab)-paclitaxel and to further assess its safety. METHODS: In this open, randomized, cross-over study, 28 female patients with breast cancer were given paclitaxel micellar and nab-paclitaxel as a 1-h intravenous infusion at a dose of 260 mg/m2. Plasma samples were collected during 10 h, which were projected to cover at least 80% of the area to infinite time, AUCinf. Unbound paclitaxel was measured in ultrafiltrate of plasma. Total paclitaxel in plasma was measured after protein precipitation with acetonitrile. Both assays used ultra-performance liquid chromatography (UPLC) followed by MS/MS for drug quantification. The unbound fraction, fu, was calculated as the ratio between the unbound and the total concentration. RESULTS: No difference in fu of paclitaxel between the two formulations was observed. Statistical comparison of AUC0-10h and Cmax of unbound paclitaxel demonstrated that the two formulations met the criteria for bioequivalence. Regarding total paclitaxel levels, Cmax but not AUC0-10h met the criteria. This study supports a safe administration of paclitaxel micellar. CONCLUSION: The two formulations, paclitaxel micellar and nab-paclitaxel, behaved similarly following infusion. Probably, both formulations dissociate immediately in the blood, whereupon released paclitaxel rapidly distributes into tissue. Judged from the bioequivalence demonstrated for unbound paclitaxel, the two formulations are considered clinically equivalent. TRIAL REGISTRATION: EudraCT no.: 2010-019838-27. FUNDING: Oasmia Pharmaceutical AB.

Maximum Tolerated Dose and Pharmacokinetics of Paclitaxel Micellar in Patients with Recurrent Malignant Solid Tumours: A Dose-Escalation Study.

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/m2 dose 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. FUNDING: Oasmia Pharmaceutical AB.

A Model-Based Approach To Assessing the Importance of Intracellular Binding Sites in Doxorubicin Disposition.

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 (Kp,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 Kp,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.

Lipiodol does not affect the tissue distribution of intravenous doxorubicin infusion in pigs.

OBJECTIVES: In liver cancer treatment, lipiodol is used as a pharmaceutical excipient to improve delivery of the cytostatic drug doxorubicin (DOX). As DOX and its metabolite doxorubicinol (DOXol) cause serious off-target adverse effects, we investigated the effects of drug-free lipiodol or ciclosporin (CsA) on the tissue distribution (Kp ) of DOX and DOXol in relevant pig tissues. METHODS: Four treatment groups (TI-TIV) all received an intravenous DOX solution at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), lipiodol (TII), CsA (TIII) or lipiodol and CsA (TIV). After 6 h, the pigs were euthanised, and liver, kidney, heart and intestine samples were collected and analysed. KEY FINDINGS: The tissue DOX concentrations were highest in the kidney (TI-TIV). All the investigated tissues showed extensive DOX Kp . Lipiodol had no effect on the Kp of DOX to any of the tissues. However, the tissue concentrations of DOX were increased by CsA (in liver, kidney and intestine, P < 0.05). CONCLUSION: Lipiodol injected into the portal vein does not affect the tissue distribution of DOX and DOXol.

In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma.

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 antitumor effects were also evaluated. In this open, prospective, nonrandomized multicenter 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.

Treatment of intermediate stage hepatocellular carcinoma: a review of intrahepatic doxorubicin drug-delivery systems.

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.

The effects of lipiodol and cyclosporin A on the hepatobiliary disposition of doxorubicin in pigs.

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 and its active metabolite doxorubicinol (DOXol). 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 DOXol were analyzed using UPLC-MS/MS. The developed multicompartment model described 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 were 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 directly interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX.

Investigation of hepatobiliary disposition of doxorubicin following intrahepatic delivery of different dosage forms.

Unresectable, intermediate stage hepatocellular carcinoma (HCC) is often treated palliatively in humans by doxorubicin (DOX). The drug is administered either as a drug-emulsified-in-Lipiodol (DLIP) or as drug loaded into drug eluting beads (DEB), and both formulations are administered intrahepatically. However, several aspects of their in vivo performance in the liver are still not well-understood. In this study, DLIP and DEB were investigated regarding the local and systemic pharmacokinetics (PK) of DOX and its primary metabolite doxorubicinol (DOXol). An advanced PK-multisampling site acute in vivo pig model was used for simultaneous sampling in the portal, hepatic, and femoral veins and the bile duct. The study had a randomized, parallel design with four treatment groups (TI-TIV). TI (n = 4) was used as control and received an intravenous (i.v.) infusion of DOX as a solution. TII and TIII were given a local injection in the hepatic artery with DLIP (n = 4) or DEB (n = 4), respectively. TIV (n = 2) received local injections of DLIP in the hepatic artery and bile duct simultaneously. All samples were analyzed for concentrations of DOX and DOXol with UPLC-MS/MS. Compared to DLIP, the systemic exposure for DOX with DEB was reduced (p < 0.05), in agreement with a slower in vivo release. The approximated intracellular bioavailability of DOX during 6 h appeared to be lower for DEB than DLIP. Following i.v. infusion (55 min), DOX had a liver extraction of 41 (28-53)%, and the fraction of the dose eliminated in bile of DOX and DOXol was 20 (15-22)% and 4.2 (3.2-5.2)%, respectively. The AUCbile/AUCVP for DOX and DOXol was 640 (580-660) and 5000 (3900-5400), respectively. In conclusion, DLIP might initially deliver a higher hepatocellular concentration of DOX than DEB as a consequence of its higher in vivo release rate. Thus, DLIP delivery results in higher intracellular peak concentrations that might correlate with better anticancer effects, but also higher systemic drug exposure and safety issues.