| CaelyxTM in EU or Doxil® in other regions/Doxorubicin/MPEG-DSPE, HSPC and cholesterol (STEALTH® liposome carrier)/Ovarian cancer, Kaposi’s sarcoma and multiple myeloma/Intravenous/8 |
Pharmacology: Testing in murine and human xenograft tumor models showed enhanced antitumor activity (including inhibiting or halting tumor growth and/or in prolonging survival of tumor-bearing animals) at equivalent dose levels with CaelyxTM/Doxil® compared to doxorubicin alone |
| Safety pharmacology: No findings in an intravenous dosing rat neurobehavioral study with the STEALTH® liposome carrier. However, in an intravenous conscious dog cardiovascular study with the carrier, clinical signs included hypoactivity, flushing, diarrhea and emesis along with decreased blood pressure; it was stated that hypotension may be related to histamine release (mast cell degranulation) in response to infusion of large amount of lipid |
| ADME: Single dose pharmacokinetic studies in rats, rabbits and dogs occurred along with multiple dose studies in rats and dogs showed that exposure (AUC) was greater after treatment with CaelyxTM/Doxil® compared to doxorubicin alone. Tissue distribution in murine models showed that tumor levels of drug were higher in CaelyxTM/Doxil®-treated animals; tissue distribution (doxorubicin and main metabolite) was also examined in tumor-free rats and dogs (with lower peak concentrations seen) along with a disposition and mass balance study in rats. Total (liposomal plus free) was mainly measured, although free drug in plasma measurement also occurred |
| Toxicology (intravenous dosing and including doxorubicin only group; the design of repeat dose studies took the long plasma half-life of the STEALTH® liposome carrier into consideration): With CaelyxTM/Doxil®, single dose toxicity studies in rodents and dogs, rat toxicity study every 3rd day dosing for 13 doses (including liposome only group), rabbit study every 5 days dosing for up to 21 doses (to examine cardiotoxicity), dog toxicity study with weekly doses for 4 weeks (including liposome only group), dog study with weekly or every 2nd or 4th week dosing for 12 weeks (to examine dermal lesions and myelosuppression) and dog study with one every 3 weeks dosing for 10 doses (including liposome only group) (to examine cardiotoxicity). Overall, a similar toxicity profile as seen for doxorubicin occurred; notably cardiotoxicity and nephrotoxicity were reduced. In the liposome-only group in the dog studies, an acute response characterized by depressed activity, salivation, emesis and/or prostration, defecation, flushing and pale mucous membranes was seen |
| Reproduction toxicology (intravenous dosing): With CaelyxTM/Doxil®, rat and rabbit embryo-fetal toxicity studies (including doxorubicin and liposome only groups in the former) confirmed embryotoxicity and teratogenicity of doxorubicin; no embryo-fetal findings for liposome only group |
| Genotoxicity: No mutagenic or genotoxic potential seen with the STEALTH® liposome carrier in reverse mutation bacterial, in vitro mouse lymphoma, in vitro chromosome aberration and mouse bone marrow micronucleus assays |
| Local tolerance: Intravenous dosing in rabbits with CaelyxTM/Doxil®, doxorubicin and liposome groups showed no evidence of irritation; some dose site inflammation was seen following subcutaneous dosing |
| Blood compatibility: Testing of CaelyxTM/Doxil® and liposome only showed compatibility with human plasma and serum and no hemolysis of human erythrocytes |
| Lipid components: A single dose intravenous toxicity study with MPEG-DSPE showed no signs of toxicity. Lysophosphatidylcholine (LPC), a degradation product of HSPC, showed no hemolysis in rat erythrocytes |
| MyocetTM liposomal/Doxorubicin/EPC and cholesterol/Metastatic breast cancer/Intravenous/9 |
Pharmacology: Tested in cancer cell lines and in murine tumor models following intravenous dosing; MyocetTM liposomal generally appeared to be as effective as doxorubicin (based on survival) in the latter studies and was better tolerated |
| ADME: At the same dose in dogs, MyocetTM liposomal resulted in higher plasma concentrations/exposure (AUC) for total drug (encapsulated + free) than did doxorubicin; lower Cmax but higher systemic exposures of free (unencapsulated) drug were also seen. Tissue distribution was examined in dogs following administration of radiolabeled MyocetTM liposomal and doxorubicin. Drug level in tumor tissue was examined in a mouse tumor model (higher than seen with doxorubicin) |
| Toxicology (dose route not specified in literature source): With MyocetTM liposomal, the following studies were reported: Single dose toxicity studies in mouse and dog (also liposome only and doxorubicin groups), single dose toxicity studies in combination with 5-fluorouracil or cyclophosphamide in mice (also doxorubicin group), study in rabbit to examine for the potential to induce thrombi and dog toxicity studies with 8 doses or once every three weeks for 8-12 cycles dosing (also doxorubicin group). Testing showed a similar toxicity profile for MyocetTM liposomal and doxorubicin. It was postulated that the increase in body temperature in dogs, only seen with MyocetTM liposomal dosing, was due to a greater uptake of doxorubicin by the phagocytic cells of the mononuclear phagocyte system, and thus, “mediators of inflammation become responsible for the observed temperature increase” |
| Local tolerance: Single perivascular or subcutaneous injection study in rabbit: MyocetTM liposomal and doxorubicin gave similar local reaction results |
| Blood compatibility: Included in the single dose toxicity studies (also liposome only group) and a low hemolytic potential was found |
| Marqibo®/Vincristine/Sphingomyelin and cholesterol/Acute lymphoblastic leukemia/Intravenous/10 |
Pharmacology: With Marqibo® better anticancer activity in murine tumor models when compared to free vincristine was seen [Tumor growth suppression was demonstrated for various cancer indications in these models using single or multiple dose regimens11] |
| Safety pharmacology: In vitro electrophysiological study (hERG assay) with Marqibo® and vincristine (result not specified in literature source) |
| ADME: Pharmacokinetic, distribution, mass balance and metabolism studies were conducted with Marqibo® (with some including vincristine). [Studies included in vitro protein binding to demonstrate low binding to human plasma proteins, single dose intravenous pharmacokinetic profiling (with encapsulated + free drug measurement) in mice, rats and dogs to show lower drug clearance and volume of distribution and corresponding greater AUC with Marqibo® than vincristine, metabolism evaluation and metabolic profile in rats, radio-label mass balance studies in rats and tissue distribution testing in mice and rats; extravasation kinetics and preferred accumulation of Marqibo® in tumors in a mouse xenograft model using intra-vital microscopy imaging also occurred11] |
| Toxicology (intravenous dosing): With Marqibo®, a 6-cycle rat toxicity study once per week (also vincristine and liposome only groups) and a study in dogs (23 weeks) were performed (no further details are available in literature source). [Toxicokinetic evaluation was confirmed in the rat study11]. Testing showed similar toxicity profile compared to vincristine, although Marqibo® induced greater peripheral neurotoxicity (nerve fiber degeneration) and secondary skeletal muscle atrophy at the same dose level in rats [No toxicity was seen for drug-free liposomes12] |
| Reproduction toxicology (intravenous dosing and including toxicokinetic evaluation): With Marqibo®, rat developmental toxicity study (including vincristine and liposome only [at dose equivalent to the liposome content of the high dose of Marqibo®] groups). Embryofetal toxicity (including teratogenicity of vincristine was confirmed; no findings occurred with empty liposome administration |
| Carcinogenicity: Literature summary showed lack of carcinogenic potential for liposome carrier |
| OnivydeTM/Irinotecan/DSPC, cholesterol and MPEG-DSPE/Metastatic adenocarcinoma of pancreas/Intravenous/13 |
Pharmacology: OnivydeTM improved tumor growth inhibition compared to equivalent doses of free irinotecan when evaluated in several xenograft tumor models |
| Safety pharmacology: No cardiovascular findings were seen in a dog study |
| ADME: Single intravenous dose pharmacokinetic studies in rats and dogs with OnivydeTM showing increased exposure and increased systemic residence time of drug with OnivydeTM use along with tissue distribution in rats. Disposition study in rats using radiolabeled liposomal and free drug as well as 2 mass balance and excretion studies in rats using radiolabeled liposomal drug also occurred. Tissue and tumor distribution was examined after single intravenous dosing in a mouse xenograft study |
| Toxicology (intravenous dosing): With OnivydeTM, acute toxicity studies in mice, rats and dogs, 4-week and 6-cycle (18 week) rat and dog toxicity studies (also irinotecan and liposome only groups), with the liposome only group serving as the control group; studies included toxicokinetic evaluation. Testing showed generally similar toxicities for OnivydeTM and irinotecan. Histiocytosis (accumulation of foamy histiocytes) in multiple organs was seen in the rat repeat dose toxicity studies in OnivydeTM and liposome-only groups; although a saline control group was not included to confirm, the finding was attributed to the presence of liposome as it was concluded that “similar findings of increased histiocytosis have occurred following treatment of animals with other liposomal drug formulations” |
| Blood compatibility: Human whole blood hemolysis and plasma flocculation study (result not specified in literature source) |
| VyxeosTM/Daunorubicin and cytarabine/DSPC, DSPG and cholesterol/Acute myeloid leukemia/Intravenous/14 |
Pharmacology: Optimal ratio of daunorubicin and cytarabine was evaluated in cancer cell lines vs individual drugs alone. In various syngeneic and xenograft murine models, VyxeosTM demonstrated greater antitumor activity (survival rate) than individual liposomal formulations of daunorubicin and cytarabine, and non-liposomal free-drug cocktail, even when dose levels of drug were greater in the comparator treatment arms |
| ADME: Pharmacokinetic and bone marrow distribution (mice) or metabolism and excretion (rats) of radiolabeled VyxeosTM and non-liposomal free-drug cocktail were evaluated following a single intravenous administration and showed increased and more sustained exposure to the 2 drugs in the liposomal formulation. VyxeosTM was shown to be stable in plasma. In work using a mouse model of disseminated leukemia, intravenous dosing of VyxeosTM or free-drug cocktail confirmed higher amounts of the 2 drugs in the bone marrow than the free-drug cocktail. Drug tissue distribution of radiolabeled VyxeosTM or non-liposomal drug was evaluated in whole body autoradiography studies in rats |
| Toxicology (intravenous dosing): VyxeosTM, single dose toxicity studies in rats and dogs and 2-cycle rat and dog toxicity studies (Days 1, 3 and 5, then Days 22, 24 and 26 dosing; groups with liposome only and the 2 free drugs together were included in the dog study); toxicokinetic evaluation occurred in repeat dose toxicity studies. VyxeosTM toxicity profile is consistent with that of daunorubicin and cytarabine. No findings were reported for the liposome-only group |
| AmBisome®/Amphotericin B/HSPC, DSPG and cholesterol/Fungal infections/Intravenous/15 |
Pharmacology: Stated that “in vitro and in vivo study results indicate that AmBisome® has retained the antifungal activity of amphotericin B” |
| ADME: With AmBisome®, a single dose pharmacokinetic study in rats, toxicokinetic evaluation in toxicity testing showed drug clearance decreased but Cmax doubled |
| Toxicology (intravenous dosing with inclusion of liposome-only group and with plasma and tissue concentration measurement of amphotericin B in repeat dose studies): With AmBisome®, single dose toxicity studies in mice and rats, 14-day toxicity study in mice, 2 × 30-day toxicity testing in rats, 30-day toxicity study in dogs and 91-day toxicity study in rats were performed. “Foamy cell accumulation” was seen in AmBisome®-treated groups in the shorter-term rat toxicity studies and also in spleen or kidney in liposome only groups and was related to phagocytosis of macrophages of the mononuclear phagocyte system. In the 91-day study, vacuolated macrophages were also seen with liposome-treatment as well as hypercholesterolemia (attributed to cholesterol content). [Latter findings were also reported elsewhere16]. Overall, no new toxicity findings than already known for amphotericin B were found |
| Reproduction toxicology (intravenous dosing and with liposome-only groups): With AmBisome®, fertility and early embryo development study in rats plus rat and rabbit embryo-fetal toxicity studies revealed no effect on fertility or evidence of teratogenicity |
| Local tolerance: With AmBisome®, dye extravasation evaluation plus paravenous and subcutaneous dosing (vs amphotericin B) and paravenous and intra-arterial dosing in rat studies revealed some evidence of a local inflammatory response |
| DepoCyt®/Cytarabine/DOPC, DPPG and cholesterol (DepoFoamTM drug delivery system)/Lymphomatous meningitis/Intrathecal/17,18 [DepoCyt® is no longer authorized in the EU] |
Pharmacology: With a liposomal formulation, a mouse tumor model study using subcutaneous dosing along with intraperitoneal dosing studies in mice demonstrated prolonged survival |
| ADME: Intrathecal pharmacokinetic study with a liposomal formulation of cytarabine in rats or with DepoCyt® in rhesus monkey plus a distribution study in rat with radiolabeled DepoCyt® were performed. Pharmacokinetic evaluation also occurred in the pharmacology studies |
| Toxicology (intrathecal dosing): Range-finding and 4-cycle (one dose/cycle, 14 days cycle) toxicity studies in rhesus monkeys as well as a separate toxicokinetic evaluation study in this species were conducted |
| DepodurTM/Morphine sulphate/DOPC, DPPG, cholesterol, tricaprylin and triolein (DepoFoamTM drug delivery system)/post-operative pain/Post-operative pain/Epidural/19 |
Pharmacology: DepodurTM and morphine sulphate were tested in dog studies using epidural dosing and improved pain response seen with liposomal formulation |
| ADME: With DepodurTM, pharmacokinetic study in dogs with epidural, intravenous and intrathecal dosing and a local clearance study in rats following subcutaneous dosing were performed. It was commented that “the lipids that comprise the DepoFoamTM liposomes are either naturally occurring or very close analogues of endogenous lipids that should be remodeled, incorporated, metabolized, and/or cleared like any endogenous lipid” |
| Toxicology: Acute epidural toxicity study in dogs, single dose intravenous, intrathecal and epidural interaction study in dogs and 2 28-day (once a week dosing) epidural toxicity studies in dogs were conducted with DepodurTM. |
| Additional data: Other supporting studies with the DepoFoamTM drug delivery system showed no evidence of toxicity. Toxicity testing with 5 subcutaneous doses over 29 days in mice and dogs only showed injection site findings of a low level inflammatory response vs saline control (increased numbers of histiocytes [considered to be resident macrophages] and the presence of polymorphonuclear leukocytes and lymphoid cells were reported). A single subcutaneous “implanted” dose in rats initially showed the presence of foamy macrophages (identified as macrophages containing vacuoles whose histological appearance was consistent with the phagocytosis of DepoFoamTM lipids); the finding was generally not seen 21 days post-dosing |
| ExparelTM/Bupivacaine/DPPG, DEPC, cholesterol and tricaprylin (DepoFoamTM drug delivery system)/Post-surgical pain/Injection/20,21 |
Pharmacology: With ExparelTM, intradermal dosing in a guinea pig surgical wound model and subcutaneous (wound infiltration) administration in surgical wound model studies in rabbit and dog was compared to bupivacaine; a sustained anesthetic effect was demonstrated |
| Safety pharmacology: Parameters were included as part of repeat dose toxicity testing with no indication of any previously unknown safety concern |
| ADME: Pharmacokinetic studies in rats with ExparelTM and bupivacaine following subcutaneous administration showed lower but prolonged elevation/sustained release of drug in plasma. Radiolabel dose site retention study (bupivacaine and DEPC) using ExparelTM or liposomal formulation following intradermal or subcutaneous injection in rats and guinea pigs (enhanced liposome presence was seen) along with single subcutaneous dose interaction studies in rats or minipigs with other anesthetics were performed. Pharmacokinetics was also included in surgical wound model studies in rabbit and dog |
| Toxicology (bupivacaine-only groups were included in most studies as was toxicokinetic evaluation; [the subcutaneous dose route was used in repeat dose toxicity studies as an alternative route of delivery to stimulate the wound infiltration route in the clinic and the intermittent dosing regimen was used to allow time for dose egress from the dose site between injections and to minimize the risk of plasma drug accumulation22]): The following studies were conducted with ExparelTM: acute rat epidural dosing toxicity study, single dose/range-finding rat intravenous or subcutaneous dosing toxicity studies, acute dog intrathecal and epidural dosing toxicity study, acute dog subcutaneous dosing toxicity study, single dose/range-finding dog subcutaneous dosing toxicity study, 4-week rabbit and dog (twice weekly subcutaneous dosing) toxicity studies and a one-month range-finding juvenile rat subcutaneous dosing study. No difference in toxicity profile was seen, other than dose site reactions with ExparelTM that did not occur with bupivacaine only treatment. Dose site reaction consisted of hemorrhage, vacuolated (foamy) macrophages, neovascularization and mild inflammation in the repeat dose rabbit study [although a role for overt irritation due to prolonged bupivacaine exposure was not ruled out, at least some of these findings were attributed to likely cellular uptake and processing of the lipid components of the formulation22]. Granulomatous inflammation in the subcutaneous tissue occurred in the repeat dose dog study and was characterized by numerous vacuolated macrophages and fewer lymphocytes, plasma cells and/or multinucleated giant cells and often associated with edema and/or mineralization. It was concluded that the mineral deposits may be related to small amounts of foreign matter (ie, DepoFoamTM particles) in the loose connective tissues of the subcutaneous space and that the effects were considered non-adverse and an expected response to liposomes (representative of clearance of the liposome and its remnants) |
| Local tolerance: Effects of ExparelTM and bupivacaine in rabbits or dogs compared following nerve area, skin wound and intra-arterial dosing as well as subcutaneous or intra-articular dosing of ExparelTM in guinea pigs; no effects were seen |
| Blood compatibility: Coagulation assessed using human whole blood; a significantly prolonged clotting time was not anticipated |
| Inadvertent intravenous dosing: Intravenous ExparelTM was not toxic at lethal doses of bupivacaine when injected into rats |
| Novel excipient DEPC testing: Safety was characterized both by inclusion as part of the formulation tested in pharmacology and toxicity studies as well as an independent testing strategy comprising a tissue distribution study in rats (using subcutaneous dosing of radiolabeled material), general toxicity (4-week daily subcutaneous dosing studies in rat and dog), reproductive toxicity (embryo-fetal development studies in rats and rabbits plus a fertility/prenatal and postnatal development study in rats) and genotoxicity (bacteria reverse mutation assay, in vitro chromosome aberration test and mouse micronucleus test) evaluation of the DEPC-containing DepoFoamTM drug delivery system (comparable to that used in ExparelTM but without bupivacaine). No significant toxicities were apparent. An increased incidence of chronic panniculitis (characterized by granulomatous inflammation and granulomas) at the injection site was seen in rats vs saline control. In dogs, dose site findings vs saline control included accumulations of vacuolated macrophages (plus cytoplasmic vacuoles and small numbers of lymphocytes within the subcutis) and occasional foci of mineralization with associated granulomatous inflammatory cell infiltrate |
| Arikayce®/Amikacin/DPPC and cholesterol/Antibacterial for lung disease/Inhalation/22,23 |
Pharmacology: In vitro studies with bacterial-infected human macrophages demonstrated that Arikayce® was more bactericidal than amikacin at equivalent amikacin concentrations. Increased update into human peripheral blood monocytes relative to amikacin was seen. In cells isolated from bronchoalveolar lavage fluid from rodents administered either Arikayce® or amikacin via inhalation, higher cell concentrations of amikacin were seen in former. In vivo testing in bacteria-infected mice demonstrated that inhaled Arikayce® showed at least similar efficacy in terms of reducing lung bacterial load relative to amikacin |
| Safety pharmacology: Endpoints where included in toxicity testing in dogs with a related form of Arikayce® |
| ADME: Pharmacokinetics and biodistribution of amikacin from inhaled Arikayce® in various studies in rats was examined in serum and various tissues (especially lung distribution and clearance). Toxicokinetic evaluation in toxicity studies included serum, lung and/or urine levels of amikacin, with serum measurement also occurring in the carcinogenicity study |
| Toxicity (inhalation dosing): With Arikayce®, 13-week toxicity study in mice, 28-day toxicity study in juvenile rats, 26-week toxicity study in rats, 3-month toxicity study in dogs, 9-month toxicity study in dogs (including liposome-only group) plus 30-day rat and one-month dog toxicity studies with a liposome-encapsulated amikacin formulation similar to Arikayce® were performed. Adverse findings were generally restricted to higher dose lung inflammation in rats and was attributed to particle overload. All 3 species showed foamy macrophages in the lung from Arikayce® dosing. As focal alveolar macrophage accumulation was also seen in the liposome-only group in the 30-day rat and 9-month dog toxicity studies, it was stated that the finding was related to the non-specific clearance of the liposomes for the lungs. Also, lipid staining of lung sections did not provide any evidence of excessive accumulation of phospholipids |
| Genotoxicity: No evidence of genotoxicity was observed from in vitro (microbial mutagenesis test, mouse lymphoma mutation assay and chromosomal aberration study) and in vivo (micronucleus study in rats) testing with a liposome-encapsulated amikacin formulation similar to Arikayce® |
| Carcinogenicity: 2-year rat inhalation carcinogenicity study with Arikayce® (including liposome only group) revealed squamous cell carcinomas in the lungs of 2/120 of rats at the highest dose tested (may be the result of a high lung burden of particulates and relevance to humans is unknown). Aggregates of foamy macrophages were present in the lungs and mediastinal and bronchial lymph nodes of Arikayce®-treated and liposome only groups and related to normal clearance of the liposomes from the lung |
| S-CKD602/Camptothecin analogue CKD-602 (Camtobell in South Korea and in development as Belotecan in other regions)/MPEG-DSPE and DSPC/Oncology/Intravenous |
Pharmacology25: S-CKD602 was evaluated in human tumor athymic nude mice xenograft models and compared to that of non-liposomal or free CKD-602 and topotecan (also a topoisomerase 1 inhibitor). S-CKD602 was more efficacious (assessed from tumour growth inhibition) than free drug and topotecan |
| ADME26: Following intravenous dosing of S-CKD602 or CKD-602 to mice bearing A375 human melanoma xenografts, plasma encapsulated, released and sum total (encapsulated plus released) CKD-602 was measured, tumour and tissue samples were processed to measure sum total CKD-602, and microdialysis sampling of tumor extracellular fluid occurred. Results showed an enhanced pharmacokinetic profile with the liposomal formulation. ADME27: Toxicokinetic evaluation was included in repeat dose toxicity studies in rats and dogs; in dogs, elimination half-life was increased 7-14 times by the liposomal formulation |
| Toxicology27: Repeat dose toxicity studies with S-CKD602 comprised 6 cycles of intravenous doses 2 or 3 weeks apart in rats and dogs (included liposome only and/or CKD-602 only groups). Expected toxicity was seen. Although no details were presented, it was reported that in the dog “rapidly reversible signs of a liposomal infusion reaction” occurred |
| Other studies: No further published data were found |
| Atragen®/Tretinoin/DMPC and soybean oil/Oncology/Intravenous |
Pharmacology: No published data were found |
| ADME28: Incubation of either Atragen® or tretinoin in rat, dog and human plasma showed that the drug’s distribution in plasma was not influenced by incorporation of the liposome. ADME29: Pharmacokinetic, distribution and elimination studies of Atragen® in laboratory animals have been performed (no further details found). Toxicokinetic analysis was included in one of the 28-day rat toxicity studies with drug level in plasma and tissues examined |
| Toxicology (intravenous dosing)28: With Atragen®, single dose rat toxicity study (including liposome only group), 28-day rat toxicity study, 28-day rat toxicity study (including tretinoin and liposome only groups) and 28-day dog toxicity study were performed. Toxicity findings were similar to those established for tretinoin. Reversible increased spleen weights in the liposomal control and the mid- and high-dose Atragen® groups correlated to prominent vacuoles within macrophages (the observation was not considered a pathological process but the result of clearance of liposome material from the circulation by phagocytosis) |
| Other studies: No further published data were found |
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