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This Phase 1, single-center, double-blind, placebo-controlled, three-period study assessed cardiovascular safety of CX157, a specific Reversible Inhibitor of Monoamine Oxidase A (RIMA), following the oral administration of tyramine. In Period 1, the sensitivity of each subject to orally administered tyramine was established by determining the dose of tyramine that elevates SBP ≥30 mmHg on ≥3 consecutive occasions (i.e., TYR303 ). Twelve subjects qualified for randomization in Period 2 during which an oral CX157 Modified Release Tablet (125 mg [N = 10]) or placebo (N = 2) were administered twice per day for 6 days to reach steady state. In Period 3, CX157 and placebo were administered with oral tyramine in fed state with daily increases in the tyramine dose of 20, 40, and 80 mg in an attempt to achieve the TYR303 . CX157 Modified Release Tablet, 125 mg administered twice per day (250 mg daily dose), was not associated with a tyramine reaction (i.e., TYR303 ). It is generally agreed that a high tyramine meal would contain up to 40 mg of dietary tyramine. These data obtained with CX157 provide an adequate margin of safety with respect to tyramine interaction and suggest that future studies can be conducted without the need for dietary tyramine restrictions.

Purpose: GRN1005 is a peptide–drug conjugate with the ability to penetrate the blood–brain barrier (BBB) and tumor cells by targeting the low-density lipoprotein receptor–related protein-1. We conducted a first-in-human phase I trial of GRN1005 in patients with recurrent glioma. Methods: Patients received GRN1005 by intravenous infusion every 3 weeks. Doses were escalated using a modified Fibonacci scheme. Study objectives included safety, tolerability, identification of the maximum tolerated dose (MTD), pharmacokinetics, and preliminary evidence of efficacy. Tumor extracted from patients undergoing surgery following administration of GRN1005 was analyzed to determine whether therapeutic concentrations of GRN1005 were achieved. Results: Sixty-three patients received GRN1005 at doses of 30 to 700 mg/m2 every 3 weeks. Therapy was well tolerated with neutropenia, leucopenia, and fatigue as the most frequent drug-associated grade 3/4 or higher toxicities. The MTD was 650 mg/m2 every 3 weeks. Dose-limiting toxicities were grade 3 mucositis and grade 4 neutropenia. There was no evidence of central nervous system toxicity or antibody production. Pharmacokinetic analysis showed that exposure to GRN1005 was dose proportional. We observed one complete and two partial responses. Eight of 27 patients dosed ≥420 mg/m2 had stable disease, which lasted a median of 51 days. Therapeutic concentrations of GRN1005 and free paclitaxel were shown in tumor tissue of surgical patients dosed with ≥200 mg/m2. Conclusion: GRN1005 delivers paclitaxel across the BBB and achieves therapeutic concentrations in tumor tissue. It has similar toxicity to paclitaxel and appears to have activity in recurrent glioma. The recommended phase II dose is 650 mg/m2 every 3 weeks. Clin Cancer Res; 19(6); 1567–76. ©2013 AACR.

Many different products containing Noni (Morinda citrifolia) fruit extracts are sold throughout the world for health restoration and maintenance. Despite a large business enterprise fueling Noni's popularity, there is a lack of standardization of products and no scientific evidence of Noni's clinical efficacy and safety. There is also no evidence to indicate an optimal therapeutic dose or dosing interval. In an initial volunteer, scopoletin was identified as a bioactive marker of Noni exposure and a candidate for product standardization and pharmacokinetic studies. Subsequently, capsules containing the whole freeze-dried fruit of Noni were orally administered to nine healthy volunteers (3 per group) at doses of 1,500 mg (3 × 500 mg), 2,000 mg (4 × 500 mg) and 2,500 mg (5 × 500 mg). Plasma and urine samples were obtained from each subject prior to dosing and at 0.5, 1, 2, 4 and 8 h after dosing. Concentrations of scopoletin were determined by HPLC with PDA (scanning at 200-700 nm) and MS detection. Scopoletin rapidly enters the plasma after Noni ingestion, maintaining levels in the range of 0.5 to 5 ng/mL for at least 8 h after dosing. Scopoletin bioavailability appears to be low, with significant intersubject variability. We conclude that scopoletin can be used as a relatively specific marker of Noni exposure in the blood and particularly in urine when its pharmacokinetics is considered appropriately.

Previous in vivo studies indicate that 2-hydroxyestradiol (2OHE) attenuates cardiovascular and renal diseases. In vitro studies suggest that the biological effects of 2OHE are mediated by 2-methoxyestradiol (2MEOE) after methylation of 2OHE by catechol-O-methyltransferase (COMT). This study tested the hypothesis that in vivo 2OHE is a prodrug of 2MEOE. We administered to male rats i.v. boluses of either 2OHE or 2MEOE and measured plasma levels of 2OHE and 2MEOE by gas chromatography-mass spectrometry at various time points after drug administration. After administration of 2OHE, plasma levels of 2OHE declined extremely rapidly [t(1/2(1)) = 0.94 min and t(1/2(2)) = 10.2 min] becoming undetectable after 45 min. Concomitant with the disappearance of 2OHE, 2MEOE occurred and then declined [t(1/2(1)) = 7.9 min and t(1/2(2)) = 24.9 min]. The peak concentration and total exposure (area under the curve) for 2OHE were much lower than for 2MEOE. 2OHE had a much higher plasma clearance (CL) and volume of distribution (V(d)) compared with 2MEOE (2OHE: CL = 1215 ml min(-1) kg(-1) and V(d) = 17,875 ml/kg; 2MEOE: CL = 50 ml min(-1) kg(-1) and V(d) = 1760 ml/kg). After administration of 2MEOE, plasma levels of 2MEOE declined [t(1/2(1)) = 2.5 min and t(1/2(2)) = 20.2 min] with a plasma CL of 50 ml min(-1) kg(-1) and a V(d) of 1500 ml/kg. We could not detect 2OHE in plasma from rats receiving 2MEOE. We conclude that the conversion of 2OHE to 2MEOE is so efficient that in terms of 2MEOE exposure, administration of 2OHE is bioequivalent to administration of 2MEOE itself.

Unilamellar liposomal amphotericin B (AmBisome) (liposomal AMB) reduces the toxicity of this antifungal drug. The unique composition of liposomal AMB stabilizes the liposomes, producing higher sustained drug levels in plasma and reducing renal and hepatic excretion. When liposomes release their drug payload, unbound, protein-bound, and liposomal drug pools may exist simultaneously in the body. To determine the amounts of drug in these pools, we developed a procedure to measure unbound AMB in human plasma by ultrafiltration and then used it to characterize AMB binding in vitro and to assess the pharmacokinetics of nonliposomal pools of AMB in a phase IV study of liposomal AMB and AMB deoxycholate in healthy subjects. We confirmed that AMB is highly bound (>95%) in human plasma and showed that both human serum albumin and α 1 -acid glycoprotein contribute to this binding. AMB binding exhibited an unusual concentration dependence in plasma: the percentage of bound drug increased as the AMB concentration increased. This was attributed to the low solubility of AMB in plasma, which limits the unbound drug concentration to −1 kg −1 ) for both formulations. Unbound drug urinary clearances were equal to the glomerular filtration rate, and tubular transit rates were

Amphotericin B (AmB) in small unilamellar liposomes (AmBisome) provides higher plasma concentrations and greater safety than the conventional deoxycholate formulation. The authors compared the disposition of the liposome's drug and cholesterol components by measuring AmB and radioactivity in plasma, urine, and feces for 1 week after a single 2-hour infusion of 14C-cholesterol-labeled AmBisome (2 mg/kg, 1 microgCi/kg) in healthy adults (4 males, 1 female). The plasma profile of 14C-cholesterol differed from that of AmB, lacking an initial rapid disappearance phase, having a lower total clearance, and having a volume of distribution (0.13 L/kg) close to that of the plasma compartment. The biphasic disappearance and long plasma half-life (147 h) of 14C-cholesterol were similar to those of other low-clearance liposomes. This and the low clearance of 14C-cholesterol from the plasma compartment suggest that it served as a liposome marker. The plasma drug-lipid ratio fell during the study, showing that AmB was cleared from plasma more rapidly than cholesterol or liposomes and suggesting that the composition of the liposomes changed over time. 14C-radioactivity was recovered mainly in the feces (9.5% of dose), consistent with the catabolism of cholesterol to bile salts. Combined fecal and renal clearances were < 18% of total clearance, suggesting that most of the liposomal drug and lipid remained in the body 1 week after dosing. Thus, AmBisome remains in the circulation for an extended period of time while releasing AmB, resulting in its markedly altered pharmacokinetic and safety profiles.

Purpose. Amphotericin B in small, unilamellar liposomes (AmBisome) is safer and produces higher plasma concentrations than other formulations. Because liposomes may increase and prolong tissue exposures, the potential for drug accumulation or delayed toxicity after chronic AmBisome was investigated.

Amphotericin B has been the mainstay of systemic antifungal therapy for over 30 years, despite its serious side-effects, and, although numerous alternative antifungal agents have been developed, none to date has matched the efficacy of amphotericin B. However, modern drug delivery technology has improved the safety of amphotericin B by incorporating it into lipid-based delivery systems, including liposomes. Three such formulations, based on the natural affinity of amphotericin B for lipids, are currently marketed. All increase the therapeutic index of amphotericin B, thereby allowing more aggressive treatment than is possible with the conventional product. However, they differ in structure, side-effect profiles and evidence of proven efficacy as discussed in this review.

Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome ®) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses.

Purpose. Amikacin in small unilamellar liposomes (MiKasome®) has prolonged plasma residence (half-life > 24hr) and sustained efficacy in Gram-negative infection models. Since low-clearance liposomes may be subject to a lower rate of phagocytic uptake, we hypothesized this formulation may enhance amikacin distribution to tissues outside the mononuclear phagocyte system.

The pharmacokinetic profiles of amphotericin B (AmB) after administration of Amphocil®, an AmB/cholesteryl sulfate colloidal dispersion (ABCD) and the micellar AmB/deoxycholate (Fungizone®) were compared after repeated dosing in rats. After administration of ABCD and Fungizone at an equal AmB dose (1 mg/kg), AmB concentrations in plasma and most tissues were lower for the ABCD dose, especially in the kidneys where reduced drug concentration correlated with reduced nephrotoxicity. In contrast, AmB concentrations in the liver were substantially higher when ABCD was administered; however, without an accompanying increase in hepato-toxicity. Daily administration of ABCD for 14 days did not lead to AmB accumulation in plasma; while a slight accumulation was observed after multiple administration of Fungizone. AmB was eliminated more slowly from the plasma and various tissues and urinary and fecal recoveries of AmB were reduced after ABCD administration. These results suggest that ABCD may be stored in tissues in a form that is less toxic and is eliminated from the systemic circulation by a different mechanism than the free and protein-bound AmB in plasma. AmB accumulation in the spleen was observed when higher doses of ABCD (5 mg/kg) were administered, which could be due to saturation of hepatic uptake of AmB. Comparison of spleen concentrations of AmB between ABCD and Fungizone® at 5 mg/kg AmB doses was not possible because of Fungizone's toxicity in rats. In all other organs, AmB concentrations reached or approached a steady state within two weeks of dosing with ABCD. Urinary and fecal clearances of AmB were not different between ABCD and Fungizone administration. In summary, the distribution and elimination characteristics of AmB in rats were substantially altered when it was administered as ABCD in comparison to Fungizone. Nephrotoxicity of AmB in rats was reduced after administration of ABCD apparently because of the altered tissue distribution pattern. Thus, ABCD (Amphocil®) may be a clinically beneficial formulation of AmB in patients with systemic fungal infections.

This Phase 1, single-center, double-blind, placebo-controlled, three-period study assessed cardiovascular safety of CX157, a specific Reversible Inhibitor of Monoamine Oxidase A (RIMA), following the oral administration of tyramine. In Period 1, the sensitivity of each subject to orally administered tyramine was established by determining the dose of tyramine that elevates SBP ≥30 mmHg on ≥3 consecutive occasions (i.e., TYR303 ). Twelve subjects qualified for randomization in Period 2 during which an oral CX157 Modified Release Tablet (125 mg [N = 10]) or placebo (N = 2) were administered twice per day for 6 days to reach steady state. In Period 3, CX157 and placebo were administered with oral tyramine in fed state with daily increases in the tyramine dose of 20, 40, and 80 mg in an attempt to achieve the TYR303 . CX157 Modified Release Tablet, 125 mg administered twice per day (250 mg daily dose), was not associated with a tyramine reaction (i.e., TYR303 ). It is generally agreed that a high tyramine meal would contain up to 40 mg of dietary tyramine. These data obtained with CX157 provide an adequate margin of safety with respect to tyramine interaction and suggest that future studies can be conducted without the need for dietary tyramine restrictions.

A sensitive and reproducible high-performance liquid chromatographic method was developed to assay ampherotericin B in plasma, blood, urine and various tissue samples. Amphotericin B was isolated from each sample matrix by solid-phase extraction (Bond-Elut). The eluate from Bond-Elut containing amphotericin B was injected onto a reversed-phase C18 column (Waters, mu Bondpak, 10 microns, 300 mm x 3.9 mm I.D.) with a mobile phase of 45% acetonitrile in 2.5 mM Na2EDTA at 1 ml/min. Detection of amphotericin B was by ultraviolet absorption at 382 nm. Blood and tissues were homogenized and extracted with methanol prior to Bond-Elut extraction. The extraction efficiencies of amphotericin B from plasma, blood and tissues were approximately 90, 70 and 75%, respectively. The sensitivity of the assay was less than or equal to 5 ng/ml for plasma, less than or equal to 25 ng/ml for blood, 2.5 ng/ml for urine and 50 ng/g for tissues. The linearity of the assay method was up to 2.5 micrograms/ml for plasma, 5 micrograms/ml for blood, 500 ng/ml for urine and 500 micrograms/g for tissues. The assay was reproducible with an intra-day coefficient of variation (C.V., n = 3) of less than 5% in general for plasma, blood and tissues. The inter-day C.V. of the assay was less than 5% for plasma (n = 5), less than 10% for blood (n = 4) and less than 5% for tissues (n = 3). The overall variability in the urine assay was generally less than 10%. This method has demonstrated significant improvement in the sensitivity and reproducibility in assaying amphotericin B in plasma and especially in blood, urine and tissues. We have employed this assay to compare the pharmacokinetic and tissue distribution profiles of amphotericin B in rats and dogs following administration of Fungizone and ABCD (amphotericin B-cholesteryl sulfate colloidal dispersion), a lipid-based dosage form. In addition, the assay method for plasma and urine samples can also be applied to pharmacokinetics studies of amphotericin B in man.

Maximum duration of bronchodilator efficacy in inhaled liposome-based formulations depends on optimizing the in vivo release rate of the encapsulated bronchodilator. We investigated the effect of several formulation variables on the pulmonary residence time of 3H-terbutaline sulfate liposomes administered intratracheally in guinea pigs, using an improved method enabling the measurement of pulmonary drug absorption for extended periods of time in conscious animals. Half-lives of liposome-encapsulated 3H-terbutaline disappearance from the lungs and airways after instillation ranged from 1.4 to 18 hr and were markedly affected by liposome size, cholesterol content, and phospholipid composition. This study demonstrates that liposomes can significantly prolong the residence time of bronchodilators in the lungs and that precise control over the pulmonary residence time of encapsulated bronchodilators can be achieved by controlling formulation variables.

Reversible inhibitors of monoamine oxidase-A (RIMA) inhibit the breakdown of three major neurotransmitters, serotonin, norepinephrine and dopamine, offering a multi-neurotransmitter strategy for the treatment of depression. CX157 (3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin-10,10-dioxide) is a RIMA, which is currently in development for the treatment of major depressive disorder. We examined the degree and reversibility of the inhibition of brain monoamine oxidase-A (MAO-A) and plasma CX157 levels at different times after oral dosing to establish a dosing paradigm for future clinical efficacy studies, and to determine whether plasma CX157 levels reflect the degree of brain MAO-A inhibition. Brain MAO-A levels were measured with positron emission tomography (PET) imaging and [(11)C]clorgyline in 15 normal men after oral dosing of CX157 (20-80 mg). PET imaging was conducted after single and repeated doses of CX157 over a 24-h time course. We found that 60 and 80 mg doses of CX157 produced a robust dose-related inhibition (47-72%) of [(11)C]clorgyline binding to brain MAO-A at 2 h after administration and that brain MAO-A recovered completely by 24 h post drug. Plasma CX157 concentration was highly correlated with the inhibition of brain MAO-A (EC(50): 19.3 ng/ml). Thus, CX157 is the first agent in the RIMA class with documented reversible inhibition of human brain MAO-A, supporting its classification as a RIMA, and the first RIMA with observed plasma levels that can serve as a biomarker for the degree of brain MAO-A inhibition. These data were used to establish the dosing regimen for a current clinical efficacy trial with CX157.

The development of Iiposome-based pharmaceuticals has progressed rapidly from the laboratory bench to the point of commercialisation, and several products now undergoing clinical trials are expected to be approved during the next decade. Because of the unique therapeutic opportunities they present, an understanding ofliposomes as drug delivery systems will be important in the optimal management of liposome-based therapies_ This article attempts to address the needs of clinicians and clinical pharmacokineticists by providing an introduction and critical overview ofliposomal drug delivery systems. Additional information is available in the many excellent reviews on the properties, production and therapeutic applications of liposomes (Gregoriadis 1984, 1988; Hwang 1987; Kimelbereg & Mayhew 1978; Lopez-Berestein & Fidler 1989; Papahadjopoulos 1978).

To improve the clinical utility of a potent fungicidal agent, amphotericin B (AB), we developed a novel drug dosage form based on the specific interaction of AB with sterols. AB and sodium cholesteryl sulfate at an equimolar ratio form a thermodynamically stable discoidal complex of uniform size. The therapeutic index of the drug is significantly improved (4–6-fold) as a direct result of the unique physical properties of this colloidal system. This drug/lipid complex does not hemolyze red blood cells, exhibits only low binding to plasma lipoproteins in vitro, alters plasma kinetics and tissue distribution compared to a deoxycholate/AB micellar formulation, and is effective in eradicating fungal infections in vivo.

The pharmacokinetics and tissue distribution of two amphotericin B dosage forms were compared in rats. A novel lipid-based colloidal delivery system for amphotericin B (Amphotericin B Colloidal Dispersion [ABCD]) which reduces the toxicity of amphotericin B in animals was compared with a conventional micellar formulation. Male Sprague-Dawley rats received a single intravenous injection of 1.0 mg of ABCD, 5.0 mg of ABCD, or 1.0 mg of micellar amphotericin B per kg. Plasma and tissue samples were obtained at 0.5 to 96 h after dosing and analyzed for amphotericin B by high-pressure liquid chromatography. Animals receiving ABCD demonstrated reduced peak levels in plasma, a three- to sevenfold reduction in amphotericin B delivery to the kidneys (the major target organ for toxicity), and prolonged residence time compared with those receiving the micellar formulation. In contrast, amphotericin B concentrations in the liver were two- to threefold higher with ABCD than with the micellar formulation: nearly 100% of the amphotericin B administered as ABCD was recovered from the liver 30 min after dosing. These results suggest that the colloidal particles of ABCD are taken up by the liver, which then acts as a reservoir of amphotericin B.

Liposomal aminoglycosides have been shown to have activity against intracellular infections, such as those caused by Mycobacterium avium . Amikacin in small, low-clearance liposomes (MiKasome) also has curative and prophylactic efficacies against Pseudomonas aeruginosa and Klebsiella pneumoniae . To develop appropriate dosing regimens for low-clearance liposomal amikacin, we studied the pharmacokinetics of liposomal amikacin in plasma, the level of exposure of plasma to free amikacin, and urinary excretion of amikacin after the administration of single-dose (20 mg/kg of body weight) and repeated-dose (20 mg/kg eight times at 48-h intervals) regimens in rhesus monkeys. The clearance of liposomal amikacin (single-dose regimen, 0.023 ± 0.003 ml min −1 kg −1 ; repeated-dose regimen, 0.014 ± 0.001 ml min −1 kg −1 ) was over 100-fold lower than the creatinine clearance (an estimate of conventional amikacin clearance). Half-lives in plasma were longer than those reported for other amikacin formulations and declined during the elimination phase following administration of the last dose (from 81.7 ± 27 to 30.5 ± 5 h). Peak and trough (48 h) levels after repeated dosing reached 728 ± 72 and 418 ± 60 μg/ml, respectively. The levels in plasma remained >180 μg/ml for 6 days after the administration of the last dose. The free amikacin concentration in plasma never exceeded 17.4 ± 1 μg/ml and fell rapidly (half-life, 1.47 to 1.85 h) after the administration of each dose of liposomal amikacin. This and the low volume of distribution (45 ml/kg) indicate that the amikacin in plasma largely remained sequestered in long-circulating liposomes. Less than half the amikacin was recovered in the urine, suggesting that the level of renal exposure to filtered free amikacin was reduced, possibly as a result of intracellular uptake or the metabolism of liposomal amikacin. Thus, low-clearance liposomal amikacin could be administered at prolonged (2- to 7-day) intervals to achieve high levels of exposure to liposomal amikacin with minimal exposure to free amikacin.

The introduction of aminoglycoside antibiotics in the mid-twentieth century led to dramatic changes in the treatment of tuberculosis followed by improved therapy of the emerging problem of Gram-negative bacterial infections. Clinical experience soon revealed that although the aminoglycosides possess a wide spectrum of antimicrobial activity, they may also produce serious, dose-related damage to the kidneys and the auditory/vestibular apparatus. As a result, aminoglycosides require therapeutic drug monitoring to maintain their plasma concentrations within a narrow therapeutic window, and aminoglycosides are now often reserved for the most severe infections despite their excellent antimicrobial properties.

A genetically engineered recombinant human hemoglobin (rHb1.1) was recently developed for use as a blood substitute (Nature 1992;356:258-60). Like other mammalian hemoglobin (Hb) molecules, it might bind and antagonize the actions of nitric oxide (NO). We used an isolated rabbit aortic ring preparation to examine the ability of rHb1.1 to inhibit acetylcholine (ACh)- and interleukin-1 beta (IL-1 beta)-induced reductions of vasoconstrictor responses to the alpha-adrenoceptor agonist phenylephrine (PE). rHb1.1 (0.04-4.4 microM) rapidly and reversibly inhibited, in a concentration-dependent manner, both ACh- and IL-1 beta-induced decreases in PE contractile responses. These inhibitory effects of rHb1.1 were non-competitive and were equipotent to those of purified, cell-free human Hb (p.hHb). These two forms of soluble Hb were at least 10 times more potent than Hb in erythrocytes (red blood cells: RBC-Hb). Both NG-nitro-L-arginine (10 microM) a NO synthase inhibitor, and LY-83583 (10 microM), a guanylyl cyclase inhibitor, mimicked the effects of rHb1.1. The inhibitory effects of rHb1.1 were not shared by either human serum albumin (HSA 44 microM), which combines with but does not deactivate NO, or cytochrome C (44 microM), a heme-containing protein that does not bind NO; neither were they reversed by L-arginine (L-ARG) (1 mM), the presumed NO precursor. These and other results suggest that the chemical antagonism of NO is likely to be the mechanism by which rHb1.1 and other Hbs inhibit ACh- and IL-1 beta-induced decreases in the response to PE in rabbit aortic rings.