In vivo and in vitro assessment of mirtazapine pharmacokinetics in cats with liver disease.

BACKGROUND: Liver disease (LD) prolongs mirtazapine half-life in humans, but it is unknown if this occurs in cats with LD and healthy cats. HYPOTHESIS/OBJECTIVES: To determine pharmacokinetics of administered orally mirtazapine in vivo and in vitro (liver microsomes) in cats with LD and healthy cats. ANIMALS: Eleven LD and 11 age-matched control cats. METHODS: Case-control study. Serum was obtained 1 and 4 hours (22 cats) and 24 hours (14 cats) after oral administration of 1.88 mg mirtazapine. Mirtazapine concentrations were measured by liquid chromatography with tandem mass spectrometry. Drug exposure and half-life were predicted using limited sampling modeling and estimated using noncompartmental methods. in vitro mirtazapine pharmacokinetics were assessed using liver microsomes from 3 LD cats and 4 cats without LD. RESULTS: There was a significant difference in time to maximum serum concentration between LD cats and control cats (median [range]: 4 [1-4] hours versus 1 [1-4] hours; P = .03). The calculated half-life of LD cats was significantly prolonged compared to controls (median [range]: 13.8 [7.9-61.4] hours versus 7.4 [6.7-9.1] hours; P < .002). Mirtazapine half-life was correlated with ALT (P = .002; r = .76), ALP (P < .0001; r = .89), and total bilirubin (P = .0008; r = .81). The rate of loss of mirtazapine was significantly different between microsomes of LD cats (-0.0022 min-1 , CI: -0.0050 to 0.00054 min-1 ) and cats without LD (0.01849 min-1 , CI: -0.025 to -0.012 min-1 ; P = .002). CONCLUSIONS AND CLINICAL IMPORTANCE: Cats with LD might require less frequent administration of mirtazapine than normal cats.

Single and multiple dose pharmacokinetics of a novel mirtazapine transdermal ointment in cats.

Single and multiple dose pharmacokinetics (PK) of mirtazapine transdermal ointment applied to the inner ear pinna of cats were assessed. Study 1 was a randomized, cross-over single dose study (n = 8). Cats were treated once with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner ear pinna (treatment) or administered orally (control) and then crossed over after washout. Plasma was collected predose and at specified intervals over 96 hr following dosing. Study 2 was a multiple dose study (n = 8). Cats were treated daily for 14 days with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner pinna. Plasma was collected on Day 13 predose and at specified intervals over 96 hr following the final dose. In Study 1, single transdermal administration of mirtazapine resulted in mean Tmax = 15.9 hr, Cmax = 21.5 ng/mL, AUC0-24 = 100 ng*hr/mL, AUC0-∞ = 260 ng*hr/mL and calculated half-life = 26.8 hr. Single oral administration of mirtazapine resulted in mean Tmax = 1.1 hr, Cmax = 83.1 ng/mL, AUC0-24 = 377 ng*hr/mL, AUC0-∞ = 434 ng*hr/mL and calculated half-life = 10.1 hr. Mean relative bioavailability (F) of transdermal to oral dosing was 64.9%. In Study 2, daily application of mirtazapine for 14 days resulted in mean Tmax = 2.1 hr, Cmax = 39.6 ng/mL, AUC0-24 = 400 ng*hr/mL, AUC0-∞ = 647 ng*hr/mL and calculated half-life = 20.7 hr. Single and repeat topical doses of a novel mirtazapine transdermal ointment achieve measurable plasma concentrations in cats.

Fabrication of Eudragit polymeric nanoparticles using ultrasonic nebulization method for enhanced oral absorption of megestrol acetate.

Megestrol acetate (MGA) is used as a progestagen to treat advanced cancers in the breast or uterus and anorexia-cachexia syndrome in cancer patients. Due to its low solubility (BCS class II), MGA bioavailability needs to be enhanced for efficacy and safety. We developed MGA-encapsulated Eudragit® L100 (EUD) nanoparticles (MGA-EUD (1:1) and MGA-EUD (2:1)) using an ultrasonic nebulization method. MGA-EUD (1:1) and MGA-EUD (2:1) consisted of MGA and EUD at the mass ratios of 1:1 and 2:1. Their physicochemical properties, i.e. particle size, loading efficiency, morphology, and crystallinity were determined. Dissolution tests were performed using USP method II. For pharmacokinetics, they were orally administered at 50 mg/kg to mice. Microcrystalline MGA suspension (MGA-MC, Megace®, BMS) was used as control. MGA-EUD (1:1) and MGA-EUD (2:1) had a smooth and spherical shape of 0.70 and 1.05 µm in diameter with loading efficiencies of 93 and 95% showing amorphous states of MGA. They significantly enhanced the dissolution potential of MGA. Oral bioavailability of MGA-EUD (1:1) and MGA-EUD (2:1) increased 2.0- and 1.7-fold compared to that of MGA-MC. It suggests that ultrasonic nebulization method for the fabrication of polymeric nanoparticles is a promising approach to improve the bioavailability of poorly soluble drugs.

Quantitative Assessment of Food Effect on the Pharmacokinetics of Nano-Crystallized Megestrol Acetate.

Megestrol acetate, an appetite stimulant with low bioavailability, shows increased bioavailability when taken together with food. However, the pharmacokinetic characteristics of megestrol acetate and its relation with food are not well understood. This study aimed to investigate the food effect on the pharmacokinetics (PK) of the recently developed nano-crystallized megestrol acetate (NCMA), using a model-based approach. Data were obtained from an NCMA PK study consisting of a single dose in fasting (39 individuals) and fed conditions (40 individuals). Plasma concentrations were measured up to 120 hr after dosing. With the incorporation of body-weight via allometry, NONMEM 7.3 was used to develop a PK model, which was then used to simulate an optimal fasting dose yielding an area under concentration (AUC) and maximum concentration (Cmax ) of NCMA close to those obtained with the fed dose. NCMA concentrations were best characterized by a two-compartment model with first-order absorption linked to a recycling compartment to account for the multiple concentration peaks observed. Food increased bioavailability 2.2 times and decreased the absorption rate constant 0.58 times. Recycling event times were estimated to be 3.56, 7.99 and 24.0 hr. The optimal fast dose was 2.0 times higher than the fed dose, and the resulting difference in drug exposure between the fasting and fed dose was 7.5%. This work suggests that the PK model developed can be applied to an optimal dosage regimen design for NCMA treatment.

Pharmacokinetics of a nanocrystal-containing megestrol acetate formulation: a single-dose, randomized, open-label, 2-part, 2-period crossover study in healthy Korean subjects.

UNLABELLED: OBJECTIVE: The conventional suspension of megestrol acetate contains micronized megestrol acetate, which was recently discovered to have a disadvantage of decreasing bioavailability when taken in a fasting state. Since megestrol acetate is taken to increase appetite, this property becomes a discouraging factor. To improve upon this, an advanced formulation was developed using a nanocrystal drug-delivery system. This study was conducted to compare the safety and pharmacokinetic characteristics between the conventional formulation of megestrol acetate and a generic version of the advanced formulation containing nanocrystals. METHODS: This was a randomized, open-label, 2-period, 2-treatment, crossover, single-dose, 2-part study (part 1 fasting and part 2 fed), conducted in healthy males aged between 20 and 50 years with weight within ± 20% of ideal body weight having no congenital abnormalities or chronic diseases. Different subjects were used in part 1 and part 2, but subjects received a single dose of the reference and test drugs separated by a 14-day washout period. Blood sampling was performed up to 120 hours after dosing using a pre-specified sampling time scheme. Primary pharmacokinetic parameters were C_max and AUC_last of the test and reference formulations of megestrol acetate. Bioequivalence evaluation was based on the standard criterion of 80 - 125% for the 90% confidence interval of geometric mean ratios of test to reference drugs calculated for the pharmacokinetic parameters. To monitor adverse events, both subject interviews and physical examinations were done on a regular time basis. RESULTS: 80 subjects (n = 40 each part) were enrolled, and 79 completed the study. The 90% CIs of the geometric mean ratios of C_max and AUC_last were 4.4625 - 5.6018 and 1.3602 - 1.6418, respectively, for part 1, and 0.9793 - 1.1327 and 0.7721 - 0.8431, respectively, for part 2. No significant difference was discovered in the incidence of adverse events (AEs) when test and reference treated groups were compared. CONCLUSIONS: Our findings suggest that the test formulation of megestrol-acetate-containing nanocrystals is better absorbed and has higher bioavailability compared to the reference formulation in a fasting state. This should allow for a lower dose and better patient compliance.

ClinicalTrials.gov identifier: NCT02446353.

Tolerability and pharmacokinetics of two formulations of megestrol acetate under fed conditions in healthy volunteers.

PURPOSE: Megestrol acetate oral suspension is an appetite stimulant indicated for cachexia. It is available in a conventional formulation and as a nanocrystal dispersion. The aim of this study was to compare the tolerability and pharmacokinetics of these formulations under fed conditions in healthy Korean volunteers. METHODS: This was a randomized, single-dose, 3-treatment, 3-period, 6-sequence, crossover study in healthy Korean volunteers. In each period, participants received single oral doses of conventional formulation 800 mg/20 mL (reference), nanocrystal dispersion 650 mg/5.2 mL (test 1), and nanocrystal dispersion 675 mg/5.4 mL (test 2) after a high-calorie, high-fat meal. The periods were separated by a washout period of 14 days. Serial blood samples were collected up to 120 hours after dosing. The plasma concentrations of megestrol acetate were determined with a validated LC-MS/MS method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability was assessed by physical examinations, vital signs, clinical laboratory test results, and electrocardiograms. FINDINGS: Thirty-eight healthy volunteers completed the study. The geometric mean ratios of the AUC(last) and C(max) for test 1/reference were 0.88 (90% CI, 0.84-0.92) and 1.07 (90% CI, 0.99-1.15), respectively. The geometric mean ratios of the AUC(last) and C(max) for test 2/reference were 0.88 (90% CI, 0.84-0.93) and1.03 (90% CI, 0.96-1.10), respectively. All formulations were well tolerated. IMPLICATIONS: The pharmacokinetic characteristics and tolerability of the 2 megestrol acetate formulations are similar in fed volunteers and suggest no relevant difference in tolerability. ClinicalTrials.gov identifier: NCT01342055.

Ghrelin agonist JMV 1843 increases food intake, body weight and expression of orexigenic neuropeptides in mice.

Ghrelin and agonists of its receptor GHS-R1a are potential substances for the treatment of cachexia. In the present study, we investigated the acute and long term effects of the GHS R1a agonist JMV 1843 (H Aib-DTrp-D-gTrp-CHO) on food intake, body weight and metabolic parameters in lean C57BL/6 male mice. Additionally, we examined stability of JMV 1843 in mouse blood serum. A single subcutaneous injection of JMV 1843 (0.01-10 mg/kg) increased food intake in fed mice in a dose-dependent manner, up to 5-times relative to the saline-treated group (ED(50)=1.94 mg/kg at 250 min). JMV 1843 was stable in mouse serum in vitro for 24 h, but was mostly eliminated from mouse blood after 2 h in vivo. Ten days of treatment with JMV 1843 (subcutaneous administration, 10 or 20 mg/kg/day) significantly increased food intake, body weight and mRNA expression of the orexigenic neuropeptide Y and agouti-related peptide in the medial basal hypothalamus and decreased the expression of uncoupling protein 1 in brown adipose tissue. Our data suggest that JMV 1843 could have possible future uses in the treatment of cachexia.

Indolyl and dihydroindolyl N-glycinamides as potent and in vivo active NPY5 antagonists.

A novel series of indolyl and dihydroindolyl glycinamides were identified as potent NPY5 antagonists with in vivo activity from screen hit 1. The dihydroindolyl glycinamide 10a significantly inhibits NPY5 agonist induced feeding at a dose of 0.1 mg/kg. The indolyl glycinamide 12c also inhibits NPY5 agonist induced feeding at a dose of 1 mg/kg. Both compounds 10a and 12c represent potential tools for further investigation into the biology of the NPY5 receptor.

The pharmacokinetics of mirtazapine in cats with chronic kidney disease and in age-matched control cats.

BACKGROUND: Cats with chronic kidney disease (CKD) often experience inappetence, and may benefit from administration of mirtazapine, an appetite stimulant. The pharmacokinetics of mirtazapine in CKD cats is unknown. HYPOTHESIS: CKD delays the clearance/bioavailability (CL/F) of mirtazapine. ANIMALS: Six CKD cats and 6 age-matched controls (AMC) were enrolled. Two CKD cats each from International Renal Interest Society (IRIS) stage II, III and IV were included. METHODS: Blood samples were collected before and 0.5, 1, 1.5, 2, 4, 8, 24, and 48 hours after a single PO dose of 1.88 mg of mirtazapine. Mirtazapine concentrations were measured by liquid chromatography coupled to tandem mass spectrometry. Non-compartmental pharmacokinetic modeling was performed. RESULTS: Mean age was 11 years (CKD cats) and 10.8 years (AMC cats). Mean serum creatinine concentration ± standard deviation (SD) was 3.8 ± 1.6 mg/dL (CKD) and 1.3 ± 0.4 mg/dL (AMC). Mean half-life ± SD was 15.2 ± 4.2 hours (CKD) and 12.1 ± 1.1 hours (AMC). Mean area under the curve (AUC) ± SD was 770.6 ± 225.5 ng/mL•hr (CKD) and 555.5 ± 175.4 ng/mL•hr (AMC). Mean CL/F ± SD was 0.6 ± 0.1 L/hr/kg (CKD) and 0.8 ± 0.16 L/hr/kg (AMC). A Mann-Whitney test indicated statistically significant differences in AUC (P = 0.01) and CL/F (P = 0.04) between groups. Calculated accumulation factor for 48-hour dosing in CKD cats was 1.15. CONCLUSION: CKD may delay the CL/F of mirtazapine. A single low dose of mirtazapine resulted in a half-life compatible with a 48-hour dosing interval in CKD cats.

Studies on the pharmacokinetics and pharmacodynamics of mirtazapine in healthy young cats.

Mirtazapine pharmacokinetics was studied in 10 healthy cats. Blood was collected before, and at intervals up to 72 h after, oral dose of 3.75 mg (high dose: HD) or 1.88 mg (low dose: LD) of mirtazapine. Liquid chromatography coupled to tandem mass spectrometry was used to measure mirtazapine, 8-hydroxymirtazapine and glucuronide metabolite concentrations. Noncompartmental pharmacokinetic modeling was performed. Median half-life was 15.9 h (HD) and 9.2 h (LD). Using Mann-Whitney analysis, a statistically significant difference between the elimination half-life, clearance, area under the curve (AUC) per dose, and AUC(∞) /dose of the groups was found. Mirtazapine does not appear to display linear pharmacokinetics in cats. There was no significant difference in glucuronidated metabolite concentration between groups. Pharmacodynamics was studied in 14 healthy cats administered placebo, LD and HD mirtazapine orally once in a crossover, blinded trial. In comparison with placebo, cats ingested significantly more food when mirtazapine was administered. No difference in food ingestion was seen between HD and LD, but significantly more behavior changes were seen with the HD. Limited serum sampling during the pharmacodynamic study revealed drug exposure comparable with the pharmacokinetic study, but no correlation between exposure and food consumed. Mirtazapine (LD) was administered daily for 6 days with no drug accumulation detected.

Food effect on the bioavailability of two distinct formulations of megestrol acetate oral suspension.

OBJECTIVE: Megestrol acetate oral suspension (MAOS) is an appetite stimulant indicated for cachexia in patients with AIDS. It is available in its original formulation, Megace (MAOS), and as a nanocrystal dispersion, Megace ES (MA-ES). Three studies were conducted to evaluate the pharmacokinetic properties of these formulations under fed and fasting conditions. METHODS: An open-label, crossover trial was conducted in 24 healthy males randomized to MA-ES 625 mg/5 mL given with a high-calorie, high-fat meal, or after an overnight fast. Blood samples were drawn at multiple time points and pharmacokinetic parameters were determined. Two separate, open-label reference studies evaluated MAOS 800 mg/20 mL in 40 fed or 40 fasting healthy male volunteers. RESULTS: In fasting MA-ES subjects, the average maximum concentration (C(max)) was 30% less than the fed C(max) value. For MAOS, fasting C(max) was 86% less than fed C(max). In fasting subjects, the area under the curve was 12,095 ng.h/mL for MA-ES, and 8,942 ng.h/mL for MAOS. In fed subjects, the absorption of the two formulations was comparable. CONCLUSION: Bioavailability and absorption are greater for MA-ES than MAOS in fasting subjects. MA-ES may be a preferred formulation of megestrol acetate when managing cachectic patients whose caloric intake is reduced.

Pharmacokinetic interaction of megestrol acetate with zidovudine in human immunodeficiency virus-infected patients.

This nonrandomized, two-period crossover study was performed to assess whether concomitant administration of megestrol acetate influences the steady-state pharmacokinetics of zidovudine and its inactive 5'-O-glucuronide metabolite. Twelve HIV-positive, asymptomatic male volunteers received a 100-mg oral capsule dose of zidovudine at least 30 min before meals five times a day at 0700, 1100, 1500, 1900, and 2300 h on study days 1 to 3 and a single 100-mg dose at 0700 h on day 4. On days 5 to 17, 800 mg of megestrol acetate, as a 40-mg/ml aqueous suspension, was administered orally immediately before the 0700 h dose of zidovudine. On days 5 to 16, zidovudine was also administered at 1100, 1500, 1900, and 2300 h. Serial blood samples were collected for 12 h after the single 100-mg dose of zidovudine on days 4 and 17; trough samples were also obtained just before the 0700 h dose on days 2 to 4 and 15 to 17. Levels of zidovudine and its glucuronide in plasma were assayed by a validated radioimmunoassay. Statistical analysis of trough plasma level data indicated that steady-state levels of zidovudine and its glucuronide in plasma had been attained when pharmacokinetic assessments were made on days 4 and 17. When megestrol acetate and zidovudine were coadministered for 13 days, differences of -14, -6.5, and -4.6% in mean zidovudine peak concentration and areas under the curve at 0 to 4 and 0 to 12 h, respectively, +22.5% in mean trough concentration, +2.6% in mean plasma half-life, and no change in median time to peak were observed compared to conditions when zidovudine was administered alone; for zidovudine 5'-O-glucuronide the respective differences were -9, -7.3, -4.4, +2.3, and +10% and no change. None of the differences were statistically significant (P > 0.05). Concomitant therapy with megestrol acetate, at the dose employed to treat anorexia, cachexia, or an unexplained, significant weight loss in AIDS patients, did not alter the steady-state pharmacokinetics of zidovudine or its 5'-O-glucuronide metabolite.