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Posaconazole

Posaconazole is a triazole antifungal medication used to prevent and treat invasive fungal infections.
It is effective against a wide range of fungal pathogens, including Aspergillus, Candida, and Zygomycetes.
Posaconazole works by inhibiting the fungal enzyme lanosterol 14-alpha-demethylase, which is essential for the biosynthesis of ergosterol, a key component of the fungal cell membrane.
This disruption of the cell membrane leads to fungal cell death or growth inhibition.
Posaconazole is often used in immunocompromised patients, such as those with cancer or organ transplants, who are at high risk of developing serious fungal infections.
It is available in oral tablet, suspension, and intravenous formulations, and its pharmacokinetics and dosing regimens have been extensively studied.
Careful monitoring of posaconazole levels is important to ensure efficacy and minimize the risk of adverse effects.

Most cited protocols related to «Posaconazole»

1
Estimating Gut Drug Concentrations
Cited 7 times
We annotated drugs by their primary target organism on the basis of their WHO Anatomical Therapeutic Chemical (ATC) classification, or, if there were uncertainties, based on manual annotation. Compounds were classified as: antibacterial drugs (antibiotics, antiseptics), anti-infective drugs (acting against protozoa, fungi, parasites or viruses), human-targeted drugs (i.e. drugs whose mechanism of action affects human cells), veterinary drugs (used exclusively in animals), and finally non-drugs (which can be drug metabolites, drugs used only in research, or endogenous substances). If a human-use drug belonged to several classes, the drug class was picked according to this order of priority (from high to low): antibacterial, anti-infective, and human-targeted drug. This ensured that drugs used also as antibacterials were not classified in the other two categories.
Drugs from the Prestwick Chemical Library were matched against STITCH 4 identifiers 52 (link) using CART 53 (link). Identifiers that could not be mapped were annotated manually. Information about drug indications, dose and administration was extracted from the ATC classification system and Defined Daily Dose (DDD) database. Dose and administration data were also extracted from the Drugs@FDA resource. Doses that were given in grams were converted to mol using the molecular weight stated in the Prestwick library information files. When the dose guidelines mentioned salt forms, we manually substituted the molecular weight. Dose data from Drugs@FDA stated the amount of drug for a single dose (e.g. a single tablet). Analyzing the intersection between Drugs@FDA and DDD, we found that the median ratio between the single and daily doses is two. To combine the two datasets we therefore estimated the single dose as half of the daily dose (Supplementary Table 1).
In general, it is difficult to estimate effective drug concentrations in intestine, since those depend on the dose, the speed of dissolution, uptake and metabolization by human cells and by bacteria, binding to proteins, and excretion mechanisms into the gut. To estimate gut concentrations of drugs based on their dose with a simple model, we relied on an in situ study for posaconazole 19 (link). When 40 mg (57 μmol) of the drug are delivered to the stomach in either an acidic or neutral solution, the maximum concentration in the duodenum reaches 26.3 ± 10.3 and 13.6 ± 5.8 μM, respectively. This is equivalent to dissolving the drug in 300 ml (240 ml of water to swallow the pill as recommended for bioavailability/bioequivalence studies plus ~43 ml resting water in small intestine 54 (link)) and an absorption rate of 90%. We collected doses for as many human-targeted drugs as we could find and used the above assumption to estimate small intestine concentrations. To estimate colon concentrations, we relied on reported fecal excretion data (Supplementary Table 1, gathered from DrugBank 5.0 55 (link) and across the literature) assumed a single daily dose, 24 h transit time 56 (link) and a volume of distribution in the colon of 0.6 litres 57 (link) (ED Fig. 3).
Maier L., Pruteanu M., Kuhn M., Zeller G., Telzerow A., Anderson E.E., Brochado A.R., Fernandez K.C., Dose H., Mori H., Patil K.R., Bork P, & Typas A. (2018). Extensive impact of non-antibiotic drugs on human gut bacteria. Nature, 555(7698), 623-628.
Publication 2018
2
Antiparasitic Drug Treatment in Mice
Cited 4 times
For drug treatment, benznidazole (Hoffmann-La Roche AG) was prepared from powder at 10 mg/ml in 7% Tween 80, 3% ethanol (vol/vol), and 90% (vol/vol) water. Posaconazole (Sequoia Research Products, Ltd.) was prepared at 2 mg/ml in 5% (vol/vol) dimethyl sulfoxide and 95% (vol/vol) HPMC-SV (0.5% [wt/vol] hydroxypropyl methylcellulose, 0.5% [vol/vol] benzyl alcohol and 0.4% [vol/vol] Tween 80). Noxafil (MSD, Ltd.), a liquid formulation of posaconazole (40 mg/ml), was diluted to 2 mg/ml in water. Mice were treated with standard doses of benznidazole (100 mg/kg/day) or posaconazole (20 mg/kg/day) by oral gavage for consecutive days, as required. To facilitate the detection of residual infection after treatment, BALB/c mice were immunosuppressed in some experiments with cyclophosphamide (200 mg/kg) by i.p. injection at 3- to 4-day intervals, for a maximum of three doses.
Francisco A.F., Lewis M.D., Jayawardhana S., Taylor M.C., Chatelain E, & Kelly J.M. (2015). Limited Ability of Posaconazole To Cure both Acute and Chronic Trypanosoma cruzi Infections Revealed by Highly Sensitive In Vivo Imaging. Antimicrobial Agents and Chemotherapy, 59(8), 4653-4661.
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Publication 2015
benznidazole Benzyl Alcohol Cyclophosphamide Ethanol Hypromellose Infection Mice, House Mice, Inbred BALB C Noxafil Pharmaceutical Preparations posaconazole Powder Sequoia Sulfoxide, Dimethyl Tube Feeding Tween 80
3
Antifungal Susceptibility Testing of Clinical Isolates
Cited 4 times
All yeast isolates were tested for in vitro susceptibility to fluconazole, isavuconazole, posaconazole, and voriconazole using CLSI (68 ) BMD methods. MIC results for all agents were read after 24 h of incubation, when the agents were tested against Candida spp., whereas MIC results were read after 48 h, when the agents were tested against non-Candida yeasts. MIC values were determined visually as the lowest concentration of drug that caused significant (≥50%) growth diminution levels relative to the growth control (69 , 70 ).
In vitro susceptibility testing of Aspergillus spp., members of the Mucorales order, and other molds against the triazoles (isavuconazole, itraconazole, posaconazole, and voriconazole) was performed by BMD as described in CLSI document M38-A2 (69 ). For Aspergillus spp., the MICs for isavuconazole and comparators were read as 100% inhibition of growth after 48 h of incubation at 35°C. Against the Mucorales isolates, MICs for isavuconazole and comparators were also read at 100% inhibition of growth, but after 24 h of incubation.
We used the revised species-specific CLSI CBPs to identify strains of the 6 most common species of Candida (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, and C. guilliermondii) that were susceptible and resistant to fluconazole and voriconazole (70 , 71 (link)). All C. krusei isolates were defined as resistant to fluconazole. CLSI has not assigned CBPs for voriconazole and C. glabrata and recommends the ECV of 0.5 μg/ml to be used to differentiate WT (MIC ≤ ECV) from non-WT (MIC > ECV) strains of this species (54 , 71 (link)).
CBPs have not been established for isavuconazole or posaconazole and the common species of Candida or for any antifungal agent and the less common species of Candida, non-Candida yeasts, Aspergillus spp., or the non-Aspergillus molds; however, ECVs have been proposed for the triazoles (fluconazole, posaconazole, and voriconazole) and 6 Candida species that are encountered less frequently (C. lusitaniae, C. guilliermondii, C. dubliniensis, C. kefyr, C. orthopsilosis, and Candida pelliculosa) (54 , 71 (link), 72 (link)). ECVs have also been developed for A. fumigatus, A. flavus, A. terreus, A. nidulans, and A. niger and isavuconazole, itraconazole, posaconazole, and voriconazole (50 (link), 54 , 73 (link)): isavuconazole, itraconazole, and voriconazole MIC values of >1 μg/ml were considered non-WT for A. fumigatus, A. flavus, and A. terreus, and itraconazole and posaconazole MIC values of >1 μg/ml and voriconazole MIC values of >2 μg/ml were considered non-WT for A. nidulans. Posaconazole MIC values of >0.25 μg/ml were considered non-WT for A. fumigatus and A. flavus, and MIC results of > 0.5 μg/ml were non-WT for A. niger and A. terreus; isavuconazole MIC values of >1 μg/ml were non-WT for A. nidulans, and MIC values of >4 μg/ml were non-WT for A. niger. Isolates of these Aspergillus spp. for which triazole MIC results exceed the ECV are considered to be non-WT and may harbor acquired mutations in the cyp51A gene (74 (link), 75 (link)).
Among the Mucorales, there are no CBPs, and ECVs have only been proposed for posaconazole and L. corymbifera (2 μg/ml), M. circinelloides (4 μg/ml), R. arrhizus (2 μg/ml), and R. microsporus (2 μg/ml) and for itraconazole and R. arrhizus (2 μg/ml) (53 (link)).
Quality control was performed as recommended in CLSI documents M27-A3 (68 ) and M38-A2 (69 ) using strains C. krusei ATCC 6258, C. parapsilosis ATCC 22019, A. flavus ATCC 204304, and A. fumigatus MYA-3626.
Pfaller M.A., Rhomberg P.R., Wiederhold N.P., Gibas C., Sanders C., Fan H., Mele J., Kovanda L.L, & Castanheira M. (2018). In Vitro Activity of Isavuconazole against Opportunistic Fungal Pathogens from Two Mycology Reference Laboratories. Antimicrobial Agents and Chemotherapy, 62(10), e01230-18.
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Publication 2018
4
Antifungal Susceptibility Testing of Aspergillus
Cited 4 times
The in vitro activity of all the standard azole antifungals was investigated using CLSI M38-A2 broth microdilution [36] . A total of 53 itraconazole resistant A. fumigatus isolates (44 ITC+ environmental and 9 ITC+ clinical) were subjected to AFST. Nine itraconazole resistant clinical isolates were cultured from patients suspected of bronchopulmonary aspergillosis. Among the 9 ITC+ A. fumigatus clinical isolates two have been reported earlier [22] (link). In addition, 35 itraconazole susceptible A. fumigatus isolates comprising 22 randomly selected wild type environmental and 13 azole susceptible clinical A. fumigatus isolates cultured from patients of suspected bronchopulmonary aspergillosis were included as controls. The drugs tested included itraconazole (ITC, Lee Pharma, Hyderabad, India, and Janssen Research Foundation, Beerse, Belgium), voriconazole (VRC, Pfizer Central Research, Sandwich, Kent, United Kingdom) and posaconazole (POS, Schering-Plough, Kenilworth, NJ, USA, now Astellas). For the broth microdilution test, RPMI 1640 medium with glutamine without bicarbonate (Sigma-Aldrich, St Louis, MO, USA) buffered to pH 7 with 0.165 M 3-N-morpholinepropanesulfonic acid (Sigma) was used. Isolates were grown on potato dextrose agar for 5 days at 28°C and the inoculum was adjusted to a final density of 0.5–2.5 x 104 cfu/ml by measuring 0.09–0.13 OD at 540 nm using spectrophotometer. The final concentrations of the drugs were 0.03 to 16 mg/L for itraconazole and voriconazole and 0.015 to 8 mg/L for posaconazole. Drug-free and mould-free controls were included and microtitre plates were incubated at 35°C for 48 h. CLSI recommended quality control strains, Candida krusei, ATCC6258 and Candida parapsilosis, ATCC22019 and reference strains Aspergillus fumigatus, ATCC204305 and Aspergillus flavus, ATCC204304 were included. The MIC end points were read visually which, for azoles were defined as the lowest concentration at which there was 100% inhibition of growth compared with the drug-free control wells. A. fumigatus isolates with high itraconazole MICs were tested twice on different days. Azole resistance was defined for itraconazole, >2 mg/L, voriconazole, >2 mg/L, and posaconazole, >0.5 mg/L as proposed by Verweij et al. [37] (link).
Chowdhary A., Kathuria S., Xu J., Sharma C., Sundar G., Singh P.K., Gaur S.N., Hagen F., Klaassen C.H, & Meis J.F. (2012). Clonal Expansion and Emergence of Environmental Multiple-Triazole-Resistant Aspergillus fumigatus Strains Carrying the TR34/L98H Mutations in the cyp51A Gene in India. PLoS ONE, 7(12), e52871.
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Publication 2012
Acids Agar Antifungal Agents Aspergillus flavus Aspergillus fumigatus Azoles Bicarbonates Bronchopulmonary Aspergillosis Candida parapsilosis Fungus, Filamentous Glucose Glutamine Itraconazole Minimum Inhibitory Concentration Patients Pharmaceutical Preparations Pichia kudriavzevii posaconazole Psychological Inhibition Solanum tuberosum Strains Voriconazole
5
Screening for Anti-Amoebic Compounds
Cited 4 times
The phenotypic drug susceptibility assays were performed as previously described using CellTiter-Glo v2.0 (CTG) (Promega, Madison, WI)44,49,63. The ReFrame collection of 12,000 compounds assembled at Calibr–Scripps were prepared in 384-well (Corning, White Flat bottom 3570) plate format at screening concentrations of 5μM (30nL of 10mM stock concentration/well in dimethylsulfoxide (DMSO)) using the Labcyte Echo 555 for acoustic compound dispensing. The first round was to screen in a single-point assay with 3,000 Naegleria/well, 600 Acanthamoeba/well or 4,000 Balamuthia/well in a total volume of 60μl. Prior to initiating drug screening, a maximum of 2% total hits from the library were predetermined for follow up from Calibr-Scripps for all screening projects. Drug spotted plates from Calibr-Scripps were left, at room temperature, to thaw overnight and parasites were plated using the Biomek NXp automated liquid handler (Beckman Coulter). Hits were defined as compounds that produced > -40% (for Naegleria) or > -50% (for Acanthamoeba and Balamuthia) of normalized growth inhibition compared to the negative growth control (0.5% DMSO) and positive controls that produced ~100% inhibition of amoebae cell populations. Posaconazole, azithromycin and DB2385A all at 1μM were used for controls for Naegleria and Acanthamoeba; artovastatin, fluvastatin and simvastatin all at 1μM were used as controls for Balamuthia. The second round was to verify the initial active hits from round I, hits were identified and serially diluted in duplicate from 5μM to 2nM in a 1:3, 8 point dilution series in 384-well plates with the same number of amoebae for Naegleria, Acanthamoeba and Balamuthia with the exact same controls and concentrations for each respective amoebae to generate the concentration for half-maximal activity derived from the hill equation model (qAC50). Dose-response curve fitting was analysed with Genedata Analyser software using the Smart Fit function. All assayed plates were incubated at the genus optimum growth temperature described above and tested for a period of 72 hours.
Rice C.A., Colon B.L., Chen E., Hull M.V, & Kyle D.E. (2020). Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae. PLoS Neglected Tropical Diseases, 14(9), e0008353.
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Publication 2020
Acanthamoeba Acoustics Amoeba Azithromycin cDNA Library Cells ECHO protocol Fluvastatin Naegleria Parasites Pharmaceutical Preparations Phenotype Population Group posaconazole Promega Psychological Inhibition Simvastatin Sulfoxide, Dimethyl Susceptibility, Disease Technique, Dilution

Most recents protocols related to «Posaconazole»

1
Posaconazole Solubilization Formulation Development
Not available on PMC !
About 10 formulation trials of posaconazole solution were designed based on solubility profile of posaconazole drug and its compatibility with the excipients as shown in table 1. The water for injection (80 %), purged nitrogen to achieve the dissolved oxygen content of 2 ppm or less. Continued nitrogen purging throughout the batch manufacturing. The pH of the water for injection was checked. A sodium ascorbate and sodium metabisulfite was added slowly under continuous stirring. The stirring was continued till get clear solution. This was followed by addition of propylene glycol, and ethanol with stirring. The pH was adjusted to 2.6. The posaconazole was then added slowly under stirring for 2 h and was observed for complete solubility of the API in the selected solvent system.
Chandel V., Singh H., Rarokar N., & Wadher K. (2024). Stabilization of the pharmaceutical finished dosages form by using various techniques. Journal of Drug Delivery and Therapeutics, 14(6), 44-50.
Publication 2024
2
Posaconazole Interaction Study in Obese Subjects
Not available on PMC !

Example 1

Inventors studied 6 obese male and female subjects (ages 18-50, BMI>35) taking Posaconazole oral tablets (300 mg qd) and Lurasidone (20 mg qd). Body weights and BMI measurements for the 6 subjects are provided below in Table 1.

TABLE 1
Subject Demographics
Subject #Weight (kg)BMI (kg/m2)
101-001111.845  
101-002136.844.4 
101-005137.751.2 
101-007103.736.8 
101-008122.339.8 
101-010120.043.9 

Subjects were dosed with Lurasidone alone on Day 1, then subsequently dosed to steady-state Posaconazole levels, with a loading dose of 300 mg twice a day on Day 2 and 300 mg once a day thereafter over a period of 14 days. Posaconazole administration was then stopped and Lurasidone (20 mg qd) administered 2, 4, and 6 days after administration had ceased (studies days 17, 19, and 21 respectively). Lurasidone AUC was measured for 24 hours after each administration. Table 2 shows subject Lurasidone AUC levels 2, 4 and 6 days after Posaconazole was stopped, Posaconazole AUC levels 2, 4, and 6 days after Posaconazole was stopped, and the ratio of post-Posaconazole Lurasidone AUC to the baseline Lurasidone AUC measured before Posaconazole treatment:

TABLE 2
Posaconazole AUCLurasidone AUC RatioSubject data
Lurasidone AUC (ng * h/mL)(ng * h/mL)relative to Day 1BMIWeight
SubjectDay 1Day 17Day 19Day 21Day 17Day 19Day 21Day 17Day 19Day 21(kg/m2)(kg)
HMS001101-92.8284234.4204.52886201913653.062.532.2045.0111.8
001
DES005101-26167.31861682512195415636.437.156.4651.2137.7
005
TRB007101-38.3173.889.5124.78245422854.542.343.2636.8103.7
007
NNJ010101-71211.71632264551368830812.982.303.1843.9120.0
010
KDH002101-110195.5146186.312996262841.781.331.6944.4136.8
002
DTG008101-45.65736.227.819078311.250.790.6139.8122.3
008

Table 3 compares Lurasidone AUC levels after Posaconazole treatment to baseline Lurasidone AUC levels.

TABLE 3
Lurasidone Levels vs. Base Line Days
After Posaconazole Was Ceased
Day 2Day 4Day 6
Mean3.3×2.7×2.9×
Min1.3×0.8×0.6×
Max6.4×7.2×6.5×
Median3.0×2.3×2.7×

As shown above in Table 3, the post-Posaconazole treatment mean AUC ratios of Lurasidone are about 3 times higher than the baseline. This data indicates that Posaconazole accumulates in obese subjects, and results in significantly higher Lurasidone AUC levels compared to baseline levels measured before Posaconazole treatment.

The AUC measurements from two patients (DTG008 and KDH002) indicates that these patients were non-compliant with the Posaconazole treatment regimen, and the corresponding AUC measurements were removed from the study. The results are shown below in Table 4.

TABLE 4
Lurasidone Levels vs. Base Line Days
After Posaconazole Was Ceased
Excluding DTG008 & KDH002
Day 2Day 4Day 6
Mean4.3×3.6×3.8×
Min3.0×2.3×2.2×
Max6.4×7.2×6.5×
Median3.8×2.4×3.2×

These results indicate that post-Posaconazole treatment mean AUC ratio values for Lurasidone are in the range of from 3.6-4.3× for 2-6 days after ceasing Posaconazole treatment.

In conclusion, the results from the clinical trials reported in Example 1 indicate that the Posaconazole accumulates in the body of obese patients after treatment has stopped, and patients should delay a first dose of Lurasidone or reduce the first dose of Lurasidone to achieve safe blood plasma levels of Lurasidone.

US11857548B2. Methods of treatment (2024-01-02). BOW RIVER LLC [US]. Inventors: Sundar Srinivasan [US], Christina Chow Wallen [US].
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Patent 2024
3
Ranolazine-Posaconazole Interaction in Obesity
Not available on PMC !

Example 3

The following studies were reported by Chow et al., J. Clin. Pharmacology. 2018; 0(0):1-7 (doi: 10.1002/jcph.1257), which is herein incorporated by reference in its entirety for all purposes.

The antianginal agent ranolazine is metabolized primarily by cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors, such as ketoconazole and posaconazole, is contraindicated due to risk of QT prolongation from high levels of ranolazine. This study evaluated the time course of recovery from the posaconazole drug interaction in normal-weight and otherwise healthy obese subjects. Subjects received single doses of ranolazine in the baseline control condition, again during coadministration of posaconazole, and at 4 additional time points during the 2 weeks after posaconazole discontinuation. With posaconazole coadministration, the geometric mean ratio of ranolazine area under the concentration curve (AUC) increased by a factor of 3.9 in normals and by 2.8 in obese subjects. Posttreatment washout of posaconazole was slow in normals (mean half-life 36 hours) and further prolonged in obese subjects (64 hours). Recovery of ranolazine AUC toward baseline was delayed. AUC remained significantly elevated above baseline in normal-weight and obese subjects for 7-14 days after stopping posaconazole. Current product labeling does not address the need for delay or a reduced dose of ranolazine after discontinuation of a strong CYP3A inhibitor before ranolazine can be safely administered. It is recommended that administration of ranolazine should be limited, for example to 500 mg twice daily for 7 days after posaconazole discontinuation in patients with body mass index 18.5-24.9 kg/m2 and for 12 days in patients with body mass index ≥35 kg/m2 after ranolazine is resumed.

Methods. Study Site and Institutional Review Board. The study was conducted at Avail Clinical Research, located in DeLand, FL. The study protocol and consent document were reviewed and approved by IntegReview, Austin, TX. All study participants provided written informed consent prior to initiation of any study procedures. In addition, this study was performed in accordance with the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice guidelines, and applicable regulatory requirements.

Subjects. A total of 30 subjects, aged 19 to 50, were enrolled in the study (Table 9). All were healthy adults without evidence of active medical disease, with the exception of obesity, and taking no prescription medications; 43% of the study subjects were male.

The study included 2 cohorts of volunteers. The first consisted of subjects of normal body habitus (BMI 18.5-24.9 kg/m2, inclusive, n 15); the second consisted of subjects of obese body habitus (BMI 2:35 kg/m2, n 15). Subjects were matched by sex and age when possible. Sample sizes were based on power calculations.

Potential study participants underwent screening and evaluation within 30 days of study initiation. Procedures included medical and psychiatric history, physical examination, electrocardiogram (ECG), hematologic and biochemical screening, and urine testing for drugs of abuse. All study participants were healthy active nonsmoking adults with no history of significant medical or psychiatric disease and taking no prescription medications. Obese subjects were free of metabolic or other complications of obesity. Potentially child-bearing women in both groups had a negative pregnancy test and agreed to avoid the risk of pregnancy during the course of the study. Subjects were also administered 12-lead ECGs in triplicate on study days 1 and 15 before and 4 hours after the ranolazine dose as well as before discharge on day 30.

Subjects' waist circumference was measured manually. Percentage android fat for all subjects was determined by dual-energy x-ray absorptiometry. Total android fat (total body fat) was calculated as the product of body weight and percentage android fat.

Procedures. Subjects received ranolazine (500 mg extended-release tablet) on the mornings of study days 1, 15, 18, 22, 25, and 29. Venous blood samples were drawn into ethylenediaminetetraacetic acid (EDTA)-containing tubes from an indwelling catheter or by separate venipuncture prior to the ranolazine dose and at 1, 2, 4, 6, 8, 12, 18, 24, and 32 hours postdose. Samples were centrifuged, and the plasma was separated and frozen at −70° C. until the time of assay of plasma ranolazine concentrations.

On study day 2, subjects received posaconazole (300 mg delayed-release tablet twice a day), and on the mornings of days 3-15, subjects received posaconazole (300 mg delayed-release tablet daily). Because posaconazole is to be taken with food,6 subjects were fed a continental breakfast in the clinical research unit after receiving posaconazole and before discharge from the unit. Venous blood samples were drawn into EDTA-containing tubes before the posaconazole dose on days 2, 5, 8, 12, and 15, and before the ranolazine dose on days 18, 22, 25, and 29. One additional blood sample was taken 5 hours after the posaconazole dose on day 15 for approximate determination of maximum plasma posaconazole concentrations. Samples were centrifuged, and the plasma was separated and frozen at −70° C. until the time of assay of plasma posaconazole concentrations.

Analytic Methods. All bioassay analysis was performed by Keystone Bioanalytical (North Wales, PA). For analysis of posaconazole, the internal standard (posaconazole-d4) was added to the biological samples. Plasma samples were precipitated using formic acid in acetonitrile and isolated using a Phree phospholipid removal tube, and then an aliquot of the sample was injected onto a high-pressure liquid chromatography with tandem mass spectrometry triple quadrupole mass spectrometer (Sciex API-5500). The analytical column was a Unison CK-218, 3 μm particle size HPLC column (50×2 mm) from Imtakt USA (Portland, OR). The mobile phase consisted of an aqueous component (0.25% formic acid and 10 mmol/L ammonium formate in water) and an organic component (0.1% formic acid in acetonitrile) and was delivered by gradient, with the organic component going from 35% to 100%. The m/z transitions monitored were 701.6→614.4 for posaconazole and 705.6→618.4 for the internal standard. The calibration curve ranged from 1 to 1000 ng/mL (8 concentrations in duplicate). The interassay precision of this method (as percentage coefficient of variance) was 4.28% to 7.14%, and the interassay accuracy (as percentage relative error) was 7.02% to 3.12%.

For analysis of ranolazine in plasma samples, the internal standard (ranolazine-d3) was added to the biological samples. Plasma samples were extracted by methyl tertiary butyl ether, centrifuged, and the upper layer was transferred to plastic injection vials with MeOH/water (50:50). An aliquot of the sample was then injected onto a high-pressure liquid chromatography with tandem mass spectrometry triple quadrupole mass spectrometer (Sciex API-5500). The analytical column was a Unison CK-218, 3 μm particle size HPLC column (50×2 mm) from Imtakt USA (Portland, OR). The mobile phase consisted of an aqueous component (0.025% formic acid and 10 mmol/L ammonium formate in water) and organic component (0.1% formic acid in acetonitrile) and was delivered by gradient, with the organic component going from 15% to 45%. The m/z transitions monitored were 428.3→279.2 for ranolazine and 431.3→282.2 for the internal standard. The calibration curve ranged from 5 to 2500 ng/mL (8 concentrations in duplicate). The interassay precision of this method (as percentage coefficient of variance) was 1.49% to 4.88%, and the intra-assay accuracy (as percentage relative error) was −30.07% to 1.83%.

Pharmacokinetic and Statistical Methods. For each ranolazine trial in each subject, the terminal log-linear phase of the plasma concentration curve was identified visually, and the terminal rate constant (β) was determined by log-linear regression analysis. This was used to calculate the half-life (t1/2). The area under the plasma concentration curve from time 0 until the last nonzero point was determined by the linear trapezoidal method. To this was added the residual area, calculated as the final nonzero concentration divided by β, yielding the total area under the plasma concentration curve extrapolated to infinity (AUC). Also tabulated was the observed maximum plasma concentration (Cmax). Variables were aggregated as arithmetic mean and SD. Ranolazine Cmax and AUC were also aggregated as geometric mean and 90% CI.

For each subject, the predose plasma posaconazole concentration on study day 15 was used as a steady-state concentration. The apparent washout half-life of posaconazole was calculated by log-linear regression analysis starting with the plasma concentration on day 15 and ending with the last nonzero value. Differences between normal-weight and obese cohorts were evaluated by Student t-test for independent groups.

Differences in kinetic variables between study days 1 and 15, 18, 22, 25, and 29 (control versus after posaconazole administration) were evaluated either from the untransformed data using Dunnett's t-test or by comparison of geometric means and the 90% CI of the difference.

QTcF values were determined electronically from 12-lead ECG readings taken for safety purposes. This protocol did not involve a thorough QT study; however, safety data were recorded, and the mean, standard deviation, and standard error of QT and QTcF values were tabulated. Differences between baseline and study days 1, 15, and 30 were evaluated by Student's t-test for independent groups.

Results. All 30 subjects completed day 1 of the study, and 27 completed the full study protocol. (One subject was inadvertently given an incorrect dosage of study drug on day 1; this subject was allowed to re-enroll with a new subject number after an appropriate washout period.) Two obese subjects and 1 normal-weight subject withdrew from the study before completion of all study procedures. In the normal-weight group, 1 subject discontinued due to abdominal pain that was possibly related to ranolazine treatment. In the obese group, 1 subject withdrew consent for personal reasons, and 1 subject discontinued due to an adverse event (paresthesia) that was unrelated to the study drug.

Obese subjects were similar in height to normal-weight subjects but were significantly higher in age, weight, BMI, and percentage of total body fat (Table 9).

TABLE 9
Demographic characteristics of study
participants (mean ± SD)
Normal-weightObese
Number1413
Age (years)27.7 ± 10.633.9 ± 7.7 
Male/female7/74/9
Weight
(Kg)71.2 ± 8.2 116.8 ± 19.6 
(Pounds) 157 ± 18.1257.5 ± 43.2 
Height
(Cm)174.0 ± 8.6 169.0 ± 11.8 
(Inches)68.5 ± 3.4 66.5 ± 4.6 
BMI (kg/m2)23.5 ± 1.6 40.9 ± 5.7 

Posaconazole plasma concentrations were lower in obese subjects than in normal-weight subjects (FIG. 5); however, this difference did not reach significance. This is consistent with previous observations of altered posaconazole pharmacokinetics in obese subjects compared to normal-weight subjects, where posaconazole plasma concentrations were observed to be lower in obese patients. Trough (predose) steady-state posaconazole concentrations on day 15 were 3071±1422 ng/mL in normal-weight subjects and 2258±952 ng/mL in obese subjects. Surprisingly, however, it was also observed that the postdosage washout half-life of posaconazole in obese subjects was significantly increased relative to that in normal-weight subjects (64.3 hours and 35.8 hours, respectively). Posaconazole plasma concentrations persisted for at least 2 weeks after stopping treatment in most subjects (FIG. 5).

The geometric mean AUC for ranolazine on day 1 was similar in normal-weight and obese subjects (6454 ng h/mL and 6955 ng h/mL, respectively). Similarly, the geometric mean Cmax on day 1 did not differ significantly between groups (664.7±318.2 ng/mL and 559.1±270.7 ng/mL in normal-weight and obese subjects, respectively). The geometric mean AUC and Cmax for ranolazine in both normal-weight and obese subjects on days 15, 18, and 22 increased significantly compared to day 1 (FIG. 6, Table 10). AUC and Cmax did not differ significantly between groups. t1/2 on day 1 was slightly prolonged in obese subjects (4.99±1.50 hours and 6.02±1.75 hours in normal-weight and obese subjects, respectively), but this difference did not reach significance (P=0.126, Table 10).

TABLE 10
Pharmacokinetic parameters of ranolazine (mean ± SD)
Normal-weightObese
Day 1Cmax (ng/mL)665 ± 318559 ± 271
AUC0-inf (ng/mL × h)7085 ± 36038126 ± 4840
T1/2 (h) 4.98 ± 1.50a 6.02 ± 1.75a 
Day 15Cmax (ng/mL)1429 ± 666*1177 ± 512*
AUC0-inf (ng/mL × h) 27477 ± 14895* 25842 ± 21638*
T1/2 (h)9.54 ± 4.3 8.78 ± 5.58
Day 18Cmax (ng/mL)1188 ± 469*1096 ± 502*
AUC0-inf (ng/mL × h) 17310 ± 10263* 19294 ± 14150*
T1/2 (h)5.73 ± 1.537.93 ± 2.98
Day 22Cmax (ng/mL) 974 ± 400*1063 ± 508*
AUC0-inf (ng/mL × h)13414 ± 6252* 15920 ± 11832*
T1/2 (h)6.47 ± 3.146.09 ± 2.10
Day 25Cmax (ng/mL) 928 ± 482* 976 ± 487*
AUC0-inf (ng/mL × h)9385 ± 459113846 ± 10600
T1/2 (h)5.05 ± 1.826.07 ± 2.10
Day 29Cmax (ng/mL)751 ± 276719 ± 333
AUC0-inf (ng/mL × h)8568 ± 380210171 ± 7942 
T1/2 (h)4.45 ± 1.386.38 ± 3.05
*Significance vs Day 1 determined by Dunnett’s t-test
aNot significant between normal-weight and obese groups (p = 0.126) by Student’s t-test

Within each cohort, the interaction between posaconazole and ranolazine was greatest on day 15 relative to day 1 as determined by the AUC geometric mean ratio (GMR) and 90% CI. The magnitude of the interaction decreased from days 18 to 29; however, plasma ranolazine concentrations on day 29 were still increased relative to day 1 (FIGS. 7A and 7B, Table 11). The lower bound of the AUC GMR 90% CI also remained above 1.0 for 7 days in both normal-weight and obese subjects. Cmax GMRs and 90% CIs followed a similar trend and can be found in Table 11.

TABLE 11
Geometric mean ratios (90% CI) of plasma ranolazine
Normal-weightObese
Day 15/Day 1AUC0-inf3.88 (2.94-5.13)2.80 (1.68-4.66)
Cmax2.16 (1.61-2.87)2.18 (1.55-3.04)
Day 18/Day 1AUC0-inf2.34 (1.70-3.22)2.25 (1.41-3.58)
Cmax1.82 (1.38-2.42)1.97 (1.42-2.80)
Day 22/Day 1AUC0-inf1.88 (1.38-2.54)1.79 (1.11-2.88)
Cmax1.50 (1.13-1.99)1.90 (1.35-2.54)
Day 25/Day 1AUC0-inf1.30 (0.97-1.76)1.57 (0.99-2.50)
Cmax1.36 (1.00-1.85)1.72 (1.20-2.47)
Day 29/Day 1AUC0-inf1.22 (0.92-1.62)1.21 (0.79-1.85)
Cmax1.16 (0.89-1.53)1.30 (0.94-1.82)

ECG data revealed that, on study day 30, the average change in QTcF interval from screening values was 12.9±16 milliseconds in normal-weight subjects who completed the study and 2.6±11 milliseconds in obese subjects who completed the study (Table 12).

TABLE 12
QTcF values relative to baseline
(msec, mean ± SD)
Normal-weightObese
Day 1, predose2.14 ± 10 7.50 ± 9.2 
Day 1, 4 h post-dose9.85 ± 12 3.83 ± 11  
Day 15, predose6.29 ± 16 2.64 ± 11  
Day 15, 4 h post-dose4.36 ± 16 −3.33 ± 13   
Day 3012.9 ± 16**2.58 ± 11  
**p = 0.012 compared to baseline

Discussion. The present study evaluated the effects of obesity on the plasma concentration of ranolazine in otherwise healthy adults during or after cessation of posaconazole administration. Due to the known linear correlation between ranolazine plasma concentration and increases in the QTc interval, the lower marketed dose of 500 mg was chosen for testing in this study to minimize safety risks.

Without or during concomitant dosing of posaconazole, obese and normal-weight subjects had similar Cmax, AUC, and t1/2 (Table 10). After cessation of posaconazole administration, both obese and normal-weight subjects demonstrated persistence of elevated ranolazine levels for several days. Interestingly, the t1/2 of ranolazine increased slightly with the magnitude of the interaction. The magnitude of the effect of posaconazole on day 15 Cmax was similar between normal-weight and obese subjects (Cmax GMR=2.16 and 2.18, respectively). The interaction persisted above a Cmax GMR of 1.5 for 7 and 10 days in normal-weight and obese subjects, respectively. The magnitude of the interaction on day 15 AUC was greater in normal-weight subjects than in obese subjects (AUC GMR, day 15/day 1=3.88 and 2.90, respectively). After day 15, however, the magnitude of the interaction was similar in obese and normal-weight subjects and decreased as posaconazole was eliminated from the body (FIGS. 7A and 7B). The interaction between ranolazine and residual posaconazole persisted above an AUC GMR of 1.5 for at least 7 and 10 days after cessation of posaconazole administration in normal-weight and obese subjects, respectively.

Cmax and AUC GMRs of 1.5 were also observed in preapproval drug-drug interaction studies between ranolazine and diltiazem, a moderate CYP3A inhibitor.

Based on the results of these preapproval studies, current prescribing instructions for ranolazine state that the maximum dosage of ranolazine should be limited to 500 mg twice a day when taken concomitantly with moderate CYP3A inhibitors, and ranolazine is contraindicated for concomitant use with strong CYP3A inhibitors such as posaconazole. These dosing recommendations are based on the linear correlation between ranolazine plasma concentrations and QT interval because risk of cardiac arrhythmias increases as the QT interval increases.

Among the 27 subjects who completed this study, an average increase in the QTcF interval of 12.9 milliseconds was observed in normal-weight patients on day 30 compared to screening. The average QTcF interval in obese subjects was 2.6 milliseconds. The increase of 12.9 milliseconds in normal subjects was statistically significant (P=0.012) (Table 12). The changes in QTcF were observed from safety ECG data and were not derived from a thorough QT study; however, given current FDA guidance on QT-prolonging drugs, it is important to note this finding.

This study is one of the first reports of a sustained drug-drug interaction with posaconazole. Although time-dependent inhibition of CYP3A by posaconazole is minimal, the results of these studies suggest that inhibition of CYP3A by posaconazole persists after cessation of administration and should be accounted for in clinical practice.

In current clinical practice, a patient on ranolazine in need of treatment with posaconazole would stop taking ranolazine while being treated with posaconazole, and then resume ranolazine shortly after finishing the posaconazole regimen to recommence treatment for chronic angina. The results of this study suggest that physicians should instruct their patients to delay/limit the dose of ranolazine for an extended period after stopping posaconazole to avoid drug-drug interactions due to residual posaconazole levels.

Conclusion. Posaconazole, a known CYP3A strong inhibitor, increases ranolazine concentrations to a clinically relevant and potentially hazardous extent during concomitant administration and for several days following its discontinuation. Although steady-state posaconazole concentrations are lower in obese subjects than in normal-weight subjects, its half-life is increased in obese subjects such that the persistence of the interaction is observed in both obese and normal-weight people. The magnitude of the interaction between ranolazine and residual posaconazole elevates ranolazine plasma concentrations to the extent that they are at risk for significant QTc prolongation and potentially fatal cardiac arrhythmias. Based on the results of this study, administration of ranolazine should be limited to 500 mg twice daily for 7 days after posaconazole discontinuation in patients with BMI 18.5-24.9 kg/m2 and for 12 days in patients with BMI ≥35 kg/m2 after ranolazine is resumed.

US11857548B2. Methods of treatment (2024-01-02). BOW RIVER LLC [US]. Inventors: Sundar Srinivasan [US], Christina Chow Wallen [US].
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Patent 2024
4
Lurasidone Pharmacokinetics in Obesity
Not available on PMC !

Example 2

The following studies were reported by Greenblatt et al., J. Clin. Psychopharmacol., 2018; 38(4):289-295 (doi: 10.1097/JCP.0000000000000892), which is herein incorporated by reference in its entirety for all purposes.

The antipsychotic agent lurasidone is metabolized by Cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors (such as ketoconazole, posaconazole, and ritonavir) is contraindicated due to the risk of sedation and movement disorders from high levels of lurasidone. This study evaluated the time-course of recovery from the posaconazole drug interaction, and the effect of obesity on the recovery process.

With posaconazole coadministration, lurasidone area under the concentration curve (AUC) increased by an arithmetic mean factor of 6.2 in normals, and by 4.9 in obese subjects. Post-treatment washout of posaconazole was slow in normals (mean half-life 31 hours), and further prolonged in obese subjects (53 hours). Recovery of lurasidone AUC toward baseline was correspondingly slow, and was incomplete. AUC remained significantly elevated above baseline both in normals (factor of 2.1) and obese subjects (factor of 3.4) even at 2 weeks after stopping posaconazole.

Product labeling does not address the necessary delay after discontinuation of a strong CYP3A inhibitor before lurasidone can be safely administered. It is recommended that normal-weight and obese patients be required to limit the dosage of lurasidone, or undergo a washout period after discontinuation of posaconazole, as set forth in the present disclosure.

Methods. Study Site and Institutional Review Board. The study was conducted at Avail Clinical Research, located in DeLand, FL. The study protocol and consent document were reviewed and approved by IntegReview, Austin, TX. All study participants provided written informed consent prior to initiation of any study procedures. In addition, this study was performed in accordance with the Declaration of Helsinki, International Conference on Harmonization Good Clinical Practice guidelines, and applicable regulatory requirements.

Subjects. The study participants consisted of two cohorts, with a total of 34 subjects receiving at least one dose of study drug, and a total of 24 subjects completing the entire study with evaluable pharmacokinetic data. In the first cohort were those of normal body habitus (n=11 completed; BMI 18.5-24.9 kg/m2, inclusive); the second group consisted of subjects of obese body habitus (n=13 completed; BMI ≥35 kg/m2). Subjects were previously known to the research center, or were recruited through notices in the public media. Subjects were matched by gender and age when possible. Sample sizes were based on power calculations.

Potential participants underwent screening and evaluation within 30 days of study initiation. Procedures included medical and psychiatric history, physical examination, electrocardiogram if indicated, hematologic and biochemical screening (including liver function tests such as alanine transaminase, asparagine transaminase, and bilirubin), and urine testing for drugs of abuse. All study participants were healthy, active, non-smoking adults with no history of significant medical or psychiatric disease and taking no prescription medications. Obese subjects were free of metabolic or other complications of obesity. Potentially child-bearing women in both groups had negative pregnancy tests and agreed to avoid the risk of pregnancy during the course of the study. Subjects were instructed to avoid alcohol use throughout the course of the study and underwent a breath alcohol analysis prior to initiation of the study protocol.

Subjects' waist circumference was measured manually. Percent android fat for all subjects was determined by dual energy X-ray absorptiometry (DXA). For three subjects whose weight exceeded the limits of the DXA instrumentation, percent android fat was imputed using population data available from the National Health and Nutrition Evaluation Survey (NHANES). Total android fat (termed total body fat) was calculated as the product of body weight and percent android fat. Ideal body weight (IBW) was determined from actuarial data based on height and gender, and percent ideal body weight calculated as the ratio of actual weight divided by IBW.

Procedures. Subjects received lurasidone (20 mg tablet) on the mornings of study Days 1, 14, 20, 23, 26, and 30. Lurasidone doses were given immediately prior to a continental breakfast provided in the clinical research unit. Venous blood samples were drawn into ethylenediaminetetraacetic acid (EDTA)-containing tubes from an indwelling catheter, or by separate venipuncture, prior to the lurasidone dose and at 1, 2, 3, 4, 8, 12, 18, 24, 48, and 72 hours post-dose. Samples were centrifuged and the plasma was separated and frozen at −70° C. until the time of assay.

On study Day 4, subjects received two doses of posaconazole (300 mg BID). On the mornings of Days 5-17, they received posaconazole 300 mg once daily. As posaconazole is to be taken with food, subjects were fed a continental breakfast in the clinical research unit after receiving posaconazole and prior to discharge from the unit. Venous blood samples were drawn into EDTA containing tubes prior to the posaconazole dose on Days 4, 7, 11, and prior to the lurasidone dose on Days 14, 20, 23, 26 and 30. An additional blood sample was taken 5 hours after posaconazole dosage on Day 17, for approximate determination of maximum posaconazole plasma concentrations, and on Day 33. Samples were centrifuged and the plasma was separated and frozen at −70° C. until the time of assay.

Analytic Methods. All bioassay analyses were performed by Keystone Bioanalytical, North Wales, PA. For analysis of posaconazole, the internal standard (posaconazole-D4) was added to the biological samples. Plasma samples were precipitated using formic acid in acetonitrile and isolated using a Phree phospholipid removal tube. An aliquot of the sample was injected onto a high-pressure liquid chromatograph with tandem mass spectrometry triple quadrupole mass spectrometer (SCIEX API-5500). The analytical column was a Unison CK-218, 3 μm particle size HPLC column (50×2 mm) from Imtakt USA (Portland, OR).

The mobile phase consisted of an aqueous component (0.25% formic acid and 10 mM ammonium formate in water) and an organic component (0.1% formic acid in acetonitrile) and was delivered by gradient, with the organic component going from 35% to 100%. The m/z transitions monitored were 701.6>614.4 for posaconazole and 705.6>618.4 for the internal standard. The calibration curve ranged from 1-1000 ng/mL (8 concentrations in duplicate).

For analysis of lurasidone, the internal standard (lurasidone-D8) was added to the biological samples. Plasma samples were isolated using a Phree phospholipid removal tube. An aliquot of the sample was injected onto a high-pressure liquid chromatograph with tandem mass spectrometry triple quadrupole mass spectrometer (SCIEX API-5500). The analytical column was a Unison UK-C18, 3 μm particle size HPLC column (50×2 mm) from Imtakt USA (Portland, OR). The mobile phase consisted of an aqueous component (0.025% formic acid and 10 mM ammonium formate in water) and an organic component (0.1% formic acid in acetonitrile) and was delivered by gradient, with the organic component going from 35% to 100%. The m/z transitions monitored were 493.4>166.1 for lurasidone and 501.4>166.1 for the internal standard. The calibration curve ranged from 0.25-200 ng/mL (8 concentrations in duplicate).

Pharmacokinetic and Statistical Methods. For each subject, pre-dose plasma posaconazole concentrations on study Days 14 and 17 were averaged, and used as a steady-state concentration (Css) to calculate apparent steady-state clearance of posaconazole according to the relation: Clearance=(dosing rate)/Css. The apparent washout half-life of posaconazole was calculated by log-linear regression analysis starting with the plasma concentration on Day 20 and ending with the last non-zero value. Differences between normal-weight and obese cohorts were evaluated by Student's t-test for independent groups. The relation between measures of body habitus and posaconazole washout half-life for individual subjects was evaluated by linear regression analysis.

For each lurasidone trial for each subject, the terminal log-linear phase of the plasma concentration curve was identified visually, and the terminal rate constant (beta) was determined by log-linear regression analysis. This was used to calculate the elimination half-life. Area under the plasma concentration curve from time zero until the last non-zero point was determined by the linear trapezoidal method. To this was added the residual area, calculated as the final non-zero concentration divided by beta, yielding the total area under the plasma concentration curve extrapolated to infinity (AUC). Also tabulated was the observed maximum plasma concentration (Cmax). AUC and Cmax both were adjusted, where necessary, for non-zero baseline (pre-dose) concentrations measured in some subjects on the Day 20, 23, 26, and 30 trials.

Variables were aggregated as arithmetic mean and SD or SE. Lurasidone Cmax and AUC were also aggregated as geometric mean and 90% confidence interval (90% CI). Differences in kinetic variables between study Day 1 and Days 14, 20, 23, 26, and 30 (control vs after posaconazole administration) were evaluated either from the untransformed data using Dunnett's t-test, or by comparison of geometric means and the 90% CI of the difference.

The relation between lurasidone AUC and plasma posaconazole concentration for individual subjects across the 5 DDI trials (Days 14, 20, 23, 26, and 30) was analyzed by nonlinear regression (SAS PROC NLIN). The following function was fitted to data points:
Y=Y0+B XA where Y is the lurasidone AUC value corresponding to X, the plasma posaconazole concentration at the start of relevant AUC measurement period. Iterated variables were: Y0, A, and B.

Results

Subject Characteristics. Screening procedures yielded 34 subjects who were potential study participants. Of these, 8 initiated participation but did not complete the study for personal or administrative reasons not related to the study or study medications. Data from 2 other subjects could not be analyzed due to apparent protocol deviations. A total of 24 subjects (11 normal-weight and 13 obese) completed the study and were included in the pharmacokinetic analysis (Table 5). The groups were comparable in age, gender composition, height, and IBW. The obese group had significantly higher values of weight, percent IBW, BMI, waist circumference, percent android fat, and total body (android) fat (Table 5). The mean weight in the obese group s 140 kg (309 pounds), and the mean BMI was 49.3 kg.

TABLE 5
DEMOGRAPHIC CHARACTERISTICS OF STUDY PARTICIPANTS
Independent
t-test: Normal
Normal-weight*Obese*vs obese
Number1113
Age (years)34 ± 8 33 ± 7 N. S.
Male/female6/56/7
Weight
(Kg)67.9 ± 9.1 140.4 ± 32  P < 0.001
(Pounds)149 ± 29 309 ± 70 P < 0.001
Height
(Cm)171 ± 10 168 ± 11 N. S.
(Inches)67.3 ± 4.0 66.3 ± 4.3 N. S.
BMI (kg/m2)23.1 ± 1.8 49.3 ± 9.6 P < 0.001
Waist circumference
(Cm)80.4 ± 6.8 129.3 ± 22.4 P < 0.001
(Inches)31.7 ± 2.7 50.9 ± 8.8 P < 0.001
Ideal body weight (kg)64.5 ± 12.361.9 ± 11.4N. S.
Percent ideal body weight106 ± 11 230 ± 46 P < 0.001
Percent android fat33 ± 1266 ± 4 P < 0.001
Total body fat (kg)22.5 ± 8.0 81.3 ± 25.8P < 0.001
*Mean ± SD

Adverse Events. Five subjects experienced adverse events considered possibly or probably related to one or both study medications. These were gastrointestinal disturbances in two cases, and one each of dry mouth, somnolence, and headache. All resolved without specific treatment.

Posaconazole Pharmacokinetics. Plasma posaconazole concentrations had reached steady-state by study Day 14 (FIG. 1). Mean Css was significantly lower, and posaconazole clearance was significantly higher, in the obese cohort compared to controls (Table 6). However, weight-normalized posaconazole clearance was not significantly different between the groups.

Washout of posaconazole after discontinuation of treatment was significantly slower in the obese group compared to controls (P<0.005) (FIG. 1). Mean washout half-life values in the two groups were 2.19 days (52.5 hours) and 1.28 days (31 hours), respectively (Table 6).

Among all subjects, the correlation between posaconazole washout half-life and each of the measures of body habitus was statistically significant, but the degree of obesity explained only a small fraction of variance in washout half-life (r2<0.32). The attenuated associations were in part attributable to two obese subjects with very long half-life values (121 hours).

TABLE 6
POSACONAZOLE PHARMACOKINETICS
Mean ± SD Value of
value for Group:Student’s t:
NormalObeseNormal vs Obese
Steady-state2377 ± 11881462 ± 649 3.33 (P < 0.005)
concentration (ng/mL)
Steady-state clearance
mL/min101 ± 71 175 ± 91 2.19 (P < 0.04)
mL/min/kg1.48 ± 1.021.25 ± 0.61N. S.
Washout half-life (hours) 31 ± 6.752.5 ± 31.12.25 (P <0.04)

Lurasidone Pharmacokinetics. Coadministration of lurasidone with posaconazole resulted in a highly significant increase in lurasidone Cmax and AUC (FIG. 2, Table 7). Comparing Day 14 values to the Day 1 pre-posaconazole values based on ratio of geometric means, Cmax increased by a factor of 4.0 in normal-weight subjects and by 2.9 in the obese subjects. Corresponding increases in AUC were greater than increases in Cmax. Geometric mean AUC increased by a factor of 5.75 in the normal-weight cohort, and by 4.34 in the obese cohort (Table 7). When calculated as arithmetic mean ratios, values were 6.2 in controls and 4.9 in obese subjects.

TABLE 7
SUMMARY OF LURASIDONE PHARMACOKINETICS
Arithmetic mean ± Geometric meanRatio of geometric means
standard error(90% CI)(RGM) vs Day 1 (90% CI)
Corrected Cmax (ng/mL)Corrected Cmax (ng/mL)Corrected Cmax
NormalObeseNormalObeseNormalObese
Day 117.1 ± 1.619.8 ± 416.3(13.5-19.6)15.1(10.2-22.6)Day 144.00(3.09-5.19)2.91(1.89-4.47)
Day 1469.4 ± 8.3*47.0 ± 5*65.2(53.5-79.5)44.1(35.9-54.2)Day 202.98(2.06-4.33)2.42(1.55-3.76)
Day 2055.9 ± 7.840.0 ± 5*48.6(34.6-68.4)36.6(29-46.3)Day 232.32(1.68-3.21)1.85(1.2-2.84)
Day 2342.5 ± 6.3*30.0 ± 337.8(28.5-50.2)28.0(22.7-34.6)Day 261.63(1.1-2.4)1.78(1.13-2.79)
Day 2632.2 ± 6.630.0 ± 426.5(18.3-30.9)26.9(21-34.5)Day 301.47(1.09-1.99)1.42(0.89-2.26)
Day 3026.2 ± 3.225.0 ± 4.424.0(18.6-30.9)21.6(16.4-28.4)
Total AUC (ng/mL × hr)Total AUC (ng/mL × hr)Total AUC (ng/mL × hr)
NormalObeseNormalObeseNormalObese
Day 157.9 ± 5.850.8 ± 954.5(43.3-68.6)42.0(30.4-57.9)Day 145.94(4.64-7.46)4.66(3.28-6.59)
Day 14 333 ± 24* 205 ± 19*324(282-372)195(166-230)Day 204.34(3-6.28)4.90(3.45-6.96)
Day 20 265 ± 27* 217 ± 20*237(175-321)205(173-244)Day 233.38(2.39-4.78)3.82(2.68-5.47)
Day 23 204 ± 27* 170 ± 17*184(139-242)160(133-193)Day 262.24(1.45-3.46)3.33(2.3-4.83)
Day 26 148 ± 27* 152 ± 19*122(83-179)140(113-173)Day 302.10(1.46-3.01)3.34(2.33-4.78)
Day 30 129 ± 20* 150 ± 17*114(85-154)140(116-170)
*P < 0.05 compared to Day 1 value, Dunnett’s t test

Kinetic variables for lurasidone recovered toward the pre-posaconazole baseline values during the posaconazole washout period. Based on ratios of geometric mean values versus the Day 1 baseline, Cmax remained elevated above Day 1 even on Day 30 (ratio=1.47, 90% CI=1.09-1.99) in the normal-weight control subjects. In the obese cohort, Cmax remained above baseline up to Day 26. Recovery of AUC in both groups was even less complete, with Day 30 ratios of 1.9 in the normal-weight group and 2.8 in the obese subjects (arithmetic mean ratios: 2.1 and 3.4, respectively). Consistent with the slower washout of posaconazole in the obese group, the rate of recovery of lurasidone AUC toward baseline values was correspondingly slower in the obese cohort compared to controls (FIG. 3).

Baseline values of lurasidone elimination half-life averaged 9.4 hours in normal-weight subjects and 10.9 hours in the obese group. These values are in the range of what has been reported previously. The half-life values were significantly prolonged during and after administration of posaconazole, and were still substantially longer than baseline values even on the Day 30 trial (FIG. 2, Table 8). Mean half-life values were longer in obese subjects compared to controls. However, half-life determinations were complicated by estimates that exceeded the sampling duration in some subjects.

TABLE 8
LURASIDONE ELIMINATION HALF-LIFE (HOURS)
Arithmetic mean ± S.E.
NormalObese
Day 19.4 ± 1.510.9 ± 4   
Day 1437 ± 4*38 ± 2*
Day 2039 ± 3*48 ± 4*
Day 2348 ± 5*52 ± 3*
Day 2650 ± 7*61 ± 4*
Day 3045 ± 9*71 ± 5*
*P < 0.05 compared to Day 1 based on Dunnett’s t test

Relation of Plasma Posaconazole to Lurasidone AUC. Based on analysis of data from all subjects, individual variations in plasma posaconazole concentrations accounted for 66% of the variance in lurasidone AUC at the corresponding times (r2=0.66), indicating that posaconazole exposure is a principal determinant of the magnitude of the posaconazole-lurasidone DDI (FIG. 4).

Discussion. The present study evaluated the pharmacokinetic DDI between lurasidone as victim (substrate) and the strong CYP3A inhibitor posaconazole as perpetrator (precipitant), both in volunteers of normal body weight and in an otherwise healthy group of subjects with BMI ≥35 kg/m2. A particular focus of the study was the time-course of recovery from the DDI during the two weeks after discontinuation of posaconazole.

Coadministration of lurasidone with typical doses of posaconazole resulted in increased lurasidone exposure (total AUC) by a factor averaging in the range of 4 to 6 in both groups of subjects. After posaconazole was discontinued, the effect on lurasidone exposure did not return quickly to baseline. Rather, the DDI persisted for at least 2 weeks after the last dose of posaconazole, and probably well beyond the study duration. The slow recovery from the DDI was consistent with the long elimination half-life of posaconazole. With all data aggregated, plasma posaconazole concentration accounted for 66% of the variability in lurasidone AUC associated with the DDI.

The pharmacokinetic properties of posaconazole were significantly modified in the cohort of obese subjects compared to those of normal body size. The clearance of posaconazole—not corrected for body weight—was higher in obese subjects compared to controls, resulting in lower values of Css when the same daily dosage was administered to both groups. Despite the higher clearance, the washout half-life was significantly prolonged in the obese subjects compared to controls. This is likely explained by the disproportionate distribution of the lipophilic drug posaconazole into excess adipose tissue, thereby causing a prolongation of elimination half-life. As a result of the longer half-life and persistence of posaconazole in blood, the duration of the lurasidone DDI was correspondingly longer. At two weeks after the last dose of posaconazole, lurasidone AUC was still elevated above baseline by a mean factor of 3.3 in the obese subject group.

This study involved a relatively small number of subjects, but the findings were statistically robust. Although lurasidone was administered as single test doses, the kinetics of lurasidone are linear, and single-dose kinetic properties will be predictive of behavior during multiple dosing as is customary in the treatment of schizophrenia.

Conclusions. The posaconazole-lurasidone DDI persists long after posaconazole is discontinued, resulting in a sustained risk of a potentially hazardous DDI. The duration of persistent risk is further prolonged in obese individuals due to the effect of obesity on the elimination kinetics of posaconazole. Revision of product labeling is needed to assure patient safety. Based on the findings of this study, it is recommended to require normal-weight and obese patients to limit the dosage of lurasidone, or undergo a washout period, as set forth in the present disclosure.

US11857548B2. Methods of treatment (2024-01-02). BOW RIVER LLC [US]. Inventors: Sundar Srinivasan [US], Christina Chow Wallen [US].
Full text: Click here
Patent 2024
5
Synergistic Antifungal Effects Against C. auris
The MICs values of posaconazole, the HIV protease inhibitors (atazanavir and saquinavir) were evaluated against C. auris isolates following the CLSI guidelines35 . The combinations of posaconazole with atazanavir or saquinavir were determined against 17 C. auris isolates using the checkerboard method, as described elsewhere36 (link). Similarly, the two combinations were evaluated against other Candida species including C. albicans, C. tropicalis, C. parapsilosis, C. krusei and C. glabrata. The FICI was calculated and interpreted as follows: FICI of > 4 was classified as antagonism, FICI of > 0.5–4: indifference, and FICI of ≤ 0.5: synergism37 (link). To confirm the ability of atazanavir and saquinavir to improve the activity of posaconazole against C. auris, we used posaconazole test strips. C. auris AR0390 was cultured in RPMI 1640 agar in the presence of atazanavir, saquinavir or dimethyl sulfoxide (DMSO). Next, the posaconazole test strip was added, and the agar plate was incubated at 35 °C for 24 h. The concentration at which a zone of inhibition intercepted with the posaconazole strip used as the MIC.
Elgammal Y., Salama E.A, & Seleem M.N. (2024). Enhanced antifungal activity of posaconazole against Candida auris by HIV protease inhibitors, atazanavir and saquinavir. Scientific Reports, 14, 1571.
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Publication 2024

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Ketoconazole by Merck Group
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More about "Posaconazole"

Posaconazole is a potent triazole antifungal medication that is widely used to prevent and treat serious fungal infections, such as those caused by Aspergillus, Candida, and Zygomycetes.
This versatile drug works by inhibiting the fungal enzyme lanosterol 14-alpha-demethylase, which is crucial for the biosynthesis of ergosterol, a key component of the fungal cell membrane.
By disrupting the cell membrane, posaconazole leads to fungal cell death or growth inhibition, effectively combating a broad range of fungal pathogens.
Posaconazole is often prescribed for immunocompromised patients, such as those undergoing cancer treatment or organ transplantation, who are at high risk of developing life-threatening fungal infections.
The drug is available in various formulations, including oral tablets, suspensions, and intravenous preparations, allowing for flexible administration and optimization of dosing regimens.
Compared to other triazole antifungals like voriconazole and itraconazole, posaconazole has demonstrated enhanced potency and a broader spectrum of activity.
It has been shown to be effective against even the more challenging fungal pathogens, such as Zygomycetes, which can be resistant to other antifungal agents like amphotericin B.
To ensure the efficacy and safety of posaconazole therapy, careful monitoring of drug levels is crucial.
This is particularly important due to the complex pharmacokinetics of the drug, which can be influenced by various factors, including food intake and concomitant medications.
In addition to its antifungal properties, posaconazole has also been investigated for its potential applications in the treatment of other conditions, such as invasive aspergillosis and mucormycosis.
Ongoing research continues to explore the versatility and therapeutic potential of this versatile antifungal agent.
Whether you're a healthcare professional, a researcher, or someone interested in the field of infectious diseases, understanding the comprehensive profile of posaconazole can provide valuable insights into the management and prevention of serious fungal infections.
By leveraging the latest scientific advancements and best practices, you can optimize your posaconazole-related studies and achieve reliable, high-quality results.