Population Pharmacokinetic Modeling to Describe the Total Plasma and Free Brain Levels of Fluconazole in Healthy and Cryptococcus neoformans Infected Rats: How Does the Infection Impact the Drug’s Levels on Biophase?

Alves, Izabel Almeida; Staudt, Keli Jaqueline; Carreño, Fernando; Lock, Graziela de Araújo; Silva, Carolina de Miranda; Rates, Stela Maris Kuze; Costa, Teresa Dalla; Araújo, Bibiana Verlindo de

doi:10.1007/s11095-018-2402-9

Cited by 4 publications

(5 citation statements)

References 35 publications

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“…Fluconazole is well known to have linear pharmacokinetics [11, 16–18]. For this reason, we used a linear regression model for predicting the plasma concentrations following oral fluconazole at 100 mg, 200 mg, 400 mg, 1200 mg, 1600 mg, and 2000 mg/day from the measured concentrations following oral fluconazole 800 mg daily given as directly observed therapy while hospitalized [15, 19].…”

Section: Methodsmentioning

confidence: 99%

Minimum Inhibitory Concentration Distribution of Fluconazole Against Cryptococcus Species and the Fluconazole Exposure Prediction Model

Chesdachai

Rajasingham

Nicol

et al. 2019

Open Forum Infectious Diseases

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Background Fluconazole is lifesaving for treatment and prevention of cryptococcosis; however, optimal dosing is unknown. Initial fluconazole doses of 100 mg to 2000 mg/day have been used. Prevalence of fluconazole nonsusceptible Cryptococcus is increasing over time, risking the efficacy of long-established standard dosing. Based on current minimum inhibitory concentration (MIC) distribution, we modeled fluconazole concentrations and area under the curve (AUC) relative to MIC to propose a rational fluconazole dosing strategy. Method We conducted a systematic review using the MEDLINE database for reports of fluconazole MIC distribution against clinical Cryptococcus isolates. Then, we utilized fluconazole concentrations from 92 Ugandans who received fluconazole 800mg/day coupled with fluconazole’s known pharmacokinetics to predict plasma fluconazole concentrations for doses ranging from 100 mg to 2000 mg via linear regression. The fluconazole AUC above MIC ratio were calculated using Monte Carlo simulation and using the MIC distribution elucidated during the systemic review. Results We summarized 21 studies with 11 049 clinical Cryptococcus isolates. Minimum inihibitory concentrations were normally distributed with a geometric mean of 3.4 µg/mL, median (MIC50) of 4 µg/mL, and 90th percentile (MIC90) of 16 µg/mL. The median MIC50 trended upwards from 4 µg/mL in 2000–2012 to 8 µg/mL in 2014–2018. Predicted subtherapeutic fluconazole concentrations (below MIC) would occur in 40% with 100 mg, 21% with 200 mg, and 9% with 400 mg. The AUC:MIC ratio >100 would occur in 53% for 400 mg, 74% for 800 mg, 83% for 1200 mg, and 88% for 1600 mg. Conclusions Currently recommended fluconazole doses may be inadequate for cryptococcosis. Further clinical studies are needed for rational fluconazole dose selection.

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Section: Methodsmentioning

confidence: 99%

Minimum Inhibitory Concentration Distribution of Fluconazole Against Cryptococcus Species and the Fluconazole Exposure Prediction Model

Chesdachai

Rajasingham

Nicol

et al. 2019

Open Forum Infectious Diseases

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“…This study demonstrated that the infection was able to alter the distribution of FLZ in the brain of infected animals. Furthermore, this study shows that when used in monotherapy, FLZ is of limited use in monotherapy to the treatment of cryptococcosis in rats and humans to a value of MIC >8 μg/mL (Alves et al, 2018). Stott et al, (2018) came to a similar conclusion, after investigating the impact of a series of clinically relevant covariates on the penetration of FLZ into the CNS in adults with cryptococcal meningitis, after oral doses of 800 mg every 24 h in combination with AmB deoxycholate at a dose of 1 mg/day.…”

Section: Fluconazolementioning

confidence: 87%

“…FLZ is a synthetic triazole antifungal used in the treatment of cryptococcal meningoencephalitis and there are countries where it is the only available drug for treating these infections (Sudan et al, 2013;Wang et al, 2017). FLZ is recommended as the main therapeutic agent for the maintenance phase of cryptococcal meningoencephalitis, it has a safety profile, low toxicity, long half-life, physicochemical characteristics that carry on good tissue distribution, is orally bioavailable, has excellent CNS penetration, and has a linear PK (Wang et al, 2017;Santos et al, 2016;Alves et al, 2018;Hope et al, 2019).…”

Section: Fluconazolementioning

confidence: 99%

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The role of modeling and simulation to improve the treatment of fungal infections caused by Cryptococcus : A literature review

Staudt,

Olivo,

Alves

et al. 2024

Braz. J. Pharm. Sci.

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The treatment of fungal infections presents problems in relation to toxicity, pharmacokinetic properties, and undesirable side effects among other factors. An alternative to clarify some of these problems is the use of mathematical modeling and simulation of the pharmacokinetics and pharmacodynamics data of antifungals, in order to seek greater support in decision making regarding the treatment of Cryptococcus infection. Here, we describe the results of

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“…However, on a fixed regimen of antifungal therapy, PK results are variable, and such levels can be quantified by population PK modeling. Monte Carlo simulation is a useful tool in replicating pharmacokinetic variability [ 162 ]. For example, the role of fluconazole is to inhibit growth, not to kill.…”

Section: Role Of Pk/pd Levelsmentioning

confidence: 99%

Antifungal Resistance in Cryptococcal Infections

Melhem,

Leite Júnior,

Takahashi

et al. 2024

Pathogens

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Antifungal therapy, especially with the azoles, could promote the incidence of less susceptible isolates of Cryptococcus neoformans and C. gattii species complexes (SC), mostly in developing countries. Given that these species affect mostly the immunocompromised host, the infections are severe and difficult to treat. This review encompasses the following topics: 1. infecting species and their virulence, 2. treatment, 3. antifungal susceptibility methods and available categorical endpoints, 4. genetic mechanisms of resistance, 5. clinical resistance, 6. fluconazole minimal inhibitory concentrations (MICs), clinical outcome, 7. environmental influences, and 8. the relevance of host factors, including pharmacokinetic/pharmacodynamic (PK/PD) parameters, in predicting the clinical outcome to therapy. As of now, epidemiologic cutoff endpoints (ECVs/ECOFFs) are the most reliable antifungal resistance detectors for these species, as only one clinical breakpoint (amphotericin B and C. neoformans VNI) is available.

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Population Pharmacokinetic Modeling to Describe the Total Plasma and Free Brain Levels of Fluconazole in Healthy and Cryptococcus neoformans Infected Rats: How Does the Infection Impact the Drug’s Levels on Biophase?

Abstract: FLC showed a limited use in monotherapy to the treatment of criptoccocosis in rats and humans to value of MIC >8 μg/mL.

Cited by 4 publications

References 35 publications

Minimum Inhibitory Concentration Distribution of Fluconazole Against Cryptococcus Species and the Fluconazole Exposure Prediction Model

Minimum Inhibitory Concentration Distribution of Fluconazole Against Cryptococcus Species and the Fluconazole Exposure Prediction Model

The role of modeling and simulation to improve the treatment of fungal infections caused by Cryptococcus : A literature review

Antifungal Resistance in Cryptococcal Infections

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