Population Pharmacokinetics and Cerebrospinal Fluid Penetration of Fluconazole in Adults with Cryptococcal Meningitis

Stott, Katharine E.; Beardsley, Justin; Kolamunnage‐Dona, Ruwanthi; Castelazo, Anahi Santoyo; Kibengo, Freddie; Hoang, Nguyen Thi; Tung, Nguyen Le Nhu; Cuc, Ngo Thi Kim; Day, Jeremy; Hope, William

doi:10.1128/aac.00885-18

Cited by 17 publications

(19 citation statements)

References 42 publications

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“…First, the fluconazole concentrations were obtained from 1 clinical study that included 92 HIV-infected Ugandans that used the linear kinetic model for predicting the exposure from different doses. Our steady plasma concentrations were within 10%–20% of observations in US, Vietnamese, and other Ugandan patients [12, 17]. Second, the timing of the fluconazole level draw was variable, which either could under- or overestimate the AUC calculation, but multiple samples were averaged.…”

Section: Discussionsupporting

confidence: 51%

“…Finally, the exact target AUC above MIC ratio for consolidation therapy is unknown, and we have made an arbitrary approximation. Human data and excellent modeling has been conducted for fluconazole induction therapy [12], yet consolidation therapy recommendations has been derived mostly from expert opinion. Based on historical experience, the doses of fluconazole used during consolidation have been less than that used for induction fluconazole monotherapy.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

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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“…The CSF‐to‐plasma fluconazole concentration ratio has been shown to exceed 0.8 in adults . Furthermore, a recently published PopPK study in adults with cryptococcal meningitis found the mean fluconazole area under the concentration‐time curve of CSF to plasma to be 0.89 . Although this ratio was previously unknown for the pediatric population, in this study the range of simulated plasma and simulated CSF concentrations were approximately the same (Figure ).…”

Section: Discussionmentioning

confidence: 99%

Physiologically‐Based Pharmacokinetic Modeling of Fluconazole Using Plasma and Cerebrospinal Fluid Samples From Preterm and Term Infants

Gerhart

Watt

Edginton

et al. 2019

CPT Pharmacom & Syst Pharma

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Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically‐based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. The model was optimized using 760 plasma samples from 166 infants (median postmenstrual age (range) 28 weeks (24–50)) and 27 cerebrospinal fluid ( CSF ) samples from 22 infants ( postmenstrual age 28 weeks (24–33)). Simulations evaluated achievement of the surrogate efficacy target of area under the unbound concentration‐time curve ≥ 400 mg • hour/L over the dosing interval in plasma and CSF using dosing guidelines. Average fold error of predicted concentrations was 0.73 and 1.14 for plasma and CSF , respectively. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children.

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“…Nevertheless, adequate concentrations do not predict successful outcomes of FCZ alone in the treatment of CNS cryptococcal infections 18 . Although FCZ monotherapy even at higher dose is not recommended for cryptococcal meningitis therapy, in many regions of the world, FCZ is the only available drug for induction therapy for cryptococcal meningitis 91 . These is a need for improved provision of available combination treatments and development of more effective drugs 91 …”

Section: Triazolesmentioning

confidence: 99%

Antifungal drugs: An updated review of central nervous system pharmacokinetics

Wirth

Ishida

2020

Mycoses

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Invasive fungal infections (IFIs) in the central nervous system (CNS) are particularly hard to treat and are associated with high morbidity and mortality rates. Four chemical classes of systemic antifungal agents are used for the treatment of IFIs (eg meningitis), including polyenes, triazoles, pyrimidine analogues and echinocandins. This review will address all of these classes and discuss their penetration and accumulation in the CNS. Treatment of fungal meningitis is based on the antifungal that shows good penetration and accumulation in the CNS. Pharmacokinetic data concerning the entry of antifungal agents into the intracranial compartments are faulty. This review will provide an overview of the ability of systemic antifungals to penetrate the CNS, based on previously published drug physicochemical properties and pharmacokinetic data, for evaluation of the most promising antifungal drugs for the treatment of fungal CNS infections. The studies selected and discussed in this review are from 1990 to 2019.

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Population Pharmacokinetics and Cerebrospinal Fluid Penetration of Fluconazole in Adults with Cryptococcal Meningitis

Abstract: Robust population pharmacokinetic (PK) data for fluconazole are scarce. The variability of fluconazole penetration into the central nervous system (CNS) is not known.

Cited by 17 publications

References 42 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

Physiologically‐Based Pharmacokinetic Modeling of Fluconazole Using Plasma and Cerebrospinal Fluid Samples From Preterm and Term Infants

Antifungal drugs: An updated review of central nervous system pharmacokinetics

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