Abstract
Neurocryptococcosis, a meningoencephalitis caused by Cryptococcus spp, is treated with amphotericin B (AmB) combined with fluconazole. The integrity of the brain-blood barrier and the composition of the cerebrospinal fluid (CSF) may change due to infectious and/or inflammatory diseases such as neurocryptococcosis allowing for the penetration of AmB into the central nervous system. The present study aimed to develop LC-MS/MS methods capable of quantifying AmB in CSF at any given time of the treatment in addition to plasma, plasma ultrafiltrate, with sensitivity compatible with the low concentrations of AmB reported in the CSF. The methods were successfully validated in the four matrices (25 μl, 5–1,000 ng ml−1 for plasma or urine; 100 μl, 0.625–250 ng ml−1 for plasma ultrafiltrate; 100 μl, 0.1–250 ng ml−1 for CSF) using protein precipitation. The methods were applied to investigate the pharmacokinetics of AmB following infusions of 100 mg every 24 h for 16 days administered as a lipid complex throughout the treatment of a neurocryptococcosis male patient. The methods allowed for a detailed description of the pharmacokinetic parameters in the assessed patient in the beginning (4th day) and end of the treatment with AmB (16th day), with total clearances of 7.21 and 4.25 L h−1, hepatic clearances of 7.15 and 4.22 L h−1, volumes of distribution of 302.94 and 206.89 L, and unbound fractions in plasma ranging from 2.26 to 3.25%. AmB was quantified in two CSF samples collected throughout the treatment with concentrations of 12.26 and 18.45 ng ml−1 on the 8th and 15th days of the treatment, respectively. The total concentration of AmB in plasma was 31 and 20 times higher than in CSF. The unbound concentration in plasma accounted for 77 and 44% of the respective concentrations in CSF. In conclusion, the present study described the most complete and sensitive method for AmB analysis in plasma, plasma ultrafiltrate, urine, and CSF applied to a clinical pharmacokinetic study following the administration of the drug as a lipid complex in one patient with neurocryptococcosis. The method can be applied to investigate the pharmacokinetics of AmB in CSF at any given time of the treatment.
Highlights
Neurocryptococcosis is a subacute meningoencephalitis caused by the inhalation of the fungus Cryptococcus spp
The methods for quantifying of Amphotericin B (AmB) in the four biological matrices were applied to the investigation of the pharmacokinetics of AmB in a male patient treated for neurocryptococcosis
The present study aimed to develop a method capable of quantifying AmB in cerebrospinal fluid (CSF) at any given time of the treatment in addition to plasma, plasma ultrafiltrate, and urine
Summary
Neurocryptococcosis is a subacute meningoencephalitis caused by the inhalation of the fungus Cryptococcus spp. Neurocryptococcosis is more prevalent in HIV and other immunosuppressed patients and less commonly in individuals considered immunocompetent (Jarvis et al, 2010; Durski et al, 2013; Pyrgos et al, 2013; Rolfes et al, 2015; Williamson et al, 2016). The treatment for neurocryptococcosis aims to sterilize the central nervous system and reduce intracranial pressure to values below 200 mmH2O considering that pressures above 350 mmH2O are associated with papilledema, decreased visual acuity, decreased hearing capacity, headaches, and confusion. Symptoms resulting from increased cerebrospinal fluid (CSF) pressure can be controlled by lumbar punctures to reduce pressure to levels below 200 mmH2O (Redmond et al, 2007). Amphotericin B (AmB; C47H73NO17) is a polyene derived from Streptomyces nodosus, a compound discovered in the 1950s that remains the first line of treatment for invasive fungal infections, new triazole antifungal drugs with a broad spectrum of action and good distribution to the central nervous system, such as voriconazole and posaconazole are available (Black and Baden, 2007; Lestner et al, 2010)
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