Clinical Pharmacokinetics of Oral Controlled-Release 5-Fluorocytosine

Abstract

5-Fluorocytosine (5FC) is an oral antifungal that is currently used in combination with amphotericin B totreat Cryptococcus neoformans meningoencephalitis. The oral dosing of 5FC could be optimized by the use of a controlled-release (CR) formulation. The objective of the current study was to develop two prototype 5FC-CR formulations and evaluate the single-dose (1,500-mg) serum pharmacokinetic profiles of those formulations relative to the profile of the commercially available, immediate-release 5FC product (Ancobon) by the use of a phase 1, open-label, randomized, three-phase, crossover pharmacokinetic study design. Hydroxypropyl methylcellulose was utilized as the rate-controlling matrix to compound the 5FC-CR tablets. The two prototype 5FC-CR formulations demonstrated 80% release at 13.0 and 18.4 h, respectively, whereas the immediaterelease product demonstrated 80% release at 0.28 h, as determined in vitro by the United States Pharmacopeia apparatus 2 dissolution method. Five subjects completed all three phases of the study without any adverse events. The mean maximum concentration, the area under the curve from time zero to 24 h, and the area under the curve from time zero to infinity were approximately 50% lower (P < 0.01) with the 5FC-CR formulations than with the immediate-release 5FC product. However, no statistically significant differences in the minimum concentrations at 24 h were noted between the formulations. The gastric absorption profile of 5FC-CR was well predicted by in vitro dissolution. Future exploration of a gastroretentive 5FC-CR formulation could overcome the marked lack of bioequivalence observed in the present study.Cryptococcus neoformans is an opportunistic fungal pathogen that is associated with significant morbidity and mortality. A 27% mortality rate has been associated with Cryptococcus neoformans meningoencephalitis (CNME) among AIDS patients in South Africa (15). An induction antifungal regimen of amphotericin B (AMB) and 5-fluorocytosine (5FC) for 2 weeks, followed by long-term fluconazole (FLZ) maintenance therapy, is considered the standard of care for AIDS patients with CNME (20). While it is effective, the use of induction therapy has been too complex for implementation in developing countries (11). The use of FLZ monotherapy in AIDS patients with CNME has been utilized but is associated with treatment failure and the emergence of resistance (3, 18). Hence, access to a simple, easy-to-administer combination oral antifungal regimen could improve CNME-related outcomes in countries without sufficient resources. The use of oral 5FC and FLZ combination regimens have demonstrated promising clinical results (4,8,10,14,16).However, currently recommended 5FC dosing regimens may not be optimal on the basis of pharmacokinetic (PK) and pharmacodynamic (PD) principles (7). For example, administration of 5FC at 25 mg/kg of body weight by mouth every 6 h yields steady-state maximum plasma concentrations (C max s) of 60 to 80 g/ml and minimum plasma concentrations (C min s) of 5 to 20 g/m...

Pharmacokinetics and tolerance of repeated oral administration of 5-fluorocytosine in healthy dogs

“…Our data showed that 5-FC presents a mean terminal slope of 163.1 ± 20.3 min after the first administration, which is less than in human patients with normal renal function where half-life ranges between 3 and 8 h [ 32 , 33 ]. Concomitant food intake has been demonstrated anecdotally to reduce the terminal half-life up to 2.6 h in human [ 34 ].…”

Cocrystallization-driven self-assembly with vanillic acid offers a new opportunity for surmounting fast and excessive absorption issues of antifungal drug 5-fluorocytosine: a combined theoretical and experimental research

“…8,9 As such, and in the light of biopharmaceuticals, the controlled-release formulations and capsules have been employed to tide over these issues of FCY. 10,11 Some countermeasures based on chemical structure modifications have also been adopted. 12,13 Despite some progress in optimizing the dissolution behavior and controlling exorbitant oral absorption, thereby reducing the toxicity and frequency of administration in these reported investigations, the expensive materials and complicated preparation processes have increased the cost of drug development, and these studies remain in the exploratory stage, which is not sufficient to immediately break the present stalemate for FCY.…”

Excited-State Structure and Dynamics of Keto–Amino Cytosine: The 1ππ* State Is Nonplanar and Its Radiationless Decay Is Not Ultrafast

“…Cytosine (Cyt) is a canonical pyrimidine nucleobase that pairs with guanine within double-stranded DNA; its derivatives play an important role in epigenetics and in medicine. − Methylation of Cyt at the 5-position is one of the central gene regulation mechanisms and has a large impact on the epigenome. − Regarding the photodynamics of isolated cytosine in aqueous solution and in the gas phase, excited-state relaxation to the ground state has been experimentally observed on the picosecond or even subpicosecond time scale. − This rapid nonradiative return to the ground state makes cytosine highly stable against UV irradiation, and the stability to UV photolysis has been taken to imply photochemical selection of cytosine as one of the molecular building blocks of life. − …”