Youjung Cho1, Elin M. Svensson1,2, Isabela Ribeiro3, Thomas P.C. Dorlo1
1Department of Pharmacy, Uppsala University, 2Department of Pharmacy, Pharmacology and Toxicology, Radboud University Medical Center, 3Drugs for Neglected Diseases initiative
Objectives: Cryptococcal meningitis (CM) is an opportunistic fungal infection that predominates HIV/AIDS-related mortality, particularly in the sub-Saharan Africa region. An effective treatment using flucytosine (5FC), a key drug in the combination therapy against CM, is available¹. The current dosing regimen based on an immediate-release (IR) 5FC formulation is sub-optimal due to the short half-life of 5FC, which necessitates four daily doses. A sustained-release (SR) formulation of 5FC is under clinical development to simplify the dosing regimen and enhance treatment accessibility. Despite the availability of 5FC for almost 70 years, the absorption of the drug has not been well characterized, nor has the effect of food. A more detailed understanding and characterization of the variability of the absorption kinetics of IR 5FC is needed as a first step to further optimize and compare IR and SR formulations under development for the treatment of CM. The objective of the study was to characterize the pharmacokinetics (PK) of IR 5FC, with a focus on the absorption phase, using phase 1 clinical data through non-linear mixed effects modeling. Methods: Study design: Rich PK data were obtained from two recent phase 1 studies with healthy individuals in fasted (n=42) and fed (n=36) states, during which 21 and 17 plasma samples were collected, respectively, for each individual. For both prandial studies, the participants received an oral IR 5FC dose of 1500 mg (3 x 500 mg) twice daily at 0 and 6 hours, along with a meal before dosing. Model development: Data management and visualization were conducted using RStudio (v4.4.1). Models were developed and diagnosed using NONMEM (v7.5.1) and PsN (v5.3.1). Below the limit of quantification data (BLQ) of 2.36% was handled using the M6 method by imputing half of the lower limit of quantification (0.4 µg/ml). One-, 2-, 3-compartment models with different absorption models: i) lag time, ii) transit compartments, iii) sequential zero-order to first-order (FO) absorption, iv) parallel FO absorptions, and v) two FO absorptions with one delay absorption, were investigated. Covariates were explored on the fixed effect parameters. Inter-individual variability (IIV), inter-occasional variability (IOV) between dosing times, and residual unexplained variability (RUV) were evaluated. The model performance was diagnosed using visual predictive checks (VPCs) and goodness-of-fit plots (GoF), and models were selected based on the objective function value (OFV) for nested models (p < 0.05), the Akaike information criterion (AIC) value for non-nested models. Results: A two-compartment model with an FO absorption and transit compartments (n=5), where the absorption rate constant (ka) was described using the transit rate constant, ktr, best characterized the short delay observed in the absorption phase. Although having estimated ka numerically performed better, graphical examinations did not indicate large differences. Thus, the model with ktr as the absorption rate constant was chosen to reduce model complexity. FO elimination was used to describe the elimination phase. The population estimate for apparent clearance (CL/F) was 6.24 L/h [relative standard error (RSE): [2.43%], apparent volume of distribution 1 (V1/F) 49.0 L [2.64%], V2/F 3.00 L [21.3%], mean transit time (MTT) 0.462 h [6.41%], and intercompartmental clearance (Q1) 0.643 L/h [31.4%]. IIV estimates for CL/F, V1/F, bioavailability (F1), were 26.9% [30.7%], 30.8% [29.5%], and 36.2% [22.0%] of the coefficient variation CV, respectively. RUV was described with a combined error model, with an estimate of 35.6% [6.34%] for proportional and additive fixed to the half of the lower limit of quantification (0.2 mg/L). A difference between fasted and fed states was observed where food intake increased MTT by 60.7% [22.1%]. However, no food effect was identified for F1. A dose occasion covariate described the non-linearity observed after the second dose, where the drug exposure was overpredicted. The dose occasion effect was identified where F1 decreased by 7.42% [22.8%] and MTT increased by 18.8% [32.4%] after the 2nd dose. IOV was explored on all absorption parameters, but only IOV on MTT showed a significant drop in the OFV (dOFV), estimated at 64.2% of the coefficient variation (CV) [16.1%]. Conclusion: The current model adequately described the PK profile of IR 5FC and indicated a food effect in the absorption phase, where food intake led to a longer mean transit time, but did not affect bioavailability. Unexpectedly, a decrease in bioavailability was identified for the second dosing occasion, possibly indicating saturation of the extent of absorption. This model will be the basis for further comparison of the absorption characteristics of the various formulations under clinical development.
[1] Molloy, S. F., Kanyama, C., Heyderman, R. S., Loyse, A., Kouanfack, C., Chanda, D., Mfinanga, S., Temfack, E., Lakhi, S., Lesikari, S., Chan, A. K., Stone, N., Kalata, N., Karunaharan, N., Gaskell, K., Peirse, M., Ellis, J., Chawinga, C., Lontsi, S., Ndong, J. G., … ACTA Trial Study Team (2018). Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa. The New England journal of medicine, 378(11), 1004–1017. https://doi.org/10.1056/NEJMoa1710922
Reference: PAGE 33 (2025) Abstr 11374 [www.page-meeting.org/?abstract=11374]
Poster: Drug/Disease Modelling - Absorption & PBPK