Physiologically-based pharmacokinetic (PBPK) modeling to predict disease effects on 5-flucytosine pharmacokinetics (PK) in the context of a switch from an immediate release (IR) to a sustained release (SR) formulation in the treatment of cryptococcal meningoencephalitis.
Johanna Eriksson (1), Erik Sjögren (1), Jean-Yves Gillon (2), Vishal Goyal (2), Vijay Satam (2), Stephen Robinson (2), Henri Caplain (2), Isabela Ribeiro (2), Marylore Chenel (1)
(1) Pharmetheus, Sweden, (2) Drugs for Neglected Diseases initiative (DNDi), Switzerland
Objectives:
5-flucytosine (5FC) is used for the treatment of cryptococcal meningoencephalitis in patients with advanced HIV. Currently, an immediate release (IR) tablet is dosed four times a day, with the risk of low adherence [1,2]; additionally, it is not well adapted for severely ill patients, who require administration by nasogastric tube. To address these issues, a sustained release (SR) pellet formulation was developed. Two PK studies were performed in healthy volunteers to evaluate the IR and SR formulations. In healthy volunteers the bioavailability of the SR formulation relative to the IR population was 54% in fasted state, indicating incomplete absorption of the SR formulation. A PBPK model was subsequently established for 5FC using these data from healthy volunteers [3,4]. Based on these initial results and PBPK simulations of multiple dosing, the SR dosing regimen was adjusted to meet the exposure metrics for the IR formulation in healthy individuals. The aim of this study was to use the 5FC PBPK model to simulate 5FC exposure in patients, including HIV-associated disease components for the two formulations, to assess the risk of switching from an IR to a SR formulation in terms of PK exposure.
Methods:
A healthy population (n=200) was generated in PK-Sim v 9.1 and modified to include the following disease components: 1) increased (20%) intestinal permeability, as a consequence of “leaky” intestine, 2) decreased (20%) intestinal permeability, as a consequence of damaged microvilli intestine, 3) diarrhea due to faster transit time in the small intestine (20%) and the large intestine (50%) [5,6], 4) diarrhea due to higher water volume in the large intestine (50%) and 5) severe malnutrition [7]. The previously established PBPK model for 5FC, including elimination via glomerular filtration and fraction unbound in plasma of 97% [3,4], was used to simulate PK exposure metrics for the IR and SR formulations under fasting conditions in the different disease populations stated above. The simulated PK parameters were then compared to the fasted PK parameters in a healthy population.
Results:
Severe malnutrition had a significant impact on the PK of both the SR and IR formulations, where there was an increase in median exposure (15-18 %) and maximum concentration (Cmax) (13-15%), due to reduced renal clearance in this population [7]. The impact was similar for both formulations, and thus shifting from an IR to an SR formulation cannot be considered a specific risk for the treatment of cryptococcal meningoencephalitis in severe malnourished patients. The main disease effect risk on exposure was identified to be diarrhea caused by fast gastro-intestinal transit time, with a 10% lower ratio (SR/IR) for simulated exposure compared to that in a healthy population. This may be explained by the shorter time available for absorption in patients with diarrhea, affecting the SR formulation to a greater extent than the IR formulation.
Conclusions:
Based on PBPK data, switching from an IR to an SR formulation for the treatment of cryptococcal meningoencephalitis is not predicted to impact the exposure ratio (IR/SR) in a patient population, except for patients with fast transit diarrhea. For malnourished patients, the effect on exposure is significant and similar between the two formulations.
References:
[1] Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. The Journal of antimicrobial chemotherapy 2000; 46(2): 171-9.
[2] Archibald LK, et al. Antifungal susceptibilities of Cryptococcus neoformans. Emerging infectious diseases 2004; 10(1): 143-5.
[3] Goyal V, et al. Bioavailability of three novel oral, sustained-release pellets, relative to an immediate-release tablet containing 500 mg Flucytosine (Ancotil®): a randomized, open-label, crossover study in healthy subjects. Clinical Translational Science, 2024, accepted for publication.
[4] Eriksson J, et al. Physiologically based pharmacokinetic (PBPK) modeling of the oral absorption of 5-flucytosine to support further development of a sustained-release formulation for the treatment of cryptococcal meningoencephalitis. PAGE abstract 2023.
[5] Sharpstone, D., et al. "Small intestinal transit, absorption, and permeability in patients with AIDS with and without diarrhoea." Gut 45.1 (1999): 70-76.
[6] Ohe, Manfred R. von der, et al. "Motor dysfunction of the small bowel and colon in patients with the carcinoid syndrome and diarrhea." New England Journal of Medicine 329.15 (1993): 1073-1078.
[7] Sjögren, Erik, et al. "A physiologically-based pharmacokinetic framework for prediction of drug exposure in malnourished children." Pharmaceutics 13.2 (2021): 204.
