Background 5-flucytosine (5FC) is used for the treatment of cryptococcal meningoencephalitis (CM) in patients with advanced HIV. The current dosing is four times a day involving high risks of low adherence and not adapted for severely ill patients. To address this, a sustained release (SR) pellet formulation was developed. Two PK studies in healthy subjects were performed, evaluating the immediate release (IR) and SR formulations. To estimate the SR formulation exposure of 5FC in patients, PBPK modelling was applied.

Methods A healthy population was generated in PK-Sim [3,4] 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) diarrhoea due to faster transit time in small intestine (20%) and large intestine (50%), 4) diarrhoea due to higher water volume in large intestine (50%) and 5) severe malnutrition.

Results The main risk in exposure with the SR formulation compared to IR formulation is for diarrhoea caused by fast transit time, resulting in a 10% lower ratio (SR/IR) exposure compared to a healthy population. This can be explained by the shorter time available for absorption in diarrhoea, affecting the SR formulation to a greater extent than the IR formulation.

Conclusion Switching from an IR to SR formulation for the treatment of CM is not predicted to impact exposure in a patient population, except for patients with fast transit diarrhoea.

Funding: This project is funded by the EDCTP2 programme supported by the EU, with additional funding from the Swiss Agency for Development and Cooperation (SDC), MSF International, and other private foundations and individuals. The findings and conclusions contained herein are those of the authors and do not necessarily reflect positions or policies of the aforementioned funding bodies.