bioRxiv2025
Sickle cell disease (SCD) is a genetic disorder that affects approximately 100,000 individuals in the United States and millions globally. Although curative therapies, such as stem cell transplant and gene therapy, are available, their application is limited by high cost and donor availability. Conseuently, drug therapy remains the most feasible treatment option for the majority of patients with SCD. To date, only four drugs have been approved by the FDA, but none of these treatments comprehensively address all SCD-related symptoms or crises, suggesting the pressing need for developing new drugs. Several high-throughput screening campaigns have been performed for SCD drug discovery based on the in vitro sickling of red blood cells (RBCs) and they have identified several hits. However, it is challenging to replicate the organ-specific oxygen level and physiological deoxygenation time in these in vitro RBC sickling assays. Furthermore, these assays do not consider the pharmacokinetics (PK) and pharmacodynamics (PD) of the identified drugs, which are essential to determine whether the drugs can provide robust and sustained efficacy in treated patients with SCD. To address these technical gaps, we have developed a computational platform to perform post-screening analysis of potential anti-sickling agents. This platform sequentially combines PK/PD models with a kinetic model of RBC sickling, enabling efficient prediction of the dosage-dependent therapeutic efficacy of various anti-sickling agents based on patient-specific hematological factors and organ-specific oxygen levels. We first demonstrate the effectiveness of our integrated platform by showcasing the therapeutic efficacy of two FDA-approved drugs, Hydroxyurea (HU) and voxelotor. Next, we evaluate the therapeutic efficacy of two potential anti-sickling agents under clinical trial, namely Bitopertin and osivelotor. Our findings suggest that Bitopertin exhibits anti-sickling effects that are considerably less pronounced than those of HU and voxelotor. On the other hand, osivelotor can achieve similar anti-sickling effects as voxelotor with significantly lower doses due to its improved PK properties. Furthermore, we show the versatility of the proposed platform in predicting the anti-sickling effect of multi-agent therapies and evaluate the conse-quences of drug noncompliance. In particular, our analysis indicates that noncompliance with voxelotor may result in rapid increases in RBC sickling, whereas osivelotor is likely to mitigate noncompliance-induced adverse effects due to improved PK properties. We further quantify the relationship between drug dosage and the duration of noncompliance that leads to loss of thera-peutic efficacy for voxelotor and osivelotor, providing guidance for optimizing dosage strategies to reduce the risk associated with noncompliance. In summary, our in silico platform serves as a valuable tool for post-screening analysis of potential anti-sickling agents by considering their PK and anti-sickling efficacy under patient-specific hemoglobin level and organ-specific oxygen level, thereby gaining insights into their potential therapeutic efficacy alone or in combination before clinical trials.