Bhargavi Srija Ramisetty, PhD

1. PBPK model built using Ordinary Differential Equations's in SimBiology to study tissue distribution of Miltefosine in mice and extrapolating to predict clinical plasma and tissue pharmacokinetic profiles. Quantifying tissue distribution is crucial for this compound as it used to treat leishmaniasis, in which the parasites are mainly localized in intracellularly in the macrophages of spleen and liver. Miltefosine is an alkylphosphocholine compound with high protein binding, extensive tissue distribution and extended terminal half-life (30 days in humans). Parameter estimation, PBPK Model validation, Interspecies scaling and Sensitivity analysis were performed in this exercise of building Miltefosine PBPK model. Skills developed- a) Designing and executing in vitro ADME experiments like protein binding, MDCK, blood to plasma ratio and metabolic stability using Waters Xevo Tq-S b) PBPK model building using ODE's c) Fitting and validation of PBPK model d) Interspecies extrapolation 2. A mechanistic rat PBPK model was built in SimBiology for predicting the plasma concentration PK profiles of Genistein, and its glucuronide metabolites. Gensitein is known to have low aqueous solubility, undergoes UGT metabolism in rat liver and intestine, excrete glucuronide in bile and intestinal bacterial deglucuronidation. The PBPK model was built incorporating these mechanisms with the help of quantitative proteomics-based transporter expression data in liver and intestine. Skills developed- a) PBPK model accounting for circulation and disposition of glucuronide metabolite b) Building compartmental absorption model for oral dosing c) IVIVE of transporter related data to be used in PBPK model d) IVIVE of microsomal liver and intestinal metabolic clearance 3. A PBTK model was built for PFOA to capture urinary elimination and reabsorption mechanisms that contributes to its extended half-life.

1. A minimal rat PBPK model was employed using Simcyp platform to design strategies for resolving issues stemming from low oral bio-availability of a small molecule inhibitor with anticancer properties and to predict first-in-human doses. 2. PK/PD model was built to evaluate the turnover rate of an anticancer target protein employing PROTAC molecule in Simbiology.

1. Contributed to lead candidate optimization process by performing metabolite identification for 3 small molecules using Thermo LTQ-XL linear ion trap 2. Performed peptide mapping of a monoclonal antibody via LC-MS/MS bottom-up proteomics using Thermo Orbitrap

1 .Experience with regulatory filings by executing sameness evaluation for 2 complex generic molecules by determining the peptides sequences (Qualitative sameness) and relative quantification of steroidal moieties (Quantitative sameness) using data obtained from LC-HRMS (Synapt G2- Si and Q-exactive Orbitrap) studies 2. Ability to innovate by establishing a new in-house peptide sequencing protocol for characterization of process-related synthetic impurities of 4 peptidomimetic drugs using BioLynx software with data obtained from Waters Synapt G2-Si. 3. Strong communication skills, diligent Electronic Lab Notebook documentation, and experience working in a multidisciplinary team to plan strategically with colleagues across scientific disciplines