Dr. Raman Venkataramanan
Personalized dosing regimen of drugs in transplant patients (tacrolimus and cyclosporine) and pregnant women (buprenorphine).
Projects
Functional capacity of regenerating liver
This project aims to characterize the hepatic metabolic function following living donor liver transplantation (LDLT) using midazolam as a probe substrate for CYP3A activity. Midazolam is a well-established probe for assessing CYP3A-mediated metabolism in humans. In this study, a subtherapeutic intravenous dose of midazolam is administered to both donors and recipients. Donors receive midazolam before donation and at four time points after surgery, while recipients receive it at four post-transplant time points (1 week, 1 month, 3 months, 6 months). Plasma concentrations of midazolam and its primary metabolite, 1′-hydroxymidazolam, will be quantified using a validated LC-MS/MS analytical method in order to evaluate the effect of hepatic regeneration.
Functional capacity of liver from circulatory death donors
Liver transplantation is the only treatment option for end-stage liver diseases. Due to the increased organ shortage, livers from circulatory death donors (DCD) have been increasingly utilized for transplantation. DCD liver transplantation increases the risk for complications associated with ischemia reperfusion injury (IRI), and ischemic cholangiopathy, leading to biliary complications and poor transplant outcomes. This project investigates the effects of treprostinil, a prostacyclin analog with vasodilatory, anti-inflammatory, and anti-platelet properties, in minimizing IRI by improving microcirculation, downregulating pro-inflammatory cytokines, and significantly improving the metabolic and transporter function and outcomes in animals and patients with DCD livers.
Xenotransplantation
Xenotransplantation using genetically engineered pig organs has recently emerged as a promising approach to address the shortage of organs for transplantation in patients with end stage organ diseases. However, the ability of pig kidney and liver to clear drugs that are commonly used in transplant patients is not completely understood. We are investigating how porcine livers metabolize and transport medications commonly administered to liver transplant patients, addressing a critical knowledge gap in pig liver xenotransplantation. By integrating experimental findings into physiologically based pharmacokinetic models, this project aims to predict drug exposure and in human recipients with pig livers thereby personalizing drug dosing in this patient population.
Buprenorphine pharmacokinetics in pregnancy
Pregnancy results in significant physiological changes that can alter drug exposure and response. Pregnant women use buprenorphine to treat substance use disorder. However, the dosing regimen used in pregnant subjects is same as non pregnant women. Our in vitro, preclinical, in silico and clinical studies evaluate the effect of pregnancy on buprenorphine exposure and response in order to improve use of buprenorphine in pregnancy.
Optimizing methadone dosing in pregnancy
Methadone is a treatment option for substance use disorder. Methadone is commonly administered once a day. Preliminary observations and physiologically based pharmacokinetic modeling indicate increased elimination of methadone during pregnancy. Clinically, a twice daily dosing option for methadone is being studied. Our study is focused on optimizing methadone use in pregnancy by understanding the pharmacokinetics and pharmacodynamics of methadone in pregnancy.
