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36 active trials for Pharmacokinetics

MDMA in Subjects With Moderate Hepatic Impairment and Subjects With Normal Hepatic Function

This study is an open-label, single dose study evaluating the effect of moderate hepatic impairment in the pharmacokinetics of MDMA and its active metabolite, 3,4-methylene-dioxyamphetamine (MDA) in order to decide whether an adjustment to the dosage would be need for individuals with moderate hepatic function in comparison to individuals with normal liver function. Eight participants with moderate hepatic impairment and eight matched participants with normal hepatic function will take part in this study. All patients will be evaluated to see if they meet criteria for study participation, with screening including a physical examination including a 12-lead electrocardiogram (ECG) and questions about mental and physical health. Participants who meet study criteria will stay at the study site for three days. On Day 1, they will receive a single dose of 80 mg MDMA. For the next seven to eight hours, participants will have blood collected and will rate their mood and other experiences. They will stay at the study sight for two more days. Blood will be drawn twice on the second day and once on the third day, and they will have their heart function measured with ECG. Blood will be collected periodically during a 12-hour interval on the day of drug administration. Blood will also be drawn 24, 36, 48, 72 and 96 hours after MDMA administration. Participant mood and feelings or experiences on-drug (subjective effects) will be measured a half-hour, one, two, four, six, and seven hours after receiving MDMA. ECG will be performed every day at the same time upon enrollment (Day -4 or -3) and from the Day 1 (day of drug administration) to Day 5. Blood pressure, heart rate and body temperature on Day 1 through 5. Blood samples will be used to compute the peak or maximum amount of MDMA and MDA in blood (Cmax), the time until reaching peak MDMA or MDA (Tmax) and the area under curve (AUC), or actual degree of exposure to drug. The primary outcome measure will be AUC for MDMA. Finding out if there are differences in drug metabolism between people with normally functioning livers and people whose livers do not function normally will help researchers performing MDMA-assisted psychotherapy.

Start: March 2022
Liposomal Bupivacaine Versus Plain Bupivacaine After Intercostal Injections For Pain Management After Thoracoscopy

The purpose of this study is to assess pharmacokinetics of liposomal bupivacaine (Exparel) after multilevel intercostal injections of this local anesthetic for pain control during and after thoracoscopic surgeries. The specific aim of this study is to evaluate plasma concentration of bupivacaine after intraoperative intercostal injections of 266 mg of liposomal bupivacaine and compare it to plasma concentrations of bupivacaine after intercostal injections of 2mg/kg of 0.5% plain Bupivacaine with maximal dose of 30 ml or 150 mg. The hypothesis of the study is that plasma concentration of bupivacaine after intercostal injections of 266 mg of liposomal bupivacaine will be similar to concentrations after injections of plain bupivacaine, and will remain below the toxic level threshold range of 2000-3000 ng/mL (2-3 mg/L) at which central nervous system and cardiovascular adverse events would be expected to occur. The secondary objective is to evaluate if intercostal injections of 266 mg of liposomal bupivacaine will significantly reduce opioid consumption and postsurgical pain, within the first 48 hours and up to 3 months after minimally invasive thoracic surgeries, to determine if both acute and chronic post-thoracotomy pain can be decreased by intraoperative intercostal injections of liposomal bupivacaine. Additionally, the rate of pneumonia, the rate of atrial fibrillation and length of hospital stay will be assessed as secondary outcomes after thoracic surgeries. These outcomes can be affected by the level of postoperative pain and inflammation. Significance of this study: If positive, the results of this research have the potential to significantly improve pain management after thoracoscopic surgery. Based on prior experience, prolonged analgesia after liposomal bupivacaine injection is safe, and may help reduce perioperative opioid consumption and decrease opioid related complications. It will improve patient comfort, eliminate need for indwelling neuraxial catheters and risks associated with them.

Start: April 2019
P-glypoprotein Inhibition Effect on the Pharmacokinetics of Two Tacrolimus Formulations: Prolonged and Extended-release

Tacrolimus is a drug administered orally available with different formulations: immediate release (Prograf®), prolonged-release (Advagraf®) and an extended-release one named LCP-Tacro (Envarsus®), formulated using the Melt-Dose process. Tacrolimus is a lipophilic macrolide drug able to passive transmembrane diffusion. Its bioavailability displays a large interindividual variability, from 9 to 43%. Indeed, tacrolimus is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). P-gp is an efflux protein mainly located at the apex of the epithelia of the intestine, lymphocyte, kidney and blood-brain barrier. P-gp therefore limits the intestinal resorption of tacrolimus and also its diffusion into its target compartment (i.e the lymphocyte. The expression of this protein is different throughout the digestive tract with maximum expression at the ileal level. CYP3A4 is a coenzyme that is responsible of more than 90% of the metabolism of tacrolimus, at the digestive and hepatic level. Both P-gp and CYP3A4 play a role in tacrolimus absorption/diffusion process. A new formulation of tacrolimus, LCP-Tacro, (Envarsus®) was approved in 2014. Its efficacy was compared to Prograf® in two phase III de novo or switch Prograf® trials in kidney transplantation. With tacrolimus, there is a strong inter-individual pharmacokinetic variability which, to date, has not been fully characterized. Variations in bioavailability may partly explain this high variability. The different formulations are resorbed at distinct gastrointestinal sites which could explain different absorptions between Prograf/Advagraf and LCP-Tacro forms. These findings raise the question of the role of P-gp in explaining the difference in bioavailability between formulations. The use of a P-gp inhibitor could therefore have a different impact on exposure to different galenic formulations. Verapamil is an inhibitor of P-gp and CYP 3A4, which is frequently prescribed and recommended by FDA for drug-drug interaction studies aiming at evaluating P-gp substrates, used in healthy volunteers at dosages up to 240 mg/D13-14. Otherwise, verapamil-tacrolimus interaction has been characterized in vitro. It has also been shown that inhibitory effect of verapamil at a single dose of 120 mg administered one hour prior to the administration of a P-gp substrate exhibited an optimum power of inhibition. The safety of Advagraf® and Envarsus® administrations have already been subjected to several phase I trials in healthy volunteers reinforcing the knowledge of their safety profile. The aim of the study is to compare the interaction profile of Advagraf® and Envarsus® when co-administered with verapamil in healthy subjects and to provide guidelines on tacrolimus dosage adjustment in such cases.

Start: September 2021
Naldebain for Pain Control After Bariatric Surgery

Laparoscopic gastric sleeve and bypass surgeries the most common bariatric procedures for weight loss and improved management of metabolic syndromes. Patients may suffer from wound pain or referred pain after laparoscopic bariatric operation. Most importantly, 11.8% of these patients complained surgical-related pain one year after operation, and 8% of them required prolonged use of opioid to control chronic postoperative pain (CPSP). However, there are currently lack of clinical practice guidelines or recommendations for prevention of CPSP after laparoscopic abdominal surgery. Although regional block techniques (i.e. truncal block or intrathecal opioid) are considered as effective supplementary analgesic approaches to improve postoperative pain control, parenteral administration of analgesics remain as the mainstay for pain management of laparoscopic abdominal surgery. Naldebain® is prodrug of nalbuphine, which was approved by the Taiwan FDA in 2017. Naldebain® is an extended-release dinalbuphine sebacate, and is rapidly hydrolyzed by tissue of plasma esterase to release nalbuphine. A number of clinical studies have shown that single-dose of pre-operative intramuscular administration of Naldebain® provides significantly higher analgesic effect up to 1 week in hemorrhoidectomy and laparotomy surgery with a well-tolerated safety profile. Therefore, this PI-initiated randomized, double-blind, placebo-control trial aims to investigate the clinical efficacy of Naldebain® in management of acute postoperative pain in patients receiving laparoscopic gastric sleeve or bypass surgery, and prevention of the development of CPSP after surgery. This study will also analyze the plasma levels of nalbuphine following a single intramuscular injection in obese patients.

Start: April 2021