Medicine and Health Sciences Commons^™

In Vitro In Vivo Methods And Pharmacokinetic Models For Subcutaneously Administered Peptide Drug Products, Amit Somani

Theses and Dissertations

Over the last several years, injectable drugs have been a growing area for the treatment of various therapeutic conditions and they are projected to comprise an even larger proportion among the drugs that will be available in the years to come. The injectable drugs are administered by various routes such as intramuscular (IM), intravenous (IV), subcutaneous (SC) and others, however, the majority of these drugs are administered subcutaneously. Even though subcutaneous delivery has been utilized for a number of years, very little is known about the processes governing the absorption of macromolecules from the interstitial space; and the resulting impact …

Prediction Of Human Systemic, Biologically Relevant Pharmacokinetic Properties Based On Physicochemical Properties Of Calcium Channel Blockers, Tafif Abdullah Al

Theses and Dissertations

This research explored quantitative relationships (QSPKR) between different molecular descriptors and pertinent, systemic PK properties for 14 calcium channel blockers (CCB). Physicochemical properties (PC) such as molecular weight (MW), molar volume (MV), calculated logP (clogP), pKa, calculated logD7.4 (clogD), % ionized at pH 6.3 and pH 7.4, hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), and number of rotatable bonds (nRot) were chosen as possible predictor variables for systemic PK properties for CCB, obtained from pertinent literature, assessing the PK of CCB after intravenous administration to healthy humans. All PC properties and molecular descriptors were computed using ACD-solubility/DB 12.01. Total …

Preclinical Study Of Potential Antiglioma Novel Tetrahydroisoquinoline Analogs: Pharmacokinetics And Mechanism Of Action, Fei Ma

Theses and Dissertations (ETD)

Gliomas, the tumors of glial cells, account for 80% of primary malignant brain tumors. In 2011, there were about 18,300 new cases of maligant gliomas in the United States alone. Patients with glioblastoma multiforme or anaplastic astrocytoma, the two major types of malignant gliomas, have a median survival of 14 months or 2 to 3 years, respectively. Therefore novel treatments for malignant glioma are urgently needed.

A novel series of tetrahydroisoquinoline derivatives with antiglioma activity has been undergoing drug metabolism/pharmacokinetics (DMPK)-guided lead optimization. EDL-291 was result from structure modification of last generation compound EDL-155. Its preclinical pharmacokinetics were characterized in …

Pharmacokinetic/Pharmacodynamic (Pk/Pd) Modeling Of Anti-Neoplastic Agents, Daniel Lexcen, Ahmed H. Salem, Walid F. Elkhatib, Virginia Haynes, Ayman Noreddin

Pharmacy Faculty Books and Book Chapters

"Development of tumor resistance to chemotherapeutics is related to inherent tumor variations regarding sensitivity to chemotherapeutics and to sub-optimal dosing regimens, including variation in patient pharmacokinetics that result in suboptimal exposure of tumor cells to anti-neoplastic drugs [1, 2]. The rate and extent of drug efficacy depends on the extent of drug exposure at the tumor site and the time above the effective concentration [3]. In vitro models that incorporate these pharmacokinetic and pharmacodynamic (PK/PD) principles to optimize therapeutic response may be considered the method of choice for optimizing dosing schedules before translating data from static assays to animals and …

Application Of Pharmacokinetics/Pharmacodynamics (Pk/Pd) In Designing Effective Antibiotic Treatment Regimens, Ghada F. Ahmed, Ayman Noreddin

Pharmacy Faculty Books and Book Chapters

"Designing antibiotic dosing regimens is often not optimal and the dose-response relationship for most antibiotics is not well-known1. Both Pharmacokinetics (PK) and Pharmacodynamics (PD) are characteristics of antimicrobial agents that should be considered in the development of effective antibiotic therapy. By linking the concentration time profile at the site of action to the drug effect (PK/PD), the effect of varying dosage regimens against pathogens could be simulated enabling the identification of effective dosage strategies. It is known that inadequate antibiotic dosing could not only lead to a therapeutic failure, but also to the development of bacterial resistance. Importantly, the evolution …

The Effects Of Laropiprant, A Selective Prostaglandin D₂ Receptor 1 Antagonist, On The Antiplatelet Activity Of Clopidogrel Or Aspirin., Aimee Dallob, Wen-Lin Luo, Julie Mabalot Luk, Lisa Ratcliffe, Amy O Johnson-Levonas, Jules I Schwartz, Victor Dishy, Walter K. Kraft, Jan N De Hoon, Anne Van Hecken, Inge De Lepeleire, Waldemar Radziszewski, John A Wagner, Eseng Lai

walter k Kraft

Laropiprant (LRPT) is being developed in combination with Merck's extended-release niacin (ERN) formulation for the treatment of dyslipidemia. LRPT, an antagonist of the prostaglandin PGD₂ receptor DP1, reduces flushing symptoms associated with ERN. LRPT also has affinity for the thromboxane A₂ receptor TP (approximately 190-fold less potent at TP compared with DP1). Aspirin and clopidogrel are two frequently used anti-clotting agents with different mechanisms of action. Since LRPT may potentially be co-administered with either one of these agents, these studies were conducted to assess the effects of steady-state LRPT on the antiplatelet activity of steady-state clopidogrel or aspirin. Bleeding time …

Ceria-Engineered Nanomaterial Distribution In, And Clearance From, Blood: Size Matters, Mo Dan, Peng Wu, Eric A. Grulke, Uschi M. Graham, Jason M. Unrine, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

AIMS: Characterize different sized ceria-engineered nanomaterial (ENM) distribution in, and clearance from, blood (compared to the cerium ion) following intravenous infusion.

MATERIALS & METHODS: Cerium (Ce) was quantified in whole blood, serum and clot (the formed elements) up to 720 h.

RESULTS: Traditional pharmacokinetic modeling showed best fit for 5 nm ceria ENM and the cerium ion. Ceria ENMs larger than 5 nm were rapidly cleared from blood. After initially declining, whole blood 15 and 30 nm ceria increased (results that have not been well-described by traditional pharmacokinetic modeling). The cerium ion and 5 and 55 nm ceria did not …

Hepatic Immunosuppressive Effects Of Systemically- Administered Novel Dextran-Methylprednisolone Prodrugs With Peptide Linkers In Rats, Imam H. Shaik, Hitesh K. Agarwal, Keykavous Parang, Reza Mehvar

Pharmacy Faculty Articles and Research

The hepatic immunosuppressive activities of two novel dextran prodrugs of methylprednisolone (MP) containing one (DMP1) or five (DMP5) amino acids as linkers were studied in rats. At various times (02 weeks) after intravenous administration of single 5 mg/kg (MP equivalent) doses of each prodrug or MP succinate (MPS), livers were isolated and immunologically stimulated ex vivo with lipopolysaccharide. The concentrations of tumor necrosis factor (TNF)-a in the outlet perfusate were then quantitated to assess immune response. Additionally, the concentrations of DMP1, DMP5, and/or MP were measured in the liver. MPS, DMP5, or DMP1 injections caused a maximum of 48.9%, 63.5%, …

Effects Of Simulations On The Learning Of Pharmacokinetic Concepts, Reza Mehvar

Pharmacy Faculty Articles and Research

Objective: Although the use of computer simulations in pharmacokinetics courses is not new, the data on the effects of simulation on student learning are scarce. The objective of this study was to design and evaluate the use of Web-based simulations on the learning of pharmacokinetic concepts by doctor of pharmacy (PharmD) students.

Method: Six online modules were designed to allow the instructor and students to use “what-if” scenarios for understanding the effects of various dosage regimens and/or pharmacokinetic parameters on the plasma concentration-time courses of drugs. The designed modules were intravenous and oral pharmacokinetic concepts, bioavailability, intravenous infusion, …

The Importance Of Active Learning And Practice On The Students' Mastery Of Pharmacokinetic Calculations For The Intermittent Intravenous Infusion Dosing Of Antibiotics, Reza Mehvar

Pharmacy Faculty Articles and Research

Estimation of pharmacokinetic parameters after intermittent intravenous infusion (III) of antibiotics, such as aminoglycosides or vancomycin, has traditionally been a difficult subject for students in clinical pharmacology or pharmacokinetic courses. Additionally, samples taken at different intervals during repeated dose therapy require manipulation of sampling times before accurate calculation of the patient-specific pharmacokinetic parameters. The main goal of this study was to evaluate the effectiveness of active learning tools and practice opportunities on the ability of students to estimate pharmacokinetic parameters from the plasma samples obtained at different intervals following intermittent intravenous infusion.