Virginia D. Schmith

In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography

BACKGROUND Converging lines of evidence are consistent with an inhibitory effect of the antidepressant and smoking-cessation aid bupropion on dopamine and norepinephrine reuptake, but the in vivo effects of the drug at the human dopamine transporter (DAT) have not been studied to date. This study employed positron emission tomography (PET) to assess the extent and duration of DAT receptor occupancy by bupropion and its metabolites under conditions of steady-state oral dosing with bupropion sustained-release (SR) in healthy volunteers. METHODS Six healthy male volunteers received bupropion SR 150 mg daily on days 1 through 3 and 150 mg every 12 hours on day 4 through the morning of day 11. PET investigations were performed between 1 and 7 days before initiation of bupropion SR dosing, as well as 3, 12, and 24 hours after the last dose of bupropion SR on day 11. RESULTS Bupropion and its metabolites inhibited striatal uptake of the selective DAT-binding radioligand (11)C-betaCIT-FE in vivo. Three hours after the last dose of bupropion SR, average DAT occupancy by bupropion and its metabolites was 26%-a level that was maintained through the last PET assessment at 24 hours after dosing. CONCLUSIONS Bupropion and its metabolites induced a low occupancy of the striatal DAT over 24 hours under conditions of steady-state oral dosing with therapeutic doses of bupropion SR. These data are consistent with the hypothesis that dopamine reuptake inhibition may be responsible in part for the therapeutic effects of the drug.

Pharmacogenetics and Pharmacogenomics in Drug Development and Regulatory Decision Making: Report of the First FDA‐PWG‐PhRMA‐DruSafe Workshop

The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory “safe harbor” for exploratory genome‐based data, and to provide a forum for industry‐regulatory agency dialogue on these important issues.

Clinical pharmacokinetics of cisatracurium besilate.

Cisatracurium besilate, one of the 10 stereoisomers that comprise atracurium besilate, is a nondepolarising neuromuscular blocking agent with an intermediate duration of action. Following a 5- to 10-sec intravenous bolus dose of cisatracurium besilate to healthy young adult surgical patients, elderly patients and patients with renal or hepatic failure, the concentration versus time profile of cisatracurium besilate is best characterised by a 2-compartment model. The volume of distribution (Vd) of cisatracurium besilate is small because of its relatively large molecular weight and high polarity.Cisatracurium besilate undergoes Hofmann elimination, a process dependent on pH and temperature. Unlike atracurium besilate, cisatracurium besilate does not appear to be degraded directly by ester hydrolysis. Hofmann elimination, an organ independent elimination pathway, occurs in plasma and tissue, and is responsible for approximately 77% of the overall elimination of cisatracurium besilate.The total body clearance (CL), steady-state Vd and elimination half-life of cisatracurium besilate in patients with normal organ function are approximately 0.28 L/h/kg (4.7 ml/min/kg), 0.145 L/kg and 25 minutes, respectively. The magnitude of interpatient variability in the CL of cisatracurium besilate is low (16%), a finding consistent with the strict physiological control of the factors that effect the Hofmann elimination of cisatracurium besilate (i.e. temperature and pH). There is a unique relationship between plasma clearance and Vd because the primary elimination pathway for cisatracurium besilate is not dependent on organ function.There are minor differences in the pharmacokinetics of cisatracurium besilate in various patient populations. These differences are not associated with clinically significant differences in the recovery profile of cisatracurium besilate, but may be associated with differences in the time to onset of neuromuscular block.

Prospective Use of Population Pharmacokinetics/ Pharmacodynamics in the Development of Cisatracurium

AbstractPurpose. The population PK/PD approach was prospectively used to determine the PK/PD of cisatracurium in various subgroups of healthy surgical patients. Methods. Plasma concentration (Cp) and neuromuscular block data from 241 patients in 8 prospectively-designed Phase I−III trials were pooled and analyzed using NONMEM. The analyses included limited Cp-time data randomly collected from 186 patients in efficacy/safety studies and full Cp-time data from 55 patients in pharmacokinetic studies. The effects of covariates on the PK/PD parameters of cisatracurium were evaluated. The time course of neuromuscular block was predicted for various patient subgroups. Results. The population PK/PD model for cisatracurium revealed that anesthesia type, gender, age, creatinine clearance, and presence of obesity were associated with statistically significant (p < 0.01) effects on the PK/PD parameters of cisatracurium. These covariates were not associated with any clinically significant changes in the predicted recovery profile of cisatracurium. Slight differences in onset were predicted in patients with renal impairment and patients receiving inhalation anesthesia. Based on the validation procedure, the model appears to be accurate and precise. Conclusions. The prospective incorporation of a population PK/PD strategy into the clinical development of cisatracurium generated information which influenced product labeling and reduced the number of studies needed during development.

Pharmacokinetics of Alvimopan and Its Metabolite in Healthy Volunteers and Patients in Postoperative Ileus Trials

Alvimopan, a μ‐opioid antagonist without anti‐analgesic effects, is being developed to manage postoperative ileus. We characterized the population pharmacokinetics of orally administered alvimopan and its primary metabolite in healthy subjects/special populations, and surgical patients at risk for ileus. Models were consistent with known physiology/pharmacology. Alvimopans model had two compartments with first‐order elimination. Metabolite was modeled with a catenary chain and lag for alvimopans metabolism within the gut followed by absorption, one systemic compartment with first‐order elimination. Weight, gender, and renal function did not affect alvimopan or metabolite. Steady‐state alvimopan and metabolite concentrations were 87 and 40% higher, respectively, in patients. Alvimopan concentrations were 35% higher in the elderly, but were not affected by race, acid blockers, or antibiotics. Metabolite concentrations were 43 and 82% lower in African Americans and Hispanics, respectively, compared to Caucasians, 49% lower with acid blockers and 81% lower with preoperative antibiotics. Although alvimopans pharmacokinetics was described with a traditional model, its metabolite required a novel model accommodating gut metabolism.

Effects of Inflammation on Pharmacokinetics/Pharmacodynamics: Increasing Recognition of Its Contribution to Variability in Response

Inflammation is an interesting phenomenon that crosses many disciplines as part of the host response to disease, whether it is the acute response to an infectious, traumatic, or surgical event or the more chronic responses to systemic disease such as malignancy, rheumatoid arthritis, asthma, inflammatory bowel disease, or diabetes. The impact of inflammatory states on the variability in drug response should be an integral part of research conducted across disciplines within clinical pharmacology.

The Pharmacokinetics and Pharmacodynamics of GW395058, a Peptide Agonist of the Thrombopoietin Receptor, in the Dog, a Large-Animal Model of Chemotherapy-Induced Thrombocytopenia

GW395058, a PEGylated peptide agonist of the thrombopoietin receptor, stimulates megakaryocytopoiesis and has previously been shown to increase platelet counts in vivo. The pharmacokinetics and pharmacodynamics of GW395058 were characterized using a randomized, crossover study in a large‐animal model (dog) of chemotherapy‐induced thrombocytopenia.

Dose Proportionality of Cisatracurium

The dose proportionality of cisatracurium pharmacokinetics was assessed using a population approach by incorporating the collection of sparse blood samples from patients in clinical trials. Plasma concentration—time data from 131 patients with limited concentration—time data and 38 patients with full sampling were pooled and analyzed using nonlinear mixed‐effects modeling (NONMEM). Dose proportionality was assessed using dichotomous parameterization and a linear model. The population pharmacokinetic approach revealed that the pharmacokinetics of cisatracurium are independent of dose between 0.1 mg/kg and 0.4 mg/kg, as was expected based on the importance of Hofmann elimination, a chemical process dependent on pH and temperature.

Development of a Population Pharmacokinetic Model To Describe Azithromycin Whole-Blood and Plasma Concentrations over Time in Healthy Subjects

ABSTRACT Azithromycin (AZI), a broad-spectrum antibiotic, accumulates in polymorphonuclear cells and peripheral blood mononuclear cells. The distribution of AZI in proinflammatory cells may be important to the anti-inflammatory properties. Previous studies have described plasma AZI pharmacokinetics. The objective of this study was to describe the pharmacokinetics of AZI in whole blood (concentration in whole blood [Cb]) and plasma (concentration in plasma [Cp]) of healthy subjects. In this study, 12 subjects received AZI (500 mg once a day for 3 days). AZI Cb and Cp were quantified in serial samples collected up to 3 weeks after the last dose and analyzed using noncompartmental and compartmental methods. After the last dose, Cb was greater than Cp. Importantly, Cb, but not Cp, was quantifiable in all but one subject at 3 weeks. The blood area under the curve during a 24-h dosing interval (AUC24) was ∼2-fold greater than the plasma AUC24, but simulations suggested that Cb was not at steady state by day 3. Upon exploration of numerous models, an empirical 3-compartment model adequately described Cp and Cb, but Cp was somewhat underestimated. Intercompartmental clearance (CL; likely representing cells) was lower than apparent oral CL (18 versus 118 liters/h). Plasma, peripheral, and cell compartmental volumes were 439 liters, 2,980 liters, and 3,084 liters, respectively. Interindividual variability in CL was low (26.2%), while the volume of distribution variability was high (107%). This is the first report to describe AZI Cb in healthy subjects, the distribution parameters between Cp and Cb, and AZI retention in blood for up to 3 weeks following 3 daily doses. The model can be used to predict Cb from Cp for AZI under various dosing regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01026064.)

Alvimopan pharmacokinetics (PK) & pharmacodynamics (PD) in patients with chronic constipation (CC)

To characterize the PK/PD of alvimopan and its active metabolite (ADL 08–0011) in CC patients.