Application of Salivary Concentration Data to Pharmacokinetic Studies with Antipyrine

1977 ◽  
Vol 66 (1) ◽  
pp. 135-137 ◽  
Author(s):  
Peter J. Meffin ◽  
Roger L. Williams ◽  
Terrence F. Blaschke ◽  
Malcolm Rowland
Keyword(s):  
Pharmacokinetic Studies ◽  
Concentration Data ◽  
Salivary Concentration

Phase I study of the EGFR tyrosine kinase inhibitor erlotinib in combination with docetaxel and radiation in locally advanced squamous cell cancer of the head and neck (SCCHN)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5545-5545 ◽  
Author(s):  
P. Savvides ◽  
S. S. Agarwala ◽  
J. Greskovich ◽  
A. Argiris ◽  
J. Bokar ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phase I ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Stage Iii ◽  
Pharmacokinetic Studies ◽  
Concentration Data ◽  
Egfr Tyrosine Kinase Inhibitor ◽  
Egfr Tyrosine Kinase ◽  
Dose Levels

5545 Background: EGFR is highly expressed in SCCHN, representing a promising therapeutic target. Erlotinib (E) is an EGFR tyrosine kinase inhibitor that may potentiate the efficacy of concurrent radiation (RT) and docetaxel (D). We sought to establish the MTD, toxicities and preliminary efficacy of the combination of RT, D and E in patients (pts) with SCCHN. Methods: Patients with previously untreated stage III-IVB SCCHN were enrolled in a phase I dose-escalating study with standard once-daily RT (70.2 Gy, 1.8 Gy/day), weekly D for the duration of RT and daily E for two weeks prior, during and up to two years following RT. 4 dose levels (DL) were evaluated [D (mg/m2)/E (mg): 15/50, 15/100, 20/100, 20/150]. A 3+3 escalation design was followed. Pharmacokinetic studies (PK) were performed. Results: A total of 23 patients were enrolled (6 pts at each DL 1–3, 5 pts at DL4). Primary site: oral cavity (n = 1), pharynx (n = 15) and larynx (n = 7). 20 patients (87%) had stage IV disease. Three dose-limiting toxicities were observed, 1 at each DL (1–3), including a death within 30 days from last treatment (DL1), grade 3 mucositis resulting in holding RT (>5 days) (DL2) and grade 4 mucositis (DL3). No DLT to date on DL4 with 3/5 pts evaluable. In patients enrolled at DL 1–3 (n = 18), post concurrent chemoRT, best response was CR (n = 15), not evaluable (n = 2), death on study (n = 1). 3/3 pts who underwent planned neck dissection had a pathologic CR. 9 patients are currently receiving adjuvant E and 1 has completed the 2-year course. 3 patients have relapsed. Interpatient variability of E peak plasma concentrations measured after the first dose was observed at all dose levels: 458 ± 173 ng/mL (DL1), 686 ± 364 (DL2), 1017 ± 241 (DL3), 833 ± 222 (DL4) (mean ± s.d., n = 6, 6, 6, 2 at DL1–4 respectively). Adjuvant erlotinib plasma concentration data will be presented separately. No significant PK interaction of erlotinib with docetaxel was noted. Conclusions: The combination of daily erlotinib with weekly docetaxel and RT for pts with stage III-IVB SCCHN is feasible and active. A phase II trial is planned. Supported in part by NIH grants nos. CA62502 and M01 RR-000080. No significant financial relationships to disclose.

Application of Physiologic Models to Predict the Influence of Changes in Body Composition and Blood Flows on the Pharmacokinetics of Fentanyl and Alfentanil in Patients 

1998 ◽  
Vol 88 (3) ◽  
pp. 657-667 ◽  
Author(s):  
Sven Bjorkman ◽  
Russell D. Wada ◽  
Donald Stanski
Keyword(s):  
Body Composition ◽  
Cardiac Output ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Studies ◽  
Concentration Data ◽  
Blood Flows ◽  
Wide Range ◽  
Regional Blood Flows ◽  
Physiologic Models

Background The influence of changes in the physiologic state of a patient on the disposition of fentanyl and alfentanil is poorly understood. The aims of this study were to determine whether physiologic pharmacokinetic models for fentanyl and alfentanil, based on data from rats, could predict plasma concentrations of these opioids in humans and to determine how changes in physiology would influence the predictions of their disposition. Methods The predictions of the models were tested against plasma concentration data from published pharmacokinetic studies. The influences of changes in body composition, cardiac output, and regional blood flows on the disposition of the opioids were simulated. Results The models could predict independently measured plasma concentrations of the opioids after short infusions in humans. Simulations then predicted that differences in body composition between men and women would have little influence on the pharmacokinetics of the opioids. Changes in cardiac output would affect drug redistribution, and consequently the early decay of the plasma concentrations, but not markedly influence rates of elimination. Further, the clearance of the opioids would decrease and their volumes of distribution increase with the age of the patient, but this would only marginally affect the early disposition of the drugs. Even large fluctuations in peripheral or hepatic blood flows would have modest effects on arterial plasma concentrations of the opioids, and sudden "postoperative" increases in peripheral blood flows would cause minor secondary plasma concentration peaks. Conclusions The ability of the physiologic models to predict plasma concentrations of fentanyl and alfentanil in humans was confirmed. When changes in physiologic condition were simulated, effects on the pharmacokinetics of the opioids with possible implications for dosing were obtained only if cardiac output was varied over a wide range.

scholarly journals Interspecies Mixed-Effect Pharmacokinetic Modeling of Penicillin G in Cattle and Swine

2014 ◽  
Vol 58 (8) ◽  
pp. 4495-4503 ◽  
Author(s):  
Mengjie Li ◽  
Ronette Gehring ◽  
Lisa Tell ◽  
Ronald Baynes ◽  
Qingbiao Huang ◽  
...  
Keyword(s):  
Compartment Model ◽  
Penicillin G ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Pharmacokinetic Studies ◽  
Population Parameter ◽  
Concentration Data ◽  
Mixed Effect ◽  
Animal Products ◽  
Swine Liver

ABSTRACTExtralabel drug use of penicillin G in food-producing animals may cause an excess of residues in tissue which will have the potential to damage human health. Of all the antibiotics, penicillin G may have the greatest potential for producing allergic responses to the consumer of food animal products. There are, however, no population pharmacokinetic studies of penicillin G for food animals. The objective of this study was to develop a population pharmacokinetic model to describe the time-concentration data profile of penicillin G across two species. Data were collected from previously published pharmacokinetic studies in which several formulations of penicillin G were administered to diverse populations of cattle and swine. Liver, kidney, and muscle residue data were also used in this study. Compartmental models with first-order absorption and elimination were fit to plasma and tissue concentrations using a nonlinear mixed-effect modeling approach. A 3-compartment model with extra tissue compartments was selected to describe the pharmacokinetics of penicillin G. Typical population parameter estimates (interindividual variability) were central volumes of distribution of 3.45 liters (12%) and 3.05 liters (8.8%) and central clearance of 105 liters/h (32%) and 16.9 liters/h (14%) for cattle and swine, respectively, with peripheral clearance of 24.8 liters/h (13%) and 9.65 liters/h (23%) for cattle and 13.7 liters/h (85%) and 0.52 liters/h (40%) for swine. Body weight and age were the covariates in the final pharmacokinetic models. This study established a robust model of penicillin for a large and diverse population of food-producing animals which could be applied to other antibiotics and species in future analyses.

Treatment of Hemophilia A with a Highly Purified Factor VIII Concentrate Prepared by Anti-FVIIIc Immunoaffinity Chromatography

1992 ◽  
Vol 67 (01) ◽  
pp. 019-027 ◽  
Author(s):  
Joseph E Addiego ◽  
Edward Gomperts ◽  
Liu Shu-Len ◽  
Patricia Bailey ◽  
Suzanne G Courter ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Virus Transmission ◽  
Human Albumin ◽  
Immunoaffinity Chromatography ◽  
Exchange Chromatography ◽  
Pharmacokinetic Studies ◽  
Enveloped Viruses ◽  
Clinically Significant ◽  
Detergent Mixture

SummaryTo reduce the risk of pathogenic virus transmission associated with the therapeutic administration of plasma-derived antihemophilic factor (FVIIIc), a process utilizing anti-FVIIIc immunoaffinity chromatography to isolate FVIIIc has been developed. In addition, the starting cryoprecipitate solution has been treated with an organic solvent/detergent mixture to inactivate lipid-enveloped viruses. A final ion exchange chromatography step is used to further remove contaminants, e.g., anti-FVIIIc antibody, potentially leached with FVIIIc during the immunoaffinity step. The purified FVTII is stabilized for lyophili-zation and storage by the addition of human albumin. The monoclonal anti-FVIIIc antibody used in the immunoaffinity step of the process is not detectable in the final preparation. Viral reduction studies performed at specific steps of the process demonstrate that 11 logs of human immunodeficiency virus (HIV) and greater than 4-5 logs of other lipid-enveloped viruses are inactivated within the first 30 s of exposure to the solvent/ detergent mixture and 4-5 logs of various model viruses, e. g. Endomyocarditis virus (EMC), are physically removed during washing of the immunoaffinity column. The lyophilized product is reconstituted using sterile water in a matter of seconds.The pharmacokinetics of Hemofil® M were compared to those obtained using a standard heat-treated concentrate (Hemofil® CT) in five severe factor VIII deficient hemophiliacs in a randomized, cross-over study. No statistically significant differences were observed in mean half life (p >0.6) or median recovery (p = 0.4) between the two preparations. No clinically significant adverse effects were observed in patients receiving either FVIII preparation.In addition, 43 patients at 18 different centers underwent pharmacokinetic studies, with a nominal dose of 50 u/kg FVIIIc Hemofil® M. The mean recovery was 103.6%, and the t 1/2 was 14.6 h. The recovery of FVIII in this group was as expected, providing an increase of assayed FVIII of approximately 2% per unit of FVTII/kg infused.Clinical trials using Hemofil® M have been initiated in 124 hemophilia A patients. The safety and efficacy of Hemofil® M has been established. To date, 0 of 60 patients tested have seroconverted to HIV. None of the previously untreated patients show clinical or laboratory evidence of Non-A, Non-B hepatitis (NANB), with 21 patients remaining negative as far as presence of antibodies to the Hepatitis C virus (a-HCV negative) at least 6 months after the initial infusion. There is no evidence of neoantigenicity, evidenced by seroconversion to murine antibody. An 8.7% (2 of 23) prevalence of anti-FVIIIc inhibitor development has been observed in previously untreated patients with FVIIIc⩽3%, receiving only the monoclonally purified solvent/ detergent treated FVIII concentrate while on study and on poststudy surveillance. All patients demonstrated clinical hemostasis following product use for either on demand bleeding or surgical prophylaxis.

A Multicenter Study of Recombinant Factor VIII (RecombinateTM) in Previously Treated Patients with Hemophilia A

1997 ◽  
Vol 77 (04) ◽  
pp. 660-667 ◽  
Author(s):  
G C White ◽  
S Courter ◽  
G L Bray ◽  
M Lee ◽  
E D Gomperts ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Recombinant Dna ◽  
Home Treatment ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Open Label ◽  
Treat Ment ◽  
Previously Treated Patients ◽  
Bleeding Episodes

SummaryA prospective, open-label multicenter investigation has been conducted to compare pharmacokinetic parameters of recombinant DNA-derived FVIII (rFVIII) and plasma-derived FVIII concentrate (pdFVIII) and to assess safety and efficacy of long-term home-treat- ment with rFVIII for subjects with hemophilia A. Following comparative in vivo pharmacokinetic studies, 69 patients with severe (n = 67) or moderate (n = 2) hemophilia A commenced a program of home treatment using rFVIII exclusively for prophylaxis and treatment of all bleeding episodes for a period of 1.0 to 5.7 years (median 3.7 years). The mean in vivo half-lives of rFVIII and pdFVIII were both 14.7 h. In vivo incremental recoveries at baseline were 2.40%/IU/kg and 2.47%/IU/kg, respectively (p = 0.59). The response to home treatment with rFVIII was categorized as good or excellent in 3,195 (91.2%) of 3,481 evaluated bleeding episodes. Thirteen patients received rFVIII for prophylaxis for twenty-four surgical procedures. In all cases, hemostasis was excellent. Adverse reactions were observed in only 13 of 13,591 (0.096%) infusions of rFVIII; none was serious. No patient developed an inhibitor to r FVIII.

Nitrogen and phosphorus in the Vistula River, Poland -- changes from source to mouth

1994 ◽  
Vol 30 (5) ◽  
pp. 177-186 ◽  
Author(s):  
Karin Sundblad ◽  
Andrzej Tonderski ◽  
Jacek Rulewski
Keyword(s):  
Central Region ◽  
Northern Region ◽  
Point Sources ◽  
Nutrient Loss ◽  
Phosphorus Concentration ◽  
Nitrogen And Phosphorus ◽  
Concentration Data ◽  
Diffuse Sources ◽  
Vistula River ◽  
South Central

Nitrogen and phosphorus concentration data representing samples collected once a month for nine months at 13 locations along the Vistula River are considered in a preliminary discussion of the sources of the nutrients transported to the Baltic Sea. Concentrations in relation to flow data indicated substantial differences between subbasins. Based on those differences, on the area-specific nutrient loss for a six-month period and on the wastewater discharge in each subbasin, four regions could be recognized in the river basin: i) the southern region with a large impact of point sources, ii) the south central region, where diffuse sources seemed to be of major importance, iii) the north central region with a combined effect of point and diffuse sources, and retention in two reservoirs, iv) the northern region where point sources seemed to be the dominating source, at least for phosphorus. Our results illustrate the importance of differences in phosphorus retention between the basins. Long-term retention along the course of the river, particularly in the two reservoirs, must be estimated to allow proper source apportionment in the Vistula basin. Concentration decreases in the Wloclawek Reservoir varied between 44 and 68% for P, and 11 to 37% for N, in the months with significant retention. In some months, however, concentrations increased, indicating a release of nutrients.

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