ALBERT — All Library Books, journals and Electronic Records Telegrafenberg

1

Electronic Resource

Pharmacokinetic and phase I studies of brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies (1998)

Burris, Howard A. ; Raymond, Eric ; Awada, Ahmad ; [et al.]

Springer

Investigational new drugs 16 (1998), S. 19-27

add to mindlist on the mindlist

Details

ISSN: 1573-0646

Keywords: phase I ; brequinar ; DUP 785 ; cisplatin ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1016066529642

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

2

Electronic Resource

Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion (1998)

Rassmann, I. ; Thödtmann, R. ; Mross, M. ; [et al.]

Springer

Investigational new drugs 16 (1998), S. 319-324

add to mindlist on the mindlist

Details

ISSN: 1573-0646

Keywords: NK611 ; dimethylaminoetoposide ; Phase I ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology , Medicine

Notes: Abstract Background: NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethyl-amino group at the D-glucose moiety. The antitumor activity of NK611 showed to be equal or superior to etoposide in a variety of in vitro and in vivo tumor models. The aim of our present study was to determine the maximum tolerated dose and the dose-limiting toxicities of NK611 administered as intravenous infusion over 30 min every 28 days. Patients and methods: 45 patients (7 female, 38 male; median age 54 [range 37–73]) were enrolled. In a first stage, NK611 was administered without hematopoietic growth factor support; in a second stage, G-CSF was used for further dose escalation. Toxicities were assessed using WHO-criteria. Results: Initially, the dose was escalated from 60 mg/m2 to 120 mg/m2. In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m2 to 250 mg/m2. Dose-limiting toxicities were granulocytopenia and thrombocytopenia. Non-hematologic toxicities consisted of alopecia, mild nausea, and infection. Four partial responses were observed: two at 200 mg/m2 (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and two at 250 mg/m2 (hepatocellular carcinoma, response duration 7 months, and non-small cell lung cancer, response duration 2 months). Pharmacokinetic analyses were performed in all patients. Using an open 3-compartment model, the terminal half-life (t1/2γ) was 14.7 ± 3.7 h. The AUC at 250 mg/m2 was determined to be 330 ± 147 μg/mlh, the plasma clearance of NK611 was 16.2 ± 8.2 ml/min · m2 and the Vss was 16.8 ± 3.3 l/m2. Protein binding of NK611 was 98.7%. Conclusion: the recommended dose for clinical Phase II studies is 120 mg/m2 without G-CSF support and 200 mg/m2 with G-CSF support.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1006293830585

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

3

Electronic Resource

Pharmacokinetics and Relative Bioavailability of Carboxyamido-Triazole with Respect to Food and Time of Administration: Use of a Single Model for Simultaneous Determination of Changing Parameters (1998)

Bauer, Kenneth S. ; Kohn, Elise C. ; Lush, Richard M. ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 673-687

add to mindlist on the mindlist

Details

ISSN: 1573-8744

Keywords: carboxyamido-triazole ; bioavailability ; chronopharmacology ; pharmacokinetics ; food

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Carboxyamido-triazole (CAI) is an anti-invasive, antimetastatic, antiangiogenic agent in clinical development for cancer treatment. It has been postulated that food might enhance the oral absorption of micronized CAI based on an apparent discrepancy in steady state maximum concentrations when taken without regard to meals vs. fasting. The purpose of this study was to determine if a standardized meal affects the absorption and pharmacokinetics of this agent. Twelve patients with refractory cancers and good end organ function were randomized to receive two doses of CAI (250 mg/m 2 ) with and without a standardized high fat meal. One cohort of 6 patients received these doses at 9 AM, and the remaining 6 patients received CAI at 9 PM. Blood was obtained prior to each dose, and serially thereafter. A series of pharmacokinetic (PK) models were fit to the concentration–time data. PK parameters were ultimately calculated using a model which allows simultaneous estimation of parameters from both test doses using nonlinear least squares analysis with ADAPT II. This model estimates independent absorption rate constants and relative fraction absorbed for each condition. AUC 0–t was determined using the trapezoidal method, extrapolated to infinity, and used to calculate the relative bioavailability. No significant differences in PK parameters were noted between the morning and evening cohorts. However, the relative bioavailability, as measured by AUC 0–∞, of CAI was significantly increased when administered with a high fat meal compared to fasting (138.9 vs. 52.2 μg * hr/ml; p=0.0005). The magnitude of the increase in relative bioavailability of CAI taken with food could have profound implications for patients who may inadvertently take this medication shortly after eating.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1020750923542

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

4

Electronic Resource

Lumping of Whole-Body Physiologically Based Pharmacokinetic Models (1998)

Nestorov, Ivan A. ; Aarons, Leon J. ; Arundel, Philip A. ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 21-46

add to mindlist on the mindlist

Details

ISSN: 1573-8744

Keywords: pharmacokinetics ; whole body physiologically based model ; lumping ; system theory ; barbiturates

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Lumping is a common pragmatic approach aimed at the reduction of whole-body physiologically based pharmacokinetic (PBPK) model dimensionality and complexity. Incorrect lumping is equivalent to model misspecification with all the negative consequences to the subsequent model implementation. Proper lumping should guarantee that no useful information about the kinetics of the underlying processes is lost. To enforce this guarantee, formal standard lumping procedures and techniques need to be defined and implemented. This study examines the lumping process from a system theory point of view, which provides a formal basis for the derivation of principles and standard procedures of lumping. The lumping principle in PBPK modeling is defined as follows: Only tissues with identical model specification, and occupying identical positions in the system structure should be lumped together at each lumping iteration. In order to lump together parallel tissues, they should have similar or close time constants. In order to lump together serial tissues, they should equilibrate very rapidly with one another. The lumping procedure should include the following stages: (i) tissue specification conversion (when tissues with different model specifications are to be lumped together); (ii) classification of the tissues into classes with significantly different kinetics, according to the basic principle of lumping above; (iii) calculation of the parameters of the lumped compartments; (iv) simulation of the lumped system; (v) lumping of the experimental data; and (vi) verification of the lumped model. The use of the lumping principles and procedures to be adopted is illustrated with an example of a commonly implemented whole-body physiologically based pharmacokinetic model structure to characterize the pharmacokinetics of a homologous series of barbiturates in the rat.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1023272707390

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

5

Electronic Resource

Population Pharmacokinetic Analysis of Mizolastine and Validation from Sparse Data on Patients Using the Nonparametric Maximum Likelihood Method (1998)

Mesnil, Florence ; Mentré, France ; Dubruc, Catherine ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 133-161

add to mindlist on the mindlist

Details

ISSN: 1573-8744

Keywords: mizolastine ; pharmacokinetics ; population analysis ; zero-order absorption ; heteroscedastic variance ; NPML ; validation ; predictive distributions

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1020505722924

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

6

Electronic Resource

Rapid Attainment of Steady State Plasma Drug Concentrations Within Precise Limits (1998)

Korman, Ben ; Jennings, Les S. ; Rigg, John R. A.

Springer

Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 319-328

add to mindlist on the mindlist

Details

ISSN: 1573-8744

Keywords: anesthetic techniques ; continuous infusion ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract We describe a method of rapidly obtaining a specified steady state plasma concentration of an intravenous drug within precise limits. The technique requires an initial bolus to raise the plasma concentration to the upper limit followed by a series of constant-rate infusions each of which is associated with a minimum plasma concentration equal to the tower limit. The infusion rate is stepped down when the plasma concentration returns to the upper limit. Computer simulation, based on the method, is used to generate plasma concentration–time curves with fluctuations of up to 10% about selected steady state concentrations of amrinone, esmolol, lidocaine, midazolam, propofol, and theophylline. The utility of this general approach to intravenous dosing and potential limitations of the method are discussed.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1023285426388

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

7

Electronic Resource

Fourth-Generation Model for Corticosteroid Pharmacodynamics: A Model for Methylprednisolone Effects on Receptor/Gene-Mediated Glucocorticoid Receptor Down-Regulation and Tyrosine Aminotransferase Induction in Rat Liver (1998)

Sun, Yu-Nien ; DuBois, Debra C. ; Almon, Richard R. ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 289-317

add to mindlist on the mindlist

Details

ISSN: 1573-8744

Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; indirect response models ; glucocorticoid receptor ; tyrosine aminotransferase ; Northern hybridization ; mRNA ; down-regulation ; receptor recycling

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for receptor/genemediated effects of corticosteroids was developed. Male adrenalectomized Wistar rats received a 50 mg/kg iv bolus dose of methylprednisolone (MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) messenger RNA (mRNA) and GR density, tyrosine aminotransferase (TAT) mRNA, and TAT activity in liver were determined at various time points up to 72 hr after MPL dosing. Down-regulation of GR mRNA and GR density were observed: GR mRNA level declined to 45–50% of the baseline in 8–10 hr, and slowly returned to predose level in about 3 days; GR density fell to 0 soon after dosing and returned to the baseline in two phases. The first phase, occurring in the first 10 hr, entailed recovery from 0 to 30%. The second phase was parallel to the GR mRNA recovery phase. Two indirect response models were applied for GR mRNA dynamics regulated by activated steroid-receptor complex. A full PK/PD model for GR mRNA/GR down-regulation was proposed, including GR recycling theory. TAT mRNA began to increase at about 1.5 hr, reached the maximum at about 5.5 hr, and declined to the baseline at about 14 hr after MPL dosing. TAT induction followed a similar pattern with a delay of about 1–2 hr. A transcription compartment was applied as one of the cascade events leading to TAT mRNA and TAT induction. Pharmacodynamic parameters were obtained by fitting seven differential equations piecewise using the maximum likelihood method in the ADAPT II program. This model can describe GR down-regulation and the precursor/product relationship between TAT mRNA and TAT in receptor/gene-mediated corticosteroid effects.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1023233409550

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

8

Electronic Resource

Optimal Experimental Design for Precise Estimation of the Parameters of the Axial Dispersion Model of Hepatic Elimination (1998)

Chou, Chen-Hsi ; Aarons, Leon ; Rowland, Malcolm

Springer

Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 595-615

add to mindlist on the mindlist

Details

ISSN: 1573-8744

Keywords: optimal design ; hepatic elimination models ; parameter estimation ; protein binding ; pharmacokinetics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract The axial dispersion model of hepatic drug elimination is characterized by two dimensionless parameters, the dispersion number, DN , and the efficiency number, RN , corresponding to the relative dispersion of material on transit through the organ and the relative efficiency of elimination of drug by the organ, respectively. Optimal design theory was applied to the estimation of these two parameters based on changes in availability (F) of drug at steady state for the closed boundary condition model, with particular attention to variations in the fraction of drug unbound in the perfusate (fuB ). Sensitivity analysis indicates that precision in parameter estimation is greatest when F is low and that correlation between RN and DN is high, which is desirable for parameter estimation, when DN lies between 0.1 and 100. Optimal design points were obtained using D-optimization, taking into account the error variance model. If the error variance model is unknown, it is shown that choosing Poisson error model is reasonable. Furthermore, although not optimal, geometric spacing of fuB values is often reasonable and definitively superior to a uniform spacing strategy. In practice, the range of fuB available for selection may be limited by such practical considerations as assay sensitivity and acceptable concentration range of binding protein. Notwithstanding, optimal design theory provides a rational approach to precise parameter estimation.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1023229318017

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

9

Electronic Resource

Single-Dose Pharmacokinetics of Rifapentine in Women (1998)

Keung, Anther C. F. ; Eller, Mark G. ; Weir, Scott J.

Springer

Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 75-85

add to mindlist on the mindlist

Details

ISSN: 1573-8744

Keywords: rifapentine ; pharmacokinetics ; gender differences ; female

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Gender can be an important variable in the absorption and disposition of some drugs. In this open-label study, 15 healthy, nonsmoking women received a single 600-mg oral dose of rifapentine. Plasma samples were obtained at frequent intervals for up to 72 hr after the dose to determine the pharmacokinetic (PK) parameters of rifapentine and its active metabolite, 25-desacetyl-rifapentine. Peak plasma rifapentine concentrations (Cmax ) were observed 5.9 hr after ingestion of the single dose. The mean area under the rifapentine plasma concentration–time curve [AUC(0 → ∞ )] was 325 μg · hr ml and the mean elimination half-life (t1/2 ) was 16.3 hr. Plasma concentrations for the 25-desacetyl metabolite peaked at 15.4 hr after the rifapentine dose and declined with a terminal half-life of 17.3 hr. These rifapentine and 25-desacetyl-rifapentine PK data in women were compared to data generated previously in healthy men. Striking similarities in the PK profiles of parent drug and metabolite were found in the two populations. Mean differences in rifapentine CL/F (12%) and t1/2 (2%) were small. The only adverse event reported in the female subjects was discoloration of the urine. Based on these PK and safety data, no dosage adjustments for rifapentine based on gender are recommended.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1023276808298

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

10

Electronic Resource

Pharmacokinetic and Pharmacodynamic Evaluation for Tissue-Selective Inhibition of Cholesterol Synthesis by Pravastatin (1998)

Hatanaka, Tomomi ; Honda, Shohei ; Sasaki, Seiji ; [et al.]

Springer

Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 329-347

add to mindlist on the mindlist

Details

ISSN: 1573-8744

Keywords: HMG-CoA reductase inhibitors ; pravastatin ; tissue-selectivity ; cholesterol synthesis ; pharmacokinetics ; pharmacodynamics

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after iv bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1023237510458

Permalink

	Location	Call Number	Expected	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext