Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer.

This study examined whether the addition of tamoxifen to the treatment regimen of patients with advanced breast cancer being treated with the aromatase inhibitor letrozole led to any pharmacokinetic or pharmacodynamic interaction. Twelve of 17 patients completed the core period of the trial in which 2.5 mg/day letrozole was administered alone for 6 weeks and in combination with 20 mg/day tamoxifen for the subsequent 6 weeks. Patients responding to treatment continued on the combination until progression of disease or any other reason for discontinuation. Plasma levels of letrozole were measured at the end of the 6-week periods of treatment with letrozole alone and the combination and once more between 4 and 8 months on combination therapy. No further measurements were done thereafter. Hormone levels were measured at 2-week intervals throughout the core period. Marked suppression of estradiol, estrone, and estrone sulfate occurred with letrozole treatment, and this was not significantly affected by the addition of tamoxifen. However, plasma levels of letrozole were reduced by a mean 37.6% during combination therapy (P<0.0001), and this reduction persisted after 4-8 months of combination therapy. Letrozole is the first drug to be described in which this pharmacokinetic interaction occurs with tamoxifen. The mechanism is likely to be a consequence of an induction of letrozole-metabolizing enzymes by tamoxifen but was not further addressed in this study. It is possible that the antitumor efficacy of letrozole may be affected. Thus, sequential therapy may be preferable with these two drugs. It is not known whether tamoxifen interacts with other members of this class of drugs or with other drugs in combination.

Pharmacokinetics of valsartan in patients with liver disease.

OBJECTIVES: Valsartan (CGP 48933), an orally active angiotensin II antagonist, is eliminated mainly by hepatic clearance. To characterize the compound(s) excreted in the bile, biliary excretion of valsartan was investigated by collection of bile after an intravenous dose of valsartan. In addition, to determine the exposure to valsartan when liver function is impaired, a pharmacokinetic study (open, single dose) was performed in patients with mild and moderate impairment of liver function. PATIENTS: Biliary excretion of valsartan (after intravenous administration of 20 mg valsartan) was assessed in a patient who underwent a hepaticojejunostomy with subsequent bile drainage. Exposure to valsartan in patients with mild (n = 6) or moderate (n = 6) impaired liver function (Child's-Pugh classification) and matching (sex, age, and weight) healthy volunteers (n = 12) was studied after oral administration of a single dose of 160 mg valsartan. RESULTS: After intravenous administration, valsartan was eliminated mainly as unchanged drug in the bile. Mean exposure (measured as area under the plasma valsartan concentration-time curve) to valsartan was increased about twofold in both the mild and the moderate groups compared with matched (age, sex, and weight) healthy volunteers. CONCLUSION: These data are consistent with the pharmacokinetics of valsartan in that biliary excretion is the main route of elimination.

Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function.

Pamidronate is a second-generation bisphosphonate that undergoes negligible biodegradation and is eliminated exclusively by renal excretions. Nineteen cancer patients were stratified according to baseline creatinine clearance (Clcr): group I, Clcr > 90 mL/min (n = 6); group II, Clcr 61 mL/min to 90 mL/min (n = 6); group III, Clcr 30 mL/min to 60 mL/min (n = 3); group IV, Clcr < 30 mL/min (n = 4). All patients received a single, 90-mg dose of pamidronate disodium administered in a 4-hour intravenous infusion. Plasma and urine samples were collected at intervals up to 36 and 120 hours, respectively, after the start of infusion and were assayed for pamidronate, using validated high-performance liquid chromatography. Pamidronate's pharmacokinetics were characterized by a short distribution phase (2-3 hours) followed by rapid elimination of the drug in urine. Elimination of pamidronate was slower in patients in group IV with a mean +/- standard deviation area under the plasma concentration-time curve (AUC0-36) of 19.0 +/- 4.60 micrograms.hr/mL compared with 8.1 +/- 3.13 micrograms.hr/mL in patients in group I. A linear relationship in Clcr was observed for AUC0-36 (r = 0.67), urinary excretion (r = 0.69), and renal clearance (r = 0.81). Renal clearance was proportional to Clcr for patients in all four renal-function groups. In the treatment of bone metastases of malignancy, successive doses of pamidronate are generally separated by weeks; thus, plasma accumulation in patients with renal impairment is not expected to be clinically relevant. A reduction in dose of pamidronate disodium should not be necessary in cancer patients with renal impairment.

Quantitative determination of norethisterone acetate in human plasma by capillary gas chromatography with mass-selective detection.

An analytical method for the determination of norethisterone acetate (NETA) in human plasma by capillary gas chromatography-mass-selective detection (GC-MS), with testosterone acetate as internal standard, was developed and validated. After addition of the internal standard, the compounds were extracted from plasma at basic pH into diethyl ether-dichloromethane (3:2, v/v), which was then evaporated to dryness. The compounds were converted into their pentafluoropropionyl derivatives which were determined by gas chromatography using a mass selective detector at m/z 486 for NETA and m/z 476 for the internal standard. Intra-day and inter-day accuracy and precision were found suitable over the range of concentrations between 0.10 to 10 ng/ml. The method was applied to clinical samples.

GLC determination of alpha- and beta-tribenosides in human plasma.

The determination of alpha-tribenoside at concentrations down to 10 ng/ml and beta-tribenoside at concentrations down to 5 ng/ml in human plasma is described. After addition of an internal standard, alpha- and beta-tribenosides are extracted at basic pH into benzene. Both compounds are derivatized with N-heptafluorobutyrylimidazole. The derivatives are determined by GLC using a 63Ni-electron-capture detector.

GLC determination of phenylbutazone in human plasma.

A GLC method for phenylbutazone at concentrations down to 10 ng/ml in human plasma is described. After addition of an internal standard, phenylbutazone is extracted at pH 5 into benzene. The dry extract is dissolved in benzene, and phenylbutazone is determined by GLC using a 63Ni-electron-capture detector.

GLC determination of free and conjugated triclosan in human plasma and urine.

A method for the determination of free and conjugated triclosan at concentrations as low as 2 ng/ml in human plasma or urine is described. Conjugated metabolites are split by enzyme hydrolysis. After addition of an internal standard, triclosan is extracted at acid pH into petroleum ether, transferred to an alkaline aqueous solution, and back-estracted into petroleum ether after acidification. Both compounds are acetylated with acetic anhydride in the presence of pyridine. The acetyl derivatives are determined by GLC using a 63Ni-electron-capture detector.

Pharmacokinetics of phenylbutazone in healthy subjects after oral administration of single and multiple doses.

Plasma concentration profiles were studied after single and oral doses of phenylbutazone of 100, 300, and 600 mg in cachets to six healthy volunteers. The pharmacokinetics of phenylbutazone can be described by a two-compartment open model. The drug is absorbed rapidly and distributed partially into an extravascular compartment; about one-third remains in the plasma. The mean elimination half-life was 77 hr (54-99 hr), and there was a linear relationship between the dose and the area under the plasma concentration curve. In a multiple-dose study, six healthy volunteers received 150 mg of phenylbutazone in cachets twice daily every 11-13 hr for 17 days. A steady state was reached after approximately 200 hr of chronic treatment. The resultant steady-state plasma concentration were about four times higher than the peak concentration produced by a single 150-mg dose. The half-lives corresponding to the apparent elimination rate constant for the first and last administrations did not differ in each subject. The theoretical minimum concentrations are higher than the pseudosteady state reached during chronic treatment.

Development, application and comparison of an enzyme immunoassay and a high-performance liquid chromatography method for the determination of the aromatase inhibitor CGS 20,267 in biological fluids.

CGS 20,267 is a new potent and selective, nonsteroidal, oral aromatase inhibitor. For its determination in human plasma and urine, an enzyme immunoassay (EIA) and an HPLC method were developed. The EIA showed good precision and accuracy (intra- and interassay variation between 3.0 and 17.7%, recoveries between 81 and 106%) and a quantitation limit of 0.7 nmol/L. A strong cross reactivity of the antibodies with the hydroxy metabolite of CGS 20,267 (CGP 44,645) was observed. The HPLC method showed a quantitation limit in plasma of 28 and 34 nmol/L for CGS 20,267 and CGP 44,645, respectively. For urine, concentrations down to 180 nmol/L (CGS 20,267) and 210 nmol/L (CGP 44,645) could be measured. A cross check between EIA and HPLC on plasma samples from healthy male volunteers or breast cancer patients treated orally with CGS 20,267 revealed an excellent correlation (slope = 0.934, intercept = 26, r = 0.991). However, the EIA measurements of urine samples yielded 3-25 times higher concentrations than those obtained by HPLC. Further, HPLC analysis revealed the presence of CGS 20,267 and cross-reacting metabolites in urine but not in plasma. Therefore, the EIA can only be used for the determination of CGS 20,267 in plasma samples.

High performance liquid chromatographic determination of nicotine and cotinine in plasma and nicotine and cotinine, simultaneously, in urine.

Three analytical procedures were developed to determine nicotine in plasma, cotinine in plasma and, simultaneously, nicotine and cotinine in urine. After liquid or solid-phase extraction, the purified aqueous phase is injected into a high performance liquid chromatograph equipped with an ultra-violet detector using a CN Spheri-5 micron cartridge-column with an inner diameter of 4.6 mm and a length of 10 or 22 cm. The limit of quantitation for nicotine in plasma was around 8 to 15 ng/ml, that of cotinine in plasma around 50 ng/ml and that of nicotine and cotinine in urine around 170 ng/ml and 70 ng/ml, respectively. The limit of detection of nicotine in plasma was around 1 ng/ml and that of nicotine and cotinine in urine around 20 ng/ml and 10 ng/ml, respectively. The passive exposure to cigarette smoke by non-smokers and the "resting levels" of nicotine in plasma and urine of smokers were studied. The analytical methods were set up to study the pharmacokinetics and bioavailability of nicotine in healthy volunteers following single and repeated administrations of different doses of transdermal nicotine systems.

Pharmacokinetics and bioavailability of nicotine in healthy volunteers following single and repeated administration of different doses of transdermal nicotine systems.

Healthy nicotine-dependent smokers were applied different doses of transdermal nicotine systems (TNS) during single and repeated administrations. Plasma and urine nicotine and cotinine concentrations were determined by high performance liquid chromatography (HPLC). After single application of TNS, the maximal concentration (Cmax) and area under curve (AUC) of nicotine in plasma as well as the amount of nicotine excreted in urine were linearly related to the dose. The stable urinary cotinine excretion was not influenced by the amount of nicotine delivered by the TNS. The relevant 24 h plasma nicotine concentration reached after TNS application compares well with the plasma nicotine footpoints--not the peaks--observed in moderate to heavy cigarette smokers. A comparison between different nicotine doses from different TNS allowed to conclude to the functionality of the systems as regards pharmacokinetics and bioavailability. One or two hours after removal of the systems, there was a very slow decline of the nicotine concentrations. After repeated application of TNS, there was evidence for only a very limited nicotine accumulation in plasma (+14%) or in urine (+9%) over 10 days. The steady-state of nicotine was reached within 4 days. The continuous delivery of nicotine over 24 h resulted in an early morning plasma concentration which probably decreases or prevents the craving for the first cigarette.

Biotransformation of tribenoside into benzoic acid in man.

In an experiment on three healthy volunteers, plasma levels of tribenoside and the elimination of benzoic acid in plasma and urine were followed up during a 7-day period of daily oral medication with tribenoside. Plasma levels of tribenoside, and plasma and urine concentrations of free and total benzoic acid were determined quantitatively. The concentrations of alpha- and beta-tribenosides found in the plasma were very low and did not increase during treatment. Total benzoic acid in the plasma remained at almost the same level during treatment as that observed before treatment. Biotransformation of tribenoside therefore does not appear to result in any significant change in the plasma concentrations of free or total benzoic acid. The average daily excretion of total benzoic acid in the urine of the 3 subjects was greater during treatment than before. The average increases in total benzoic excretion in the 3 subjects correspond to 23.5, 11.9, and 23.7% of the theoretical amount that would be produced by the metabolic oxidation of the 3 benzyl groups. This study demonstrates that tribenoside does not accumulate in plasma. Around 20% of the administered dose is metabolized to benzoic acid, which is almost entirely present in the body as hippuric acid. Hippuric acid is excreted at such a rate that it does not accumulate in plasma and does not exceed the normal concentration range.

Bioequivalence assessment: a pharmaceutical industry perspective.

Various aspects of bioequivalence are investigated in this paper. Some aspects dealing with bioequivalence studies conducted either during the development of the drug or after its marketing will be presented and discussed: Bioequivalence of highly variable drugs with the associated problem of widening the acceptance range or alternative solutions. Bioequivalence for the final market image. Bioequivalence for investigating the food effect. Bioequivalence in special population such as children, non Caucasian population. Bioequivalence based on in vitro data or literature. New approaches in bioequivalence interpretation. Bioequivalence and analytical methods which are not sensitive or specific enough.

Pharmacokinetics of pirprofen in children with juvenile chronic arthritis.

Pirprofen (100 or 200 mg; Rengasil) was administered to experimental groups of children (children with juvenile chronic arthritis, JCA) and to a control group of children (children without JCA) as a single dose or as repeated doses. The pharmacokinetics of pirprofen in these children were compared to the pharmacokinetic parameter values obtained in healthy volunteers and in elderly arthritic adults receiving 400 mg of pirprofen. The children were examined regularly and laboratory values were determined in order to detect possible side effects. The results demonstrated that the pharmacokinetics of pirprofen were similar for children and adults when taking into account the dose and the body weight. There was no drug accumulation after repeated administration of pirprofen. As already observed in rheumatic adults, pirprofen remains in synovial fluid longer than in plasma.

[Blood concentrations of maprotiline in depressive patients]. / Etude des concentrations sanguines de maprotiline chez des patients déprimés.

Blood levels of Maprotiline were analysed and their relationship to the clinical response was examined in 89 depressed inpatients, according DSM III criteria for Major Depressive Episode, given the drug treatment for 3 weeks. Maprotiline produced marked decreases in mean MADRS and COVI scale scores by the end of treatment. On day 21, no correlation between blood levels of Maprotiline and MADRS or COVI scores were found when all patients were considered. Nevertheless, significant correlations were observed on day 14 (r = .22; p less than .05 for MADRS and r = .23; p less than .05 for COVI scale). In addition, a significant correlation between MADRS or COVI scale scores and Maprotiline blood levels were observed on days 14 and 21 in subgroups of young patients, severe depression (high scores to clinical global investigations), during of at least 3 months, treated without other drug than Maprotiline and good responders.

[Comparative elimination of pirprofen from the plasma and synovial fluid of the knee. 26 cases]. / Elimination comparée du pirprofène à partir du plasma et du liquide synovial du genou. 26 observations.

Twenty-six patients with various inflammatory diseases of the knee were treated with a 400 mg dose of pirprofen orally twice a day for 2 days. On the third day, samples of blood and synovial fluid were taken 3 h and 10 h approximately after a fifth 400 mg dose of the drug. Pirprofen concentrations, as determined by gas-liquid chromatography, were higher in plasma than in synovial fluid during the 2-5 h period post-dosing. They decreased with an elimination half-life of 6 h in plasma as against 41 hours in synovial fluid. This study demonstrates that pirprofen diffuses into the synovial fluid where it remains significantly longer than in plasma.

Determination of isosorbide as a metabolite of isosorbide dinitrate in human urine by capillary gas chromatography with electron-capture detection.

A method for the determination of isosorbide as a metabolite of isosorbide dinitrate at concentrations down to 200 ng/ml in human urine is described. After addition of a known amount of isomannide as internal standard to 50 microliter of urine, both compounds are extracted at basic pH into chloroform-isopropanol (4:1, v/v), which is then evaporated to dryness. They are then derivatized with heptafluorobutyric anhydride, and isosorbide is quantitated by capillary gas chromatography with electron-capture detection. A conjugate of isosorbide is determined in urine after enzymatic hydrolysis.

Determination of the two mononitrate metabolites of isosorbide dinitrate in human plasma and urine by gas chromatography with electron-capture detection.

This paper describes a sensitive method for the determination of 2-isosorbide mononitrate and 5-isosorbide mononitrate as metabolites of isosorbide dinitrate at concentrations down to 2 ng/ml of 2-isosorbide mononitrate in both plasma and urine, and 5 ng/ml and 10 ng/ml of 5-isosorbide mononitrate in plasma and urine, respectively. The two mononitrate metabolites are extracted at basic pH into ethyl acetate, which is then evaporated to dryness. The residue is dissolved in a basic aqueous solution, which is washed with heptane and then re-extracted into ethyl acetate. The metabolites are quantitated by gas chromatography, using a 63Ni electron-capture detector. Conjugates of 2- and 5-isosorbide mononitrate are determined in urine after enzymatic hydrolysis.