Pharmacokinetics and metabolism of the anti-oestrogen droloxifene in female human subjects.

1. Single oral doses of a solution formulation of (14)C-droloxifene citrate (141 mg) appeared to be rapidly and well absorbed in four post-menopausal female subjects. Peak plasma concentrations (C(max)) of total (14)C (1260 ng eq. ml(-1)), droloxifene (196 ng ml(-1)) and the major metabolite droloxifene glucuronide (851 ng eq. ml(-1)) occurred at 0.9-1.1 h (T(max)) and declined bi-exponentially with terminal half-lives of 45.0, 31.6 and 32.0 h respectively. The mean AUCs of droloxifene and the major metabolite were 21 and 37% respectively that of total (14)C. 2. Total (14)C was excreted slowly, mainly in the faeces. Mean totals of 6.6 and 90.3% of the dose were excreted in the urine and faeces respectively during 11 days. The data were consistent with biliary excretion and enterohepatic circulation of the major metabolite, droloxifene glucuronide. 3. GC-MS showed that the major (14)C-components in 0-24-h urine were droloxifene (mean 0.4% dose) and its glucuronide (2.3% dose), and in faeces were droloxifene (60.2% dose) and N- desmethyldroloxifene (4.2% dose). Other components in faeces corresponded chromatographically to reference standards, droloxifene N-oxide (1.9% dose), side-chain hydroxylated droloxifene (dimethylamine moiety of droloxifene side-chain replaced by hydroxyl, 1.3% dose) and droloxifene glucuronide (10.7% dose). The latter was resistant to enzymic hydrolysis by the beta-glucuronidase used. 4. Intersubject variability in the pharmacokinetics of droloxifene in this study was relatively low (CV < 20% for AUC and half-life).

[Relative bioavailability of diclofenac after a single administration of a new multiple-unit formulation of enteric-coated pellets]. / Relative Bioverfügbarkeit von Diclofenac nach Einmalgabe einer neuen Multiple-Unit-Formulierung mit magensaftresistent befilmten Pellets.

The relative bioavailability of diclofenac (CAS 15307-86-5) was investigated after a single administration of a multiple-unit formulation containing 75 mg diclofenac sodium in enteric-coated pellets (A) in comparison to an enteric-coated tablet with 50 mg diclofenac sodium (B), a capsule containing 140 mg diclofenac resinate (C) and a dispersible tablet containing 46.5 mg diclofenac acid (D). The study was carried out in a four-way crossover design in 16 healthy male volunteers. Serum concentrations of diclofenac were determined with a validated and specific HPLC-method. After dose normalisation, a mean relative bioavailability of 99% (B), 142% (C) and 116% (D) was determined for the pellet formulation. According to the corresponding 90%-confidence interval, bioequivalence for the extent of bioavailability of the test formulation can be concluded compared to the enteric-coated tablet. In comparison to the formulations C and D, the test formulation showed an increased extent of bioavailability. Further differences in pharmacokinetics were observed for the rate-dependent parameters. For the test formulation, the highest mean maximum serum concentration (1595 ng/ml) was measured with a corresponding tmax of 0.8 h. For the reference formulations, mean peak serum concentrations of 1285 ng/ml after 2.0 h (B), 370 ng/ml after 1.8 h (C) and 735 ng/ml after 1.9 h (D) were observed. Despite the enteric-coating of the pellets, a short lagtime of 0.4 h was determined for the test formulation. For the other rapid-release formulation (D), the lagtime was of a similar magnitude (0.3 h), while drug release and absorption from the enteric-coated tablet and the diclofenac resinate capsule were delayed (1.8 and 0.7 h, respectively). Due to the rapid and high bioavailability of diclofenac, the multiple-unit formulation fulfills the prerequisites for the oral treatment of acute painful conditions when prompt analgesic and anti-inflammatory efficacy is desired.

[Requirements for product quality of theophylline sustained-release preparations]. / Anforderungen an die Produktqualität von Theophyllin-Retardpräparaten.

In consideration of the narrow therapeutic range and the pharmacology of theophylline (CAS 58-55-9), the pharmaceutic quality of sustained release theophylline preparations should be monitored carefully. During the last few years, the following pharmacokinetic study programme was established as quality criterion to verify the safety and predictability of theophylline concentration-time profiles: bioequivalence from batch to batch, lack of relevant food interaction, lack of relevant gastrointestinal pH or surfactant effects on absorption, pharmacokinetic profile following once-a-day and twice-a-day application, and pharmacokinetics in high-clearance patients. Smooth, predictable and safe concentration-time profiles can be guaranteed exclusively for preparations which fulfill all these quality criteria. Only such high quality formulations allow to reduce or even avoid therapeutic drug monitoring and can be considered as safe and effective drugs for the chronic treatment of asthma.

[The effect of different variables on the in vitro dissolution of a theophylline sustained-release preparation]. / Einfluss verschiedener Variablen auf die In-vitro-Freisetzung eines Theophyllin-Retardpräparates.

In vitro dissolution studies are valuable tools to judge quality and stability of sustained release dosage forms and are often utilised to predict the in vivo performance. For this reason, in vitro dissolution experiments with varying pH, osmolarity, rotation speed, and with addition of surfactants were performed with a sustained release theophylline (CAS 58-55-9) dosage form (Bronchoretard). In order to mimic the physiological situation of the gastrointestinal tract more closely, the pH of the dissolution media was changed and human bile was added at different time points. The results obtained show that the in vitro dissolution of the dosage form differs only slightly for the parameters pH, osmolarity and stirring speed and always lies within in vivo verified dissolution limits. However, the addition of sodium dodecyl sulphate to the dissolution medium markedly altered the dissolution rate whereas addition of the physiologically surface active human bile did not change the dissolution rate. A comparison with in vivo results indicated, that only the physiologically adapted model guarantees reliable results whereas the addition of synthetic surfactants cannot allow for the prediction of bile or food effects. The meaning of in vitro dissolution tests thus is limited to development studies of dosage forms and to routine quality and stability control testing. For judging the in vivo characteristics in vitro studies have only limited value and have to be verified by pharmacokinetic studies.

[In vivo verification of in vitro release specifications of a theophylline sustained-release preparation]. / In-vivo-Verifizierung der In-vitro-Freisetzungsspezifikation eines Theophyllin-Retardpräparates.

Especially in drugs with a narrow therapeutic range, "within product bioequivalence" i.e. "batch-to-batch bioequivalence" should be scrutinized. Therefore, pharmacokinetics and bioavailability of to batches at the upper and lower in vitro specification range as well as a batch representing the middle of the specification range was evaluated in an in vivo bioequivalence study. An open, randomized, 3-way crossover, multiple dose study in 18 healthy, male volunteers was selected for this purpose. Bioequivalence regarding rate (Cmax ss; t75%Cmax) and extent (AUCss) of absorption could be established for both extreme batches at the lower and upper in vitro specification range. Additionally both batches proved to be bioequivalent compared to the batch in the middle of the in vitro specification range. As a result, reproducible concentration-time profiles can be guaranteed for all batches of this sustained release theophylline (CAS 58-55-9) preparation. Furthermore, pharmacokinetic characteristics of all three batches meet the quality criteria defined for sustained release theophylline preparations, guaranteeing optimal concentration/time profiles for the therapy of asthma.

[Pharmacokinetics of a theophylline sustained-release formulation after single and twice daily dosage]. / Pharmakokinetik einer Theophyllin-Retardformulierung nach einmal und zweimal täglicher Mehrfachdosierung.

Sustained release theophylline (CAS 58-55-9) preparations may be dosed once or alternatively twice-a-day, depending on the intention of a theophylline therapy. A once-a-day dosage regimen is considered appropriate in patients with nocturnal asthma attacks, whereas a twice-a-day regimen is advantageous for guaranteeing bronchodilatation and to control the underlying inflammatory disease. Therefore, pharmacokinetic characteristics of both modes of administration were evaluated in a randomised, two-way crossover study in 18 female and male elderly volunteers under multiple-dose conditions. The shape of the pharmacokinetic profiles showed the expected and pronounced differences, while the extent of absorption was bioequivalent. Twice daily administration decreased the nocturnal maximum concentration and at the same time increased the minimum concentration. At the expense of the nocturnal excess, the peak-trough fluctuations (PTF) were reduced from 92.1% to 39.5%. Plateau times of 11.4 h and 20.2 h were achieved with both modes of administration. As for theophylline with its narrow therapeutic range, high quality sustained release preparations distinguish themselves by long plateau times and small peak-trough fluctuations such as those observed with the preparation under investigation. When using this preparation, therapeutic concentrations necessary for safety and efficacy are assured under either a once- or a twice-daily dosing regimen.

[Pharmacokinetics of theophylline in sustained-release formulation in young asthmatics]. / Pharmakokinetik von Theophyllin in einer Retardformulierung bei jugendlichen Asthmatikern.

Pharmacokinetics of two theophylline (CAS 58-55-9) sustained release preparations (T: Bronchoretard Capsules/R: Capsule formulation from the US market) were investigated in an open randomised two-way crossover design. The capsules of the test formulation were opened and administered on a tablespoonful of apple sauce. Nineteen asthmatics aged 6 to 12 years participated in this study. Following individual dosing of 100-300 mg theophylline twice a day, a pharmacokinetic profile for 24 h was derived after seven days of multiple dosing. All relevant parameters for rate (Cmax ss, Cmin ss, Cav ss, plateau time, peak-trough fluctuation, nocturnal excess, tmax ss) and extent of absorption (AUCss) were calculated for both formulations. With long plateau times (T: 17.3 h) and small peak-trough fluctuations (T: 49.0%), established quality criteria for high quality theophylline preparations were fulfilled by the test formulation. Furthermore, symmetrical peaks resulted after morning and evening administration of the test formulation. In conclusion, smooth and predictable concentration/time profiles were achieved, enabling an efficacious and safe therapy of asthma. This individual mode of administration allows not only a perfect dose titration in young asthmatics, but is also helpful to patients who have difficulty in swallowing large dosage forms.

[The effect of bile secretion on the pharmacokinetics of a theophylline sustained-release preparation]. / Einfluss einer Gallenausschüttung auf die Pharmakokinetik eines Theophyllin-Retardpräparates.

Bile excretion changes the physiological milieu of the duodenum, possibly resulting in enhanced absorption of a drug due to increased solubilisation. This possible influence of bile salts following stimulation of gallbladder emptying by the release of cholecystokinin on the pharmacokinetics of a sustained release theophylline (CAS 58-55-9) preparation (Bronchoretard) was evaluated in this study. An open, randomised, 3-way crossover study in 12 healthy, non-smoking volunteers was selected to prove or reject this hypothesis. All subjects received 500 mg of the sustained release theophylline formulation under two different cholagogia stimulating test conditions compared with a fasting reference condition. A standard breakfast and i.m. administration of cholecystokinin enabled a reproducible modulation of bile flow: a moderate and extreme contraction of the gallbladder could be induced after a standard breakfast and after i.m. administration of cholecystokinin, respectively. Following a standard breakfast, gallbladder volumes were approximately halved (50.6%) compared to the baseline volume after 79 min. Injection of 0.3 microgram/kg body weight cholecystokinin resulted in fast and complete gallbladder evacuation (94.6%) 36 min after the application of this cholagogue stimulus. Gallbladder volumes remained more or less constant under fasting conditions. This manipulation of bile flow did not influence concentration/time profiles of the sustained release theophylline preparation compared to the fasting condition. Even almost complete evacuation of the gallbladder after administration of cholecystokinin did not modify the concentration/time profile of theophylline in a relevant way. An unintentional rapid release of theophylline could be excluded for this sustained release formulation for all three treatments, as not a single case of dose dumping was observed. Furthermore, in vitro dissolution investigations using synthetic surfactants can predict neither food effects nor bile influence on the in vivo absorption at least for the sustained release formulation tested.

[Pharmacokinetics of a new fluid theophylline sustained-release drug form. Microcapsules in a sachet]. / Pharmakokinetik einer neuen flüssigen Theophyllin-Retardarzneiform. Mikrokapseln als Sachet.

A new sustained release theophylline (CAS 58-55-9) formulation was especially designed for the elderly and children. Microcapsules of theophylline, administered as a suspension in water, proved to be a suitable dosage form for a clientele with impaired or difficult deglutition. Pharmacokinetic characteristics of 2 batches at the lower (T1) and upper (T2) in vitro dissolution specification range of this new formulation and a pellet formulation (R) as a comparator were evaluated in an open, randomised, 3-way, multiple dose, crossover study with an asymmetric dosage regimen of 400 mg and 200 mg theophylline. Smooth and safe plasma concentrations with a high and long-lasting plateau were achieved with this new formulation. Plateau times which are independent of the asymmetric dosage regimen ranged from 16.4 h (T1) to 13.8 h (T2) and could therefore cover sufficient time of the dosage interval. Maximum plasma levels of 9.6 micrograms/ml and 10.0 micrograms/ml were attained 6.6 and 6.1 h after dosing of T1 and T2, coinciding perfectly with the time of the critical morning dip at 2-6 a.m. With a nocturnal excess of 15.5% (T1) and 17.9% (T2), this circadian-tailored asymmetric dosage regimen proved to take into account the chronopathology of asthma and the chronopharmacokinetics of theophylline sustained release preparations. Bioequivalence of all 3 formulations compared with each other with regard to rate (Cmax ss) and extent (AUCss) of absorption could be established for the 2 batches at the upper and lower in vitro specification range and for both batches of the new formulation compared to the reference. All in all, the safety and efficacy of this new liquid sustained release theophylline preparation could be established. Furthermore, in vitro specifications were justified according to current EC guidelines.

Pharmacokinetic characteristics of a new liquid sustained-release formulation of theophylline designed for the elderly and children: microcaps as sachet.

A new sustained-release theophylline formulation was especially designed for the elderly and children. Microcapsules of theophylline, administered as a suspension in water, proved to be a suitable dosage form for a clientele with impaired or difficult deglutition. Pharmacokinetic characteristics of 2 batches at the lower (T1) and the upper (T2) in vitro dissolution specification range of this new formulation and a pellet formulation (R) as a comparator were evaluated in an open, randomized, 3-way, multiple-dose, crossover study design with an asymmetric dosage regimen of 400 mg and 200 mg theophylline. Smooth and safe plasma concentrations with a high and long-lasting plateau were achieved with this new formulation. Plateau times which are independent of the asymmetric dosage regimen ranged from 16.4 hours (T1) to 13.8 hours (T2) and could therefore span sufficient time of the dosage interval. Maximum serum levels of 9.6 micrograms/ml and 10.0 micrograms/ml were attained 6.6 and 6.1 hours after dosing of T1 and T2, coinciding perfectly with the time of the critical morning dip at 2-4 a.m. With a nocturnal excess of 15.5% (T1) and 17.9% (T2) this circadian-tailored asymmetric dosage regimen proved to take into account the chronopathology of asthma and the chronopharmacokinetics of theophylline sustained-release preparations. Bioequivalence of all 3 formulations versus each other with regard to rate (Cmaxss) and extent (AUC(tau)ss) of absorption could be established for the 2 batches at the upper and lower in vitro specification range and for both batches of the new formulation compared to the reference. All in all, safety and efficacy of this new liquid prolonged-release theophylline could be established. Furthermore, in vitro specifications could be justified according to current EU guidelines.

Effect of gallbladder contraction induced cholagogia on the pharmacokinetic profile of a sustained-release theophylline formulation.

Bile excretion might change the physiological milieu of the duodenum resulting in enhanced absorption of a drug due to increased solubilisation. This possible influence of bile salts following stimulation of gallbladder emptying via the release of cholecystokinin on the pharmacokinetics of a sustained-release theophylline (CAS 58-55-9) preparation (Bronchoretard) was evaluated in this study. An open, randomised 3-way cross-over study in 12 healthy, non-smoking volunteers was selected to prove or reject this hypothesis. All subjects received 500 mg of the sustained-release theophylline formulation under two different cholagogia stimulating test conditions and under a fasting reference condition. A standard breakfast and i.m. application of cholecystokinin enabled modulation of bile flow; a moderate and extreme contraction of the gallbladder could be induced after a standard breakfast and after i.m. application of cholecystokinin, respectively. Following a standard breakfast, gallbladder volumes were approximately halved (50.6%) compared to the baseline volume after 79 min. Injection of 0.3 micrograms/kg body weight cholecystokinin resulted in quick and complete gallbladder evacuation (94.6%) 36 min after the application of this cholagogue stimulus. Gallbladder volumes remained approximately constant under fasting conditions. This manipulation of bile flow did not influence concentration/time profiles of the sustained-release theophylline preparation compared to the fasting condition. Even almost complete evacuation of the gallbladder after application of cholecystokinin did not modify concentration/time profiles of theophylline in a relevant way. An unintentional rapid release of theophylline could be excluded for this sustained-release formulation for all three treatments, as not a single case of dose-dumping was observed. Furthermore, in vitro dissolution investigations using surfactants are neither predictive of food effects nor bile influence on in vivo absorption at least for the sustained-release formulation tested.

Pharmacokinetics and bioavailability of tamoxifen in postmenopausal healthy women.

A randomised cross-over study in 24 postmenopausal women was selected to establish bioequivalence of two tamoxifen (CAS 10540-29-1) formulations. In addition, this study compiled pharmacokinetic parameters for the current 30 mg regimen in postmenopausal women, the target population of tamoxifen therapy. Mean Cmax values of 59.1 +/- 8.9 (T) and 63.6 +/0 11.1 (R) ng/ml were attained 3.6 +/- 1.2 (T) and 3.2 +/- 1.1 (R) h after administration of 30 mg tamoxifen for the test (T) and the reference (R) formulation. The mean AUC (0-480) of tamoxifen was calculated as 3299.7 +/- 761.2 (T) and 3370.1 +/- 701.9 (R) ng x h/ml. The corresponding AUC (0-480) of the active metabolite, N-desmethyl-tamoxifen, exceeded that of the parent drug with 4359.7 +/- 830.5 (T) and 4306.3 +/- 835.2 (R) ng x h/ml, whereas maximal concentrations of the metabolite were distinctly decreased with 14.4 +/- 3.3 (T) and 14.3 +/- 2.4 (R) ng/ml. The pharmacokinetic parameters evaluated in this study are well in line with already known pharmacokinetic data generated with young male volunteers and postmenopausal patients with breast cancer. Precise analytics and an extremely long blood sampling period facilitated an accurate determination of tamoxifen's half-life in postmenopausal women with 210.1 +/- 60.8 (T) and 209.8 +/- 59.9 (R) h. Based on the extremely long half-life, the suitability of a cross-over design is discussed and recommended for further studies.

[Biological availability of gastric juice-resistant coated diclofenac preparations. 1. Bioavailability study following a single administration of a multiple-unit formulation in comparison with a single-unit formulation]. / Untersuchungen zur Bioverfügbarkeit von magensaftresistent überzogenen Diclofenac-Zubereitungen. 1. Mitteilung: Bioverfügbarkeitsstudie nach Einmalgabe einer multiple-unit-Formulierung im Vergleich zu einer single-unit-Formulierung.

Bioavailability Study of Enteric Coated Diclofenac Formulations/1st Communication: Bioavailability study following single-dose administration of a multiple-unit formulation compared with a single-unit formulation Relative bioavailability of diclofenac (CAS 15307-86-5) was investigated after single-dose administration of an enteric coated multiple-unit formulation (Diclo-Puren 50, test) in comparison to a single-unit dosage form (reference). The study was carried out in a three-way changeover design with a group of 18 healthy male volunteers. Diclofenac plasma concentrations were measured using a selective and sensitive GLC-MS method after liquid-liquid extraction and subsequent derivatisation. Area under the curve (AUC) and maximum plasma concentrations (Cmax) were evaluated as pharmacokinetic characteristics. Moreover, time of maximum plasma concentration (tmax), lag-time (tlag) and plateau time of concentrations above minimum effective concentrations (MEC) of 50 ng/ml (tMEC(50)) and 100 ng/ml (tMEC(100)), respectively were calculated. Bioequivalence concerning AUC and Cmax was assessed by calculating 90%-confidence intervals using parametric (ANOVA, ANOVAlog) and non-parametric (Mann-Whitney) methods. Due to the inclusion rule bioequivalence was accepted if one of the calculated intervals was completely in the range of 80 to 125% (AUC) and 70 to 143% (Cmax). tmax, tlag and tMEC were evaluated considering the differences of mean values. Individual plasma profiles of diclofenac are more homogeneous after administration of the test formulation than after administration of the reference product. Mean relative bioavailability of the test formulation was calculated as 99%. Maximum plasma concentrations (mean +/- SD) were determined as 1159 +/- 632 ng/ml (test) and as 1481 +/- 637 ng/ml (reference). Maximum plasma concentrations (mean +/- SD) occurred 1.4 +/- 0.7 h (test) and 1.8 +/- 0.7 h (reference) after administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of nilvadipine.

Nilvadipine is absorbed rapidly and completely and its absolute bioavailability is about 14-19% because of its high first-pass metabolism. Maximum plasma levels and the extent of bioavailability increase proportionally with the dose. Nilvadipine is mainly excreted via the kidney as inactive metabolites. Slow tissue redistribution is probably the reason for the terminal elimination half-life of 15-20 h. There was a good correlation between the estimated tissue concentration and the reduction in blood pressure in patients. The use of the sustained-release pellet formulation can prevent plasma level peaks and thereby lessen the typical side effects of dihydropyridine calcium antagonists. The pharmacokinetics of nilvadipine were not affected by impaired renal function, and although the bioavailability was increased in liver cirrhosis, there was no accumulation after repeated doses. There was no effect on plasma digoxin levels. The plasma concentration of nilvadipine can be affected by either activation or inhibition of the cytochrome P450 system. The use of a sustained-release once-a-day formulation to lower the peaks in plasma levels along with nilvadipine's long terminal half-life means that this well-tolerated pharmaceutical formulation can be employed in clinical trials for the treatment of hypertension and expected to work over 24 h.