Multiple-dose pharmacokinetics, pharmacodynamics and tolerability of the oral ET(A) endothelin-receptor antagonist SPP301 in man.

BACKGROUND: SPP301 is a competitive antagonist of ET-1 with a high selectivity for the ET(A) receptor. The multiple-dose pharmacokinetics, pharmacodynamics, safety and tolerability of SPP301 were investigated in healthy male subjects. METHODS: In an ascending-dose, double-blind, placebo-controlled trial doses of 5, 20, 40 and 60 mg SPP301 were given orally on Day 1 and, after a wash-out period of 48 hours, once daily for seven days. At regular intervals, blood pressure and pulse rate, plasma levels of ET-1, and of SPP301 and its hydroxymethyl metabolite as well as urinary excretion of the parent drug and its metabolite were determined. RESULTS: SPP301 was generally well-tolerated. With the higher doses asymptomatic and transient increases in liver transaminases were observed. No other clinically relevant effects of SPP301 on hematology, biochemistry or urinalysis parameters were observed. Vital signs, ECG parameters and physical examinations showed no time or treatment effect. The pharmacokinetics of SPP301 and its hydroxymethyl metabolite (Ro 68-5925) were linear up to 40 mg SPP301. Steady state was reached after 3-4 days. The apparent terminal half-life of SPP301 and the metabolite was in the range of 7-10 hours after single and repeated doses. At the 60 mg dose level plasma concentrations of SPP301 decreased from the first to the last day of oral treatment. The average decreases in Cmax and AUC were 33% and 37%, respectively. Cmax and AUC of the metabolite amounted to about 4-6% of the values for SPP301 under single and repeated-dose conditions. Urinary excretion of SPP301 and of its metabolite were below 0.1% and 5%, respectively. CONCLUSION: SPP301 is quite well-tolerated, pharmacokinetics are linear and time-independent up to 40 mg multiple doses. Steady state is reached after 3-4 days. Urinary excretion of the unchanged drug plays a minor role in the elimination process of SPP301. ET-1 plasma concentrations increased about 1.5-fold at 20 mg and all further doses.

A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly.

We investigated the pharmacokinetics of bromocriptine and octreotide, both individually and in combination, in 12 patients with active acromegaly. The pharmacodynamics of the drugs were assessed by 12-h profiles of GH secretion and insulin-like growth factor-I (IGF-I) measurements. During the 42-day study period, bromocriptine was administered for 28 days (from day 8; 5 mg, orally, twice daily) and octreotide (200 micrograms, sc, twice daily) from days 15-42. IGF-I levels, 12-h GH, and plasma bromocriptine and octreotide profiles were obtained on days 0, 14, 28, and 42. During bromocriptine treatment, both the area under the GH day curves (AUC) and mean IGF-I decreased to 64% (95% confidence limits, 43-72% and 48-82%, respectively) of initial values. During octreotide treatment, the respective values were 23% (18-30%) and 32% (21-36%), which were greater decreases than those during bromocriptine treatment [36% (95% confidence limits, 32-54%) for AUC for GH and 50% (95% confidence limits, 34-58%) for IGF-I]. With combined treatment, the AUC for GH was reduced to 16% (12-21%) and that of IGF-I to 25% (16-27%) of initial values. This combination was more effective than bromocriptine [25% (95% confidence limits, 22-37%) for AUC for GH and 39% (95% confidence limits, 25-43%) for IGF-I] and octreotide alone [78% (95% confidence limits, 53-89%) for AUC for GH and 78% (95% confidence limits, 57-98%) for IGF-I]. The pharmacokinetic parameters of octreotide were unchanged by the coadministration of bromocriptine. The bioavailability of bromocriptine increased by approximately 40% when bromocriptine was administered together with octreotide compared with administration alone (P < 0.01). Bromocriptine disposition parameters were unaltered. In conclusion, treatment of acromegalics with a combination of octreotide and bromocriptine increases the bioavailability of bromocriptine and reduces both GH and IGF-I levels more effectively than treatment with either drug alone. This presents the possibility of less frequent drug administrations, lower doses of octreotide, and, consequently, lower treatment costs.

Pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine in renal allograft recipients--a concentration-controlled comparison with the commercial formulation.

The steady-state pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine (Sandimmune Neoral) were compared with Sandimmune in 18 clinically stable renal allograft recipients. In study period I (2 weeks duration), patients entered the study on a stable, individualized twice-daily dosage regimen of Sandimmune. Two approaches were assessed for changing patients over from Sandimmune to Sandimmune Neoral. In period II (2 weeks), doses were converted based on the area under the curve ratio derived from a relative bioavailability study comparing the two formulations in healthy volunteers. In period III (2 weeks), doses were titrated to provide comparable steady-state trough concentrations as at study entry. Sandimmune was reinstituted during period IV (2 weeks). Safety and tolerability were assessed at weekly clinic visits and the steady-state pharmacokinetics of cyclosporine in whole blood were characterized at the end of each study period. Dose conversion in period II based on the AUC ratio derived from healthy volunteers was inadequate for achieving comparable cyclosporine exposure as assessed by steady-state AUC and troughs. The concentration-controlled approach (period III) indicated that maintaining the same cyclosporine dose when changing between formulations yields comparable steady-state trough concentrations. Concomitant with this conversion, steady-state peak concentration and AUC increased on average by 39% and 15%, respectively, due to absorption-related differences between the formulations. These increases were not associated with adverse events or changes in blood pressure or clinical laboratory parameters. Furthermore, they were not detrimental to the transplanted kidney as monitored by ultrasound examination. The pharmacokinetic profiles from Sandimmune Neoral exhibited less variability and yielded a stronger correlation between trough concentration and systemic exposure (AUC) compared with Sandimmune.

Cyclosporine pharmacokinetics and variability from a microemulsion formulation--a multicenter investigation in kidney transplant patients.

The steady-state pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine (Sandimmune Neoral) were compared with the commercial formulation (Sandimmune) in 55 clinically stable renal allograft recipients. In study period I (2 weeks' duration), patients entered the study on a stable, individualized twice-daily dosage regimen of the commercial formulation. In period II (2 weeks), they were changed over to the microemulsion formulation at the same dose as at study entry. In period III (2 weeks), dose titration was subsequently allowed if necessary to provide comparable steady-state trough concentrations as at study entry. The commercial formulation was reinstituted during period IV (2 weeks). Safety and tolerability were assessed at weekly clinic visits, and the steady-state pharmacokinetics of cyclosporine in whole blood were characterized at the end of each study period. A milligram-to-milligram dose conversion was adequate when making the initial change between formulations in order to maintain steady-state trough concentrations in the target therapeutic range. Concomitant with this conversion, the steady-state peak concentration and area under the curve increased on average by 59% and 30%, respectively, due to absorption-related differences between the formulations. These increases were not associated with an increase in adverse experiences or changes in blood pressure or clinical laboratory parameters over the first four weeks after the change-over. Trough concentrations were more stable and were more strongly correlated with systemic exposure (area under the curve) during treatment with the microemulsion formulation. Intraindividual coefficients of variation in steady-state peak concentration, time to attain the peak, area under the curve, and percent peak-trough fluctuation ranged from 18% to 74% from the commercial formulation. Variability from the microemulsion formulation was significantly less, ranging from 10% to 22%.

Lack of interaction between fluvastatin and oral hypoglycemic agents in healthy subjects and in patients with non-insulin-dependent diabetes mellitus.

Human drug interaction studies in vivo are conducted when in vitro and/or animal interactions suggest clinical relevance. Studies in vitro have indicated that the new, entirely synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin affects the metabolism of the nonsteroidal anti-inflammatory drug diclofenac and the oral hypoglycemic tolbutamide. Diclofenac and tolbutamide are both model substrates of the CYP2C isozymes, suggesting that this enzyme could be involved in the underlying mechanism of interaction. The concomitant use of lipid-lowering drugs with oral hypoglycemic agents has been recommended in patients with non-insulin-dependent diabetes mellitus (NIDDM). Therefore, 2 studies were initiated to explore potential pharmacokinetic and pharmacodynamic interactions between fluvastatin, simvastatin, or placebo and the oral hypoglycemic agents tolbutamide (study I) and glyburide (study II), each in 16 healthy subjects. These compounds were selected because of a demonstrated in vitro interaction with tolbutamide and widespread clinical use of glyburide. A further study (study III) was conducted to investigate the potential pharmacokinetic and pharmacodynamic interactions between fluvastatin and glyburide under therapeutic conditions in 32 patients with NIDDM. Single and multiple coadministration of fluvastatin 40 mg or simvastatin 20 mg increased the mean maximum plasma concentration and area under the concentration-time curve of glyburide by about 20%. The pharmacokinetics of tolbutamide were influenced to only a minor extent. Fluvastatin concentration-time profiles were unaffected by tolbutamide or glyburide coadministration. However, the pharmacokinetic interactions between fluvastatin or simvastatin and tolbutamide and glyburide were not associated with clinically relevant changes in blood glucose and insulin concentrations and, therefore, are not considered to be relevant in therapeutic practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioequivalence of a slow-release and a non-retard formulation of isradipine.

Pharmacokinetic studies were carried out in 48 healthy male volunteers to determine the pharmacokinetic properties of a new modified-release formulation of isradipine (SRO) and to compare these with the pharmacokinetic properties of the nonretard form of isradipine (NR). Studies were carried out in the fasting state and also following a light meal. The time required to reach maximum plasma concentration (tmax) was extended from approximately 1.5 h with NR to 5 to 7 h with SRO, and the maximum plasma concentration [Cp(tmax)] was reduced by around 50%. The bioavailability of SRO was increased by less than 20% compared with the same daily dose given as NR, indicating that the two forms are bioequivalent and that no adjustment in the total daily dose of isradipine is necessary when switching from one form to the other. Administration with a light meal altered the pharmacokinetic parameters by less than 20% compared with administration without food.

Pharmacokinetics of orally administered cyclosporine in patients with Crohn's disease.

Cyclosporine pharmacokinetics were reported to be influenced in patients with Crohn's disease. To explore the relationship between Crohn's disease and cyclosporine pharmacokinetics, this investigation was performed in 20 patients with varying Crohn's Disease Activity Index (CDAI). A single oral dose of 300 mg of cyclosporine was given and serial blood samples were obtained over 52 hours. Cyclosporine whole blood concentrations were determined by a specific monoclonal radioimmunoassay. Pharmacokinetic parameters were comparable with those of healthy volunteers. No statistically significant difference between the pharmacokinetic parameters of the patients with CDAI values less than 150 and those with CDAI values 150 or greater could be shown. Although several factors associated with the pathology of Crohn's disease theoretically could influence the pharmacokinetics of orally administered cyclosporine, this investigation did not identify statistically significant differences in cyclosporine pharmacokinetics in Crohn's disease patients with different disease activities or different localization of inflammation as compared with healthy volunteers. However, if large parts of the small bowel were removed, a decrease of absorption of cyclosporine could be observed. In any case, it is important to be aware of the clinical variability of Crohn's disease and its potential implications in cyclosporine absorption.

Bioequivalence of soft gelatin capsules and oral solution of a new cyclosporine formulation.

STUDY OBJECTIVE: To compare the bioavailability of cyclosporine from two oral dosage forms of a new microemulsion formulation. DESIGN: Open, randomized, three-treatment, three-period crossover investigation. SETTING: University-affiliated clinical pharmacology research unit. PATIENTS: Twenty-four healthy male volunteers. INTERVENTIONS: Single oral administrations of cyclosporine 180 mg given as a soft gelatin capsule (reference), an oral solution under fasting conditions, and the oral solution mixed with orange juice. MEASUREMENTS AND MAIN RESULTS: Serial venous blood samples were obtained over 48 hours after each administration to measure cyclosporine in whole blood by a specific monoclonal radioimmunoassay. For all three treatments, the mean maximum blood concentration (Cmax) of approximately 1100 ng/ml was reached at about 1.3 hours (tmax) after administration; the area under the blood concentration-time curve (AUC) was, on average, 4700 ng.hr/ml. Bioequivalence was conclusively demonstrated for both the absorption rate (Cmax and tmax) and extent (AUC) of cyclosporine among the treatments inasmuch as the point estimates and 90% confidence intervals were within the respective equivalence ranges. CONCLUSIONS: When administered in conjunction with routine concentration monitoring, the two oral dosage forms of the new microemulsion formulation of cyclosporine can be interchanged without need for dosage adjustments. In addition, the oral solution can be mixed with fruit juice without affecting the rate or extent of cyclosporine absorption.

Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation.

The inter- and intraindividual variability of cyclosporine pharmacokinetics from a microemulsion formulation were compared with the currently marketed formulation in a sequential bioreplication study. Twenty-four healthy male volunteers were randomized to receive each formulation on two separate occasions; the reference treatment was a single oral dose of 300 mg of Sandimmune and the test treatment was a single oral dose of 180 mg of Sandimmune Neoral, both given as soft gelatin capsules. Serial venous blood samples were obtained over a period of 48 h after each administration, and cyclosporine concentrations were measured in whole blood by a specific monoclonal RIA method. Between- and within-subject variabilities were quantified from the appropriate sums of squares from analysis of variance and statistically compared between formulations. Both inter- and intraindividual variation for the peak concentration, time to reach the peak, area under the curve, and terminal half-life of the test formulation were significantly reduced (p < 0.05) with two exceptions. For area under the curve between subjects (p < 0.2) and peak concentration within subjects (p < 0.1), trends toward reduced variability for the test formulation were evident. These results were further reflected in the inter- and intraindividual coefficients of variation of the pharmacokinetic parameters that ranged from 3 to 22% for the test formulation compared with 19 to 41% for the reference formulation. In comparison with the currently marketed formulation, reduced variability in the pharmacokinetics of cyclosporine following oral administration of Sandimmune Neoral provides a more predictable and consistent concentration-time profile.

Treatment of relapsing bleeding peptic ulcers with the somatostatin analogue SMS 201 995 in a patient with Zollinger-Ellison syndrome.

SMS 201-995 is an octapeptide analogue of natural somatostatin characterized by pharmacological properties similar to those of somatostatin itself. In addition, its serum half-life of about 60 minutes after i.v. injection is significantly longer than that of the natural compound. A patient with active bleeding from a peptic ulcer jejuni due to a Zollinger-Ellison syndrome was successfully treated with SMS 201-995. Bleeding stopped after continuous infusion (25 micrograms/h) within the first 24 hours of infusion. The serum gastrin concentration dropped from 3,300 pg/ml to 170 pg/ ml (normal range 40-100 pg/ml). Continuation of the treatment by subcutaneous injections of SMS 201-995 (100 micrograms twice daily) maintained serum gastrin concentrations between 300 to 400 pg/ml over a period of 8 months. Side effects have not been observed. Four subsequent endoscopic examinations have revealed no ulcer relapse.

Pharmacokinetics of SMS 201-995 in healthy subjects.

The pharmacokinetics of a new somatostatin derivative, SMS 201-995, was investigated in a group of eight healthy subjects. SMS 201-995 was given intravenously in doses of 25 micrograms, 50 micrograms, 100 micrograms, and 200 micrograms and also subcutaneously in doses of 50 micrograms, 100 micrograms, 200 micrograms, and 400 micrograms in accordance with a randomized Latin-square design. Blood samples were taken up to 8 h. The tolerability of SMS 201-995 was very good. Routine blood chemistry variables remained normal. After intravenous administration of SMS 201-995 initial half-lives ranging from 9 +/- 2 min to 14 +/- 4 min and second half-lives of from 72 +/- 22 min to 98 +/- 37 min were calculated for the different doses. SMS 201-995 was rapidly absorbed after subcutaneous injection with a half-life ranging from 5.3 +/- 2.2 min to 11.7 +/- 7.6 min. The disposition half-life was from 88 +/- 20 min to 102 +/- 16 min for the different doses. Cp(tmax) and AUC (0 - infinity) increased dose-dependently after both routes of administration, pointing to linear pharmacokinetics for SMS 201-995. On the basis of its good tolerability, slow plasma clearance, and long action, SMS 201-995 represents a valuable tool for further clinical studies.

BBR 3438, a novel 9-aza-anthrapyrazole, in patients with advanced gastric cancer: a phase II study group trial of the Central European Society of Anticancer-Drug Research (CESAR).

BBR 3438, a member of the 9-aza-anthrapyrazole family designed to decrease anthracycline dependent cardiotoxicity and to improve efficacy provided high in vivo activity in gastric carcinoma xenograft models. The present study was carried out to assess the efficacy and safety of BBR 3438 applied at a dose of 50 mg/m(2) four-weekly as an 1-hour infusion to pretreated patients with gastric cancer. Twenty-seven patients received at least one administration of BBR 3438. Lymph nodes and liver were the most common sites of metastases. A total of 94 cycles were administered (median 2, range 1-6). The main toxicity consisted of (worst per patient [%]; NCIC CTC grades 1/2/3/4) neutropenia 7/7/19/52 (one case of febrile neutropenia), stomatitis 15/19/4/-, nausea 22/26/7/-, vomiting 19/7/7/-, alopecia 15/33/-/-. Neutrophil nadir (520/mul) was reached after a median 15 days. The median time to recovery to < or = grade 1 neutropenia was 13.5 days. The median average cumulative dose of BBR 3438 was 166.8 mg, and the median dose intensity was 48.8 mg/m(2). Left ventricular ejection function (LVEF) was monitored with multiple-gated angiography (MUGA). Median LVEF values at baseline and at the end of cycle 2 were 67.5% and 65%, respectively, and no patient showed a relevant decrease of LVEF. In 25 patients evaluable for response no remission was observed. Four patients (16%) had stable disease. Median time to progression was 51 days, median overall survival was 64 days. In all, the feasibility and tolerability of BBR 3438 applied 4-weekly at a dose of 50 mg/m(2) was confirmed and neither relevant LVEF decreases nor hints of cardiac toxicity were observed. In terms of antitumor activity, BBR 3438 was found to be ineffective in the treatment of gastric cancer.

Pharmacology, toxicology and human pharmacokinetics of tropisetron.

Tropisetron is a novel, potent and highly selective 5-HT3 receptor antagonist, which is active in the treatment of nausea and vomiting induced by highly emetogenic chemotherapeutic drugs such as cisplatin. Tropisetron selectively blocks the excitation of the presynaptic 5-HT receptors of the peripheral neurones involved in the emetic reflex, and may have other direct actions in the CNS on 5-HT3 receptors, mediating the actions of vagal inputs to the area postrema. Toxicological studies show that tropisetron is generally well tolerated by all animal species investigated and no specific organ toxicity was observed, other than slight loss of body weight development. In man, tropisetron metabolism is linked to the cytochrome P-450 2D6 isoenzyme system, which determines the polymorphism of debrisoquine/sparteine metabolism. As a result, there are phenotypical populations of extensive and poor metabolizers. The two main adverse events in human volunteer tolerability studies with tropisetron were headache and constipation. These adverse events tended to be slightly more intense and to last longer in poor metabolizers, compared with extensive metabolizers. Tropisetron had similar pharmacokinetic characteristics in elderly patients and renal patients, compared with healthy subjects. From a toxicological and pharmacokinetic point of view, therefore, daily doses of 5 mg tropisetron can be administered to both poor and extensive metabolizers, as well as to special populations, without any particular precautions.

Effect of cimetidine on the metabolism of cholephilic dyes in Gilbert's syndrome.

The metabolism of indocyanine green, bromsulphophthalein and bilirubin was studied before and after a treatment for 2 weeks with cimetidine 1.0 g/day in 12 subjects with Gilbert's syndrome. There was no effect on the plasma clearance of indocyanine green and bromsulphophthalein, on the maximal biliary excretion capacity of bromsulphophthalein, on serum bilirubin concentrations or on the biliary metabolites of bromsulphophthalein and bilirubin. It is concluded that in Gilbert's syndrome two weeks of treatment with cimetidine had no effect on liver blood flow or on conjugation mechanisms which were independent of cytochrome P450.