Assessment of the safety, tolerability, and PK/PD properties of two new formulations of subcutaneously administered IFN-beta1a: a double-blind, placebo-controlled comparison with the currently available formulation.

OBJECTIVE: Application-site disorders are well-known adverse events (AEs) associated with subcutaneous (s.c.) injection. With high-dose, high-frequency interferon (IFN)-beta1a (Rebif) these AEs are generally mild but may lead to the discontinuation of some patients. The objective of this study was to compare the safety, tolerability, and the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of two new formulations of Rebif (Rebif New Formulation: RNF1 and RNF2) with the current formulation (hereafter referred to as R) and placebo. METHODS: In this double-blind, placebo-controlled, parallel-group, Phase I study, healthy volunteers of both sexes were randomized 1:1:1:1 to receive a single 0.5 ml s.c. dose of RNF1, RNF2, R or placebo (normal saline). The three active treatments contained 44 microg IFN-beta1a. During the 24-hour post-dose period, safety and tolerability assessments were conducted and blood samples were taken at regular intervals for PK and PD analyses. Pain intensity on injection was measured using the short-form McGill questionnaire and a 100 mm visual analogue scale (VAS). Further safety assessments were performed and blood samples taken at 24-hour intervals until Day 7 post-dose, with a final post-study visit 10- 14 days after dosing. RESULTS: A total of 48 subjects (22 men, 26 women) were recruited and allocated equally to each treatment (12 subjects per group). AEs were reported by 10 subjects in each active treatment group and by 3 subjects in the placebo group. All AEs were consistent with the known safety profile of R. The number of treatment-emergent AEs was lower in the RNF2 group than the RNF 1 or R groups (21, 31 and 33 events, respectively). Redness at the injection site was mostly mild and occurred in fewer subjects in the RNF2 group (n = 3) than the RNF 1 or R groups (n = 7 and n = 4, respectively). Injection site pain was reported by 1 subject in the RNF2 group, compared with 4, 6 and 3 subjects, respectively, in the RNF1, R and placebo groups. The worst pain intensity, as measured by VAS, was lower in the RNF2 and RNFI groups than either the R or placebo groups. There was considerable intersubject variability in the PK and PD profiles of the three formulations of IFN-beta1a. Nevertheless, the PK and PD characteristics of RNF2 were similar to those of R. CONCLUSIONS: The results from this study suggest that RNF2 may offer improved tolerability compared with the current formulation of R, but retains comparable pharmacokinetic and pharmacodynamic characteristics.

Tolerability, safety and pharmacokinetics of single dose and multiple dosing of the selective D1 antagonist NNC 01-0687 in healthy subjects.

Selective dopamine D1-receptor antagonists have been shown to exhibit similar effects in animal models for antipsychotic action as the selective D2 antagonists. NNC 01-0687, a benzazepine with selective and high affinity to the D1-receptor, was well tolerated by healthy subjects allocated to double blind, placebo controlled studies. Complaints of moderate restlessness and drowsiness were reported after administration of 25 mg NNC 01-0687, indicating the dose to be the maximum tolerated single dose. The highest multiple dose level of a daily dose of 45 mg NNC 01-0687 administered t.i.d. for 14 days was assessed as safe and well-tolerated with few reports of adverse events. Some alanine aminotransferase (ALT) elevations appeared in both treatment groups (active and placebo) and no evident influence of NNC 01-0687 on the liver function could be derived. No statistically significant or clinically relevant effects were observed in haematological parameters, urinalyses, blood pressure, heart rate, ECG or plasma levels of prolactin, cortisol or growth hormone. The plasma drug concentration curves indicated a fast absorption with tmax at 0.5-1 h and an apparent elimination half-life of 3-4 h. Both AUC and Cmax appeared to be linearly correlated to the dose, indicating linear pharmacokinetics. With similar Cmax and AUC on day 1 and day 10 no accumulation was observed. When administered just after lunch, the Cmax was reduced by 50-60% and the tmax increased to 3 h, but without change of AUC.

Laboratory values and vital signs in male smokers and nonsmokers in phase I trials: a retrospective comparison.

In a retrospective analysis of 13 phase I multiple-dose trials, clinical data from 100 volunteers who received placebo were investigated for differences in routine safety laboratory parameters and vital signs between smokers and nonsmokers. Of the 100 subjects, 47 were classified as smokers (cigarettes only) and 53 were classified as nonsmokers. Objectives of the analysis were to offer a basis for decision whether certain deviations of laboratory values or vital signs might be related to smoking rather than to a study drug or some external influence, and to explore whether smokers tend to present changes in laboratory values or vital signs during a trial that are different from changes that occur in nonsmokers. Regarding baseline values, which were defined as the mean of values at screening and the first day of the in-house stay, clinically and statistically significant differences between smokers and nonsmokers were found for total leukocytes and triglycerides (mean greater for smokers than nonsmokers), and total bilirubin (mean greater for nonsmokers than smokers). Comparison of changes during the study in smokers and nonsmokers showed a statistically and clinically significant difference only for triglyceride levels. Smokers had a slight decrease in triglyceride levels, whereas nonsmokers showed a marked increase in the respective values during the trials. Prospective studies with sufficiently large sample sizes are required to confirm the results of this retrospective analysis on a wider basis, and to possibly achieve significance for further differences between smokers and nonsmokers.

Elevation of liver enzymes in multiple dose trials during placebo treatment: are they predictable?

The present study examined the increase in transaminases, especially in ALT in young healthy males during placebo treatment in phase I multiple dose trials. The primary objective was to investigate whether volunteers showing increasing ALT levels also present characteristic patterns of demographic data, laboratory parameters, and vital signs. The secondary objective was to determine whether there is a possibility to predict increases of ALT during a trial by analyzing demographic data and baseline levels of routine safety laboratory parameters and vital signs. In a meta-analysis of 13 placebo-controlled multiple dose phase I studies, volunteers showing elevations of ALT during placebo treatment were compared with those presenting no clinically significant changes of ALT levels. Demographic data as well as routine safety laboratory values and vital signs measured at screening and on the first day of the in-house stay were subject to the analysis. Using Wilcoxon's rank sum test, significant differences between ALT-susceptibles and ALT-nonsusceptibles were found for baseline values (mean values of screening and the first day of the in-house stay) of ALT, gamma GT, AST/ALT, and AST/ gamma GT. Differences found for the screening values of the heart rate were statistically rather than clinically significant. Cut-off values were found for baseline levels of ALT and AST/ALT ratio. Their use resulted in a sensitivity of 73% and a specificity of 74% with regard to predictability of ALT levels increasing during the trial.

Single-dose interaction study of diprafenone HCl and propranolol HCl in healthy volunteers.

Using a 3 x 3 Latin Square design, a possible interaction between diprafenone HCl a class IC antiarrhythmic drug with nonspecific beta-antagonist activity and propranolol HCl was investigated in nine young, healthy, caucasian, male volunteers. The volunteers randomly received 3 single-dose treatments: (A) 200 mg DHCl, (B) 80 mg PHCl, and (C) 200 mg DHCl and 80 mg PHCl. Scheduled blood samples were taken and plasma concentrations of both diprafenone and propranolol were measured by sensitive and specific assay methods. Lead II electrocardiogram intervals at rest, heart rate during erect bicycle ergometry, and echocardiographic variables at rest and shortly after exercise were recorded. The data analysis used compartment model independent methods. There was no evidence for a pharmacokinetic interaction between the two drugs. With DHCl, two of the nine subjects showed greatly increased areas under the plasma concentration-time curves and apparent disposition half-lives in the presence and absence of PHCl, indicating that metabolism of diprafenone may be subject to pharmacogenetic polymorphism. There was evidence for a pharmacodynamic interaction between DHCl and PHCl regarding the negative chronotropic effect at rest and during exercise. There was no difference in the pharmacodynamics and tolerability of the three treatments in suspected "poor" and "extensive metabolizers" of DHCl.

Dose linearity and steady state pharmacokinetics of the new antiparkinson agent budipine after oral administration.

The dose-dependency of budipine pharmacokinetic characteristics was studied. Eighteen healthy male subjects were given 10, 20 and 30 mg oral single doses according to a randomized, open, 3-period crossover design. Additionally, the steady state conditions were investigated after repeated intake of 10 mg t.i.d for 10 days and compared to the 10 mg single dose. The area under the concentration vs time curve (AUC) and the maximum serum concentration (Cmax) showed a linear increase in line with ascending doses of orally given budipine. Time to maximum serum concentration (tmax) and terminal half-life (t1/2) were independent of the administered dose. As compared to the 10 mg single dose pharmacokinetics, the repeated oral administration of budipine 10 mg t.i.d. resulted in an increase in AUC of 11% and 93% for budipine and its metabolite p-OH-budipine, respectively. In clinical practice, a predictable response in proportion to the dose is to be expected.

[Comparative study of the pharmacokinetics of amitriptyline oxide and trimipramine after single administration in healthy male probands and patients with renal failure]. / Vergleichende Untersuchung zur Pharmakokinetik von Amitriptylinoxid und Trimipramin nach Einmalgabe bei gesunden männlichen Probanden und Patienten mit Niereninsuffizienz.

The pharmacokinetics of the antidepressants amitriptyline oxide and trimipramine and their major metabolites amitriptyline, nor-triptyline and desmethyltrimipramine, were studied in twelve healthy male subjects (aged from 22 to 62 years) and twelve patients (aged from 25 to 73 years) with severe renal impairment (glomerular filtration rate < 10 ml/min). Oral single doses of 60 mg amitriptyline oxide and 50 mg trimipramine, separated by a washout period, were administered to all study participants. Blood and urine samples were collected up to 120 hours after administration. For trimipramine and desmethyltrimipramine, a new HPLC method was developed. The "Fischer Somatic and Undesired Effects Check List" was used for the assessment of adverse events. The mean plasma half-life and AUC of amitriptyline oxide and its metabolites were significantly higher in patients than in healthy adults. For trimipramine the AUC was significantly higher in patients. The plasma half-life of trimipramine was longer in patients, but statistically not significant. The maximum plasma concentrations for both drugs and metabolites were at an average distinctly higher in patients. Clearance rate of amitroptylinoxide and trimipramine also differed between the two groups. Correlating with these results a high incidence and a longer persistence (in most cases > 12 hours) and more pronounced adverse effects were noted in the patient group, whereas in volunteers adverse events were only observed up to approximately eight hours.

Investigation in healthy volunteers to evaluate serum concentrations and urinary excretions of aluminium, magnesium, calcium and phosphate after multiple administration of hydrotalcit (Talcid) suspension.

The aim of this study was to evaluate the extent of aluminium absorption after repeated administration of Talcid suspension. Therefore, the serum concentrations of aluminium and the amount of urinary excreted aluminium were determined. Furthermore, the influence of repeated Talcid administration on serum concentrations and urinary excretion of magnesium, calcium and phosphate was studied. The trial was carried out as a randomized, double-blind, parallel-group, placebo-controlled investigation in 17 healthy male volunteers and 1 female volunteer, aged between 18-34 years.

Effects of oral posaconazole on the pharmacokinetics of atazanavir alone and with ritonavir or with efavirenz in healthy adult volunteers.

BACKGROUND: Patients with HIV/AIDS are at increased risk for opportunistic fungal infections. These patients may require concomitant treatment with antiretrovirals and azole antifungals, and interactions between these classes of drugs should be anticipated. METHODS: A phase 1, open-label, randomized, crossover, drug interaction study was conducted to assess the pharmacokinetic effects of coadministration of posaconazole (400 mg twice daily), with atazanavir (ATV) (300 mg/d alone) and with ritonavir (100 mg/d) or with efavirenz (400 mg/d) in healthy volunteers. RESULTS: Posaconazole increased maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of ATV by 2.6-fold and 3.7-fold, respectively. Posaconazole increased ATV Cmax and AUC when administered with ritonavir by 1.5-fold and 2.5-fold, respectively. Most subjects who received ATV (with and without ritonavir) and posaconazole experienced clinically relevant increases in total bilirubin. Coadministration of posaconazole and efavirenz resulted in clinically relevant decreases of posaconazole Cmax and AUC of approximately 45% and 50%, respectively. CONCLUSIONS: Frequent monitoring of adverse events and toxicity related to antiviral exposure is recommended in the event of coadministration of posaconazole and ATV with or without ritonavir. In addition, because of decreased posaconazole exposure, coadministration with efavirenz should be avoided unless the benefit to patients outweighs the risk.

[The relative bioavailability and pharmacokinetics of standardized myrtol]. / Untersuchungen zur relativen Bioverfügbarkeit und zur Pharmakokinetik von Myrtol standardisiert.

An open, randomized cross-over trial was performed in 20 healthy volunteers to evaluate the relative bioavailability and the pharmacokinetics of myrtol standardized, the active ingredient of Gelomyrtol and Gelomyrtole forte capsules (abbreviated as GE and GF, respectively, in the following text). The male subjects, aged 19 to 42 years, were given in a randomized manner 1 capsule of GE (120 mg myrtol stand.) uncrushed, 1 capsule of GE crushed, 1 capsule of GF (300 mg myrtol stand.) uncrushed and 1 capsule of GF crushed on 4 different days. The time of administration was always about 8 a.m. and the medication had to be swallowed with 200 ml water. The 4 study sessions were separated (correction of spearated] by at [correction of a] least 6 days. Prior to and 15, 30, 45, 60, 75, 120, 150 min and 3, 4, 5, 8, 12 and 24 h after medication at least 10 ml blood were taken from an antecubital vein. The blood samples were centrifuged within 20 min, the plasma was separated, and transferred into tubes and immediately deep-frozen at -20 degrees centigrade. From GE capsules cineol as main component was absorbed to 93,2% and from GF capsules to 95,6% based on the comparison of the uncrushed with the crushed capsules. The geometric mean of Cmax was 72,4 ng/ml for GE uncrushed capsules, a value of 33% below that for the crushed ones. The time to peak (tmax) was three times higher. With GF Cmax reached 238,2 ng/ml for the uncrushed capsules, a value of 36% below the one for the crushed ones and tmax was 67% higher. The time until the appearance of measurable plasma concentrations (tlag) was 7 and 5 times higher, respectively. These results show, that the main components of myrtol standardized, the active ingredient of GE and GF, are absorbed about 100% compared to the liquid form of administration (crushed capsule). The enteric coating of the capsules produces lower plasma peak-concentrations at later time points. This results in a plateau-like phase of the concentration/time curve between the 2nd and the 8th hour after application and reveals a considerable therapeutic advantage of the enteric coating.

Clinical pharmacology of two specific bradycardiac agents.

The effect of two i.v.-infusion regimens of falipamil on atropine-induced changes of heart rate and the effect of ULFS 49 Cl in 3 different oral doses during a 7-day medication period were studied in volunteers. Both studies were double-blind, randomized and placebo controlled. Under placebo, low doses of atropine caused a 16% reduction in heart rate, a 1 mg cumulative dose increased heart rate by 23%. 100 mg falipamil was followed by a 9% reduction in heart rate. Low doses of atropine enhanced this decrease to 14%, whereas a 1 mg cumulative dose of atropine increased heart rate by only 3%. Similar results were obtained after administration of 200 mg falipamil. ULFS 49 Cl induced a constant reduction of heart rate at rest and during ergometry without changing systolic and diastolic blood pressure. Because no interrelation was found between efficacy and corresponding plasma levels of the drug, it can be concluded that the concentration of the drug in the tissue is responsible for efficacy and duration of action. The minimal effective and the therapeutic doses were 3 X 2.5 mg p.o. and 3 X 5 mg p.o. respectively. In contrast to falipamil, which increased the QT-interval by approximately 20%, ULFS 49 Cl did not change QT-time. Side-effects typical for 'specific bradycardic agents', such as coruscation were seen. Peak occurrence was between day 1 and day 4, thereafter a decreasing frequency was observed. In general, both drugs were effective and well tolerated.

[The effect of a nasal spray consisting of a standardized mixture of citrus limon (succus) and an aqueous extract of Cydonia oblongata (fructus) on nasal mucociliary clearance]. / Einfluss eines Nasensprays bestehend aus einer standardisierten Mischung von Citrus limon (succus) und eines wässrigen Auszugs aus Cydonia oblonga (fructus) auf die nasale mukoziliäre Clearance.

In a three-way-crossover study in 18 healthy male and female subjects aged from 20 to 49 years the influence of a 1% and 3% solution of a standardized composition of Citrus limon, succus, and extract from Cydonia oblonga, fructus (Gencydo) on the intranasal mucociliar clearance was investigated after multiple administration. The pH of the solution was about pH 2.3-3.2. The dose regimen consisted of 20 puffs (0.13 ml per puff) in each nostril within 24 h, which was by factor 3-10 higher than the usual therapeutic dosage of 2-6 puffs per nostril and 24 h. The mucociliar transport time was measured by a modified saccharin test, where 1 microliter of a 3-molar aqueous sodium saccharinate solution was applicated at the inferior nasal turbinate 1 cm from its anterior end using a glass capillary microliter pipet. This test was performed at screening examination, before each administration period, directly after each 24 h treatment period and 24 h after the end of each treatment. The time of initial taste perception could be defined with high precision by the volunteer since it appeared very spontaneously. Neither after intranasal administration of the 1% and 3% Citrus/Cydonia solution nor after placebo solution a prolongation of the perception time was found. It could be concluded that there is no measurable influence of the test products on the intranasal ciliar function.

Influence of the H2-receptor antagonists cimetidine and ranitidine on the pharmacokinetics of nimodipine in healthy volunteers.

A possible interaction between the calcium antagonist nimodipine and the H2-receptor antagonists cimetidine and ranitidine has been investigated in two separate studies in healthy subjects. In eight young volunteers the concomitant administration of nimodipine 30 mg t.i.d. and cimetidine 1000 mg/d for 7 days led to a significant increase of the relative bioavailability of nimodipine. The changes in the pharmacokinetic parameters were not accompanied by discernible haemodynamic effects or any change in the tolerability of nimodipine. There was no evidence of any significant change in the steady-state pharmacokinetics of nimodipine during five days of combined treatment with 30 mg t.i.d. nimodipine and ranitidine 300 mg/d given as single morning dose to twelve healthy, elderly subjects. Analysis of haemodynamics, clinical chemistry and tolerance also did not reveal any difference between the two treatment periods.

[Immunological studies on glucosephosphate isomerase deficiency: instability and impaired synthesis of the defective enzyme (author's transl)]. / Immunologische Untersuchungen zur Glucosephosphat Isomerase Defizienz: Instabilität und verminderte Synthese des defekten Enzyms

The content of GPI protein in normal and GPI deficient red cells was studied by immunological methods. In normal cells almost all enzyme protein is catalytically active. In the four inherited variants with non-spherocytic hemolytic anemia studied the content of GPI protein was decreased to a variable degree. Furthermore, the catalytically active portion of GPI protein varied markedly. It can be concluded that in the pathogenesis of this hereditary disorder an increased lability as well as an impaired synthesis of the defective enzyme play a role.

[Comparison of the relative bioavailability and pharmacokinetics of estrone after oral administration of esterified estrogens in a tablet formulation and an aqueous suspension]. / Vergleichende Untersuchung zur relativen Bioverfügbarkeit und Pharmakokinetik von Estron nach oraler Gabe von veresterten Estrogenen als Drageeformulierung und als wässrige Suspension.

In a two-way crossover study in 18 young female volunteers aged from 22 to 38 years the relative bioavailability and pharmacokinetics of esterified estrogens were investigated after single administration of a sugar-coated tablet formulation (Femavit 1.25) in comparison to a single dose of an oral suspension. The content of active ingredients was in both cases 1.25 mg esterified estrogens. As marker compound the dominating active compound estrone (CAS 53-16-7) was chosen. Estrone in serum was measured using a validated radioimmuno assay. The administration of the test and reference preparation was performed on either day 3-7 of two subsequent menstruation cycles in order to obtain low endogenous hormone levels. The relative bioavailability of estrone from the test preparation, based on the total AUC (AUC under the baseline + AUC over the baseline), was 99.2% (90%-confidence interval 91.8-107.1%) und therefore fulfilled the bioequivalence criterion. After deduction of the baseline-AUC a relative bioavailability of the sugar-coated formulation of 113.9% was found, with a broad 90% confidence interval of 72.5-178.9%, due to a higher variability. The absolute Cmax values were similar (255 pg/ml after tablet administration and 279 pg/ml after suspension), bioequivalence also in regard to Cmax was proven. The value of tmax was 4 h for both preparations.

Evaluation of the safety and pharmacokinetic profile of a new, pasteurized, human tetanus immunoglobulin administered as sham, postexposure prophylaxis of tetanus.

In a monocentric, double-blind, randomized trial, we examined the safety and pharmacokinetic profile of a new, pasteurized, human tetanus immunoglobulin (P-HTIG). As part of the purification process, P-HTIG has undergone a heat treatment step (10 h at 60 degrees C) and the removal of Merthiolate. Forty-eight adults with a history of tetanus vaccination were randomized into four groups (n = 12 per group) to receive one of two different batches of this P-HTIG simultaneously with either tetanus-diphtheria (Td) vaccine (sham, postexposure prophylaxis of tetanus) or placebo. Local reactions at the injection site were followed for the first 3 days after injection, and systemic reactions were followed during the entire study period, i.e., up to 42 days posttreatment. Blood samples for tetanus antibody titer determination (enzyme-linked immunosorbent assay method) were drawn prior to treatment on day 0 and on days 1, 2, 3, 7, 14, 21, 28, 35, and 42. A normalization of tetanus antibody titers (subtraction of the day 0 value for each subject at each time period) was performed to assess the additive effect of P-HTIG on tetanus antibody titers. The pharmacokinetic parameters were determined by both a compartmental analysis (modelization) and a noncompartmental analysis. No severe adverse reactions were reported. The rate of local reactions at the P-HTIG injection site was 27%. All local reactions were mild and resolved within 2 days. In contrast, local reactions at the vaccine injection site were seen in 79% of the subjects. The rate of systemic reactions was similar in the P-HTIG plus Td vaccine group (33%) and in the P-HTIG plus placebo group (21%), and all these reactions were mild. In the P-HTIG plus placebo group, tetanus antibody titers rose to a maximum of 0.313+/-2.49 IU/ml after 4.4 days; in the P-HTIG plus Td vaccine group, a maximum concentration of 15.2+/-2.42 IU/ml was reached 19 days postinjection. In both groups, 100% of the patients had seroprotective levels of tetanus antibodies (> or = 0.01 IU/ml) 2 days following treatment. An anamnestic response to Td vaccine appeared 7 days postimmunization. In conclusion, P-HTIG has a good safety and pharmacokinetic profile. Our results confirm that immunoglobulin should be associated with vaccine in the treatment of tetanus-prone wounds.

The effect of anastrozole on the single-dose pharmacokinetics and anticoagulant activity of warfarin in healthy volunteers.

AIMS: The aims of this study were to determine the effects of the nonsteroidal, selective aromatase inhibitor, anastrozole, at steady-state concentrations, on the pharmacokinetics and pharmacodynamics of warfarin, and to assess whether or not anastrozole alone has any anticoagulant activity. METHODS: This was a randomized, double-blind, placebo-controlled, two-way crossover trial conducted at a single centre. The study comprised two treatment periods of 11 days, separated by a 3 week washout. Healthy male volunteers (n = 16, median age 28.5 years) were randomized to receive either anastrozole (7 mg loading dose on day 1, followed by 1 mg daily on days 2-11) in the first treatment period and placebo in the second treatment period, or vice versa. In addition to their randomized treatment, all volunteers received a single dose of 25 mg warfarin on day 3 of each treatment period. Blood samples for pharmacokinetic and pharmacodynamic assessment were taken at frequent intervals during each treatment period. The safety of volunteers was monitored throughout the study. RESULTS: Administration of anastrozole resulted in no clinically significant changes in the pharmacokinetics of either R- or S-warfarin compared with placebo for AUC (ng ml-1 h) (glsmean, R-warfarin; anastrozole 93619.9, placebo 91127.91, 95%CI 0.988-1.068; S-warfarin; anastrozole 57129.21, placebo 55676.34, 95%CI 0.979-1.076), CL/F (ml min-1) (glsmean, R-warfarin; anastrozole 2.23, placebo 2.29, 95%CI 0.937-1.012; S-warfarin; anastrozole 3.65, placebo 3.74, 95%CI 0.929-1.021) and t1/2 (h) (lsmean, R-warfarin; anastrozole 55.40, placebo 55.15, 95%CI-2.083-2.592; S-warfarin; anastrozole 39.38, placebo 40.98, 95%CI-6.189-2.996). In addition, anastrozole had no clinically significant effect on the pharmacodynamic effects of warfarin, as assessed 240 h after warfarin dosing by measurement of prothrombin time (s) (glsmean, anastrozole 11.56, placebo 11.31, 95%CI 0.987-1.059), thrombin time (s) (glsmean, anastrozole 19.06, placebo 18.75, 95%CI 0.980-1.054) activated partial thromboplastin time (s) (glsmean, anastrozole 29.94, placebo 29.74, 95%CI 0.968-1.047) and factor VII (%) (glsmean, anastrozole 97.81, placebo 107.26, 95%CI 0.821-1.012). Anastrozole alone had no effect on these indicators of the clotting process. CONCLUSIONS: Overall, there was no evidence to suggest that anastrozole has any clinically relevant effects on the pharmacokinetics of warfarin. Anastrozole had no effect on clotting mechanisms or on the pharmacodynamic activity of warfarin, as assessed by prothrombin time, thrombin time, activated partial thromboplastin time, and factor VII.

Safety and pharmacokinetics of mifentidine after increasing oral doses in healthy subjects.

Eight healthy men were each given single oral doses of mifentidine 20, 40 and 80 mg, a new H2-receptor antagonist, in a four-way, double-blind, placebo-controlled, cross-over, dose-proportionality study. No significant objective or subjective effects were noted. Mifentidine showed unusual pharmacokinetic behaviour, producing a significant secondary peak in the drug concentration profile. The plasma AUC of mifentidine increased linearly with dose (r = 0.983). The apparent plasma clearance was 38.1 l.h-1, 31.0 l.h-1, and 47.4 l.h-1 for the 20, 40 and 80 mg doses, respectively, and the corresponding terminal plasma half-lives were 10.3 h, 12.0 h, and 8.6 h. About 20% of the parent drug was excreted in urine over 24 h. The renal clearance (9.41 l/h for 20 mg, 9.5 l/h for 40 mg, and 12.8 l/h for 80 mg mifentidine) indicates that some of the drug was excreted by active tubular secretion. The results indicate that mifentidine is safe after single oral doses up to 80 mg. The pharmacokinetics of the 20 and 40 mg doses were similar, but after 80 mg the total body and renal clearances were significantly greater than after the two lower doses. As the terminal plasma half-life of mifentidine is longer than of other available H2-receptor antagonists, it may have clinical implications for once-a-day therapy of peptic ulcer diseases.

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers.

A study was conducted to (i) characterize the multiple-dose pharmacokinetics of oral montelukast sodium (MK-0476), 10 mg d-1 in healthy young subjects (N = 12), (ii) evaluate the pharmacokinetics of montelukast in healthy elderly subjects (N = 12), and (iii) compare the pharmacokinetics and oral bioavailability of montelukast between elderly and young subjects. Following oral administration of montelukast sodium, 10 mg d-1 (the therapeutic regimen for montelukast sodium) for 7 d, there was little difference in the plasma concentration-time profiles of montelukast in young subjects between day 1 and day 7 dosing. On average, trough plasma concentrations of montelukast were nearly constant, ranging from 18 to 24 ng mL-1 on days 3-7, indicating that the steady state of montelukast was attained on day 2. The mean accumulation ratio was 1.14, indicating that this dose regimen results in a 14% accumulation of montelukast. In elderly subjects, mean values of plasma clearance (Cl), steady-state volume of distribution (Vss), plasma terminal half-life (t1/2), and mean residence time in the body (MRTIV) following a 7 mg intravenous (5 min infusion) administration of montelukast sodium in the elderly were 30.8 mL min-1, 9.7 L, 6.7 h, and 5.4 h, respectively. Following a 10 mg oral dose, the bioavailability of montelukast in healthy elderly averaged 61%, very close to that (62%) determined previously in healthy young subjects. Also following the 10 mg oral administration, the mean values of AUC0-->infinity, Cmax, tmax, and t1/2, and the mean plasma concentration-time profile of montelukast in the elderly, were generally similar to those in young subjects, indicating that age has little or no effect on the pharmacokinetics of montelukast. There is no need to modify dosage as a function of age.