Effect of gemfibrozil on the metabolism of brivaracetam in vitro and in human subjects.

Brivaracetam (BRV) is a new high-affinity synaptic vesicle protein 2A ligand in phase III for epilepsy. Initial studies suggested that the hydroxylation of BRV into BRV-OH is supported by CYP2C8. Other metabolic routes include hydrolysis into a carboxylic acid derivative (BRV-AC), which could be further oxidized into a hydroxy acid derivative (BRV-OHAC). The aim of the present study was to investigate the effect of gemfibrozil (CYP2C9 inhibitor) and its 1-O-ß-glucuronide (CYP2C8 inhibitor) on BRV disposition both in vivo (healthy participants) and in vitro (human liver microsomes and hepatocytes). In a two-period randomized crossover study, 26 healthy male participants received a single oral dose of 150 mg of BRV alone or at steady state of gemfibrozil (600 mg b.i.d). Gemfibrozil did not modify plasma and urinary excreted BRV, BRV-OH, or BRV-AC. The only observed change was a modest decrease (approximately -40%) in plasma and urinary BRV-OHAC. In human hepatocytes and/or liver microsomes, gemfibrozil potently inhibited the hydroxylation of BRV-AC into BRV-OHAC (K(I) 12 µM) while having a marginal effect on BRV-OH formation (K(I) ≥153 µM). Gemfibrozil-1-O-ß-glucuronide had no relevant effect on either reaction (K(I) >200 µM). In conclusion, gemfibrozil did not influence the pharmacokinetics of BRV and its hydroxylation into BRV-OH. Overall, in vitro and in vivo data suggest that CYP2C8 and CYP2C9 are not involved in BRV hydroxylation, whereas hydroxylation of BRV-AC to BRV-OHAC is likely to be mediated by CYP2C9.

Likert pain score modeling: a Markov integer model and an autoregressive continuous model.

Pain intensity is principally assessed using rating scales such as the 11-point Likert scale. In general, frequent pain assessments are serially correlated and underdispersed. The aim of this investigation was to develop population models adapted to fit the 11-point pain scale. Daily Likert scores were recorded over 18 weeks by 231 patients with neuropathic pain from a clinical trial placebo group. An integer model consisting of a truncated generalized Poisson (GP) distribution with Markovian transition probability inflation was implemented in NONMEM 7.1.0. It was compared to a logit-transformed autoregressive continuous model with correlated residual errors. In both models, the score baseline was estimated to be 6.2 and the placebo effect to be 19%. Developed models similarly retrieved consistent underlying features of the data and therefore correspond to platform models for drug effect detection. The integer model was complex but flexible, whereas the continuous model can more easily be developed, although requires longer runtimes.

A pharmacodynamic Markov mixed-effects model for determining the effect of exposure to certolizumab pegol on the ACR20 score in patients with rheumatoid arthritis.

The American College of Rheumatology (ACR) 20% preliminary definition of improvement in rheumatoid arthritis (RA) (ACR20) is widely used in clinical trials to assess response to treatment. The objectives of this analysis were to develop an exposure-response model of ACR20 in subjects receiving treatment with certolizumab pegol and to predict clinical outcomes following various treatment schedules. At each visit, subjects were classified as being ACR20 responders or ACR20 nonresponders or as having dropped out. A Markov mixed-effects model was developed to investigate the effects of the drug on the transitions between the three defined states. Increasing certolizumab pegol exposure predicted an increasing probability of becoming a responder and remaining a responder, as well as a reduced probability of dropping out of treatment. Data from simulations of the ACR20 response rate support the use of dosing regimens of 400 mg at weeks 0, 2, and 4 followed by 200 mg every 2 weeks, or an alternative maintenance regimen of 400 mg every 4 weeks.

Effect of brivaracetam on cardiac repolarisation--a thorough QT study.

OBJECTIVES: To assess the effect on cardiac repolarisation of the investigational synaptic vesicle protein 2A (SV2A) ligand brivaracetam. RESEARCH DESIGN AND METHODS: Subjects received double-blind, multiple bid doses of placebo (n = 53), brivaracetam 75 mg (n = 39) or brivaracetam 400 mg (n = 40), or open-label single-dose moxifloxacin 400 mg (positive control, n = 52). Continuous 12-lead ECG recordings were performed at baseline and after last dosing, using a Mortara Holter device. Plasma samples were obtained before and up to 12 h after last dosing for drug determination. Triplicate ECGs were extracted before each sample, and read centrally in a blinded manner. QT was corrected using a centre- and gender-specific correction (QTc(SS) ). MAIN OUTCOME MEASURES: The primary endpoint was the largest time-matched mean difference of QTc(SS) change from baseline between drug and placebo (maximum DeltaDeltaQTc(SS)). The same approach was adopted using the Fridericia's correction (QTc(F)). The relationships between DeltaQTc(SS) and plasma concentration of brivaracetam and moxifloxacin were fitted to a straight line using linear least-squares regression. RESULTS: Mean maximum DeltaDeltaQTc(SS) for brivaracetam 75 and 400 mg bid, and moxifloxacin 400 mg was 0.2 ms, -1.1 ms and 12.4 ms, respectively. The one-sided 95% upper limit for 75 mg and 400 mg brivaracetam was 4.3 ms and 3.0 ms, respectively; the one-sided 95% lower limit for moxifloxacin was 8.6 ms. After brivaracetam no QTc(SS) intervals > 480 ms or changes from baseline of > 60 ms were observed. DeltaQTc(SS) did not increase with plasma concentration of brivaracetam, whereas there was a statistically significant rise with increasing moxifloxacin concentrations. CONCLUSIONS: The study was found to be valid in terms of assay sensitivity and the results demonstrated the absence of effects of brivaracetam on cardiac repolarisation. These results suggest that no intensive cardiac monitoring is required during the subsequent stages of brivaracetam development.

Evaluation of brivaracetam, a novel SV2A ligand, in the photosensitivity model.

OBJECTIVE: To assess the activity of brivaracetam, a novel SV2A ligand, in the photosensitivity model as a proof-of-principle of efficacy in patients with epilepsy. METHODS: A subject-blind placebo-controlled study in patients with photosensitive epilepsy was performed to investigate the effect of single-dose brivaracetam (10, 20, 40, or 80 mg) on photosensitive responses. Each patient was exposed to intermittent photic stimulation that evoked a generalized photoparoxysmal EEG response. Individual standard photosensitivity ranges (SPRs) were recorded post-placebo (day -1) and post-brivaracetam until return to baseline (day 1 to 3). Plasma concentrations of brivaracetam and any concomitant antiepileptic drugs were determined. RESULTS: Of the 18 evaluable patients, none achieved SPR abolishment post-placebo, whereas 14 (78%) achieved complete abolishment post-brivaracetam. Decrease in SPR was seen in 8 patients (44%) post-placebo compared to 17 (94%) post-brivaracetam. Duration of response was twice as long post-brivaracetam 80 mg (59.5 hours) compared with lower doses, although the overall effect was not dose-dependent. Time to maximal photosensitive response was dose-related with the shortest time interval observed at the highest dose (0.5 hours post-brivaracetam 80 mg). The area under the effect curve (SPR change from pre-dose vs time) appeared linearly correlated with the area under the plasma concentration curve. Brivaracetam was well tolerated. The most common adverse events were dizziness and somnolence. CONCLUSIONS: Our findings show that brivaracetam clearly suppresses generalized photoparoxysmal EEG response. As such, investigations of the antiepileptic properties and tolerability of brivaracetam are warranted in further clinical studies of patients with epilepsy.

Comparison of plasma and saliva concentrations of levetiracetam following administration orally as a tablet and as a solution in healthy adult volunteers.

OBJECTIVE: Concentrations in saliva, as an alternative to concentrations in blood, can be advantageous for the monitoring of antiepileptic agents. This study assesses the relationship between saliva and plasma concentrations of levetiracetam after administration orally as a solution and as a tablet. The possibility that saliva concentrations of the drug are altered by contamination in the buccal cavity was also examined. METHODS: 4 healthy male subjects received a single 750 mg oral dose of levetiracetam as a 10% solution and 4 subjects received three 250 mg tablets (750 mg). Levetiracetam concentrations in plasma and saliva were monitored for 24 hours post dose. RESULTS: In subjects receiving the levetiracetam solution, maximum saliva concentrations were observed at the first collection point (15 min) after administration and these were 19-74 times higher than corresponding plasma levels. The mean saliva/plasma ratio rapidly decreased thereafter, becoming stable after 4 hours. In subjects receiving tablets, levetiracetam concentration profiles for saliva paralleled the plasma concentration profiles with a fairly constant saliva/plasma concentration ratio throughout the 24-hour sampling period. A significant linear correlation between levetiracetam saliva and plasma concentrations was demonstrated (Pearson r = 0.88; p < 0.001 for tablet (n = 35) and r = 0.87; p < 0.001 for solution at times > or = 4 hours post-dose (n = 20)). The saliva to plasma concentration ratio was 1.11 (95% confidence interval: 0.99 - 1.22) following tablet intake, and 1.55 (95% CI: 1.34 1.77) following oral solution (> or = 4 hours post dose). CONCLUSIONS: Using saliva to monitor therapeutic exposure to levetiracetam is feasible beginning 15 minutes after tablet intake but beginning 4 hours after intake of an oral solution.

Nitazoxanide pharmacokinetics and tolerability in man using single ascending oral doses.

OBJECTIVES: Nitazoxanide (N) is a new broad-spectrum intestinal antiparasitic agent. Deacetyl-N or tizoxanide (T) and its glucuronide (TG) are the major circulating species metabolites after oral administration of N. Bioavailability is substantially increased by food. The objectives of this phase IA study were to assess the tolerability and to determine the pharmacokinetic linearity of T and TG after single oral administration of increasing doses of N with and without food in healthy volunteer subjects. METHODS: Thirty-two healthy male volunteers were randomly assigned to 1 of 4 treatment groups. In each successive group, 2 subjects received a placebo and 6 received a single oral dose of 1 g, 2 g, 3 g, or 4 g of N, first under fasted conditions and a week later with a standardized breakfast. Blood samples were collected during 24 h for plasma determination of T and TG. General tolerability, adverse reactions, ECG, vital signs and laboratory tests were recorded. RESULTS: Tolerability was good up to the maximum dose of 4 g. Mild, mostly gastrointestinal side effects were observed and their frequency increased significantly with the dose level. No significant changes were noted in the ECGs, vital signs and laboratory tests. Plasma concentrations increased linearly with the dose from 1 - 4 g, although a trend to increased bioavailability was observed at 4 g. Food approximately doubled the concentrations of T and TG irrespective of dose. Peak times and apparent half-lives increased in proportion to the dose. The apparent body clearance for total T (T+TG) at the highest dose was only half that at the low dose. TG was eliminated more slowly than T. CONCLUSION: Nitazoxanide can be safely administered up to 4 g single oral doses, with or without food. The slow elimination of TG and the overproportional concentrations at the highest dose can be accounted for by solubility- or transport-limited elimination mechanisms becoming apparent at the upper dose level.

Nitazoxanide pharmacokinetics and tolerability in man during 7 days dosing with 0.5 g and 1 g b.i.d.

OBJECTIVES: Nitazoxanide (N) is a new broad-spectrum intestinal antiparasitic agent. Deacetyl-N or tizoxanide (T) and its glucuronide (TG) are the major circulating metabolites after oral administration of N. The objectives of this phase IB study were to assess the tolerability and to determine the phannacokinetics of T and TG after 7 days of 0.5 g and 1 g b.i.d. dosing of N in healthy volunteer subjects. METHODS: Sixteen healthy male volunteers were randomly assigned to 1 of 2 treatment groups. In each group, 2 subjects received a placebo and 6 received a single oral dose of 0.5 or 1 g of N followed by 7 days of b.i.d. dosing. Blood samples were collected during the first and last dosing intervals for plasma determination of T and TG. General tolerability, adverse reactions, ECG, vital signs and laboratory tests were recorded before and during treatment days. RESULTS: The 0.5 g b.i.d. dose was well-tolerated with only mild adverse events not differing significantly from the placebo. The 1 g b.i.d. dose was associated with an increased frequency of gastrointestinal side effects, primarily diarrhea and abdominal discomfort. No significant changes were noted in the ECGs, vital signs and laboratory tests. At the 0.5 g b.i.d. dose, the bioavailability of T and TG was only slightly influenced by repeated administration. At the 1 g b.i.d. dose regimen, the extent of bioavailability of both T and TG was increased by 50-70%, indicating significant accumulation. Tmax was not significantly modified. CONCLUSION: Oral administration of 0.5 g of nitazoxanide b.i.d. for 7 days with food in healthy volunteers is well-tolerated and is not associated with any significant accumulation of T or TG. A higher 1 g dose results in an increased frequency of gastrointestinal discomfort and is associated with significant accumulation of T and TG.

Nitazoxanide: pharmacokinetics and metabolism in man.

OBJECTIVES: Nitazoxanide (N), a new broad-spectrum parasiticidal agent, is rapidly deacetylated to tizoxanide (T). The objective of the study was to determine if metabolites other than T are present in the plasma and excreted after single dose oral administration of radiocarbon-labelled N in healthy subjects. METHODS: Six healthy volunteers received a single 500 mg oral dose of N labelled with 2.92 MBq radiocarbon. The radioactivity in blood, plasma, urine, feces and expired air was monitored at scheduled intervals for up to 10 days. Selected samples were assayed by HPLC for T and submitted to metabolite identification by mass spectrometry. In vitro experiments were also conducted (incubation with animal and human microsomes, deacetylation kinetics). Plasma and bile samples obtained in a patient treated with N for sporozoal infection were also assayed for T. RESULTS: Elimination of radiocarbon occurred both in the urine (31.5% of the dose on average) and in the feces (66.2% on average). T and T-glucuronide contributed 15% of total urine radioactivity. N was found to deacetylate extremely rapidly to T in plasma (half-life of about 6 minutes at 37 degrees C) as well as in presence of liver microsomes. T was the only species obtained by incubation with human microsomes while rat microsomes yielded hydroxylated T in addition. The main species identified in human plasma, urine and bile was T-glucuronide, the identification of which was confirmed by comparison with an authentic sample. No species other than T was detected in feces, indicating intensive intestinal deconjugation, while radioactivity and absorbance detectors showed largely unresolved clusters.

LIMS: from theory to practice.

This paper gives a definition and some basic knowledge about Laboratory Information Management Systems (LIMS) as well as their impact on the organisation, the laboratory and the co-workers. The major advantages and disadvantages of LIMS are pointed out. Two practical experiences are described. The first is related to an in house development of a PC based system which has to integrate a Vax VMS system (Multichrom) and PC based analytical and analysis softwares. The second experience is dealing with the selection and implementation of a commercial package in a pharmacokinetic laboratory. In both cases the human and time aspects were important.

Food effect on the oral bioavailability of Manidipine: single dose, randomized, crossover study in healthy male subjects.

The effect of food on the oral bioavailability of a manidipine 20 mg tablet was studied after a single administration in 12 male healthy subjects. The clinical trial was conducted as an open, randomised, crossover study. In two different administration sessions, the subjects received a 20 mg manidipine tablet either in the fasting state or after a standardized breakfast. Plasma samples were collected before and at different times after each administration for up to 24 h. The concentrations of manidipine and its pyridine metabolite (M-XIII metabolite) were determined by HPLC with coulometric detection. The tolerability of manidipine was good. Only two cases of mild headache, one with each treatment, were reported. Food significantly improved the absorption, with an increase in AUC from 19.1 to 27.2 ng.h/ml (geometric mean, p<0.01) but did not modify the rate of absorption (tmax unchanged, median = 1.5 h). Peak plasma concentration was also increased (from 6.2 to 7.8 ng/ml), but the difference was not statistically significant (p=0.18). Other pharmacokinetic parameters (apparent elimination half-life and mean residence time) remained unchanged. The increase in bioavailability of manidipine administered with food is related to its high lipophilicity and may be explained through a solubilization effect produced by food and bile secretions.

Single dose pharmacokinetics of manidipine in hepatic impaired patients and healthy controls.

The pharmacokinetics and safety of a single oral dose of 20 mg manidipine dihydrochloride have been studied in 8 patients with mild to moderate hepatic impairment (grade A or B in Child's classification, or score < or = 7 in Pugh's modification of Child's classification), and in 12 healthy subjects. They received one 20 mg manidipine dihydrochloride tablet with 100 ml of tap water after a standard breakfast. Manidipine was determined using HPLC with electrochemical detection from plasma samples taken up to 24 or 36 h after dosing. The medication was well tolerated. A trend toward higher Cmax, AUC, and MRT was observed in patients with a more severe hepatic impairment, as a consequence of reduction in the liver metabolic function. Patients with grade A hepatic impairment did not exhibit significantly altered pharmacokinetics with respect to healthy subjects, while grade B impairment patients had significantly higher AUC and MRT. Tmax values pointed to reduced absorption rate in patients compared to healthy subjects; the changes were more evident in grade B than grade A patients, although statistical significance was not reached. The reduction in absorption rate in grade B patients is probably related to their higher mean age, since this effect has been reported for manidipine. The pharmacokinetics of manidipine seem only modified in patients with a certain degree of hepatic impairment (at least Pugh grade 6 and Child grade B); therefore, adaptation of the dosing regimen does not seem to be generally recommendable, but should be modulated according to the liver status of the patient.

Pharmacokinetics of nitazoxanide after single oral dose administration in 6 healthy volunteers.

The objective of this study was to gather first information on the time course of plasma concentrations and urinary excretion of the antiprotozoal nitazoxanide (N) and to identify potential metabolites in healthy subjects after a single oral dose of 500 mg of nitazoxanide. The clinical trial was conducted as an open single oral dose study in 6 healthy male subjects. After a standardized continental breakfast the subjects took a single oral dose of 500 mg nitazoxanide (coated tablet) with 100 ml tap water. The plasma concentration and the urinary excretion of nitazoxanide (N), desacetyl-nitazoxanide (DN), aminonitrothiazole (ANT), acetylsalicylate (AS), salicylate (S), gentisate (G) and salicylurate (SU) were monitored up to 72 h after administration. The only measurable species in plasma was DN, which reached a Cmax of 1.9 mg/l (range 1.1-2.5) 2-6 h after dosing, and an AUC of 3.9-11.3 mg x h/l. Its terminal half-life ranged from 1.03 to 1.6 h. DN was extensively bound to plasma proteins (> 97.5%). Only 8% of the dose was recovered in the urine, in the form of DN (5%), SU (3%), and traces of ANT (0.1%). In vitro N was very rapidly hydrolyzed to DN by plasma esterases.

Comparative bioavailability of a metoprolol controlled release formulation and a bisoprolol normal release tablet after single oral dose administration in healthy volunteers.

The bioavailability patterns of a 100 mg metoprolol controlled release tablet and a 10 mg bisoprolol normal release tablet were compared in a single dose crossover study in 12 healthy subjects. The plasma drug concentration levels were measured for 36 h post-dose, using HPLC with fluorimetric detection. The 2 formulations were equally well tolerated, headache being the most frequently reported adverse event. Episodes of bradycardia (heart rate < 50 bpm) occurred at a similar rate with both formulations. The plasma metoprolol profile differed significantly (p < 0.05) from the bisoprolol profile regarding time to maximum concentration, mean residence time, the ratio of peak concentration (Cmax) to the area under the curve (AUC) and the plateau time as estimated from the half-value duration. The average drug plasma concentration observed 24 h after administration still accounted for 54% of the Cmax value for the metoprolol controlled release tablet, but only 23% with the bisoprolol normal release tablet. A large inter-individual variability was seen in the bioavailability of metoprolol, with 3 subjects (characterised as CYP2D6 deficient) exhibiting AUC values 8 - 10 times larger than in the other subjects. The controlled release pattern of the formulation was similar in slow and fast metabolizers. No such variability pattern was apparent for bisoprolol. The findings allow to conclude that, after administration of the metoprolol controlled release tablet, the rate of absorption of the active principle is significantly slower, therefore yielding more constant plasma concentration levels over the 24 h post-dose period, than after administration of the bisoprolol normal release tablet.

Relative bioavailability of carbinoxamine and phenylephrine from a retard capsule after single and repeated dose administration in healthy subjects.

The plasma pharmacokinetics of carbinoxamine (CA, CAS 486-16-8) and phenylephrine (PE, CAS 59-42-7) after single dose administration of a retard capsule (Rhinopront) containing 20 mg PE hydrochloride and 4 mg CA maleate, were compared to those of the same active principles given as an aqueous solution. The study was performed in 20 healthy subjects according to a standard crossover design with a one-week wash-out. The pharmacokinetic profile of the active ingredients of the retard capsule was also investigated in the same subjects under repeated dosing conditions (one capsule b.i.d. during 4 days). Blood samples were collected before each administration and up to 36 h after the first and last doses. CA and total PE (free + conjugated) were assayed in the plasma samples by HPLC with coulometric detection and by gas chromatography with electron-capture detection, respectively. The pharmacokinetic parameters obtained after single dose administration indicated an effective slow release of PE and CA with the retard capsule, compared to the solution. Significantly dampened Cmax, delayed tmax and prolonged plateau time were observed. Despite the clear decrease in absorption rate, the two formulations yielded a similar extent of absorption for CA (90% confidence interval of AUC ratio: 61-111%), but not for PE (90% confidence interval of AUC ratio: 56-69%). At steady-state, accumulation of the two active principles apparently followed simple superposition (accumulation index R = 1.6 for PE and 3.9 for CA). The slow absorption pattern of the formulation was maintained at steady-state with tmax and plateau time similar to single dose conditions.

Oral bioavailability of CHF1194, an inclusion complex of piroxicam and beta-cyclodextrin, in healthy subjects under single dose and steady-state conditions.

CHF1194 is an inclusion complex of beta-cyclodextrin with the nonsteroidal anti-inflammatory drug piroxicam. In man, beta-cyclodextrin acts as a carrier of piroxicam. As the inclusion complex of piroxicam-beta-cyclodextrin is wettable and more water soluble, the absorption rate of the drug is increased whilst its other pharmacokinetic characteristics remain unchanged. The aim of the present study in 12 healthy subjects was to compare the oral bioavailability of 20 mg piroxicam in a CHF1194 tablet and a plain piroxicam capsule after a single dose and after two weeks of once daily administration, and also to assess the plasma levels and urinary excretion of beta-cyclodextrin after CHF1194 administration. The two treatments were administered in cross-over fashion, separated by a wash-out period of three weeks. Piroxicam, 5'-hydroxypiroxicam and beta-cyclodextrin were monitored in plasma and urine for 120 h after the first and last doses. Clinical tolerance was excellent and no adverse event occurred during either phase of the study. The extent of absorption of piroxicam from the CHF1194 tablet after the single dose was equivalent to that after the plain piroxicam capsule, within confidence limits of less than 80-125%. After repeated dosing, CHF1194 yielded the same steady-state systemic concentrations of piroxicam and 5'-hydroxypiroxicam as the reference capsule, and similar excretion pattern of the metabolite. After both single and multiple dosing, piroxicam was absorbed more rapidly after CHF1194, an expected consequence of the complexation of piroxicam with beta-cyclodextrin.(ABSTRACT TRUNCATED AT 250 WORDS)

Exploratory study of the decongestive effect of Rhinopront syrup in adults and in children with acute rhinitis.

The decongestive effect of Rhinopront syrup was assessed in 18 adults and 18 children with acute rhinitis, by comparison to a matching placebo syrup and to a commercial standard decongestant (Triaminic tablets or drops). The evolution of symptoms following single dose administration of each treatment was estimated both by objective measurements of nasal resistance using bilateral rhinomanometry and by subjective evaluation of nasal congestion and aspect of the mucosa. In children, the treatment was continued over the next 4 days and the global clinical efficacy of the formulations was subjectively evaluated by the parents. In adult patients, a significant decrease in nasal resistance was obtained after a single dose of Rhinopront (15 g). The effect was already important after 0.5 h and reached a minimum of approximately 50% of baseline within 1 to 2 h; the drop in nasal resistance was significantly less intense for Triaminic (p < 0.05; 0.5-1-h period) and for the placebo (p < 0.05; 0.5-2-h period). In children, the scatter of rhinomanometric measurements precluded the observation of any significant within- or between-group differences; however, a significantly lower nasal congestion score was observed for Rhinopront than placebo, between 4 and 10 h after single dose administration (1 g per year of age). The present work suggests that Rhinopront is an effective nasal decongestant in adults and children with acute congestive rhinitis and supports the adequacy of the proposed twice-daily dosing rate.

Pharmacokinetics of brodimoprim in special populations.

The pharmacokinetics of brodimoprim have been investigated after single oral dose administration in children, in healthy adults, and elderly subjects, as well as in patients with mild renal failure (creatinine clearance 40-70 mL/min) or liver insufficiency (Child-Pugh grade A or B). The plasma half-life increased moderately with age. The percent brodimoprim bound to plasma proteins, 93%, was identical in renally impaired patients and in healthy controls but decreased to 90% or less in liver insufficiency. The apparent distribution volume and clearance were much higher in children than in adults. Urinary excretion of unchanged brodimoprim amounted to 5-10% of the administered dose. The steady-state pharmacokinetics of brodimoprim has also been investigated in elderly subjects (400 mg loading dose followed by 7 days 200 mg once daily). There was no significant modification of elimination half-life and of clearance upon repeated dosing. Renal excretion of brodimoprim and hydroxy metabolite at steady-state reached 9% and 14% per 24 hours in the elderly, compared to 9% and 24% in young adults. The accumulation factor reached 3.3 +/- 0.4 and 2.7 +/- 0.3 respectively.

Relative bioavailability of carbinoxamine and phenylpropanolamine from a retard suspension after single dose administration in healthy subjects.

The plasma pharmacokinetics of carbinoxamine (CA, CAS 486-16-8) and phenylpropanolamine (PP, CAS 14838-15-4) after single dose administration of a retard suspension (Rhinopront), containing a resinate as sustained-release agent, were compared to those of the same active principles given as an aqueous solution. The study was performed in 20 healthy subjects who received the two formulations according to a standard crossover design with a one-week wash-out. Blood samples were obtained up to 24 h post-dose. PP and CA were assayed in the plasma samples by gas chromatography with electron-capture detection and HPLC with coulometric detection, respectively. The pharmacokinetic results indicated sustained release of the two active principles with the retard suspension: CA appeared in plasma at a much slower rate than with the solution, a 30% lower Cmax being reached after 8.0 h instead of 3.0 h post-dose. For PP, Cmax was 23% lower and occurred 3.0 post-dose instead of 1.5 h with the solution. The extent of absorption of the two drugs, as assessed by AUC (0-24 h), was slightly smaller with the retard suspension than with the aqueous solution. However, the test/reference ratio remained within 95% confidence intervals of 80-87% and 88-98% for CA and PP, respectively, indicating bioequivalence of the two formulations. A simulation of the plasma levels during repeated administration indicated that dosing with the retard suspension at 12-h intervals should yield the same steady-state plasma levels as a 5 times daily administration of a divided dose of the aqueous solution, for both drugs.

The pharmacokinetics of oxybutynin in man.

We have studied the pharmacokinetics of oxybutynin (Ditropan) after single oral (5 mg) and intravenous administration (1 and 5 mg), and after repeated oral administration in healthy volunteers. Oxybutynin was rapidly absorbed, maximum plasma concentrations (8 ng.ml-1) being reached in less than 1 h. The absolute systemic availability averaged 6% and the tablet and solution forms displayed similar relative systemic availability. Plasma concentrations of oxybutynin fell biexponentially, the elimination half-life being about 2 h. There was a large interindividual variation in oxybutynin plasma concentrations. Almost no intact drug could be recovered in the urine. During repeated oral administration steady-state was reached after eight days of treatment. The low absolute systemic availability of oxybutynin, the large interindividual variability in its plasma concentrations, and the apparent absence of intact oxybutynin in the urine suggest that its major pathway of elimination is hepatic metabolism.