Pharmacokinetics of sarizotan after oral administration of single and repeat doses in healthy subjects.

OBJECTIVE: Sarizotan is a 5-HTIA receptor agonist with high affinity for D3 and D4 receptors. Here we report the pharmacokinetic and tolerability results from four Phase 1 studies. MATERIALS: Two single-dose (5 -25 mg, n = 25, 0.5 - 5 mg, n = 16) and two multiple-dose (10 and 20 mg b.i.d., n = 30, 5 mg b.i.d., n = 12) studies with orally administered sarizotan HCl were carried out in healthy subjects. METHODS: Plasma sarizotan HCl concentrations were measured using a validated HPLC method and fluorescence or MS/MS detection. Pharmacokinetic parameters were obtained using standard non-compartmental methods. RESULTS: Sarizotan was rapidly absorbed, group-median times to reach maximum concentration (tmax) ranged from 0.5 -2.25 h after single doses and during steady state. Maximum plasma concentration (Cmax) and tmax were slightly dependent on formulation and food intake, whereas area under the curve (AUC) was unaffected by these factors. AUC and Cmax increased dose-proportionally over the tested dose range. Independently of dose and time, sarizotan HCl plasma concentrations declined polyexponentially with a terminal elimination half-life (t1/2) of 5 - 7 h. Accumulation factors corresponded to t1/2 values, and steady state was reached within 24 h. Plasma metabolite concentrations were considerably lower than those of the parent drug. The ratio metabolite AUC : parent drug AUC was time- and dose-independent for all three metabolites suggesting that the metabolism of sarizotan is non-saturable in the tested dose range. CONCLUSIONS: The pharmacokinetics of sarizotan were dose-proportional and time-independent for the dose range 0.5 -25 mg). The drug was well-tolerated by healthy subjects up to a single dose of 20 mg.

Pharmacokinetic and dynamic interactions of the angiotensin-converting enzyme inhibitor imidapril with hydrochlorothiazide, bisoprolol and nilvadipine.

OBJECTIVE: The pharmacokinetic and dynamic interactions of the angiotensin-converting enzyme (ACE) inhibitor imidapril with other therapeutic principles used in hypertension and heart failure were evaluated. METHODS: In three separate, double-blind, placebo-controlled, four-way cross-over studies in healthy volunteers (n = 16 each), single oral doses of imidapril 10 mg (I), hydrochlorothiazide 12.5 mg (H), bisoprolol 5 mg (B) and nilvadipine 8 mg (N) were administered as monotherapies, and in IH, IB and IN combinations. Plasma concentrations of imidaprilat and H were followed up to 48 h, those of B and N up to 24 h and area under the concentration time curve (AUC), maximum plasma concentration (Cmax) and time to Cmax (tmax) were determined. Blood pressure (BP), heart rate (HR) and non-invasive haemodynamics [total peripheral resistance (TPR, N and H), systolic time intervals (STI, N and H), and plasma renin activity (PRA)] were assessed up to 24 h. RESULTS: There were no pharmacokinetic interactions between I plus H, B or N. Bioequivalence between single and combined administrations was verified for all investigational compounds [AUC point estimates (90% confidence interval CI): imidaprilat IH 109% (97.8, 122.8); IB 99.6% (91.2, 109.4); IN 105.7% (92.1, 121.3); H 96.6% (92.5, 100.8); B 103% (100.2, 105.8); N 98% (89, 108)]. The haemodynamic effects were mostly additive and without relevant pharmacodynamic interactions. I significantly reduced the BP by 5-8 mmHg, B by 4-8 mmHg and N by 4-6 mmHg. In addition, H induced a significant reduction of the preload as seen from STI, and B significantly reduced HR (-5 bpm). N induced a significant decrease in TPR (about 15% of baseline values) and showed corresponding changes in STI. PRA increased significantly following I alone (1.5-2.0 ng/ml/h), as well as combined with N (2.5 ng/ ml/h) or H (3.1 ng/ml/h). This increase was clearly blunted by the co-administration of B (0.6 ng/ml/h). CONCLUSIONS: The combination of imidapril with a diuretic, beta-adrenoceptor antagonist or calcium-channel blocker seems a reasonable and safe treatment option when striving for additive pharmacodynamic effects not accompanied by relevant pharmacokinetic interactions.

Pharmacokinetics of imidapril and its active metabolite imidaprilat following single dose and during steady state in patients with chronic renal failure.

OBJECTIVE: An open study on the single dose and steady-state pharmacokinetics of imidapril, a novel prodrug-type angiotensin-converting enzyme (ACE) inhibitor, and its active metabolite imidaprilat was conducted in eight patients with moderate chronic renal failure [mean creatinine clearance (CL(CR)) 64 ml x min(-1); range 42-77 ml x min(-1)], eight patients with severe chronic renal failure (mean CL(CR), 18 ml x min(-1); range 11-29 ml x min(-1)) and eight healthy volunteers with normal renal function. Subjects received an oral dose of 10 mg imidapril once per day for 7 days. RESULTS: No statistical differences of either maximum concentration (Cmax) or the area under the curve (AUC) were found between patients with moderate renal failure and healthy subjects. However, Cmax and AUC for both imidapril and imidaprilat were significantly higher in patients with severe renal impairment than in healthy volunteers. There were no clinically relevant differences among the three subject groups with regard to total urinary excretion of both imidapril and imidaprilat. CONCLUSION: The smallest imidapril dose which is clinically effective should be used in patients with severe renal insufficiency.

Single dose and steady state pharmacokinetics and pharmacodynamics of the ACE-inhibitor imidapril in hypertensive patients.

AIMS: To investigate the pharmacokinetic profile of the ACE-inhibitor imidapril in 10 hypertensive patients after a first single dose (10 mg) and after 28 days therapy with imidapril 10 mg once daily. METHODS: Cmax, tmax, t1/2 and AUC of imidapril and imidaprilat were obtained. ACE-activity and arterial blood pressure during imidapril were corrected by a preceding placebo-investigation. RESULTS: The AUC of imidapril was 140 (43 s.d.) ng ml(-1) h after the first dose and 123 (34 s.d.) ng ml(-1) h at steady state. AUC of the active moiety imidaprilat averaged 211 (101 s.d.) ng ml(-1) h after the first dose and 240 (55 s.d.) ng ml(-1) h at the steady state investigation. Maximal ACE-inhibition was 75% after the single dose as well as at steady state. ACE inhibition before drug intake at day 28 (i.e. trough) was 50%. The (placebo-corrected) maximal drop in diastolic blood pressure after imidapril was 22 mm Hg after the first dose and 25 mmHg at steady state. Exploratory analysis of imidaprilat plasma concentration vs effect profiles suggests a hyperbolic concentration effect relationship where data of the single dose contribute to the ascending part of an Emax-curve, whereas the plateau around Emax is maintained at steady state. CONCLUSIONS: In this group of hypertensive patients, the pharmacokinetic profile and the drop in ACE-activity as well as in blood pressure seen after a single dose of imidapril and at steady state were similar. The initial response to a test dose might therefore predict the response during chronic dosing.

Pharmacokinetics of imidapril and its active metabolite imidaprilat following single dose and during steady state in patients with impaired liver function.

OBJECTIVE: The possible influence of impaired liver function on the pharmacokinetic disposition of imidapril, a novel prodrug type angiotensin-converting enzyme (ACE) inhibitor, and its active metabolite, imidaprilat, was investigated. METHODS: Eight subjects with normal liver function and eight patients with liver dysfunction received an oral dose of 10 mg imidapril once daily for 7 days. RESULTS: Plasma imidapril concentrations after single and, although less pronounced, after repeated dosing were higher in the liver disease patients, whereas imidaprilat concentrations were lower. This suggests that the conversion of imidapril into imidaprilat in the liver is delayed in patients with impaired liver function. However, the slower biotransformation did not result in statistically significant differences in Cmax and AUC for either imidapril or its active metabolite following repeated administration. Moreover, no relevant accumulation of either imidapril or imidaprilat occurred after repeated dosing. CONCLUSIONS: Imidapril is regarded as an ACE inhibitor of which the pharmacokinetic disposition is only slightly affected in patients with impaired liver function.

Pharmacokinetics and first clinical experiences with an antihypertensive dopamine (DA2) agonist.

The pharmacokinetic properties and first clinical experiences with the antihypertensive dopamine (DA2) agonist, carmoxirole, are summarized. In man carmoxirole was rapidly absorbed. On oral administration the maximum plasma concentration was reached after 2-3 h. The drug was metabolized, mainly to an ester-type glucuronide, and was excreted (unchanged carmoxirole plus glucuronide) largely by the kidneys. The plasma half-life of the parent compound was 5.5 h. For the dose range tested (0.5 to 1.5 mg) the pharmacokinetics were linear. The drug was rapidly distributed in animals but only very small amounts penetrated the blood-brain barrier. Carmoxirole did not affect supine blood pressure in healthy subjects, but under the conditions of the Schellong's test some orthostatic reactions occurred with high doses. In patients the blood pressure was reduced for at least 8 h after single oral doses. On repeated administration for several weeks a relevant antihypertensive effect was still measurable 12 and 24 h after dose. The most frequently reported adverse events have been headache, dizziness, tiredness, nausea, and gastric disorders. These symptoms are considered to be mainly due to blood pressure reduction, as is frequently observed at the beginning of antihypertensive therapy. In patients the incidence of orthostatic reactions is appreciably lower than in healthy subjects, and in both change of position was sufficient to relieve the symptoms.

Placebo controlled comparison of acute effects of ebastine and clemastine on performance and EEG.

The effects of single oral doses of 10 and 20 mg ebastine were compared with placebo and 2 mg clemastine in a double-blind cross-over study in 16 healthy male volunteers. Clemastine produced the known pattern of changes, namely impairment of psychomotor performance, drowsiness, and a selective effect on cognitive processes. Earlier encoding in a perceptual stage was slowed whereas abstract classification processes were not affected. Electrophysiological measures of vigilance showed a general decrease in vigilance especially 2.5 and 4.5 h after dosing. In contrast at no time was any effect of ebastine different from that of the placebo. Ebastine 10 and 20 mg differed positively from clemastine in its effect on pursuit tracking, subjective rating of drowsiness and general discomfort. Ebastine 10 mg also differed positively from clemastine in the EEG features of vigilance. It is concluded that 10 and 20 mg ebastine were free from sedative adverse effects.

Study on the interaction between sucralfate and diclofenac/piroxicam in healthy volunteers.

The possible interaction between sucralfate (Ulcogant, CAS 54182-58-0) on the one hand and diclofenac (CAS 15307-86-5) and piroxicam (CAS 36322-90-4) on the other hand was investigated in two groups each consisting of twelve healthy volunteers. The AUC (0-t) was calculated at 1670 +/- 492 ng/ml x h for diclofenac alone and at 1817 +/- 682 ng/ml x h for diclofenac plus sucralfate. The mean AUC (0-t) for piroxicam alone was 91 +/- 19 micrograms/ml x h whilst that for piroxicam plus sucralfate was 91 +/- 20 micrograms/ml x h. The mean relative bioavailability was 116% for diclofenac plus sucralfate compared to diclofenac alone, and 100% for piroxicam plus sucralfate compared to piroxicam alone. Thus there is no interaction between sucralfate and diclofenac resp. piroxicam.

Relative bioavailability of three cefixime formulations.

Three galenic formulations of cefixime (tablet, syrup and dry suspension) containing 200 mg each were compared with respect to their relative bioavailability in twelve healthy volunteers. All three formulations showed reliable absorption. Mean peak plasma concentrations were reached after 3.3-3.5 h, mean terminal half lives were 2.9-3.1 h. 18-24% of the dose administered were recovered unchanged in the urine. Best bioavailability was obtained with the dry suspension (AUC0-infinity = 25.8 +/- 7.0 micrograms/ml h; Cmax = 3.4 +/- 0.9 microgram/ml), followed by the tablet (AUC0-infinity = 20.9 +/- 8.1 micrograms/ml h; Cmax = 3.0 +/- 1.0 micrograms/ml) and the syrup which is based on triglycerides (AUC0-infinity = 17.8 +/- 5.9 micrograms/ml h; Cmax = 2.4 +/- 0.7 micrograms/ml). The statistical analysis resulted in bioinequivalence between dry suspension and syrup. It is concluded that best bioavailability of cefixime after oral administration is guaranteed when taken in an "aqueous medium" either as dry suspension or as tablet with "plenty of liquid".

Basic pharmacokinetics of bisoprolol, a new highly beta 1-selective adrenoceptor antagonist.

The basic pharmacokinetics of bisoprolol were investigated in three independent studies involving 23 healthy volunteers. After administering 20 mg of 14C-bisoprolol orally, mean elimination half-lives of 11 hours for the unchanged drug and 12 hours for total radioactivity were observed. The enteral absorption of bisoprolol was nearly complete. Fifty percent of the dose was eliminated renally as unchanged bisoprolol and the other 50% metabolically, with subsequent renal excretion of the metabolites. Less than 2% of the dose was recovered from the feces. Intraindividual comparison of the pharmacokinetic data measured after oral and intravenous administration of 10 mg bisoprolol to 12 subjects yielded an absolute bioavailability of 90%. Total and renal clearance were calculated as 15.6 L/hr and 9.6 L/hr, respectively. The volume of distribution was 226 L. Concomitant food intake did not influence the bioavailability of bisoprolol.

Pharmacodynamic profile of bisoprolol, a new beta 1-selective adrenoceptor antagonist.

The pharmacodynamic profile of bisoprolol, a new beta 1-selective adrenoceptor antagonist, was investigated in four independent studies including 36 healthy male volunteers. Using the model of exercise-induced tachycardia (ET) the beta-adrenoceptor blocking properties of bisoprolol (2.5-40 mg) were examined in comparison to metoprolol (50 and 100 mg), propranolol (40 and 80 mg) and atenolol (50 and 100 mg). The maximal reduction of ET was achieved between 1 and 4 h following single oral administration. The dose-response relationship using individual maximal reduction of ET showed, on a molar basis, that bisoprolol is about 5, 7 and 10 times more effective than propranolol, atenolol and metoprolol, respectively. In the model of insulin-induced hypoglycaemia bisoprolol behaved as a beta 1-selective adrenoceptor antagonist. There was a good correlation (r = 0.94) between the log bisoprolol concentration and the reduction in exercise-induced tachycardia. Bisoprolol is a potent new cardioselective beta-adrenoceptor antagonist with a competitive action at beta 1-adrenoceptors.

Clinical pharmacology phase I of cefazedone, a new cephalosporin, in healthy volunteers. I. Tolerance in comparison with cefazolin.

In conjunction with pharmacokinetic investigations, the tolerance of (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1 (4H)-pyridyl]-acetamido)-3-([(5-methyl-1,34-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen), a new semisynthetic cephalosporin, was compared with that of cefazolin in two consecutive cross-over studies conducted on 10 healthy male volunteers each. The systemic tolerance of cefazedone after 1 X 500 mg and 1 X 1000 mg i.v., and 1 X 500 mg i.m. injections was very good and comparable with that of cefazolin. The same holds true for the local tolerance after i.v. administration. The local tolerance of i.m. administered cefazedone can also be classified as good when compared with that of cefazolin.

Clinical pharmacology phase I of cefazedone, a new cephalosporin, in healthy volunteers. II. Pharmacokinetics in comparison with cefazolin.

In two consecutive cross-over studies, each involving 10 healthy volunteers, the pharmacokinetics of (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl]-acetamindo)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid (cefazedone, Refosporen) in comparison with cefazolin were investigated after single i.v. and i.m. administration. The doses were: i.v. cefazedone 500 mg and 1000 mg; cefazolin 1000 mg; i.m. cefazedone 500 mg, cefazolin 500 mg. The pharmacokinetic parameters were analysed by applying an open two-compartment model. The pharmacokinetics of cefazedone are nearly identical with those of cefazolin. In particular, it must be noted that cefazedone has a relatively long serum elimination half-life (1.64 +/- 0.23 h after i.v. and 1.85 +/- 0.51 h after i.m. administration) and that cefazedone exhibits, in comparison with cefazolin, a more favourable concentration ratio of central vs. peripheral (= tissue) compartment (1:2).

Clinical pharmacology in normal volunteers of praziquantel, a new drug against schistosomes and cestodes. An example of a complex study covering both tolerance and pharmacokinetics.

The tolerance of Praziquantel (2-cyclohexylcarbonyl-1, 3, 4, 6, 7, 11b-hexahydro-2H-pyrazino-[2, 1-a]isoquinoline-4-one) in oral doses of 1 X 20 mg/kg, 1 X 50 mg/kg, 3 X 10 mg/kg and 3 X 25 mg/kg body weight (tau = 4 h) was tested in a complex study involving 36 healthy volunteers. In addition to the usual assessment of clinical chemistry, haematology, coagulation physiology, urinalysis, clinico-physiological examination including EEG, and medical examination, clinico-psychological parameters were also recorded and special neurological investigations were performed. No clinically relevant changes were found in any of the laboratory parameters, nor in the medical-neurological or clinico-physiological examinations. Based on a few clinico-psychological parameters and subjective comments, the largest daily dose tested (3 X 25 mg/kg = 75 mg/kg) produced a slight, transient disturbance in general well-being, which was barely detectable on objective clinical examination. The pharmacokinetic behaviour was dominated by rapid metabolism and pronounced first-pass metabolism of praziquantel, which greatly limits the value of results obtained by GC analysis of unchanged drug in serum. The peak concentration in serum was reached after 1--2 h, and the elimination half-life for the period 2--8 h was 1--1.5 h.