Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment.

The pharmacokinetics, efficacy and safety of glimepiride were investigated in a single- and a multiple-dose open study in patients with non-insulin-dependent diabetes mellitus and renal impairment and an initial creatinine clearance above 10 ml/ min. Patients were divided into three groups with creatinine clearance above 50 ml/min, 20-50 ml/min and under 20 ml/min. Fifteen fasting patients received a single dose of 3 mg glimepiride and serial blood and urine samples were taken over 24 h for pharmacokinetic and efficacy analyses. A further 16 patients received glimepiride over a 3-month period, an initial dose of 1 mg glimepiride being adjusted within the range 1 to 8 mg to achieve good glucose control. Pharmacokinetic evaluation was done on day 1 and after 3 months. Mean relative total clearance and mean volume of distribution of both single (41.6 ml/ min and 8.47 litres, respectively, when creatinine clearance was above 50 ml/min) and multiple doses of glimepiride increased in proportion to the degree of renal impairment (to 91.1 ml/min and 14.98 litres, respectively, when creatinine clearance was below 20 ml/min, single dose), whereas the terminal halflife and mean time remained unchanged. Lower relative total clearance and renal clearance of both glimepiride metabolites correlated significantly with lower creatinine clearance values. Of the 16 patients 12 required between 1 and 4 mg glimepiride to stabilize their fasting blood glucose. Glimepiride was well-tolerated and there were no drug-related adverse events. In conclusion glimepiride is safe, effective and has clearly-definable pharmacokinetics in diabetic patients with renal impairment. The increased plasma elimination of glimepiride with decreasing kidney function is explainable on the basis of altered protein binding with an increase in unbound drug.

Pharmacokinetics of levofloxacin in comparison to the racemic mixture of ofloxacin in man.

After oral administration of a single dose of 200 mg of levofloxacin and 400 mg racemic mixture of ofloxacin to 6 healthy male volunteers in a double-blind, randomised cross-over study, concentrations of the unchanged isomers were determined at various times in serum and urine, over 28 hours and 48 hours, respectively. Each dosing was followed by a wash-out period of one week. Ofloxacin concentrations were determined using an enantioselective and a non-enantioselective high pressure liquid chromatography (HPLC) assay. The two measurements obtained were compared by linear distribution independent regression, and were found to be equivalent. Maximum serum concentration (Cmax) of levofloxacin after the administration of 200 mg of the levo-isomer was 2.42 mg/l (chiral derivatization HPLC, mean values); the corresponding area under the serum concentration-time curve (AUC0-28) was 17.0 mg x h/l. The corresponding Cmax values after the administration of 400 mg (+/-)-isomer (chiral derivatization HPLC and reversed phased HPLC, mean values) were 2.05 mg/l, 1.98 mg/l and 4.41 mg/l for (-)-, (+)- and (+/-) isomer, respectively. The AUCS0-28 were 17.0, 14.6 and 32.7 mg x h/l, respectively. The pharmacokinetics of the (-)- and (+)-isomer were shown to be almost equal. In serum and urine no reracemisation of the (-)-isomer to a racemic mixture was observed. General tolerability was good; no side effects were reported.

Pharmacokinetics and pharmacodynamics of the hydroxymetabolite of glimepiride (Amaryl) after intravenous administration.

Glimepiride is a new sulphonylurea which is eliminated by the formation of a hydroxy-metabolite (hydroxy-gli) and a carboxymetabolite (carboxy-gli). Animal studies have shown hydroxy-gli to exhibit some hypoglycaemic effects while carboxy-gli does not appear to have any pharmacological activity. Pharmacokinetic and pharmacodynamic effects of hydroxy-gli were assessed in humans. 12 healthy male volunteers received an intravenous injection of hydroxy-gli (1.5 mg) or placebo in a single blind, randomised, cross-over study. Samples were collected for up to 24 hours (blood) or 48 hours (urine) following administration of hydroxy-gli or placebo. Hydroxy-gli significantly decreased the minimum serum concentration (Cmin) of glucose by 12% and the average serum glucose concentration over the first four hours of treatment (Cavg0-4) by 9% compared with placebo (P < or = 0.05). In addition, maximum serum C-peptide concentration (Cmax) and Cavg0-4 were both increased by 7% after hydroxy-gli (p < or = 0.05). Serum insulin concentrations (Cmax and Cavg0-4) increased by 4% but the differences from placebo were not statistically significant. No adverse events were reported during the study. In conclusion, the hydroxymetabolite of glimepiride shows pharmacological activity in human subjects.

Absolute bioavailability of glimepiride (Amaryl) after oral administration.

Twelve healthy fasting male volunteers received a single 1.0 mg dose of glimepiride either as an intravenous injection over one minute or as a tablet. Blood and urine samples were taken before drug administration and afterwards for up to 24 hours (blood) and 48 hours (urine) to determine serum and urinary concentrations of glimepiride and its hydroxy- and carboxy-metabolites (M1 and M2). There were no statistically significant differences between mean serum pharmacokinetic parameters for the oral and intravenous formulations either with glimepiride or M1. Mean urinary recovery of M1 plus M2 was 50% of the dose for the glimepiride tablet and 51% for the intravenous injection. The absolute bioavailability of the tablet formulation was 107% (AUDC(glimepiride)), 109% (AUDC(M1)) and 97% (urinary recovery). The tablet formulation of glimepiride is completely bioavailable and was safe and well tolerated in healthy volunteers.

Dose linearity assessment of glimepiride (Amaryl) tablets in healthy volunteers.

Twelve healthy fasting male volunteers received glimepiride in 1, 2, 4 or 8 mg single oral doses. On the days when glimepiride was taken, the subjects were given a standardised carbohydrate diet (18 bread exchange units) and drank 125 ml of water hourly. Blood and urine samples were taken before drug administration and afterwards for up to 36 hours (blood) and 48 hours (urine) to determine serum and urinary concentrations of glimepiride and its hydroxy- and carboxy-metabolites (M1 and M2). The areas under the curve for glimepiride after oral doses of 1 to 8 mg and the urinary recovery of its metabolites M1 and M2 were dose linear. All confidence intervals were well contained within the bioequivalence range of 80-125%. There was a statistically significant difference for Cmax values of glimepiride between doses after dose normalisation. A dose-dependent increase for Cmax was nevertheless clearly observed with a correlation coefficient of r=0.90. The pharmacokinetics of glimepiride are dose linear in the dose range 1 to 8 mg, and glimepiride was safe and well tolerated in healthy volunteers.

Single-dose pharmacokinetics of cefpirome in patients receiving hemodialysis and in patients treated by continuous ambulatory peritoneal dialysis.

Cefpirome is eliminated primarily by renal excretion, compelling dosage reduction in kidney failure. We studied the elimination kinetics after intravenous administration of 1 gm cefpirome in patients undergoing hemodialysis (n = 9) and after intravenous (n = 6) or intraperitoneal administration (n = 6) of 1 gm cefpirome in subjects treated by continuous ambulatory peritoneal dialysis (CAPD). Four hours of hemodialysis removed 48% +/- 9% of the drug present in the body at the start of hemodialysis. Consequently, a supplementary dose equal to 50% of the daily dose recommended in end stage renal disease (ESRD) should be administered after each hemodialysis treatment. In patients receiving CAPD, therapeutic levels in both serum and dialysate were reached after intravenous and intraperitoneal administration. The bioavailability after intraperitoneal administration was 84%. After systemic administration, the elimination of cefpirome in the dialysate was negligible. Consequently, systemic dosage of cefpirome in patients receiving CAPD and in patients with ESRD should be identical.

Dose relationship of stimulated insulin production following intravenous application of glimepiride in healthy man.

This study evaluates stimulated insulin production rate (incremental AUC x MCR (metabolic clearance rate) of C-peptide) and blood glucose (BG) response after i.v. administration of glimepiride (Hoe 490, GLI, CAS 93479-97-1) (0.25, 0.50, 0.75, 1.00, 1.25, 1.50 mg) in healthy man (27 +/- 4 yrs). It was shown that i.v. bolus administration of GLI (0.25, 0.50, 1.25 and 1.50 mg) caused a dose-related rise in insulin production from 18 +/- 17 to 25 +/- 13, 36 +/- 14 and 54 +/- 34 pmol/kg body weight, respectively. This effect did not yet plateau at 1.5 mg GLI and was paralleled by a fall in BG (decremental area below BG baseline) by 40 +/- 36, 69 +/- 20, 161 +/- 47 and 113 +/- 62 mmol.min/l. It is concluded that insulin release is increased by i.v. GLI in a dose related manner, while a parallel decline in BG was induced only up to 1.25 mg GLI. The less marked fall of BG after injection of 1.50 mg GLI may reflect interference by insulin-counterregulatory hormones secondary to induced hypoglycaemia.

Single-dose pharmacokinetics of cefpirome in patients with renal impairment.

The pharmacokinetic parameters of cefpirome (HR 810) were examined in 22 patients with different degrees of renal impairment. HPLC was used to analyze samples of blood and urine for cefpirome; and enzymatic assay of creatinine in serum and urine was used to assess kidney function. Creatinine clearance correlated linearly with both total and renal clearance of cefpirome. The loss of kidney function resulted in a decreased renal clearance, whereas the volume of distribution remained the same. This result led to an increase in the terminal half-life of the drug, from 2 hours in healthy subjects to 14 1/2 hours in patients with uremia. This increase also resulted in a prolonged high serum concentration well above the minimum inhibitory concentration. The following dosages are thus recommended: (1) creatinine clearance greater than 50 ml/min: normal daily dose, (2) creatinine clearance from 20 to 50 ml/min: 50% of normal daily dose, and (3) creatinine clearance less than 20 ml/min: 25% of normal daily dose. An initial loading dose of 1 gm, independent of renal function, is advised. Cefpirome was safe and well tolerated.

Ofloxacin pharmacokinetics in chronic renal failure and dialysis.

Data on the pharmacokinetics of ofloxacin in chronic renal failure, in patients who were not dialysed or were receiving haemodialysis or continuous ambulatory peritoneal dialysis (CAPD), are reviewed. In addition, a large pool of data obtained in patients with a wide range of renal dysfunction is provided. The good absorption of ofloxacin after oral administration is not influenced by renal failure. Total plasma clearance (CL) is largely dependent on renal elimination of the drug, and renal clearance (CLR) and urinary recovery are reduced in parallel with reductions in renal function. Consequently, the serum half-life progressively increases when creatinine clearance decreases. Although there is wide variation in the published absolute values for the CL and CLR of ofloxacin, all studies show a similar pattern in the pharmacokinetic behaviour of the drug in chronic renal failure. A proposed protocol for ofloxacin dosage adjustment in chronic renal failure is reported which differs slightly but significantly from that recommended by the manufacturer. This new dosage regimen was derived from the pharmacokinetic results after single and multiple oral administration of the drug to patients with chronic renal failure. Since no clinically relevant losses of ofloxacin occur during haemodialysis or continuous ambulatory peritoneal dialysis (CAPD), the same protocol should be followed in these patients as in undialysed patients with terminal chronic renal failure.

Pharmacokinetics of cefodizime during continuous ambulatory peritoneal dialysis.

In a single-dose open cross-over trial we studied the pharmacokinetics of cefodizime 1 g in four uraemic patients treated by continuous ambulatory peritoneal dialysis (CAPD). Cefodizime was administered, successively with a wash out, (a) iv over 3 min and (b) by intraperitoneal (ip) administration together with the dialysate fluid (2 litres). Concentrations of cefodizime were measured by HPLC in blood and dialysate samples collected during an 8-h dwell period and in additional dialysate samples collected up to 48 h after drug administration. The mean (relative) total clearances following the iv and ip administration were 23 and 31 ml/min, respectively, and the terminal half-lives 5.5 and 6.7 h, respectively. Following iv administration, the peritoneal clearance was approximately 0.5 ml/min. After ip administration high concentrations of cefodizime were measured in the dialysate throughout the dwell period and systemic availability was good (80%) but variable.

Bioavailability of a new liquid formulation of penicillin V (Isocillin syrup) and the influence of ethanol on bioavailability of penicillin V.

In an open, randomized four-way crossover study, four different formulations of penicillin V each containing 1.2 mega units were tested: A) new liquid formulation of Isocillin syrup, B) new liquid formulation of Isocillin syrup plus ethanol, C) commercially available penicillin V syrup containing ethanol as solubilizer and D) Isocillin film tablets. Six male and eight female healthy volunteers participated in the study. Serum concentration and urinary excretion of penicillin V were measured by HPLC or bioassay. The new liquid formulation of Isocillin syrup showed highest Cmax and AUC values. Correspondingly, urinary excretion of the new liquid formulation of Isocillin syrup was highest (38% of the given dose). Mean pharmacokinetic data of the new liquid formulation of Isocillin syrup were: tmax (h) = 0.81, Cmax (mg/l) = 9.92, AUC0-8h (mgh/l) = 13.67, lambda z (h) = 0.68, Cltot/f (ml/min) = 964. Ethanol (4.6%) had no absorption-enhancing effects. From a clinical point of view, all four formulations investigated in this trial showed serum concentrations well above bactericidal concentrations (greater than 1 mg/l) for more than 3 h. Although the interindividual variability of serum levels was high, the levels observed would guarantee therapeutic efficacy against penicillin sensitive bacterial strains.

Absence of interaction between ramipril, a new ACE-inhibitor, and phenprocoumon, an anticoagulant agent.

In a double-blind, placebo-controlled crossover trial, the effects of ramipril, a long-acting non-sulphydryl angiotensin I converting enzyme inhibitor, on phenprocoumon steady-state pharmacodynamics were investigated in 8 healthy male volunteers taking individually fixed doses of phenprocoumon. The results showed that 5 mg ramipril or placebo once daily for 7 days did not alter the anticoagulant response (Quick values) to phenprocoumon after a stabilization phase of 2 weeks. Mean Quick values during the steady-state phase with ramipril and placebo were 67.5% and 69.3%, respectively. The clotting factors II, VII, IX and X as well as protein C decreased in the run-in phase and remained stable both during ramipril and placebo treatment. There were no differences between ramipril or placebo treatments. As the phenprocoumon dosage was kept unchanged during the double-blind phase, the results indicate that ramipril does not interfere with the vitamin K-dependent cascade.

Dose linearity and relative bioavailability testing of oxilofrine, a sympathicomimetic drug, in healthy volunteers.

Single oral doses of 16, 32 and 64 mg oxilofrine as dragées as well as 16mg as drops were given to 12 healthy male volunteers in an open Latin-square design with one week interval between dosing days. Concentrations of unchanged drug were monitored in plasma over 24 hours, in urine concentrations of free and total oxilofrine were monitored over 36 hours. Drug concentrations were measured by a specific high pressure liquid chromatography method with electrochemical detection. Medians of maximum plasma concentrations (Cmax) of oxilofrine were 9.1 ng/ml, 11.4 ng/ml, 31.4 ng/ml and 122.9 ng/ml for 16 mg drops, 16, 32, and 64 mg dragées, respectively. The times to maximum plasma concentration (tmax) were between 0.7 and 1.7 h, respectively. The values for areas under the plasma concentration-time curve (AUC0-24) were 12.8, 17.7, 61.0 and 268.2 ng/ml.h for the four treatments. The results show that both Cmax- and AUC0-24-values increase faster with increasing dosing than a linear first-pass would suggest and give evidence for a saturable first-pass metabolism. There is also evidence for an enterohepatic circulation. About 50% of the administered dose is found in the urine, urinary recovery shows a dose-linear dependency. General tolerability was good; no side-effects were reported.

Serum selenium levels in diuretic-treated hypertensives: a double-blind trial of piretanide against hydrochlorothiazide plus amiloride.

In a double-blind parallel group study carried out on 47 patients with mild to moderate essential hypertension, the effects of 6 mg piretanide once or twice daily on serum selenium levels were compared with 50 mg hydrochlorothiazide plus 5 mg amiloride before treatment and after 6 and 12 weeks of treatment. Serum levels of the trace element, selenium, over a treatment period of 12 weeks remained unchanged in all three treatment groups, indicating that the selenium homeostasis is not disturbed during a treatment period of three months with either piretanide or a potassium sparer/thiazide-diuretic combination.

Dose linearity testing of intravenous ofloxacin, a novel gyrase inhibitor.

After intravenous bolus injection of single doses of 25, 50, 75 and 100 mg of ofloxacin (HOE 280) to 34 healthy male volunteers, concentrations of unchanged drug were estimated at various times in serum and urine over 32 and 48 h. Ofloxacin concentrations were determined using high-pressure liquid chromatography (HPLC). A linear relationship between dose and Cmax (r = 0.91), AUC0-32 (r = 0.95), AUC infinity (r = 0.96) and urinary recovery (r = 0.98) was demonstrated for the doses tested (25-100 mg). The biological half-life (t1/2,beta was determined by fitting a two-compartment open model to the data: t1/2,beta was about 4.5-5.1 h (HPLC, mean values) and was not dose-dependent. Clinically relevant high concentrations of unchanged ofloxacin were detected in urine after the lowest dose (25 mg) for about 24 h, and after the highest dose (100 g) for at least 36 h. General tolerance was good. A slight transient drop in blood pressure was seen after 25 mg in one case; in another, local venous irritation and later restlessness were observed after 75 mg. No specific countermeasures, except for a saline injection into the vein, were needed. All volunteers completed the study as planned.

Safety, tolerance and pharmacokinetics of 2.0 g cefpirome (HR 810) after single and multiple dosing.

After intravenous injection of a single dose of 2.0 g cefpirome (HR 810) and multiple doses of 2.0 g b.i.d. (11 doses) to 10 healthy male volunteers in an open design, concentrations of unchanged drug were measured at various times in serum and urine over 24 and 96 h, respectively. Cefpirome concentrations were determined using high-pressure liquid chromatography (HPLC). The biological half-life (t1/2, beta) found by fitting a two-compartment open model to the data was 2 h. No accumulation of the serum levels could be detected during the multiple-dose phase. Urinary concentrations of unchanged cefpirome effective against most clinically relevant bacteria were detected for at least 36 h. The drug was safe and well tolerated. No drug-related changes were observed for blood pressure, heart rate, ECG, haematology, clinical chemistry or urinalysis, including beta 2-microglobulin in serum and creatinine clearance.

Absence of crystalluria and estimation of renal parameters after oral and intravenous ofloxacin as compared to placebo in healthy volunteers.

An open placebo-controlled study on eleven healthy male volunteers was carried out to investigate renal tolerance and the possibility of crystalluria after oral and intravenous administration of ofloxacin. Subjects received single doses of 200 and 400 mg ofloxacin orally, 200 mg ofloxacin intravenously, or placebo. Urine was collected in several fractions on each study day and the urine volume, excretion of ofloxacin, and excretion of creatinine, alanine aminopeptidase, N-acetyl-beta-D-glucosaminidase, and gamma-glutamyltransferase were calculated in each fraction collected. Furthermore, the urine was investigated microscopically to determine whether ofloxacin crystals were present. Serum creatinine and creatinine clearance were also calculated. No relevant changes in creatinine clearance were observed and no drug crystals were found in the urine which indicates that renal tolerance was good. There were no differences in ofloxacin recovery after oral or intravenous administration, confirming that absolute bioavailability of the oral form is excellent.