Pharmacokinetics of teicoplanin in man after intravenous administration

The pharmacokinetics of teicoplanin, a new glycopeptide antibiotic active against gram-positive aerobic and anaerobic bacteria, was studied in adult male volunteers given 2- and 3-mg/kg doses by a constant-rate 0.5-hr infusion. Serum and urine samples were collected up to 96 hr. Mean peak serum levels after the two doses were 15.7 and 22.4 micrograms/ml. Postinfusion serum teicoplanin levels showed triexponential decay. A three-compartment body model gave close values for pharmacokinetic parameters after the two doses. The mean half-life of the lambda 1 phase was 20.3 min, that of the lambda 2 phase was 2.9 hr, and the half-life of the estimated lambda 3 phase was 40.5 hr, in good agreement with that of the lambda z phase (45.9 hr) calculated from the last urine data. The mean volume of distribution of the central compartment was 0.09 liter/kg and the steady-state volume of distribution using noncompartmental analysis was 0.84 liter/kg. Total clearance averaged 16.05 ml/hr/kg, with renal clearance arbout half this (9.51 ml/hr/kg), calculated by two different methods. The average total recovery of active teicoplanin in urine over 4 days was 52%, suggesting that both renal and nonrenal mechanisms are involved in elimination of the drug. The concentrations of teicoplanin in serum and urine exceeded the MIC (ranging from 0.02 to 2 micrograms/ml) on many pathogenic organisms for at least 1 day after administration.     

Clinical pharmacokinetics of trospium chloride

Trospium chloride, a quaternary amine with anticholinergic properties, is used for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and urinary frequency. The pharmacokinetics of trospium chloride have been investigated in healthy volunteers, in patients with renal and hepatic impairment, and in those with symptoms of overactive bladder, after oral, intravenous and intravesical administration.After oral administration, absorption of the hydrophilic trospium chloride is slow and incomplete. Peak plasma concentrations (Cmax) of approximately 4 ng/mL are reached 4-5 hours after administration of a 20 mg immediate-release preparation. The mean bioavailability is approximately 10% and decreases by concomitant food intake (to a mean of 26% of the fasting area under the plasma concentration-time curve [AUC]). Trospium chloride displays dose proportional increases in AUC and Cmax after a single dose within the clinically relevant dose range (20-60 mg). The mean volume of distribution is approximately 350-800 L. The drug is minimally (mean approximately 10%) metabolised to spiroalcohol by hydrolysis, is 50% plasma protein bound and does not cross the blood-brain barrier. Urinary excretion of the parent compound plays a major role in the disposition of the drug, with a mean renal clearance of 29 L/h (accounting for approximately 70% of total clearance) and a mean elimination half-life ranging from 10 to 20 hours. Elimination of the drug is slowed in patients with renal insufficiency, and population pharmacokinetic modelling has demonstrated that drug clearance is correlated with serum creatinine concentration. Thus, dose reduction is needed in patients with severe renal impairment (i.e. creatinine clearance < 30 mL/min).To date, no clinically relevant pharmacokinetic drug-drug interactions have been identified; the drug does not bind to any of the drug metabolising cytochrome P450 enzymes.The pharmacokinetics of the drug are compatible with twice-daily administration. A once-daily schedule may also be appropriate, but this regimen needs formal clinical evaluation.     

Pharmacokinetics and antidiuretic effect of high-dose desmopressin in patients with chronic renal failure

High-dose desmopressin shortens the bleeding time in uraemia. The aim of this study was to investigate the pharmacokinetics and the antidiuretic effect of desmopressin when given in a dose normally used for haemostasis to patients with reduced renal function. Ten patients with chronic renal failure of varying aetiology were enrolled in the study. The age was 58 (20-76) years (median and range), serum creatinine 447 (309-691) micromol/l and plasma clearance of iohexol 16 (8-19) ml/min./1.73 m2 body surface. After baseline measurements, desmopressin was infused at a dose of 0.3 microg/kg. The plasma concentration of desmopressin was followed for 26 hr during and after the infusion and the pharmacokinetic parameters were estimated by compartmental analysis. Urine volume and osmolality, as well as body weight, blood pressure, heart rate, haematocrit, serum osmolality, electrolytes and creatinine, were measured repeatedly during the day before and for two days after the infusion. The total clearance of desmopressin was 0.35 (0.21-0.47) ml/min./kg, the volume of distribution at steady state was 0.30 (0.17-0.38) l/kg and the terminal half-life 9.7 (8.4-16) hr. After administration of desmopressin, urine osmolality increased significantly, by approximately 10%, and this increase lasted for 48 hr. Concomitantly, there was a modest but significant decrease in haematocrit. Thus, the clearance of desmopressin was on average decreased to approximately one quarter, and the terminal half-life was prolonged 2-3 times in the patients as compared to previously published values for healthy adults. The single haemostatic dose of desmopressin given to patients with severe renal failure did not cause fluid overload or changes in serum electrolytes.     

Pharmacokinetics and Antidiuretic Effect of High‐Dose Desmopressin in Patients with Chronic Renal Failure

Abstract: High‐dose desmopressin shortens the bleeding time in uraemia. The aim of this study was to investigate the pharmacokinetics and the antidiuretic effect of desmopressin when given in a dose normally used for haemostasis to patients with reduced renal function. Ten patients with chronic renal failure of varying aetiology were enrolled in the study. The age was 58 (20–76) years (median and range), serum creatinine 447 (309–691) μmol/l and plasma clearance of iohexol 16 (8–19) ml/min./1.73 m² body surface. After baseline measurements, desmopressin was infused at a dose of 0.3 μg/kg. The plasma concentration of desmopressin was followed for 26 hr during and after the infusion and the pharmacokinetic parameters were estimated by compartmental analysis. Urine volume and osmolality, as well as body weight, blood pressure, heart rate, haematocrit, serum osmolality, electrolytes and creatinine, were measured repeatedly during the day before and for two days after the infusion. The total clearance of desmopressin was 0.35 (0.21–0.47) ml/min./kg, the volume of distribution at steady state was 0.30 (0.17–0.38) l/kg and the terminal half‐life 9.7 (8.4–16) hr. After administration of desmopressin, urine osmolality increased significantly, by approximately 10%, and this increase lasted for 48 hr. Concomitantly, there was a modest but significant decrease in haematocrit. Thus, the clearance of desmopressin was on average decreased to approximately one quarter, and the terminal half‐life was prolonged 2–3 times in the patients as compared to previously published values for healthy adults. The single haemostatic dose of desmopressin given to patients with severe renal failure did not cause fluid overload or changes in serum electrolytes.     

Enteral fluconazole population pharmacokinetics in patients in the surgical intensive care unit

STUDY OBJECTIVE: To determine the population pharmacokinetic parameters of enterally administered fluconazole in patients in a surgical intensive care unit (SICU). DESIGN: Population pharmacokinetics component of a prospective, randomized clinical study. SETTING: The SICU at a university hospital. PATIENTS: One hundred ten patients with an expected length of stay in the SICU of 3 or more days and a need for intubation, in whom at least one fluconazole plasma concentration-time measurement was available. Intervention. Patients received fluconazole as an 800-mg loading dose and as a 200- or 400-mg (depending on renal function) daily maintenance dose. Fluconazole suspension was administered enterally followed by a 30-ml free water flush. MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected, and population pharmacokinetic analysis was performed with NONMEM software; a one-compartment pharmacokinetic model was used. Fluconazole clearance was dependent on creatinine clearance, and volume of distribution was dependent on body weight and age. In patients with creatinine clearance values greater than 80 ml/minute, between 30 and 80 ml/minute, and less than 30 ml/minute, geometric mean (percentage coefficient of variation) fluconazole clearance was 14.39 ml/minute (21%), 10.53 ml/minute (28%), and 5.47 ml/minute (30%), respectively. The geometric mean (percentage coefficient of variation) volume of distribution in all patients was 1.27 L/kg (28%) and decreased with increasing age. CONCLUSIONS: Fluconazole clearance values in patients in the SICU who had normal renal function and in those with renal impairment were in agreement with previously reported data. Fluconazole volume of distribution was larger and half-life was longer in the SICU population than in healthy subjects.     

Effects of age and chronic renal failure on the urinary excretion kinetics of famotidine in man

Summary The plasma and urine concentrations of famotidine, a new, potent H₂-receptor antagonist, have been measured in 16 healthy young adults, 8 healthy elderly people and 18 patients with varying degrees of renal dysfunction after intravenous administration.Both the plasma elimination and renal excretion of famotidine were decreased in the elderly volunteers and renal patients. The renal clearance of famotidine averaged 4.43 ml/min/kg (310 ml/min) in normal young volunteers, which exceeded the mean creatinine clearance 1.55 ml/min/kg (109 ml/min), suggesting net secretion is a significant mechanism for elimination of famotidine.The ratio of famotidine renal clearance to creatinine clearance decreased as creatinine clearance decreased; these results suggest that the deterioration in the secretion process was much faster than that in glomerular filtration and are incompatible with the intact nephron hypothesis. Nevertheless, both total body clearance and renal clearance were significantly correlated with creatinine clearance.The apparent half-life was also significantly correlated with creatinine clearance. Since famotidine is essentially free of dose-related adverse effects, dose adjustment in patients with mild renal insufficiency and in elderly people is not required; however, either a prolonged dosing interval or a decrease in daily dose during long-term therapy may be adapted for the patients with severe renal insufficiency to avoid accumulation and the potential undesirable effects.     

Pharmacokinetics of iloprost in patients with chronic renal failure and on maintenance haemodialysis.

Iloprost is a potent, chemically stable prostacyclin-mimetic for which therapeutic efficacy has been proven in patients with peripheral arterial occlusive disease (PAOD) and in those suffering from Raynaud's phenomenon. In volunteers and PAOD-patients the pharmacokinetics of iloprost after intravenous (i.v.) infusion treatment was characterized by dose-dependent steady-state plasma levels, a terminal half-life of approximately 20-30 min, and a total clearance of 15-20 ml/min/kg. Bioinactivation was mainly due to beta-oxidation. In the present study the pharmacokinetics of iloprost was investigated in 21 patients suffering from renal insufficiency, which either required haemodialysis or not. They were treated by one hour i.v. infusion with 1 ng/kg/min and blood samples were taken during and after the end of infusion. Due to technical sampling problems iloprost pharmacokinetics could only be calculated for seven dialysis and eight non-dialysis patients. In the dialysis patients steady-state levels were 114 to 320 pg/ml as compared to 36 to 70 pg/ml in the non-dialysis group. Half-lives were similar in both groups: alpha-phase: 0.05 h and beta-phase: 0.5 h. The total clearance was 2.6 to 8.0 ml/min/kg (dialysis patients) and 13.2 to 25.8 ml/min/kg (non-dialysis patients). The present study demonstrated that the pharmacokinetic profile of iloprost in patients with renal failure (not subject to haemodialysis) was similar to that observed in PAOD-patients and volunteers. In patients on maintenance haemodialysis, iloprost clearance was reduced by a factor of four. The iloprost dose regimen required in general (due to interindividual variability in response) a careful dose titration.     

Pharmacokinetics of cephradine administered intravenously and orally to young and elderly subjects

The pharmacokinetics of IV and oral cephradine in healthy young male and female volunteers (ages 19 to 25, n = 10) were compared to those of older individuals (ages 65 to 81, n = 9). Subjects received 1 gram of cephradine by a 5-minute intravenous (IV) infusion followed the next day by a 1-gram oral dose. Serial serum and urine samples collected over a period of 12 hours after the dose were analyzed for cephradine concentration by a microbiologic assay. After IV administration, mean serum cephradine concentrations in the elderly group were significantly higher at both 6 hours (1.52 +/- 0.41 mcg/mL) and 8 hours (0.73 +/- 0.22 mcg/mL) than in the young group at 6 hours (0.43 +/- 0.11 mcg/mL). Total systemic clearance was significantly lower (2.64 +/- 0.34 vs. 4.81 +/- 0.59 ml/min/kg) and the elimination half-life was significantly longer (1.71 +/- 0.20 vs 1.12 +/- 0.13 hours) in the elderly group (P = .0001). Systemic cephradine clearance correlated positively with creatinine clearance (r2 = 0.34, P = .0110) and negatively with age (r2 = 0.79, P = .0052). The mean volume of distribution was not significantly different between the two groups. Mean renal clearance was significantly lower in the elderly group (P = .0001), but more than 80% of the dose was excreted in the urine within 6 hours in both groups. After oral administration, the mean peak concentration and time to peak concentration did not differ between groups. The relative oral bioavailability was approximately 94% in both groups. The mean serum concentrations in the elderly were higher at both 6 and 8 hours than in the young group at 6 hours. There were no differences in pharmacokinetic parameters between male and female subjects. Because of reduced cephradine clearance secondary to an age-related decline in renal function, administration of cephradine every 8 hours, rather than every 6 hours, may be sufficient in elderly patients.     

Cefamandole pharmacokinetics and dosage adjustments in relation to renal function.

The pharmacokinetic characteristics of cefamandole were determined after intravenous administration of a 1-Gm dose to 10 subjects with normal renal function, 10 patients with stabilized renal failure, and five chronic nephritic patients included in a intermittent hemodialysis program. In normal subjects, biological half-life (t1/2) averaged 0.94 hour, the overall elimination rate constant (Ke) was 0.7378 (hr-1), total clearance (Ct) was 223 ml/min/1.73 m2, renal clearance (Cr) was 164 ml/min/1.73 m2, and urine recovery of cefamandole over the 6 hours following a dose amounted to 74 per cent of the administered dose. In patients with stabilized renal failure and in patients on hemodialysis, biological half-life was markedly increased, with a theoretical value of 10.4 hours in case of a creatinine clearance of zero. The amount of antibiotic extracted over a 6-hour dialysis period accounted for 29 per cent of the cefamandole present in the vascular compartment at the beginning of the dialysis procedure. A significant correlation was established between the values of Ke and creatinine clearances, Ccr: Ke = 0.0289 + 0.0063Ccr (r = 0.937). This relationship was used to calculate the loading dose (LD), maintenance doses (D), and dosage intervals (tau) with regard to renal function. From these data recommendations regarding the adjustment of cefamandole dosage to the renal status can be made.     

Pharmacokinetics of iopamidol in adults with renal failure

The pharmacokinetics of iopamidol 370 (Iopamiro), a non-ionic water soluble organic iodine compound, were studied in adults with different degrees of chronic renal failure and in healthy volunteers. After 50 ml were administered i.v., plasma and urine levels were determined. The main pharmacokinetic parameters were calculated on the basis of bi-compartimental open model. There were significant differences from healthy volunteers in t1/2 beta, which increased with the degree of renal failure as the clearance values decreased. t1/2 beta was equal to 1.67 h in healthy volunteers, 4.24 h in patients with mild renal failure and 10.03 h in patients with severe renal failure. The clearance decreased as follows: 0.11 (l/h kg) in healthy volunteers, 0.06 (l/h kg) in patients with mild renal failure and 0.02 (l/h kg) in patients with severe renal failure. No significant differences were found in distribution volume values nor in t1/2 alpha.     

Pharmacokinetics of sisomicin in patients with normal and impaired renal function; its efficacy in urinary tract infection

Summary Serum concentration, biological half-life, distribution space and serum clearance of sisomicin, a new aminoglycoside antibiotic, have been studied in twenty-three patients in comparison with the pharmacokinetics of¹²⁵I-labelled iothalamate, a compound only filtered by the kidney. 10 patients had normal or borderline abnormal serum creatinine (<1,5 mg/100 ml), 8 had various degrees of renal insufficiency (serum creatinine 1.7 – 9.6 mg/100 ml) and 6 were being treated by intermittent haemodialysis. After intravenous injection of sisomicin 1 mg/kg body weight in patients with normal or borderline renal function its half-life was 3.5 h, very similar to that of iothalamate, 3.2 h. The mean distribution space was 20.1 % per cent of body weight; iothalamate, 23.7 %. In patients with renal insufficiency there was a positive correlation between serum creatinine level and the half-life of sisomicin, and an even stronger correlation between the clearances of iothalamate and sisomicin. In patients dependent on haemodialysis, the mean serum half-life between dialysis was 40 h, compared to approximately 100 hours for iothalamate, which implies additional extrarenal clearance or tubular secretion of sisomicin. The results of pharmacokinetic studies indicated that a regime of sisomicin 1 mg/kg every 8 to 12 hours in patients with normal renal function would result in serum and urine levels sufficiently high to treat most urinary tract infections. In patients with impaired renal function the dosage interval should be increased according to the serum creatinine level, and in patients dependent on haemodialysis one standard dose at the end of each dialysis period should suffice. 9 patients with a chronic urinary tract infection severely complicated by an underlying disease were treated according to this dosage regimen with a satisfactory bacteriological and clinical result. No adverse reactions or signs of accumulation were observed.     

Pharmacokinetics of cibenzoline in patients with renal impairment

Pharmacokinetic values of cibenzoline, a new, investigational, antiarrhythmic drug, were determined in 13 patients with varying degree of renal impairment, creatinine clearance range between 5 and 53 mL/min. Cibenzoline plasma levels were measured after direct intravenous injection of one single 1 mg/kg dose. The apparent volume of distribution of the drug (276 1) was similar to that reported in healthy subjects. Total body clearance decreased with creatinine clearance, and there was a close correlation between cibenzoline renal clearance and creatinine clearance (r = 0.956; P less than 0.001). Plasma elimination half-life was prolonged, with values ranging from 7:4 to 23.6 hours. This study showed that cibenzoline total body clearance correlated with the degree of renal impairment, and it is suggested that in patients with chronic renal failure dosage should be adjusted according to creatinine clearance values.     

Pharmacokinetics and dose recommendations of carumonam in renal failure

The pharmacokinetics of (Z)-[[[(2-aminothiazol-4-yl)[[(2S,3S)-2-(hydroxymethyl)-4-oxo-1- sulfoazetidin-3-yl]carbamoyl]methylene]amino]oxo]acetic acid, disodium salt (carumonam, Ro 17-2301) after a 2 g intravenous infusion (20 min) were evaluated in 10 healthy volunteers and 20 patients with various degrees of renal failure. The main results of the kinetic parameters in healthy volunteers (mean + SD) corrected for zero infusion time and 70 kg body weight were: t1/2 alpha, 29 +/- 12 min; t1/2 beta, 108 +/- 27 min; AUCtot, 327 +/- 40 mg h/l; Vdss, 12.2 +/- 1.5 l/70 kg; urinary recovery, 78.7 +/- 8.2%; total clearance 103 +/- 13 ml/min; renal clearance, 85 +/- 13 ml/min. Because of the large variation in the degree of renal insufficiency, calculations of the mean values for the pharmacokinetic parameters in the patient group were not generally justified with the exception of the volume of distribution (Vdss = 14.4 +/- 3.0 l/70 kg). To derive dose recommendations, a regression analysis was performed using values from both the volunteer and patient group for the total area under curve (AUCtot) and glomerular filtration rate (GFR), divided by the mean AUCtot value for the volunteers. This curve can be interpreted as giving the dose reduction factor (DRF) as a function of GFR, where by definition, DRF = 1 for healthy (and young) subjects. Using this method of equivalent areas, no (or only a slight) dose reduction is necessary for patients with GFR values above 40 ml/min.(ABSTRACT TRUNCATED AT 250 WORDS)     

The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction

STUDY OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of argatroban in healthy volunteers and patients with hepatic or renal dysfunction. DESIGN: Prospective, open-label study (studies 1 and 3); prospective, open-label, parallel-group study (study 2). SETTINGS: Two research centers and an inpatient clinic. SUBJECTS: Study 1, healthy volunteers; study 2, healthy volunteers and volunteers with hepatic disease; study 3, volunteers with normal to severely impaired renal function assigned to one of four groups based on creatinine clearance. INTERVENTION: Study 1, argatroban 125-microg/kg bolus followed by 4-hour continuous infusion of 2.5 microg/kg/minute; study 2, 4-hour infusion of 2.5 microg/kg/minute (1.25 microg/kg/minute in one patient with hepatic impairment); study 3, 5-microg/kg/minute continuous infusion over 4 hours. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained to assess plasma argatroban concentration, plasma activated partial thromboplastin time (aPTT), and whole blood activated clotting time (ACT). Study 1: the pharmacokinetic profile was well described by a two-compartment model with first-order elimination; effect response and plasma argatroban concentrations were well correlated. Mean +/- SD clearance, steady-state volume of distribution, and half-life values (40 healthy volunteers) were 4.7 +/- 1.1 ml/minute/kg, 179.5 +/- 33.0 ml/kg, and 46.2 +/- 10.2 minutes, respectively. The only effect of age or gender was the approximately 20% lower clearance in elderly men versus elderly women, which did not translate to clinically or statistically significant differences in pharmacodynamic response. Study 2: in patients with hepatic impairment, area under the concentration versus time curve (AUC) from time zero (t0) to last measurable concentration, AUC from t0 to infinity, maximum concentration, and half-life of argatroban were increased approximately 2- to 3-fold; clearance was one-fourth that of healthy volunteers. For aPTT and ACT, AUC over time for mean effect and mean maximum effect was higher in these volunteers. Study 3: no significant differences were detected. All four groups had predictable response profiles over time. CONCLUSION: Argatroban should be easy to monitor and control, with little potential for underdosing or overdosing, regardless of age, gender, or renal function. Dosing precautions are recommended, however, in patients with hepatic dysfunction.     

Pharmacokinetics of ornidazole in patients with renal insufficiency; influence of haemodialysis and peritoneal dialysis.

The pharmacokinetics of ornidazole (Tiberal) was studied after intravenous administration of a single 500 mg dose in eight patients with advanced chronic renal failure (ACRF) (creatinine clearance 2-16 ml/min), in seven patients treated by haemodialysis (residual renal creatinine clearance 0-5 ml/min) and in five patients treated by continuous ambulatory peritoneal dialysis (CAPD) (residual renal creatinine clearance 0-6 ml/min). In ACRF patients, the half-life of ornidazole was 10.8 +/- 1.4 h, the total plasma clearance 46.3 +/- 2.3 ml/min and the volume of distribution 0.73 +/- 0.06 l/kg. During haemodialysis, ornidazole was partly removed: the dialyser extraction ratio was 42 +/- 5% and the dialysis clearance 64 +/- 7 ml/min. During CAPD, peritoneal excretion was low: the dialysis clearance was 3.0 +/- 0.4 ml/min and in 48 h 6.0 +/- 1.1% of the administered dose was found in the peritoneal fluids. In these patients, the half-life of ornidazole was 11.8 +/- 0.8 h and total plasma clearance was 48.3 +/- 5.5 ml/min, values which were close to those determined in non dialysed patients. In patients with end-stage renal disease, the half-life of ornidazole is comparable to that of subjects with normal renal function. This is due to the predominantly extra-renal elimination of the drug. Therefore, there is no need to modify the usual dosage of ornidazole for these patients. Because of the large elimination of the drug during haemodialysis it is necessary to administer the drug after the dialysis session.     

Pharmacokinetics of aztreonam in patients with chronic renal failure

The elimination kinetics of aztreonam (SQ 26,776), a new, completely synthetic, monocyclic beta-lactam antibiotic, were studied after the administration of a single 1g intravenous dose. Five healthy volunteers and 20 patients with various degrees of renal insufficiency were enrolled in this study. Concentrations of aztreonam in serum and urine were determined by both microbiological and high pressure liquid chromatography (HPLC) assays. The pharmacokinetic parameters for aztreonam were calculated on the basis of a 2-compartment open model. Serum concentrations of aztreonam at 10 minutes after administration were approximately 100 micrograms/ml in all subjects, regardless of renal function (HPLC assay). The mean serum half-life during the alpha-phase showed no important variation with renal function. The mean serum half-life during the beta-phase was 1.8 hours in normal subjects and 8.4 hours in haemodialysis patients (HPLC assay). There was a linear correlation between the serum clearance of aztreonam and creatinine clearance. The mean cumulative urinary recovery of aztreonam in 48 hours was 60 to 70% of the administered dose in normal subjects but this was reduced in the presence of renal insufficiency. SQ 26,992, the microbiologically inactive metabolite of aztreonam resulting from hydrolytic opening of the beta-lactam ring, was undetectable in the serum of normal subjects but was found in low levels in uraemic patients. Half of a 1g intravenous dose of aztreonam was eliminated during 4 hours of haemodialysis. Guidelines for administration of aztreonam in the presence of renal failure are given.     

Pharmacokinetics of low-dose methotrexate in adult asthmatics.

Several reports have been published on the disposition of methotrexate (MTX) when given in low dosages, but none in asthmatic patients. To address this matter, pharmacokinetic studies were performed in nine patients with severe, steroid-requiring asthma (ages 18-76 yrs) after the sixth weekly intramuscular dose of MTX. Theophylline pharmacokinetic studies were also performed at baseline prior to the start of MTX treatment and at the time of the MTX studies. Total systemic clearance of MTX, given as mean (SD), was 122.6 (25.1) ml/minute, volume of distribution at steady state 0.49 (0.2) L/kg, half-life 3.1 (0.3) hours, mean residence time 5.0 (0.6) hours, and renal clearance 89.1 (36.3) ml/minute. These values are similar to those previously reported for other patient populations receiving low-dose MTX. Eight of these patients were evaluated for changes in theophylline pharmacokinetics. Theophylline clearance at week 6 decreased an average of 19% from baseline and correlated inversely with total MTX clearance. Percentage change in theophylline clearance from baseline was inversely correlated with MTX nonrenal clearance, but was not statistically significant. This finding may indicate competition for clearance pathways between MTX and theophylline.     

Single-dose pharmacokinetics and safety of pegylated interferon-alpha2b in patients with chronic renal dysfunction

This study evaluates the pharmacokinetics and safety of pegylated interferon-alpha2b (PEG-Intron) following a single-dose subcutaneous injection into subjects with normal renal function, subjects with chronic renal impairment, and patients on hemodialysis. In this open-label, single-dose, parallel group study, subjects were divided into five groups according to their degree of renal function: four groups as defined by measured creatinine clearance and a fifth hemodialysis dependent group. They received 1 microg/kg PEG-Intron subcutaneously after a 10-hour fast. Pharmacokinetic and safety assessments were performed up to 168 hours postdose. Hemodialysis patients had a second PEG-Intron dose 12 hours prior to a hemodialysis session. PEG-Intron pharmacokinetic parameters (AUCtf, Cmax, and t1/2) increased progressively as CL(CR) declined. All subjects reported at least one adverse event, which were typical of those reported after alpha-interferon administration (e.g., flu-like symptoms, headache). Single-dose PEG-Intron administration to volunteers with normal renal function and chronic renal impairment was safe and well tolerated. In patients with CL(CR) < 30 ml/min, AUCand Cmax values were increased 90% compared with controls, while half-life was increased by up to 40% over controls. Based on the relationship between PEG-Intron apparent clearance and CL(CR), renal clearance accountsfor less than half of its total clearance. Hemodialysis did not affect PEG-Intron apparent clearance.     

Pharmacokinetics of n-propyl-ajmaline-bitartrate in elderly patients with ventricular ectopic activity

11 patients (9m, 2f, median age 59 years) with ventricular ectopic activity of at least Lown grade III received 20 mg N-Propyl-ajmaline-bitartrate (N-PAB) p.o. Plasma concentrations of N-PAB were determined with HPLC from blood samples within 26 hours after administration. An open two-compartment model was used. In 8 patients with normal function of the liver and the kidneys, the median clearance of N-PAB was 6.86 ml/min/kg and the median volume of distribution was 1.56 l/kg. Two patients had a clearly diminished clearance of 1.58 ml/min/kg without obvious impairment of liver or renal function. One patient with chronic glomerulonephritis (plasma creatinine 3.4 mg/dl) had a N-PAB clearance of 2.79 ml/min/kg. None of the Spearman rank correlation coefficients between the pharmacokinetic parameters of N-PAB with age, plasma albumin/globulin-quotient, plasma creatinine and cholin-esterase were significant. All calculated parameters were in the range determined in young subjects. It is concluded that physiological changes with age do not lead to significant changes of the pharmacokinetics of N-PAB. On the other hand in patients with increased levels of plasma creatinine a diminished clearance of N-PAB can be expected. It is also possible that patients without an obvious impairment of liver or renal function may have diminished N-PAB clearance.     

The effect of age and cardiac failure on xamoterol pharmacokinetics.

1. Xamoterol is a cardioselective beta-adrenoceptor partial agonist which may have a role in the management of cardiac failure. Excretion is mainly by the renal route. 2. The kinetics of a single 200 mg oral dose of xamoterol were studied in eight elderly (age 67-82 years) volunteers, eight young (age 21-43 years) volunteers; eight patients with mild to moderate cardiac failure and eight age and sex matched controls. 3. Elderly volunteers had a significantly longer time to reach peak concentration (mean +/- s.e. mean 2.1 +/- 0.2 vs 1.1 +/- 0.1 h) and elimination half-life time (27.0 +/- 2.8 vs 16.4 +/- 3.1 h) compared with young volunteers. The renal clearance of xamoterol was lower in the elderly (115 +/- 12 vs 185 +/- 19 ml min-1) and showed a significant correlation with creatinine clearance (r = 0.85, P less than 0.001). 4. There was no significant difference in any of the pharmacokinetic parameters measured in patients with cardiac failure compared with healthy age and sex matched controls. 5. These results suggest that the maintenance dose of xamoterol could be reduced in elderly patients in relation to impairment of renal function.