Pharmacokinetics of cibenzoline after single and repetitive dosing in healthy volunteers

Twenty-five healthy, adult male volunteers entered two open-label parallel studies, each designed to define the pharmacokinetics of single and multiple oral doses of cibenzoline. Each volunteer received a single 160-mg oral dose of cibenzoline followed two or three days later by 160 mg of cibenzoline q12h for seven days. Plasma concentration-time profiles and urinary excretion rate data were used to determine pharmacokinetic parameters for unchanged drug. The apparent half-life following administration of the last dose (9.7 hours) was slightly longer than that observed after the first dose (8.4 hours). Total body clearance and nonrenal clearance were decreased after the last dose compared with the first dose, whereas renal clearance was not significantly altered. After both the first and last dose, the renal clearance greatly exceeded the glomerular filtration rate, suggesting that tubular secretion participates in the renal excretion of cibenzoline. Plasma concentrations from samples collected during the multiple-dose regimen suggest that a slight but statistically significant diurnal variation in the absorption and/or clearance of drug occurred during the course of the study. Overall, the pharmacokinetics of cibenzoline are characterized by a slightly longer half-life during multiple dosing than that observed following a single dose, due to a decrease in the nonrenal clearance. The multiple-dose pharmacokinetics reported herein are consistent with bid dosing for the maintenance of therapeutic plasma concentrations in patients taking chronic therapy.     

A comparison of two sparse sampling population pharmacokinetic approaches for the estimation of pharmacokinetic parameters in children

BACKGROUND AND OBJECTIVE: The objectives of this study were to assess pharmacokinetic parameters (clearance, volume and half-life) in children using sparse sampling population as well as Bayesian (post hoc) approach. METHODS: Three drugs were selected for this study. Two sparse sampling methods (variable or fixed) using population and Bayesian approaches were used to assess pharmacokinetic parameters in children following a single oral dose. The initial estimates of the model parameters and inter- and intrasubject variability were obtained from the pharmacokinetic studies conducted in adults. The estimated pharmacokinetic parameters using sparse sampling (3 blood samples) were compared with the pharmacokinetic parameters obtained by extensive sampling (> or = 7 blood samples). RESULTS AND CONCLUSIONS: The results indicated that both variable and fixed sampling approaches could be used to estimate mean population as well as individual pharmacokinetic parameters in children with fair degree of accuracy. The methods described here can be used to assess either population or individual pharmacokinetic parameters in children, provided there is a prior knowledge of the pharmacokinetics of a drug in adult population.     

Clinical pharmacokinetics of inhaled budesonide

The corticosteroid budesonide is a 1:1 racemic mixture of 2 epimers, (22R)- and (22S)-, and is available in 3 different inhaled formulations for the management of asthma: a pressurised metered dose inhaler (pMDI), a dry powder inhaler (DPI) and a solution for nebulised therapy. Inhaled corticosteroids such as budesonide reach the systemic circulation either by direct absorption through the lungs (a route that is much more important than previously recognised) or via gastrointestinal absorption of drug that is inadvertently swallowed. Although the pharmacokinetics of budesonide have been extensively investigated following oral and intravenous administration, relatively few studies have defined the systemic disposition of budesonide after inhalation. Drug deposition in the lungs depends on the inhaler device: 15% of the metered dose of budesonide reached the lung with a pMDI compared with 32% with a breath-actuated DPI. In patients with asthma (n = 38) receiving different doses of budesonide by DPI (Turbuhaler), the pharmacokinetic parameters peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) were dose-dependent after both single dose and repeat dose (3 weeks) administration: time to Cmax (tmax) was short (0.28 to 0.40 hours) and the elimination half-life approximately 3 hours. Both AUC and Cmax were linearly related to budesonide dose. In a small group of healthy male volunteers (n = 9), the pharmacokinetics of budesonide 1,600 microg twice daily via pMDI were assessed on the fifth day of administration. Mean model-independent parameters for (22R)-budesonide were as follows: Cmax 1.8 microg/L, tmax 0.46 hours, elimination half-life 2.3 hours and oral clearance 163 L/h, and there were no enantiomer-specific differences in drug disposition. Budesonide undergoes fatty acid conjugation within the lung, but very limited pharmacokinetic data are available to define the pulmonary absorption characteristics. There is evidence from a population analysis that the pulmonary absorption of budesonide is prolonged and shows wide interindividual variation. Further pharmacokinetic studies are required to define the time-course of budesonide absorption through the lung in specific patient groups, and to investigate the effect of new inhaler devices (especially chlorofluorocarbon-free pMDIs) on the pharmacokinetic profile and systemic drug exposure.     

Pharmacokinetics of 2',3'-dideoxycytidine in rats: application to interspecies scale-up

The effects of dose on the pharmacokinetics of 2',3'-dideoxycytidine (DDC), a potent inhibitor of HIV replication, have been studied in rats. DDC was administered intravenously at doses of 10, 50, 100 and 200 mg kg-1. Plasma and urine drug concentrations were determined by HPLC. Non-compartmental pharmacokinetic parameters were calculated by area/moment analysis. DDC plasma concentrations declined rapidly with a terminal half-life of 0.98 +/- 0.18 h (mean +/- s.d.). No statistically significant differences were observed in pharmacokinetic parameters between the four doses. Total, renal and non-renal clearance values were independent of dose and averaged 1.67 +/- 0.24, 0.78 +/- 0.11, and 0.89 +/- 0.27 L h-1 kg-1, respectively. Approximately 50% of the dose was excreted unchanged in urine. Steady state volume of distribution was also independent of dose and averaged 1.2 +/- 0.21 L kg-1. Protein binding of DDC to rat serum proteins was independent of drug concentration with the fraction of drug bound averaging 0.45 +/- 0.12. Thus, the disposition pattern of DDC in the rat is independent of the administered dose even at high doses. Significant interspecies correlations were found for total, renal and non-renal clearance and steady state volume of distribution. Interspecies scaling resulted in superimposable plasma DDC concentration-time profiles from four laboratory animal species and man. Thus, plasma DDC concentrations in humans can be predicted from pharmacokinetic parameters obtained in laboratory animals.     

Comparison of the pharmacokinetics of chloroquine after single intravenous and intramuscular administration in healthy Africans.

The pharmacokinetics of chloroquine were studied after intramuscular and intravenous administration of the drug to healthy African adults. Chloroquine was analysed in plasma using an h.p.l.c. method and pharmacokinetic parameters were derived from the concentration-time data using a non-linear computer programme. A two-compartment open model was assumed. Chloroquine was rapidly absorbed from an intramuscular site, producing a plasma concentration-time profile similar to that obtained after a 15 min i.v. infusion of a comparable dose. The pharmacokinetics of chloroquine after i.m. and i.v. administration were characterised by a long half-life and a very large volume of distribution. There was no significant difference between the values of each parameter obtained from the different routes. It is suggested that the high Cmax obtained after i.m. and i.v. administration of chloroquine might contribute to its toxicity when these routes are used in treatment.     

Pharmacokinetics and dose proportionality of oral moxidectin in beagle dogs

PURPOSE: To study the pharmacokinetics and dose proportionality of moxidectin in beagle dogs experimentally infected with the filarial parasite Brugia pahangi, and to evaluate and compare the results obtained from population pharmacokinetic analysis and individual compartmental analysis. METHOD: Thirty-six infected dogs were selected and randomly allocated into six treatment groups of six dogs each. Doses of 250 or 1000 microg/kg were given orally. The plasma drug concentration-time data were analyzed by population compartmental and individual compartmental methods. RESULTS: The best pharmacokinetic model was a two-compartment model with first-order absorption. According to the results obtained from population compartmental analysis, moxidectin is a low clearance drug with a relatively high volume of distribution, resulting in a mean terminal half-life of 458 h. Absorption was rapid with a mean absorption half-life of 0.6 h and T(max) of 2.75 h. Significant weight effect was found on Vc. These results were compared with results obtained from individual compartmental approach. A statistically significant (p<0.01) gender difference in T1/2beta was observed with the 250 microg/kg dose, and a trend was observed with a greater T1/2beta in females at the 1000 microg/kg dose. No gender effect on other pharmacokinetic parameters was found. CONCLUSIONS: A pronounced distribution phase was observed and there was a significant weight effect on Vc. Dose proportionality of moxidectin was assessed by comparing the AUC (0-last determination) values for 250 and 1000 microg/kg. The pharmacokinetics are independent of dose over this dose range.     

Application of allometric principles for the prediction of pharmacokinetics in human and veterinary drug development

The concept of correlating pharmacokinetic parameters with body weight (termed as pharmacokinetic interspecies scaling) from different animal species has become a useful tool in drug development. Interspecies scaling is based on the power function, where the body weight of the species is plotted against the pharmacokinetic parameter of interest. Clearance, volume of distribution, and elimination half-life are the three most frequently extrapolated pharmacokinetic parameters. The predicted pharmacokinetic parameter clearance can be used for estimating a first-in-human dose. Over the years, many approaches have been suggested to improve the prediction of aforementioned pharmacokinetic parameters in humans from animal data. A literature review indicates that there are different degrees of success with different methods for different drugs. Interspecies scaling is also a very useful tool in veterinary medicine. The knowledge of pharmacokinetics in veterinary medicine is important for dosage selection, particularly in the treatment of large animals such as horses, camels, elephants, or other large zoo animals. Despite the potential for extrapolation error, the reality is that interspecies scaling is needed across many veterinary practice situations, and therefore will be used. For this reason, it is important to consider mechanisms for reducing the risk of extrapolation errors that can seriously affect animal safety and therapeutic response. Overall, although interspecies scaling requires continuous refinement and better understanding, the rationale approach of interspecies scaling has a lot of potential during the drug development process.     

Pharmacokinetics of sulpiride after intravenous administration in patients with impaired renal function

Single intravenous doses of sulpiride 100 mg were administered to 18 patients with renal function impairment, and 6 healthy volunteers. The plasma concentration-time profile is described by a 2-compartment open model. The differences between the pharmacokinetic parameters of sulpiride for the 2 groups were statistically significant. Elimination half-life, mean residence time and area under the plasma concentration-time curve are significantly greater in renal failure; renal and total clearance, and the cumulative amount of unchanged sulpiride in urine, are significantly reduced but volume of distribution remains unchanged. Creatinine clearance was strongly correlated with renal clearance of sulpiride, elimination rate constant, area under the curve and cumulative amount excreted in urine. For patients with impaired or physiologically reduced renal function receiving long term sulpiride treatment, a 35 to 70% reduction in dose, or extension of the dosage interval by a factor of 1.5 to 3, may be required.     

Butofilolol pharmacokinetics in chronic renal insufficiency

The pharmacokinetics of butofilolol, a new beta-blocking drug used in the treatment of hypertension, were investigated in 9 patients with varying degrees of renal impairment (creatinine clearance ranging from 65 ml/min to 6.6 ml/min). The drug was administered as a single oral 100-mg dose. Plasma and urine concentrations of the parent drug were measured. The pharmacokinetic parameters of butofilolol calculated from examination of patients with renal failure were compared to those obtained from healthy subjects. Renal failure was found to be associated with a marked increase of the areas under the plasma concentration-time curves of the parent drug whereas its elimination rate constant tended to increase, especially in severe renal failure. A highly significant relationship between the amounts of unchanged drug excreted in urine and the creatinine clearance was observed (r = 0.90, p less than 0.001). The higher plasma levels of the parent drug observed in renal failure might be due to a decrease in the first-pass hepatic extraction of the drug. But these changes in plasma clearance were probably counteracted by modification of the volume of distribution, so that the net result of these alterations was a slight increase in the elimination half-life.     

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 metabolism of the proton pump inhibitor pantoprazole in man

Pantoprazole, a second-generation proton pump inhibitor, is absorbed after oral administration as enteric-coated tablet with maximum plasma concentrations within 2-3 h and a bioavailability of 77%. Food has no relevant effect on absorption. The pharmacokinetics of pantoprazole are dose linear in the therapeutic range. The parent drug is totally metabolized, mainly by the polymorphically expressed CYP2C19 and by CYP3A. The pharmacokinetic profile is practically unchanged after multiple dosing, as is expected for a drug with a short half-life of about 1 h. A lack of pharmacokinetic interactions with various drugs has been shown. No clinically relevant changes in the pharmacokinetics of pantoprazole are observed in elderly subjects and patients with severe renal insufficiency. However, clearance is decreased in poor metabolizers of (S)-mephenytoin and in patients with liver cirrhosis.     

Pharmacokinetics of CM 57755, a new histamine H2-receptor antagonist, after single oral doses in man

The plasma pharmacokinetics and urinary excretion of CM 57755, an H2-receptor antagonist, were studied after administration of single oral doses in a range between a 100 and 700 mg in human volunteers. Pharmacokinetic parameters were calculated model-independent. Absorption of CM 57755 was bimodal and the maximum plasma concentration was reached between 2 and 4 h after dosing. The drug was widely distributed with an apparent volume of distribution between 140 and 200 l. The plasma clearance was between 56 and 69 L/h. The plasma concentrations declined following a monoexponential function with an elimination half-life of 2 h. No modification in the plasma clearance or other pharmacokinetic parameters with these doses was observed. Therefore, a linear pharmacokinetic profile of CM 57755 was proposed. About 40% of the parent drug was unchanged in urine excreted over the 24 h. The drug was compared with cimetidine and ranitidine, the three compounds seemed to exhibit a consistent pharmacokinetic profile.     

Pharmacokinetics of meropenem in preterm neonates

The objective of this study was to evaluate and compare the pharmacokinetics of meropenem in premature neonates, both after the first dose and during steady state at day 5, after a 1-minute intravenous administration to evaluate the possibility of twice-daily administration. Seven premature neonates received 15 mg/kg meropenem twice daily on clinical grounds as a 1-minute infusion. After the first dose and during steady state at day 5, serum levels of meropenem were measured for 12 hours after intravenous administration. Meropenem pharmacokinetics at the first dose were studied in seven children (mean birth weight 925 g, mean postnatal age 21 days). Serum concentration-time curves could be described with a one-compartment model. Mean total body clearance was 0.157 L/kg per hour, volume of distribution was 0.74 L/kg, and half-life was 3.4 hours. At day 5 at steady state, pharmacokinetic properties did not differ significantly. No side effects were noted. A 1-minute intravenous administration is feasible. Pharmacokinetic properties are comparable at day 5 compared with the first dose, and half-life is such that twice-daily administration of 15 mg/kg produces adequate serum concentrations.     

Comparison of different reduced sampling approaches for the estimation of pharmacokinetic parameters for long half-life drugs in patients with renal or hepatic impairment

OBJECTIVE: To compare 3 different reduced sampling approaches (truncated area, population and Bayesian; sampling schedule till 48 or 72 hours) with the extensive sampling for the estimation of pharmacokinetic parameters for long half-life drugs in healthy subjects and in patients with renal or hepatic impairment. METHODS: Two drugs (extensively metabolized or extensively excreted) whose half-lives were greater than 30 hours were used in this analysis. Pharmacokinetic parameters such as maximum plasma concentration, clearance and half-life were estimated in healthy subjects and in patients using the above-mentioned 3 reduced sampling approaches and then compared with the extensive sampling. RESULTS: The truncated area method failed to detect the same magnitude of difference in pharmacokinetic parameters between healthy subjects and patient populations that was determined using extensive sampling. On the other hand, the population or Bayesian approach provided the same magnitude of difference in pharmacokinetic parameters between the 2 populations that was observed with extensive sampling. CONCLUSION: This study indicates that the truncated area method may be a less suitable method to accurately characterize the pharmacokinetics of a long half-life drug either in healthy subjects or in patients with renal or hepatic impairment compared to a population or Bayesian approach.     

Pharmacokinetics of daptomycin in a critically ill adolescent with vancomycin-resistant enterococcal endocarditis

Daptomycin is a lipopeptide antibiotic active against multidrug-resistant gram-positive organisms. Our search of the literature found no published pediatric pharmacokinetic data. We report the use of pharmacokinetic analysis of daptomycin in a 13-year-old boy with vancomycin-resistant Enterococcus faecium endocarditis. Pharamcokinetic parameters were found to be significantly different from published adult parameters, such as a faster elimination rate, shorter half-life, and increased clearance. These age-related differences in the pharmacokinetic profile of daptomycin have significant dosing implications. As the use of this drug for off-label indications and in pediatric populations increases, it is important for clinicians to better understand the drug's pharmacokinetic profile in these patient populations.     

Clinical pharmacokinetics of verapamil, nifedipine and diltiazem

The calcium antagonists diltiazem, nifedipine and verapamil are widely used in the treatment of coronary heart disease, arterial hypertension, certain supraventricular tachyarrhythmias and obstructive hypertrophic cardiomyopathy. During recent years their pharmacokinetic properties and metabolism have been studied in more detail. Although these 3 calcium antagonists exhibit great diversity in chemical structure, they exhibit common pharmacokinetic properties. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. Their systemic plasma clearances are high and dependent on liver blood flow. Therefore, their bioavailabilities (diltiazem 40 to 50%; nifedipine 40 to 50%; verapamil 10 to 30%) are low despite almost complete absorption following oral administration. During long term treatment, oral clearance decreases and bioavailability increases due to saturation of hepatic first-pass metabolism. Pronounced intra- and inter-individual variations in clearance and bioavailability are observed. In patients with liver cirrhosis the various pharmacokinetic parameters are grossly altered. Clearance decreases, elimination half-life is substantially prolonged, and bioavailability more than doubles. In addition, the volume of distribution increases. Whereas renal disease has no impact on the pharmacokinetics of diltiazem and verapamil, elimination half-life of nifedipine increases in relation to the degree of renal impairment due to an increase in volume of distribution. Systemic clearance, however, remains unchanged. The data so far available indicate that the plasma concentrations of these drugs correlate with both their electrophysiological and haemodynamic effects. However, no effective therapeutic plasma concentration range has been firmly established. As reliable clinical end-points are available for dose titration of calcium antagonists, it is doubtful whether therapeutic drug monitoring will be of great value. Calcium antagonists are often administered in combination with a variety of other drugs. Thus, the potential for both pharmacodynamic and pharmacokinetic drug interaction exists. The interaction between digoxin and these drugs is of clinical importance. Verapamil and diltiazem cause a significant increase in plasma digoxin concentrations. In contrast, nifedipine does not lead to a significant increase in the plasma digoxin concentration. The mechanism responsible for this interaction is inhibition of both renal and non-renal digoxin clearance.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clinical pharmacokinetics of antibacterial drugs in the elderly. Implications for selection and dosage

A review of the clinical pharmacokinetics of antibiotics in the healthy elderly reveals that for most compounds a decrease occurs in renal clearance (associated with age-related decreases in renal function), as well as a prolonged half-life and increased area under the plasma concentration-time curve. These changes are amplified in the sick infected elderly. It is important that the treating physician be aware of the potential side-effects of antimicrobial agents, and whenever possible choose those which are associated with the least adverse effects. Individual patient variability, including underlying diseases and other prescribed medications, must be taken into account when dosage is selected. beta-Lactam compounds have a remarkable safety record: specifically in the elderly, their therapeutic/toxic ratio is much higher than that observed with aminoglycosides. Regimens for this class of drugs in the elderly should maintain antibiotic concentrations above the minimum inhibitory concentrations for maximum efficacy. In the treatment of elderly patients, it is suggested that dosage and interval be based on estimated or measured creatinine clearance. Usually, for drugs that are excreted primarily by the kidney (i.e. amino-glycosides, beta-lactams and quinolones), dosage intervals must be increased when there is an associated fall in creatinine clearance. The pharmacokinetic parameters suggest that as an alternative to increasing dosage interval the usual dose may be decreased, but further studies are necessary for confirmation.     

Clinical pharmacokinetics of the newer neuromuscular blocking drugs

The pharmacokinetics of 6 new neuromuscular blocking drugs are described. These are the aminosteroids pipecuronium bromide, rocuronium bromide and rapacuronium bromide (ORG-9487) and the benzylisoquinolinium diesters doxacurium chloride, mivacurium chloride and cisatracurium besilate. In healthy individuals, these drugs all have similar volumes of distribution. Their pharmacokinetics are influenced little by age or anaesthetic technique, but renal and hepatic disease may significantly alter their distribution and elimination. Pipecuronium resembles pancuronium in its pharmacokinetic and neuromuscular blocking profile, but is devoid of cardiovascular effects. It has a low clearance (0.16 L/h/kg) and long elimination half-life (120 minutes). It is largely eliminated through the kidney. Rocuronium has a similar pharmacokinetic profile to vecuronium but its onset of action is more rapid and duration of action slightly shorter. Its clearance (0.27 L/h/kg) is intermediate between those of pipecuronium and rapacuronium, but its elimination half-life is long (83 minutes). The pharmacokinetics of rocuronium are altered by renal and hepatic disease; the latter probably has the more significant effect. Rapacuronium has a rapid onset, and a bolus dose has a short duration of action. It has a high clearance (0.59 L/h/kg) but a long elimination half-life (112 minutes). Doxacurium has a pharmacokinetic and pharmacodynamic profile similar to pipecuronium. It has a high potency and is devoid of cardiovascular effects. In adults, it has a low clearance (0.15 L/h/kg) and long elimination half-life (87 minutes). Mivacurium is a mixture of 3 stereoisomers. It has a short to intermediate duration of action. It is hydrolysed by plasma cholinesterase. Inherited or acquired alterations in plasma cholinesterase activity are associated with changes in the pharmacokinetics and time course of action of mivacurium. The 2 active isomers (cis-trans and trans-trans) have a high clearance (4.74 L/h/kg) and very short elimination half-lives (approximately 2 minutes). Cisatracurium is the 1R-cis 1'R-cis isomer of atracurium. It has similar pharmacokinetics and pharmacodynamics to atracurium. It is mainly broken down by Hofmann (non-enzymatic) degradation. Cisatracurium has an intermediate clearance (0.3 L/h/kg) and short elimination half-life (26 minutes). Hepatic and renal disease have little effect on its pharmacokinetics.     

Pharmacokinetics of cisplatin and relation to nephrotoxicity in paediatric patients

BACKGROUND: Cisplatin is a highly effective and frequently used drug in the chemotherapy of solid tumours in children, but only limited data are available on the pharmacokinetics of cisplatin and its associated nephrotoxicity in paediatric patients. METHODS: We investigated the pharmacokinetics of free platinum (Pt) in 12 children (25 courses) receiving cisplatin (75-120 mg/m2) either as a continuous 72-h infusion, prolonged single 6-h infusion or repetitive 1-h infusions. Plasma and urinary Pt concentrations were analysed using atomic absorption spectroscopy. Cisplatin-induced nephrotoxicity was determined using creatinine clearance and several glomerular and tubular marker proteins. RESULTS: Using a two-compartment model the pharmacokinetic parameters for free Pt were: initial half-life 21.6 +/- 9.6 min, terminal half-life 25.9 +/- 16.2 h, area under the plasma concentration-time curve (AUC) 13.5 +/- 4.97 (microg/ml) x h/(100 mg/m2) and cumulative renal elimination(infinity) 41.7 +/- 6.6% of dose. Higher cisplatin delivery rates led to higher peak concentrations of free Pt in plasma and urine and to lower cumulative renal Pt elimination (P < 0.01). During all courses, increases of urinary albumin and alpha1-microglobulin excretion were documented. The creatinine clearance decreased significantly to 70% of baseline values. Correlations were found between both peak free Pt concentrations in plasma and in urine and the maximum of urinary excretions of albumin and of N-acetyl-beta-D-glucosaminidase and the nadir of the glomerular filtration rate (P < 0.05). CONCLUSIONS: With respect to nephrotoxicity, long-term infusions of cisplatin seem to be preferable over intermittent bolus administration in paediatric patients. The best predictive pharmacokinetic parameters for cisplatin-associated nephrotoxicity in children are peak free Pt concentrations in plasma and urine.     

Single-dose and steady-state pharmacokinetics of doxazosin given in combination with chlorothiazide to hypertensive subjects

The pharmacokinetics of doxazosin were determined in hypertensive subjects after a single dose of 1 mg, and at steady-state while receiving doses of 1, 2, 4 and 8 mg of the drug daily. Chlorothiazide 500 mg once daily was administered as additional therapy throughout the study. After a single dose doxazosin was rapidly absorbed, with peak plasma drug concentrations (Cmax) occurring after 2.1 +/- 0.4 hours. The elimination half-life in plasma was 10.7 +/- 1.2 hours. These parameters remained essentially unchanged during maintenance administration of doxazosin at each of the dose levels. Calculations of Cmax and area under the concentration-time curve (AUC0----infinity) indicated that the pharmacokinetic disposition of the drug remained linear over the dose range 1 to 8 mg.