Human pharmacokinetics of a perfluorocarbon ultrasound contrast agent evaluated with gas chromatography.

The purpose of this study was to prospectively study the human pharmacokinetics of an ultrasound (US) contrast agent through its active ingredient, dodecafluoropentane (DDFP). Expired air and blood samples were collected from 24 volunteers after IV administration from 0.01 to 0.1 mL/kg. They were analyzed by a gas chromatographic method specially adapted to the study of DDFP. Blood data fitted to an open one-compartment model. Elimination half-life range was 1.8 to 2.5 min. The area under the curve was correlated to the dose (r(2) = 0.99). Mean blood clearance ranged from 30 to 49 mL/min kg. Blood apparent distribution volume ranged from 0.09 to 0.15 L/kg. In expired air, DDFP concentration exhibited a biexponential decay. The percentage of recovery was 98 +/- 19% at 2 h. No extraneous peaks were observed, indicating no detectable DDFP metabolites. It was concluded that DDFP pharmacokinetics in blood fitted to an open one-compartment model with a fast elimination half-life. Recovery in expired air was almost complete 2 h after administration.

Sputum itraconazole concentrations in cystic fibrosis patients.

Itraconazole diffusion in sputum was studied in 11 cystic fibrosis patients with allergic bronchopulmonary aspergillosis. There was a high interindividual variability in sputum itraconazole concentration and sputum/serum drug concentration ratio. Three children had sputum drug concentrations before oral administration that were lower than the itraconazole MIC at which 90% of Aspergillus fumigatus strains were inhibited, although their serum drug concentrations were within the therapeutic range.

Simultaneous high-performance liquid chromatographic determination of the antiretroviral agents amprenavir, nelfinavir, ritonavir, saquinavir, delavirdine and efavirenz in human plasma.

This article describes a method for the simultaneous determination of four licensed HIV protease inhibitors (amprenavir, nelfinavir, saquinavir and ritonavir) and two novel non-nucleoside reverse transcriptase inhibitors (efavirenz and delavirdine) in human plasma in a single run. Plasma samples (500 microl) were treated by liquid-liquid extraction with methyl tert.-butyl ether. The compounds were separated by reversed-phase liquid chromatography on a C(18) column with spectrophotometric detection at 260 nm. The method is linear over the specific ranges investigated, accurate (inaccuracy <11.7%) and showed intra-day and inter-day precision within the ranges of 0.9-7.0 and 1.9-8.8%, respectively. The six compounds were stable in plasma after 6 months of storage at -20 degrees C and after five freeze-thaw cycles.

[Traceability of drugs derived from blood: regulation and pharmaco-economic implications after 24 months of application in Paris CHU]. / Traçabilité des médicaments dérivés du sang: réglementation et implications pharmaco-économiques après 24 mois d'exercice dans un CHU Parisien.

Since January 1, 1995, the supply, stockage, dispensing and traceability of Blood Derivative Medicinal Products (BDMP) are subject to pharmaceutical regulations. A review of 24 months' application at Necker-Enfants Malades Hospital is presented and analysed. A distinction is drawn between two categories of BDMP: 1) anti-hemophilia BDMP, factors of plasma or recombinant origin; 2) non-anti-hemophilia BDMP, covering albumin, immunoglobulins (Ig), biological glues and other clotting factors. BDMP are subject to a hospital traceability procedure. In this respect, we have constructed a tryptic nominative model prescription, though dotations are granted for only certain prescription sectors (operating room, ICU) and certain products (biological glues, albumins). A dispensing-administration form is invariably attached to each bottle. Between January 1, 1995 and December 31, 1996, 8225 dispensing procedures for BDMP were recorded, with a total cost of 52,931,586 francs (i.e. 69% anti-hemophilia products v.s. 31% non-antihemophilia products). The Factor VIII market is divided more or less equally between factors of human and recombinant origin. The risk of viral transmission is considered to be virtually nil with recombinant products, despite their being stabilized by human albumin. The traceability rate of anti-hemophilia factors was 100%. Albumin consumption was 182,106 g at a cost of 3,358,250 francs. The following indications were adopted at a Local Medicines Committee: 1) in adults: hypoalbuminemia associated with edema or ascites; 2) in children: digestive disorders leading secondarily to exsudative enteropathy and/or hypoalbuminemia. Consumption of polyvalent Ig was 69,213 g, i.e. 10,856,722 francs. These products were prescribed in accordance with the directives of the Committee for Evaluation and Distribution of Technological Innovations. Consumption of specific Ig and biological glues may seem modest in relation to that of other products. BDMP expenditure appears particularly heavy here (about 26.5 MF/year) but consensual adoption of therapeutic guidelines has enabled rationalization of prescribing conditions with the best possible consideration of benefit/risk vs costs ratios. Traceability and drug safety monitoring procedures are linked to and integrated in the more global concept of Quality Assurance. Since January 1995, several withdrawals of batches have been recorded because of suspicion (or death due to) Creutzfeld-Jakob, or post-donation HIV seroconversion. In this area, the Hospital Pharmacist acts by the establishment in real time of a permanent safety link between the patient, a prescriber, an indication, a product prescribed and the product actually administered.

Drug interactions with antiviral drugs.

Antiviral drug interactions are a particular problem among immuno-compromised patients because these patients are often receiving multiple different drugs, i.e. antiretroviral drugs and drugs effective against herpesvirus. The combination of zidovudine and other antiretroviral drugs with different adverse event profiles, such as didanosine, zalcitabine and lamivudine, appears to be well tolerated and no relevant pharmacokinetic interactions have been detected. The adverse effects of didanosine and zalcitabine (i.e. peripheral neuropathy and pancreatitis) should be taken into account when administering these drugs with other drugs with the same tolerability profile. Coadministration of zidovudine and ganciclovir should be avoided because of the high rate of haematological intolerance. In contrast, zidovudine and foscarnet have synergistic effect and no pharmacokinetic interaction has been detected. No major change in zidovudine pharmacokinetics was seen when the drug was combined with aciclovir, famciclovir or interferons. However, concomitant use of zidovudine and ribavirin is not advised. Although no pharmacokinetic interaction was documented when didanosine was first administered with intravenous ganciclovir, recent studies have shown that concentration of didanosine are increased by 50% or more when coadministered with intravenous or oral ganciclovir. The mechanism of this interaction has not been elucidated. Lack of pharmacokinetic interaction was demonstrated between foscarnet and didanosine or ganciclovir. Clinical trials have shown that zidovudine can be administered safely with paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, oxazepam or codeine. Inhibition of zidovudine glucuronidation has been demonstrated with fluconazole, atovaquone, valproic acid (valproate sodium), methadone, probenecid and inosine pranobex; however, the clinical consequences of this have not been fully investigated. No interaction has been demonstrated with didanosine per se but care should be taken of interaction with the high pH buffer included in the tablet formulation. Drugs that need an acidic pH for absorption (ketoconazole, itraconazole but not fluconazole, dapsone, pyrimethamine) or those that can be chelated by the ions of the buffer (quinolones and tetracyclines) should be administered 2 hours before or 6 hours after didanosine. Very few interaction studies have been undertaken with other antiviral drugs. Coadministration of zalcitabine with the antacid 'Maalox' results in a reduction of its absorption. Dapsone does not influence the disposition of zalcitabine. Cotrimoxazole (trimethoprim-sulfamethoxazole) causes an increase in lamivudine concentrations by 43%. Saquinavir, delavirdine and atevirdine appeared to be metabolised by cytochrome P450 and interactions with enzyme inducers or inhibitors could be anticipated. Some studies showed that interferons can reduce drug metabolism but only a few studies have evaluated the pathways involved. Further studies are required to better understand the clinical consequences of drug interactions with antiviral drugs. Drug-drug interactions should be considered in addition to individual drug clinical benefits and safety profiles.

Cimetidine does not alter sparfloxacin pharmacokinetics.

The interaction between cimetidine and sparfloxacin was studied in 10 healthy volunteers who received a single oral dose of 400 mg sparfloxacin on the third day of an 8 day cimetidine (400 mg t.i.d.) or placebo randomly assigned treatment. No statistically significant differences were observed in the pharmacokinetic parameters (Cmax-AUC-T1/2-urinary excretion and metabolic ratio) of sparfloxacin following the 2 treatment. Cimetidine does not affect absorption, metabolism or urinary excretion of sparfloxacin; consequently, patients exposed to this drug combination are not at risk.

[Clinical pharmacokinetics of azithromycin]. / Pharmacocinétique clinique de l'azithromycine.

The bioavailability of azithromycin is approximately 37%. Concomitant administration of oral azithromycin with food significantly decreases by 50% drug bioavailability. Following a single oral 500 mg dose, peak plasma concentrations of about 0.35-0.45 mg/l are attained within approximately 2 hours. With a 500 mg oral dose on day 1, followed by 250 mg daily on days 2 to 5, peak and through plasma concentrations on day 5 are around 0.25 and 0.05 mg/l respectively. These low plasma concentrations are the consequence of extensive and rapid distribution from plasma to tissues. Plasma protein binding is low, less than 50% at plasma concentrations obtained with the usual dosage regimen. Apparent volume of distribution is very large, 25 to 35 l/kg. Azithromycin is mainly eliminated unchanged in the faeces via biliary excretion and transintestinal secretion. Urinary excretion is a minor elimination route: about 6% and an oral dose and 12% of an intravenous dose are recovered unchanged in urine. The mean terminal elimination half-life of azithromycin is 2 to 4 days. The pharmacokinetics of azithromycin is not significantly altered in elderly subjects and in patients with mild to moderate renal or hepatic insufficiency.

Pharmacokinetic comparison of oral and local action transcutaneous flurbiprofen in healthy volunteers.

Flurbiprofen is a propionic acid-derived non-steroidal anti-inflammatory drug (NSAID) used widely in the treatment of rheumatism and non-arthritic pain. The pharmacokinetics of topically and orally administered flurbiprofen were compared in a two-part, open study involving healthy adult volunteers. In the first (cross-over) part of the study, 12 Caucasians were randomized to receive either a single oral dose of 50 mg flurbiprofen or a single topical application of a novel 40 mg flurbiprofen-containing patch on the right wrist for 12 h. In the second part of the study, each subject applied a flurbiprofen-containing patch twice daily to the same wrist for 7 days. Plasma concentrations of flurbiprofen and urinary concentrations of the NSAID and its metabolites were measured by high-performance liquid chromatography assay, to enable comparison of the pharmacokinetic parameters for delivery of the drug by both routes. Maximum concentrations of the NSAID in plasma (Cmax) were much lower after a single application of the topical 40 mg flurbiprofen patch than after a single oral dose of 50 mg of the NSAID (mean +/- SD: 43 +/- 16 ng/ml versus 5999 +/- 1300 ng/ml, respectively). After repeated application of the topical patch, Cmax increased only slightly to 103 +/- 57 ng/ml. The mean relative bioavailability of flurbiprofen from the patch was 3.5 +/- 1.7%, calculated from plasma area under the curve data and 4.4 +/- 2.8% from urinary excretion data.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of a low molecular weight heparin (reviparine) in hemodialyzed patients.

Low-molecular-weight heparins (LMWHs) are used to prevent clotting in hemodialysis extracorporeal blood circuits. In order to test the possibility of using reviparine (a LMWH of 3,900 D) in this indication, we studied the pharmacokinetics of the drug after a mean dose of 3,300 IU anti-Xa in 10 hemodialyzed patients. Reviparine was administered subcutaneously between two dialysis sessions and intravenously at the start of 20 dialysis sessions performed either with high (HP) or low-permeability (LP) membranes. We observed a moderate increase of the elimination half-life of reviparine (T1/2: 5 +/- 1.6 h between dialysis, 3.6 +/- 1.3 during dialysis with an HP membrane and 4.7 +/- 1.8 during dialysis with an LP membrane) versus 3.3 +/- 1 in healthy volunteers. Dialysis procedures with an HP or an LP membrane do not importantly modify the pharmacokinetics of reviparin compared with data observed in healthy volunteers. During the sessions, we observed no clotting in the extracorporeal circuit, no hemorrhagic event and no prolongation of the fistula compression times. Further clinical studies are required to define the optimal dosage of reviparine to prevent coagulation in hemodialysis blood circuits.

Penetration of foscarnet into cerebrospinal fluid of AIDS patients.

The diffusion of foscarnet into cerebrospinal fluid (CSF) was studied in 27 patients with AIDS. Foscarnet was administered intravenously at various dosages at 12-h intervals. Concentrations in plasma and CSF at the end of foscarnet infusion or 1, 3, 5, 6, and 12 h after infusion were determined by high-performance liquid chromatography. Thirty-seven samples were obtained. The median concentration of foscarnet in CSF was 80 mumol/liter (range, 0 to 500 mumol/liter). The CSF foscarnet concentration was greater than the 50% inhibitory concentration for human immunodeficiency virus type 1 and was equal to or greater than the 50% inhibitory concentration for cytomegalovirus in most cases. The penetration of foscarnet into CSF, as expressed by the ratio of the concentration in CSF to the simultaneous concentration in plasma, ranged from 0 to 3.4 (median, 0.27) and was highly correlated with the presence of cells within CSF and the length of foscarnet therapy. Good diffusion of foscarnet in CSF allows evaluation of this drug in central nervous system cytomegalovirus and human immunodeficiency virus infections in patients with AIDS.

Randomized study of two doses of didanosine in children infected with human immunodeficiency virus.

2'3'-Dideoxyinosine (didanosine) is a nucleoside analog active in vitro against human immunodeficiency virus. Few data are available regarding its use for the treatment of children. In a single-center, randomized, open-label trial, we compared two dosages of didanosine (120 vs 270 mg/m2 per day) for at least 6 months in 34 children infected with human immunodeficiency virus who had become resistant to or were intolerant of zidovudine. Serum levels of didanosine 1 hour after administration were significantly different in the two groups and remained stable with time. There was a significant reduction in human immunodeficiency virus-p24 antigenemia and quantitative cellular viremia with time but no difference between the two groups. The intensity of the biologic response, however, was significantly higher in the patients who had more than 50 CD4+ cells 10(6)/L at inclusion. No pancreatic or neurologic toxic effects were observed. In five children, liver function abnormalities developed that are unusual in this setting, and the death of one child from unexplained hepatocellular failure suggests that didanosine may be hepatotoxic. Three of these five children had preexisting liver disease. Although no definite conclusion can be made as to the optimal dose, there were no major differences between the two administration schedules in terms of biologic effects and tolerability.

Absorption of zidovudine in patients with diarrhoea.

Many patients with AIDS have gastrointestinal complaints, including the major clinical disorder of chronic diarrhoea. The pharmacokinetics of zidovudine was studied in 9 male patients with HIV infection and diarrhoea to establish whether drug absorption was impaired in them. The peak plasma concentration and AUC after a single oral dose of 200 mg, were the same as those reported in 6 healthy male volunteers (3.1 vs 4.0 mumol.l-1 and 7.2 vs 5.2 mumol.h.l-1, respectively). Since the bioavailability of zidovudine is not particularly impaired, oral zidovudine therapy can be maintained in patients with diarrhoea.

Pharmacokinetics of lamotrigine in patients with renal impairment: influence of haemodialysis.

The pharmacokinetics of a single 100 mg oral dose of lamotrigine, a new anticonvulsant drug, were studied in six healthy volunteers and in twenty patients with various degrees of renal impairment. Six of these patients were regularly haemodialysed. Lamotrigine concentrations in plasma and urine were measured by the HPLC method. The mean peak plasma concentrations of lamotrigine, tmax, volume of distribution and total clearance were not significantly modified by the degree of renal impairment. The elimination half-life of lamotrigine was approximately 25 h in subjects with normal renal function and 50 h in uraemic patients. These are very large variations in uraemic patients and the results were not statistically significant. Renal clearance of lamotrigine is significantly reduced. Urinary elimination of unchanged and conjugated lamotrigine was reduced in uraemic patients. Thus it seems necessary to treat carefully patients with a very severe renal insufficiency since very large variations in pharmacokinetics were found. A 100 mg oral dose every two days is recommended if creatinine clearance is below 10 ml/min. Haemodialysis shortened the elimination half-life from 59.6 +/- 28.1 h during the interdialysis period to 12.2 +/- 6.4 h during the dialysis period; 17% of the dose was extracted by haemodialysis.

Pharmacokinetics of foscarnet after twice-daily administrations for treatment of cytomegalovirus disease in AIDS patients.

The pharmacokinetics of foscarnet were evaluated in 11 AIDS patients with cytomegalovirus disease after twice-daily infusion of 90 mg/kg of body weight for 2 weeks. All patients were hydrated during foscarnet infusion. Blood and urine samples were collected on days 1, 7, and 14 of therapy. Foscarnet concentrations were measured by high-pressure liquid chromatography. Despite large interindividual variations, no significant differences were seen between day 1, day 7, and day 14 concentrations in plasma. Mean peak and trough concentrations on day 14 of therapy were 605 +/- 118 and 52 +/- 59 microM, respectively. In all patients, peak concentrations were well above those necessary to inhibit cytomegalovirus. Pharmacokinetic parameters remained stable throughout the study. On day 14, the mean half-life was 3.4 h, total and renal clearances were 118 and 92 ml/min, respectively, and the volume of distribution was 0.6 liter/kg. These data and previous clinical trials demonstrate that this more convenient dosage regimen can be safely used for patients with cytomegalovirus disease. The side effects were comparable to those reported with other dosage regimens, although no renal impairment was seen in this study, probably because of the hydration.

Didanosine pharmacokinetics in patients with normal and impaired renal function: influence of hemodialysis.

The pharmacokinetics of didanosine were investigated following oral administration of a single 375-mg dose to eight human immunodeficiency virus-seropositive patients with normal renal function and eight human immunodeficiency virus-seropositive uremic patients. In uremic patients, the plasma half-life was longer than that in control patients (respectively, 4.5 +/- 2.2 and 1.6 +/- 0.4 h). The ratio of total plasma clearance to absolute bioavailability was four- to fivefold lower in uremic patients than in patients with normal renal function (respectively, 491 +/- 181 and 2,277 +/- 738 ml/min). Because of the decrease in elimination, concentrations in plasma were higher for uremic patients than for control patients; the maximum concentrations of drug in plasma were, respectively, 3,978 +/- 1,607 and 1,948 +/- 994 ng/ml; the areas under the concentration-time curve were, respectively, 14,050 +/- 4,262 and 3,000 +/- 956 ng.h/ml. Didanosine was removed by hemodialysis with an extraction ratio of 53% +/- 8%, a hemodialysis clearance value of 107 +/- 21 ml/min, and a fractional drug removal during a 4-h dialysis of 20% +/- 8% of the dose. Dosage adjustments are necessary in uremic patients.

Theophylline steady state pharmacokinetics is not altered by omeprazole.

The effect of omeprazole treatment on theophylline pharmacokinetics was studied in eight, non-smoking healthy male volunteers during repeated administration of a slow release formulation of theophylline. In a randomized double-blind cross-over study, the subjects received theophylline 5 mg.kg-1 per day with omeprazole 20 mg per day or identical placebo during two periods, each of 7 days, separated by a washout period of 7 days. The oral clearance of theophylline remained unchanged whether it was administered alone or with omeprazole (54.2 ml.min-1). The average urinary excretion of theophylline and its metabolites, 1,3 dimethyluric acid (1,3-DMU), 3-methylxanthine (3-MX), 1-methyluric acid (1-MU) amounted to 9%, 32%, 12% and 22% of the administered dose, respectively, and no significant change occurred during concomitant treatment with omeprazole. Thus, the formation and clearance of the metabolites was not altered by omeprazole. Consequently, omeprazole in the recommended dose of 20 mg daily can safely be administered to patients on theophylline therapy.

Placental passage of azathiothymidine (AZT) during the second trimester of pregnancy: study by direct fetal blood sampling under ultrasound.

AZT-therapy during pregnancy is actually contraindicated. Two HIV-positive pregnant women who were due to have an induced abortion in the second trimester of pregnancy, were treated with AZT. Blood samples from mothers and fetuses and amniotic fluid samples were taken simultaneously. AZT crossed the placental barrier in the two patients. AZT and GAZT concentrations from the two fetuses were close to those obtained in the two women and in six non-pregnant volunteers.

Pharmacokinetics of newer drugs in patients with renal impairment (Part II).

Cardiovascular diseases occur frequently in patients with renal failure. Any pharmacokinetic impairment in these diseases should be considered when individualizing drug therapy. The pharmacokinetics of new cardiovascular drugs in uraemic patients are reviewed: alpha- and beta-blocking agents, ACE inhibitors, centrally acting antihypertensive agents, calcium antagonists, antiarrhythmic agents and inotropic agents. Guidelines are proposed for adjustment of dosage regimens as a function of renal impairment. Renal or extrarenal elimination of drugs and their metabolites, and the activity of the latter, are taken into account. The disposition of new drugs such as flestolol, alacepril, delapril, propafenone, milrinone or enoximone, is not well documented in patients with renal failure. Further characterizations of the elimination of these compounds are needed and the potential therapeutic or toxic effects of the metabolites require evaluation to determine whether the dosage needs to be adjusted. Until such investigations are performed, those drugs should not be used in uraemic patients; if no therapeutic alternative is available, clinical controls are necessary at regular intervals. Relationships between pharmacological or therapeutic effects and drug plasma concentrations should be evaluated for such long term use drugs. The knowledge of a plasma concentration therapeutic window is important to provide information which will be useful in determining appropriate drug dosage in renal failure.

Pharmacokinetics of newer drugs in patients with renal impairment (Part I).

Many drugs are eliminated via the renal route and the usual dose must be modified in patients with severe renal impairment. This review is an attempt to supply physicians with the more recent data on pharmacokinetic studies of new drugs administered in uraemic patients. The review is in 2 parts: the first indicates the results of studies on the pharmacokinetics of antibiotic agents, antifungal, antiviral and antiulcer drugs, and nonsteroidal anti-inflammatory drugs. Special mention is made of epoetin (recombinant human erythropoietin). It was not possible to give all the information collected from the recent literature: since mild renal failure has little effect on the fate of a drug, pharmacokinetic data obtained in patients with a creatinine clearance (CLCR) of more than 50 ml/min has been omitted. Both the text and tables give recommendations for treating patients with moderate renal insufficiency (CLCR of about 50 ml/min), more severe renal impairment (CLCR between 10 and 50 ml/min) and end-stage renal failure with a very low creatinine clearance (below 10 ml/min). It was not possible to give uniform recommendations (i.e. reducing the dose while maintaining the same interval, or giving the same dose and prolonging the interval). This article follows the recommendations of the authors, which may vary for drugs in similar classes.