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.

Clinical pharmacokinetics of ciprofloxacin in patients with major burns.

OBJECTIVE: To better master the use of ciprofloxacin (CPF) in burn patients, a clinical study, including pharmacokinetics in serum and urine, was undertaken in a pathophysiologically homogeneous population of major-burn subjects. METHODS: Twelve major-burn patients who were infected with Pseudomonas aeruginosa, enterobacteria and gram-positive cocci, received CPF (600 mg t.i.d.). The mean body surface area affected by third-degree burns was 31.8 +/- 14.5%. Two series of blood samples were drawn after the first and seventh doses; urine was collected during the first infusion. Levels of CPF in serum and urine were measured by means of high-performance liquid chromatography. A non-compartmental method was used for kinetic and graphic analysis of concentration-time pairs. RESULTS: No adverse effects were noted. Trough concentrations measured on day 3 (mean +/- SD) were above the minimum inhibitory concentration (MIC) for the organism responsible for infection; i.e., 2.0 +/- 1.2 microg. ml(-1), and maximum concentrations were high 9. 9 +/- 3.4 microg. ml(-1). An area under the concentration-time curve (AUC)/MIC ratio above 125 SIT(-1) (where SIT is the serum inhibitory titer), which has been strongly correlated with clinical response and time to bacterial eradication, was achieved in 11 patients with a MIC of 0.5 microg. ml(-1). There was a statistically significant difference between C(min) and AUC determined on day 1 and day 3. In contrast to healthy volunteers, CPF clearance rates were notably decreased. CONCLUSION: The pharmacokinetics of CPF was altered in major-burn patients. The recommended dosage regimen for administration of CPF, i.e. 600 mg t.i.d. shows no adverse effects and a good microbiological efficacy.

[Pharmacokinetics of fusidic acid in patients with seriously infected burns]. / Pharmacocinétique de l'acide fusidique administré au sujet gravement brûlé infecté.

The pharmacokinetics of fusidic acid (FA) were studied in 10 infected severe burns patients (35 +/- 5 yrs, 81 +/- 17 kg) i.e. 43 +/- 10% in 3rd degree. Treatment was given at the dose of 500 mg/8 hours (2-hour infusion). The kinetics of FA were evaluated on D1 (1st infusion) and at steady state on D4 (10th infusion), each sequence involving 9 whole blood samples. Samples were assayed by high-performance liquid chromatography. Data were analysed by a non-compartmental method. Mean duration of treatment, considered effective in all cases, was 5.9 +/- 2.1 days. The systemic safety of FA was felt to be good. Kinetic analysis revealed the existence of significant differences between D1 and D4 concerning the parameters Cmax, Cmin, AUC, Cl and Vss. These events are attributable to the non-linear nature of the human kinetics of FA. Accumulation ratios R1 and R2 did not differ i.e. 1.51 +/- 0.25 and R2 = 2.44 +/- 0.68. Kinetic modelling based upon the experimental tracing obtained on D1 revealed good coincidence of the predictive tracing in relation to data determined on D4. The dosage algorithm of 500 mg/8 hours was microbiologically satisfactory with Cmin measured on D1 and at steady state constantly greater than the MIC of the main organisms concerned (< to 2 micrograms/ml). Reduction in the parameters Cmax and AUC in comparison with a group of healthy subjects ultimately led to shortening of the mean T1/2 of FA. In the absence of impaired liver function, this is attributable to the known increase in hepatic clearances in burns patients and, to a certain extent, to the existence of translesional extra-hepatic clearance, which could contribute to the success of treatment.

Influence of pregnancy on the pharmacokinetic behaviour and the transplacental transfer of the piperacillin-tazobactam combination.

The safety/acceptability, blood pharmacokinetics and urinary excretion of the piperacillin-tazobactam (PPR-TZB) combination were studied in six patients between 25 1/7 and 31 5/7 weeks of amenorrhea. The combination was given for a materno-fetal infection due to susceptible organisms i.e. 4/0.5 g/6 h. Whenever possible, the trans-placental transfer (TPT) of the combination was assessed in several sub-compartments of the feto-placental unit i.e. maternal blood sample, cord blood, amniotic fluid, placenta tissue and fetal urine. Two series of nine blood samples were scheduled for each patient, i.e. on D1 (first dose) and D3 (at plateau). Samples were assayed by HPLC and data were analyzed by a non-compartmental method. Safety/acceptability of the treatment proved to be good. The kinetic behavior of both beta-lactams appeared to be identical. Evidence was found during pregnancy of an increase in Vss and Cl of the combination. These increases can be linked to a notable decrease in AUCs. The TPT of the combination was significant. Regarding other accessible compartments (i.e. placenta tissue, amniotic fluid and fetal urine), the ratio of PPR-TZB concentrations was invariably about 8. Maternal circulating levels of PPR-TZB were, by 4 h, less than the MIC of target organisms (i.e. < or = 8 micrograms/ml), both on D1 and at steady state. This raises the question of the pertinence of the dosage regimen. Regarding PPR, it is accepted that antibacterial protection is satisfactory when circulating concentrations are kept at a Css (steady state concentration) of the order of 20 micrograms/ml or more. PPR-TZB combination would be administered by continuous infusion i.e. 8 mg/min to obtain 3 h later a Css of more than 20 micrograms/ml. The daily dosage would then be 12/1.5 g instead of 16/2 g, which is also more satisfactory from a pharmaco-economic standpoint. This proposal must be validated in a sufficient number of patients and, could avoid disqualification of the combination PPR-TZB in the treatment of serious infections during certain pathological pregnancies.

Influence of acute renal failure on FPIA rapid serum assay of midazolam and its main metabolite.

We recently developed a simple and fast assay technique, providing the possibility of monitoring of midazolam (M) during sedation. We compared HPLC vs FPIA for the measurement of the sum M plus alpha 1-hydroxymidazolam (OM), its main and pharmacologically active metabolite, in the serum of sedated ICU patients; this activity referred to as M-like. We identified certain patients in whom M-like activity appeared abnormally high in comparison with HPLC assays. Their common denominators were: long-term sedation with M, and seriously impaired renal function. Further, the conjugates of OM (OMG) accumulated in patients with acute renal failure could contribute to the sedation. We compared the metabolic and analytic behavior of M, OM, and OMG in 2 groups of sedated patients either presenting with normal renal functions (group 1) or with a picture of acute renal failure (group 2). Blood samples were assayed by HPLC and by FPIA and analysis was performed before and after hydrolysis of OMG. Before hydrolysis there was a dramatic accumulation of OMG in the patients of group 2, HPLC vs FPIA results were not different within group 1, while in group 2 the FPIA response exceeded that of HPLC. After hydrolysis, measurement by HPLC was greatly increased in group 2, in each group (vs HPLC) and from one group to another, the FPIA signal (the M-like activity) showed a significant increase. It would be important to take OMG into account as a coprotagonist in sedation whenever circumstances predispose to its accumulation.

[Therapeutic monitoring of teicoplanin in a severely burned patient]. / Suivi thérapeutique de la teicoplanine chez un sujet gravement brûlé.

The authors report the study of the kinetics in serum and urine and the clinical safety of a high dose of teicoplanin administered in a 19 year-old patient with major burns (60% of body surface area, the half of which consisting of third-degree burns and UBS at 150) and S aureus meticillin-resistant infection. At day 1, he was given two loading infusions of 12 mg.kg-1 teicoplanin followed by 12 mg.kg-1 per day of treatment. At all times, Cmin concentrations were below the limit value of 8 mg.mL-1. Therefore the therapeutic regimen was increased on several occasions. On days 5, 8 and 15, Cmin were measured by FPIA. Pharmacokinetic analysis was performed at day 16, (i.e., 20 mg.kg-1) and urine was also collected over at least 12 hours. At day 16, serum and urine samples were assayed by HPLC. Data were analyzed with a noncompartmental method. The duration of treatment was 20 days and no adverse events were noted. Bacteriological tests performed at the end of treatment demonstrated the elimination of the agent responsible over the infection. While pharmacokinetics were not assessed at plateau, Cmin remained very low. Vss was similar to values obtained in healthy subjects while total clearance was increased. This phenomenon was explained by the increase of total clearance and a nonrenal translesional diffusion suggested by the body surface area affected by third-degree burns. Finally, the cost of increasing doses of teicoplanin must be taken in account.

[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.

Perioperative pharmacokinetics of piperacillin during liver transplantation.

There have been few evaluations of the perioperative pharmacokinetics of antibiotics. Piperacillin (PPR) is a widely prescribed ureidopenicillin of established efficacy against enterobacteria and P. aeruginosa. The serum pharmacokinetics and perioperative safety of PPR were evaluated in 8 patients hospitalized for an orthotopic liver transplantation. The subjects were given a 60 mg/kg infusion of PPR once every 8 hours. PPR was assayed by HPLC and data were analyzed by a noncompartmental method. There were no adverse events during surgery. It seems that kinetics of PPR showed no variation during the anhepatic period. However, transplants notably modified the kinetics of PPR in comparison with data previously published in healthy volunteers. Trends were as follows: flattening of Cmax and prolongation of T1/2 (2.2 h vs 0.92 h). This phenomenon seems to be due to a marked increase in V(area) (44.0 1 vs 16.2 1) while C1 were similar. The increase in V(area) is probably the combined results of multiple factors including blood loss, vascular filling, combined prescription of vasoactive drugs, and, obviously, the surgical procedure itself. Concentrations of PPR were after 4 hours below (i.e. 5/8 patients) the MIC of P. aeruginosa (i.e. < or = 16 micrograms/ml). From 6 hours onwards antibacterial cover was insufficient against the majority of enterobacteria (i.e. < or = 8 micrograms/ml). This inadequate protection included the critical anhepatic period. Measured concentrations achieved by the initial dosage regimen were compared to those obtained by simulation using modified dosing pattern in order to ensure circulating levels constantly of 16 micrograms/ml or more. This leads to a suggested modified dosage pattern in which PPR would be given as 1 dose of 60 mg/kg every 4 hours. Under these conditions the expected concentrations should be constantly over 16 micrograms/ml and any risk of systemic accumulation is excluded.

Comparison of high-performance liquid chromatography and polyclonal fluorescence polarization immunoassay for the monitoring of midazolam in the plasma of intensive care unit patients.

Midazolam (M) is used as an induction agent for anesthesia. The main metabolite is alpha-hydroxymidazolam (OM), which is pharmacologically active. Use of M for sedation is a recent application, rapidly gaining favor. Monitoring of the level of sedation is fundamental in that an excessive and prolonged effect is associated with the risk of complications. Thus, it was felt both necessary and useful to measure circulating M levels. We compared a high-performance liquid chromatography (HPLC) assay with fluorescence polarization immunoassay (FPIA) for the measurement of M in the serum of 138 sedated patients in the intensive care unit (i.e., 179 samples). Response of the OM was also assessed. The degree of crossover of the metabolite was between 76.8 and 32.7%. The equation of the regression line for sigma HPLC (i.e., the sum M + OM) versus FPIA was TDx = 1.1585 sigma HPLC + 143.42 (R = 0.966). The 95% confidence interval for the slope was 1.1551, 1.1619. The regression slope differed significantly from 1 (p < 0.001) and shows that FPIA measurements overestimated concentrations obtained by HPLC on the order of 19%. The discrepancy between the two techniques was all the more notable when concentrations were > 1,000 ng/ml. The relative selectivity of Abbott industrial reagent in terms of benzodiazepines leads to the identification of what might be called a midazolam-like (M-like) activity covering both M and OM. The development of a global FPIA method for measurement of this M-like activity in sedated patients provides a satisfactory solution to the question raised.

Clinical pharmacokinetics of piperacillin-tazobactam combination in patients with major burns and signs of infection.

The pathophysiology associated with major burns is complex and subject to a state of flux. The combination of beta-lactamase inhibitors with powerful penicillins is an interesting and an attractive potential solution to the emergence of bacterial resistance. The kinetics in serum and urine and the clinical safety of a fixed combination of 4 g of piperacillin (PPR) and 0.5 g of tazobactam (TZB) were studied in 10 patients (22 to 50 years old and weighing 45 to 105 kg) with major burns who were infected with Pseudomonas aeruginosa and various entero-bacteria. All of them received additional antimicrobial drugs. Treatment involved one dose every 6 h. The mean body surface area affected by third-degree burns was 30.0% +/- 4.0%. The study took place in accordance with current ethical guidelines. Two series of blood samples were drawn after the first (day 1) and ninth (day 3 at steady state) doses; urine was collected during the same periods. Levels of PPR and TZB in serum and urine were measured by high-pressure liquid chromatography. A noncompartmental method was used for kinetic and graphic analysis of concentration-time pairs. The safety of the treatment was excellent. There was no systemic accumulation of the beta-lactam combination. Residual concentrations measured on days 1 and 3 [mean (standard error of the mean)] were above the MIC for the organism responsible for infection; i.e., C(min)day1 = 26.3 (8.5) and C(min)day3 = 21.0 (9.1) for PPR and C(min)day1 = 1.9 (0.6) and C(min)day3 = 1.4 (0.3) for TZB. There was no statistically significant difference between pharmacokinetic parameters determined for day 1 and day 3. Evidence was found in burn patients, in contrast to healthy subjects, of a marked increase in apparent volumes of distribution, in such a way that the apparent elimination half-lives of the combination were notably prolonged, i.e., 1.8 (0.3) versus 1.5 (0.3) h for PPR in patients and healthy subjects, respectively, and 1.7 (0.3) versus 1.4 (0.3) h for TZB. These findings indicate the possibility of nonrenal translesional diffusion of PPR-TZB in burn patients. The polarity of the association would further support this hypothesis. It has been shown here that the recommended dosage regimen for administration of PPR-TZB must be high in major-burn patients, i.e., 4 g/0.5 g every 6 h. The data obtained provide valuable information, which is suitable for immediate application in everyday clinical practice.

Study of the bioequivalence of two controlled-release formulations of morphine.

The management and treatment of chronic pain in cancer patients is a clear priority for practitioners regularly confronted by the situation. This investigation was carried out to evaluate the bioavailability of a recent sustained-release (SR) formulation of morphine sulphate (30 mg), Skenan, consisted of capsules, relative to a recognized product, Moscontin which is a matrix tablet SR form. The bioavailability was carried out on 12 healthy male volunteers who received a single dose (30 mg) of the test (T) and the recognized (R) products in a randomized balanced 2-way crossover design. After dosing, serial blood samples were collected for a period of 24 hours. Morphine and its main metabolites (i.e. glucuronides M6G and M3G) were assayed by high-performance liquid chromatography using a ion-pair formation. Data were analyzed by a noncompartmental method and were compared by ANOVA method and, each subject taken as his own control, by the Wilcoxon T test. Mean bioavailability of the T formulation was greater than that of R. The parametric confidence intervals (90%) of the mean values of the pharmacokinetics characteristics for T:R ratio were in each case without the bioequivalence acceptable ranges of 0.8-1.25 and 0.70-1.43 respectively for AUCs (i.e. AUCo-->24h and AUCo-->infinity) and Cmax, while confidence intervals symmetric of Westlake (CIW90%) was invariably greater than 20%, i.e. 62.8, 71.1 and 39.3% respectively. Further, the test formulation was not found bioequivalent to the reference formulation by Schuirmann's 2 one-sided t-test. These results justify the conclusion of the non-bioequivalence of the two forms at the unit dose of 30 mg. This information must be considered above all as a dosage adjustment tool enabling use of the two forms by application of a correction factor of the order of 15% when prescribing Skenan in comparison with Moscontin. Assessment is needed of the possible clinical consequences of this finding.

[Pharmacokinetics of antibiotics in burn patients]. / Pharmacocinétique des antibiotiques chez le sujet brûlé.

The pathophysiology associated with major burns is complex and subject to a state of flux (coexistence of pain, infectious diseases, multiple trauma, disturbances of metabolism and acid-base status, etc) which could affect the disposition and the pharmacokinetic behaviour of drugs. In current clinical practice, practitioners often use powerful antimicrobial agents; however, few pharmacokinetic studies are available in burns patients (of the order of 30 studies). Furthermore, the methods used are sometimes questionable. After dealing with the ethical and physiological context in which such research is undertaken, the authors report a review of the pharmacokinetic studies done during the last 15 years. Concerning both aminoglycosides and glycopeptides, no therapeutic recommendations are available (therapeutic schedules). However, in this case, therapeutic monitoring is available and represents a suitable tool to better master their use. In the case of beta-lactam antibiotics and quinolones, more data are available. Some investigations have shown the possibility of translesional diffusion of certain agents in burns (such as gentamicin, piperacillin/tazobactam combination, or fosfomycin). This phenomenon could be a co-factor of success in treatment. Considering the relatively meager pharmacokinetic and pharmacodynamic data available in burns, it is important in the future to refine our knowledge of the distribution and metabolism of drugs in burns patients in order to better master their use. Finally, ethical and methodological considerations need to be taken in account.

Disposition of a new rate-controlled formulation of prazosin in the treatment of hypertension during pregnancy: transplacental passage of prazosin.

Prazosin (PRZ) in conventional tablet form (P-CT) has the disadvantages of a relatively short terminal half-life, a slight solubility in water and the well-recognized adverse effect of symptomatic orthostatic hypotension. The pharmacokinetic study of a new rate-controlled formulation of prazosin (Prazosin-Gastrointestinal System: P-GS) was performed in 9 pregnant women during the third trimester of pregnancy. Patients had persistent elevation of blood pressure. The subjects gave their informed consent for oral administration of 1 daily dose of 5 mg P-GS at 8 a.m. A first analysis period on day 1 enabled definition of the initial pharmacokinetic behavior of the drug, while the aim of a second was to evaluate its fate at plateau. The clinical course of both mother and fetus was subsequently monitored. This was an open, non-randomized study, each patient serving as her own control. For 3 patients, we aimed to determine the possible transplacental passage of PRZ at delivery. PRZ levels were measured by HPLC and data were analysed by noncompartmental linear pharmacokinetic methods. The data show: (i) P-GS was well tolerated by all patients and there were no significant changes in fetal heart rate during the study. (ii) A significant decrease in diastolic blood pressure was observed after the 36th hour following the first dose of P-GS while a reduction in systolic blood pressure was observed on day 4. (iii) An approximated relative bioavailability (f'P-GS) of 36.5% was calculated. P-GS appears to have a lower bioavailability than P-CT in women of similar gestational age. (iv) Both Cmax and AUC0-->infinity are significantly increased at plateau. Further, terminal half-life is increased with regard to the value determined with P-CT. No accumulation of PRZ was noted at steady-state. (v) P-GS is an example of an oral zero-order absorption product that offers one approach to control and improve the outcome of hypertensive therapy during pregnancy. This treatment could represent an alternative to methyldopa as a first treatment of pregnancy-associated hypertension. (vi) There is a slight transplacental passage of the drug (of the order of 10-20%).