René Verbesselt

Tolerance and pharmacokinetics of propacetamol, a paracetamol formulation for intravenous use

Summary— In 12 healthy volunteers, paracetamol pharmacokinetics were compared following administration of 1 g propacetamol HCl given intravenously over a 15‐min period and 500 mg paracetamol given orally. Mean ± SD total AUC (μg/ml·h) following the iv formulation was significantly (P < 0.01) greater than following oral paracetamol (25.53 ± 4.27 vs 21.04 ± 4.49) corresponding to a mean oral bioavailability of paracetamol of 82.2 ± 9.4%. Between 1 and 2 h after administration, paracetamol plasma concentrations became very similar following both formulations. In another study, 2 g propacetamol HCl was given both as a 15‐min infusion and as a 2‐min bolus injection to six healthy volunteers. Contrary to mild to moderate local discomfort experienced during the 2‐min bolus injection, the 15‐min infusion was well tolerated without any complaints reported.

In vitro activity and human pharmacokinetics of teicoplanin.

The in vitro activity of teicoplanin, a new antibiotic related to vancomycin, was determined against 456 gram-positive cocci. The activity of teicoplanin in comparison with that of vancomycin was similar against staphylococci but 4 to 40 times higher against enterococci and beta-hemolytic and viridans streptococci. The single-dose pharmacokinetics of teicoplanin were studied in six healthy volunteers after administration of 3 and 6 mg/kg intravenously and of 3 mg/kg intramuscularly. The kinetic parameters after both intravenous doses were very similar. The curves for concentration in plasma for the 3- and 6-mg/kg intravenous doses showed a triexponential decline with elimination half-lives of 47.3 and 44.1 h, respectively. The percentages of the doses recovered in urine (0 to 102 h) were 43.2 and 44.1%, respectively. The areas under the plasma curves were dose related: 256.5 and 520.9 micrograms/h per ml, respectively. The bioavailability of teicoplanin after injection of 3 mg/kg intramuscularly was 90%, and the peak level was 7.1 micrograms/ml. The mean levels in plasma 24 h after the 3-mg/kg doses were 2.1 and 2.3 micrograms/ml, respectively, and the mean level in plasma 24 h after the 6-mg/kg intravenous dose was 4.2 micrograms/ml.

Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study

Objective. To determine the impact of physiologic changes of pregnancy on pharmacokinetics of chemotherapeutic agents. Design. A preclinical and a clinical case–control trial. Setting. Institute of Primate Research Nairobi and collaborating hospitals in Belgium, the Netherlands and Czech Republic. Population. Pregnant and nonpregnant women and baboons receiving chemotherapy. Methods. Chemotherapy pharmacokinetics was compared between the pregnant and nonpregnant state. Standard‐dosed chemotherapy regimens were administered in pregnant and nonpregnant baboons/women, followed by serial blood samplings. Drug plasma levels were determined using high performance liquid chromatography and atomic absorption spectrometry. Main outcome measures. Area under the curve (AUC), maximal plasma concentration, terminal elimination half‐life, clearance and distribution volume of each drug in pregnant and nonpregnant state. Results. Intraindividual comparative pharmacokinetic data were obtained for doxorubicin and paclitaxel/platinum in three and two baboons, respectively. In the clinical trial, two patients were exposed to doxorubicin and one patient was exposed to paclitaxel/platinum during and after pregnancy. Furthermore, a pooled analysis was performed based on 16 cycles of pregnant and 11 cycles of nonpregnant women. Numbers of pregnant/nonpregnant patients were 5/2, 7/5, 4/4 and 2/2 for paclitaxel, doxorubicin, epirubicin and platinum, respectively. For all drugs tested in the preclinical and clinical study, a decreased AUC and maximal plasma concentration and an increased distribution volume and clearance were observed in pregnancy. Conclusions. Although numbers were too small for statistical significance, pregnancy‐associated physiologic alterations appear to lead to a decrease in plasma exposure of chemotherapeutic drugs. The importance of long‐term follow‐up of women treated with chemotherapy during pregnancy is underscored.

Maturational pharmacokinetics of single intravenous bolus of propofol

Background:  Our aim was to document propofol pharmacokinetics in preterm and term neonates following a single intravenous bolus and compare these estimates with pharmacokinetics findings in toddlers and young children.

Transplacental transfer of paclitaxel, docetaxel, carboplatin, and trastuzumab in a baboon model.

Background: The paucity of data on fetal effects of prenatal exposure to chemotherapy prompted us to study the transplacental transport of commonly used anticancer agents in a pregnant baboon model. Methods: Single or combination chemotherapy with paclitaxel, docetaxel, carboplatin, and trastuzumab was administered to 9 baboons at a mean (SD) gestational age of 117 (26) days (paclitaxel, 100 mg/m2 [n = 2]; docetaxel, 100 mg/m2 [n = 2]; paclitaxel, 175 mg/m2 with carboplatin, area under the curve of 6 at standard dosage [n = 2] and 50% dosage [n = 1]; docetaxel, 75 mg/m2 with carboplatin, area under the curve 6 [n = 1]; and docetaxel, 75 mg/m2 with trastuzumab, 8 mg/kg [n = 1]). Serial fetal and maternal blood samples, amniotic fluid, maternal urine, and fetal and maternal tissue samples were collected for the first 76 hours after drug infusion. Levels of carboplatin were determined by atomic absorption spectrometry, docetaxel and paclitaxel by high-performance liquid chromatography, and trastuzumab by enzyme-linked immunosorbent assay. Results: Fetal plasma concentrations of carboplatin averaged 57.5% (14.2%) of maternal concentrations (n = 7). Fetal plasma concentrations were 1.5% (0.8%) of maternal concentrations (n = 7). Immediately after ending the infusion, paclitaxel was not detectable in fetal tissues, whereas, after 3 hours, fetal tissues contained 15% of maternal tissue concentrations. Docetaxel could not be detected in fetal blood samples (n = 9). In the first 3 hours after docetaxel infusion, fetal tissues contained 5.0% to 50.0% of maternal tissue concentrations, whereas equal fetal and maternal tissue concentrations were found after 26 and 76 hours. The transplacental passages of trastuzumab were 85.0% and 3.0%, 2 and 26 hours after trastuzumab infusion, respectively. After 26 hours, amniotic fluid contained 36.4% of the fetal plasma concentration. Fetal tissue concentrations varied between 5.0% and 14.0% of the maternal concentration. Conclusion: Variable plasma and/or tissue concentrations of taxanes, carboplatin, and trastuzumab were encountered in the fetal compartment. These data are important when cancer treatment is considered during pregnancy and underline the need for long-term follow-up of children after prenatal exposure to these cytotoxic agents.

Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation

OBJECTIVES During extracorporeal membrane oxygenation (ECMO), drug disposition changes significantly. Plasma concentrations are altered due to an expanded circulating volume leading to a decreased elimination. In addition, adsorption and sequestration of drugs by the ECMO circuit components may further alter pharmacokinetics. Treating patients during the ECMO period with antifungals is difficult. Loss in the ECMO circuit can potentially result in sub-therapeutic levels. METHODS Two cases are presented in which caspofungin and voriconazole levels and pharmacokinetic parameters were determined during the ECMO period. RESULTS Mean caspofungin trough and peak levels were 3.73 and 11.95 microg/mL. These are comparable to previously reported ones. Also pharmacokinetic parameters were identical to those reported in the literature. It seems that caspofungin is not sequestrated by the ECMO circuit, which is expected based on its low log P value. During the first days of ECMO therapy, voriconazole trough and peak levels did not differ much from those determined prior to ECMO therapy. However, at the start of ECMO therapy, the voriconazole dose was increased from 280 to 400 mg twice daily as loss due to binding to the circuit was expected. This increase was not immediately reflected in higher voriconazole levels, which may be due to drug sequestration by the circuit. However, the voriconazole half-life was extended up to 20 h in our patient. Two days after the dose increase, levels reached troughs >10 microg/mL and peaks of around 15 microg/mL, exceeding the therapeutic interval for voriconazole. This can possibly be explained by the saturation of binding sites on the ECMO circuit. CONCLUSIONS Our results suggest that adequate caspofungin plasma levels are maintained during ECMO. In the case of voriconazole, it is recommended to monitor plasma levels to ensure efficacy and avoid toxicity.

DEVELOPMENTAL PHARMACOLOGY: NEONATES ARE NOT JUST SMALL ADULTS…

Abstract Neonatal drug dosing needs to be based on the physiological characteristics of the newborn and the pharmacokinetic parameters of the drug. Size-related changes can in part be modelled based on allometry and relates to the observation that metabolic rate relates to weight by a kg0.75 trend. Until adult metabolic activity has been reached, ontogeny, i.e. isoenzyme-specific maturation and maturation of renal clearance also contributes to drug metabolism, making isoenzyme-specific documentation of maturation necessary. Changes in body composition and ontogeny are most prominent in neonates. The body fat content (/kg) is markedly lower and the body water content (/kg) is markedly higher in neonates. These findings have an impact on the distribution volume of both lipophilic and hydrophilic drugs. Drugs are cleared either by metabolism or elimination. While the first is mainly hepatic, the second route is mainly renal. Both hepatic metabolism and renal clearance display maturation in early life although other covariables (e.g. polymorphisms, co-administration of drugs, first pass metabolism, disease characteristics) further contribute to the interindividual variability in drug disposition. Documentation of these maturational processes based on in vivo ‘case’ studies is of value since these drug-specific observations can subsequently be extrapolated to other drugs which are either already being prescribed or even considered for use in neonates by the introduction of these observations in ‘generic physiologically-based pharmacokinetic’ models.

Piperacillin: Human Pharmacokinetics After Intravenous and Intramuscular Administration

The pharmacokinetics of piperacillin were studied in a total of 26 Caucasian normal male volunteers. Single intramuscular doses of 0.5, 1.0, and 2.0 g were given to three groups, each containing eight volunteers. Mean peak serum concentrations of 4.9, 13.3, and 30.2 μg/ml were assayed at 30 to 50 min, and measurable levels were present up to 4, 6, and 8 h, respectively, after dosing. Single intravenous bolus doses of 1.0, 2.0, 4.0, and 6.0 g were given to four groups of five subjects, and mean serum concentrations of 70.7, 199.5, 330.7, and 451.8 μg/ml were measured at the end of the injections. The antibiotic had a mean terminal serum half-life of 60 to 80 min after the intramuscular doses and 36 to 63 min after intravenous administrations, depending on the dose. The apparent distribution volume was 20 to 24 liters/1.73 m2, and distribution volume at steady state was 16 to 19 liters/1.73 m2. Mean urinary recovery in 24 h was 74 to 89% for the intravenous doses and 57 to 59% for the intramuscular doses. The piperacillin-creatinine clearance ratios indicated that the proportion of renal excretion of piperacillin through tubular secretion was 56 to 73%, and this was confirmed by the renal clearance data from eight volunteers receiving probenecid treatment before the piperacillin dose. Probenecid (1 g given orally before administration of piperacillin) increased peak serum concentration by 30%, terminal serum half-life by 30%, and the area under the plasma concentration curve by 60%, and it decreased the apparent distribution volume by 20% and the renal clearance of the intramuscularly administered (1 g) antibiotic by 40%. Injections of piperacillin by both parenteral routes were well tolerated.

Transplacental transfer of anthracyclines, vinblastine, and 4-hydroxy-cyclophosphamide in a baboon model

OBJECTIVE The paucity of data on the fetal effects of prenatal exposure to chemotherapy prompted us to study transplacental transport of chemotherapeutic agents. METHODS Fluorouracil-epirubicin-cyclophosphamide (FEC) and doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) were administered to pregnant baboons. At predefined time points over the first 25 h after drug administration, fetal and maternal blood samples, amniotic fluid (AF), urine, fetal and maternal tissues, and cerebrospinal fluid (CSF) were collected. High-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) were used for bioanalysis of doxorubicin, epirubicin, vinblastine, and cyclophosphamide. RESULTS In nine baboons, at a median gestational age of 139 days (range, 93-169), FEC 100% (n = 2), FEC 200% (n=1), ABVD 100% (n = 5), and ABVD 200% (n = 1) were administered. The obtained ratios of fetal/maternal drug concentration in the different simultaneously collected samples were used as a measure for transplacental transfer. Fetal plasma concentrations of doxorubicin and epirubicin averaged 7.5 ± 3.2% (n = 6) and 4.0 ± 1.6% (n = 8) of maternal concentrations, respectively. Fetal tissues contained 6.3 ± 7.9% and 8.7 ± 8.1% of maternal tissue concentrations for doxorubicin and epirubicin, respectively. Vinblastine concentrations in fetal plasma averaged 18.5 ± 15.5% (n=9) of maternal concentrations. Anthracyclines and vinblastine were neither detectable in maternal nor in fetal brain/CSF. 4-Hydroxy-cyclophosphamide concentrations in fetal plasma and CSF averaged 25.1 ± 6.3% (n = 3) and 63.0% (n = 1) of the maternal concentrations, respectively. CONCLUSION This study shows limited fetal exposure after maternal administration of doxorubicin, epirubicin, vinblastine, and 4-hydroxy-cyclophosphamide.

The effect of rofecoxib on the pharmacodynamics and pharmacokinetics of warfarin

The objective of this study was to examine the effect of 3 doses of rofecoxib (12.5, 25, and 50 mg) on the pharmacodynamics and pharmacokinetics of warfarin.