Edyta Szałek

Continuous infusion of antibiotics in critically ill patients.

Antibiotics are the most commonly used drugs in intensive care unit patients and their supply should be based on pharmacokinetic/pharmacodynamic rules. The changes that occur in septic patients who are critically ill may be responsible for subtherapeutic antibiotic concentrations leading to poorer clinical outcomes. Evolving in time the disturbed pathophysiology in severe sepsis (high cardiac output, glomerular hyperfiltration) and therapeutic interventions (e.g. haemodynamically active drugs, mechanical ventilation, renal replacement therapy) alters antibiotic pharmacokinetics mainly through an increase in the volume of distribution and altered drug clearance. The lack of new and efficacious drugs and increased bacterial resistance are current problems of contemporary antibiotic therapy. Although intermittent administration is a standard clinical practice, alternative methods of antibiotic administration are sought, which may potentialise effects and reduce toxicity as well as contribute to inhibition of bacterial resistance. A wide range of studies prove that the application of continuous infusion of time-dependent antibiotics (beta-lactams, glycopeptides) is more rational than standard intermittent administration. However, there are also studies which do not confirm the advantage of one method over the other. In spite of controversy the continuous administration of this group of antibiotics is common practice, because the results of both studies point to the higher efficacy of this method in critically ill patients. Authors reviewed the literature to determine whether any clinical benefits exist for administration of time-dependent antibiotics by continuous infusion. Definite specification of the clinical advantage of administration this way over standard dosage requires a large-scale multi-centre randomised controlled trial.

The pharmacokinetics and hypoglycaemic effect of sunitinib in the diabetic rabbits.

BACKGROUND Diabetes is one of the most common metabolic diseases in the world, which may influence changes in the pharmacokinetics and pharmacodynamics of drugs. Sunitinib is a tyrosine kinase inhibitor (TKI) broadly used for treatment of numerous cancers, which exhibits the side hypoglycaemic effect. The aim of the study was a comparison of concentrations and pharmacokinetics of sunitinib after a single administration in rabbits with hyperglycaemia and normoglycaemia (control group). Additionally, the effect of sunitinib on glucose levels was investigated. METHODS The research was carried out on a control group (n=6) and a group of rabbits with diabetes (n=6). The rabbits were treated with sunitinib in the oral dose of 25mg. Plasma concentrations of sunitinib and its metabolite (SU12662) were measured with validated HPLC method with UV detection. RESULTS The comparison of the sunitinib Cmax and AUC0-∞ in the diabetic group with the control group gave the ratios of 1.63 [90% confidence interval (CI) [1.59; 1.66] and 2.03 [1.97; 2.09], respectively. Statistically significant differences between the analyzed groups were revealed for Cmax (p=0.006), AUC0-∞ (p=0.0088), and AUCkel (p=0.009). The maximum glycaemia drop of 14.4-69.6% and 15.4-33.5% was observed in the diabetic animals and in the control group, respectively. The glycaemia values returned to the initial values in 24h after the administration of the drug. CONCLUSIONS The research proved the significant influence of diabetes on the pharmacokinetics of sunitinib and it confirmed the hypoglycaemic effect of the TKI in diabetic rabbits and in normoglycaemia.

The physical and chemical stability of cisplatin (Teva) in concentrate and diluted in sodium chloride 0.9

Aim of the study The subject of study was the stability of cisplatin in concentrate in glass vials and diluted in polyethylene (PE) bags stored at 15–25°C for up to 30 days. Material and methods Original vials of cisplatin injection (1 mg/ml, Teva) were stored at room temperature and subjected to re-piercing after 1, 2, 3, 7, 14, 21, 28 and 30 days following the initial piercing. Cisplatin infusions at nominal concentrations of 0.1 mg/ml were prepared in 0.9% sodium chloride (1000 ml) in PE bags. Chemical stability was measured by means of a stability-indicating high-performance liquid chromatography (HPLC) assay. Physical stability was assessed by visual inspection in normal light. Results The concentration of cisplatin at each sampling time in the analysed solutions remained within 92.0–100.7% of initial concentration, regardless of the container. No changes in colour or turbidity were observed in any of the vials or prepared solutions. Conclusions Cisplatin, both undiluted in glass containers and diluted with NaCl 0.9% in PE bags, remains stable (< 10% degradation) for at least 30 days at room temperature when protected from light.

Sunitinib in combination with clarithromycin or azithromycin – is there a risk of interaction or not?

BACKGROUND Macrolides are the most widely prescribed antibiotics. Clarithromycin is a well-known inhibitor of cytochrome P450 CYP3A4 and causes numerous drug interactions that are not found for azithromycin. CYP3A4 is involved in the metabolism of the new oral multikinase inhibitor sunitinib and its active N-desethyl metabolite (SU012662). This study investigated the effects of oral single dose of clarithromycin or azithromycin on the pharmacokinetics of sunitinib. METHODS Rabbits were subjected to one of three study drug groups: sunitinib + clarithromycin (n = 6), sunitinib + azithromycin (n = 6), or sunitinib (n = 6). The rabbits were treated with sunitinib in the oral dose of 25 mg. Plasma concentrations of sunitinib were measured with validated HPLC method with UV detection. RESULTS Comparison of the sunitinib C(max) for the sunitinib + clarithromycin group with that of the sunitinib group gave a ratio of 94.4% [90% confidence interval (CI) (76.1, 117.1)]; for the sunitinib + azithromycin group, the ratio was 106.2% (90% CI 85.5, 131.7). Comparison of the sunitinib AUC(0-t) of the sunitinib + clarithromycin and sunitinib + azithromycin groups with that of the sunitinib group showed ratios of 86.86% (90% CI 69.7, 108.3) and 99.8% (90% CI 80.1, 124.5), respectively. CONCLUSIONS No significant effect of the coadministration of clarithromycin or azithromycin on the pharmacokinetics of sunitinib in rabbits was found in this study.

Pharmacokinetics of paracetamol in patients with chronic pancreatitis

BACKGROUND Chronic pancreatitis (CP) is a progressive, irreversible disease causing damage of the gland. Abdominal pains are a typical symptom of pancreatitis both in the chronic and acute form. Paracetamol is one of analgesics used for treating mild or moderate pain. Functional and anatomical changes in the gastrointestinal tract caused by pancreatitis may influence on the pharmacokinetics of administered drugs. METHODS In the present study we analysed the pharmacokinetics of paracetamol after oral and intravenous administration to patients with CP. The patients were allocated to one of the two groups of the drug under study: I iv, intravenous administration of paracetamol 1000mg (n=17; mean [SD] age, 46.18 [13.78] years; and BMI, 22.03 [2.62]kg/m(2)) and II po, oral administration of paracetamol 1000mg (n=17; mean [SD] age, 48.29 [10.08] years; and BMI, 22.50 [2.92]kg/m(2). The plasma concentrations of paracetamol and its metabolite (glucuronide) were measured with the validated high-pressure liquid chromatography (HPLC) method with ultraviolet (UV) detection. RESULTS The main pharmacokinetic parameters for paracetamol after iv and po administration to patients with CP were as follows: Cmax, 19.00 [4.50] and Cmax, 9.26 [3.35]μg/ml; AUC0-t, 42.37 [13.92] and 36.68 [11.7]μg×h/mL, respectively. After iv and po administration the AUC ratio between the metabolite (glucuronide) and paracetamol was enhanced. CONCLUSIONS The research findings revealed that patients with chronic pancreatitis had lower concentrations of paracetamol. Therefore, it may be necessary to apply additional analgesic therapy. Moreover, we observed enhanced glucuronidation in our patients.

Pharmacokinetics of sunitinib in combination with fluoroquinolones in rabbit model

BACKGROUND Fluoroquinolones are widely prescribed antibiotics. Ciprofloxacin is a well-known inhibitor of cytochrome P450 CYP3A4 and causes numerous drug interactions that are not found for levofloxacin and moxifloxacin. CYP3A4 is involved in the metabolism of the new oral multikinase inhibitor sunitinib which is indicated for the treatment of gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC). This study investigated the effects of single intravenous dose of ciprofloxacin, levofloxacin or moxifloxacin on the pharmacokinetics of sunitinib. METHODS Rabbits were subjected to one of four study drug groups: sunitinib + ciprofloxacin (n = 6), sunitinib + levofloxacin (n = 6), sunitinib + moxifloxacin (n = 6), or sunitinib alone (n = 6). The rabbits were treated with sunitinib in the oral dose of 25 mg. The antibiotics were administered intravenously at the doses of 20, 25 and 20 mg/kg, respectively. Plasma concentrations of sunitinib and active metabolite (SU12662) were measured with validated HPLC method with UV detection. RESULTS The comparison of sunitinib Cmax for the sunitinib + ciprofloxacin, sunitinib + levofloxacin, sunitinib + moxifloxacin group and that for the sunitinib group gave ratios of 1.81 (90% CI 1.33, 2.44), 1.59 (90% CI 1.18, 2.16), 1.06 (90% CI 0.79, 1.44), respectively. The comparison of sunitinib AUC0-∞ for the sunitinib + ciprofloxacin, sunitinib + levofloxacin, sunitinib + moxifloxacin group and that for the sunitinib group gave ratios of 2.90 (90% CI 1.32, 6.37), 2.45 (1.11, 5.39), 1.58 (0.70, 1.56), respectively. The mean sunitinib tmax was similar for all four groups. The mean Cmax for SU12662 was similar for both the sunitinib + moxifloxacin and sunitinib groups (p = 0.9593). However, the mean Cmax for SU12662 for the groups: sunitinib + ciprofloxacin and sunitinib + levofloxacin were higher (p = 0.0045 and 0.0672, respectively). CONCLUSIONS The study proved a significant effect of the coadministration of ciprofloxacin and levofloxacin on the pharmacokinetics of sunitinib in rabbits. The influence of moxifloxacin on the pharmacokinetics of sunitinib was insignificant. Therefore, this fluoroquinolone seems to be the most appropriate in combination with this tyrosine kinase inhibitor.

Comparison of the pharmacokinetics of paracetamol from two generic products in patients after total gastric resection.

Gastrectomy leads to pathophysiological changes within the alimentary tract, which may affect drug absorption and pharmacokinetic parameters (PK). The need to apply orally administered analgesics in this group of patients is often related with alternative application of currently available generic products. Thus, from the clinical point of view it is necessary to evaluate the PK of these drugs to confirm their equivalence. The aim of the study was therefore an analysis of the pharmacokinetics of paracetamol from two generic products in patients after total gastric resection. The research was carried out on two groups of patients after gastrectomy with Roux-en-Y reconstruction (n = 30; mean [SD] age, 63.0 [11.5] years; weight, 67.6 [13.7] kg; and height, 166.4 [9.1] cm). The patients received paracetamol in a single orally administered dose of 1,000 mg. Blood samples were collected within 6 h of drug administration. The concentration of paracetamol and paracetamol glucuronide in the blood plasma was marked by means of a validated high-pressure liquid chromatography with ultraviolet detection (HPLC-UV). The main PK for paracetamol in group 1 (n = 17) and 2 (n = 13) were as follows: C(max), 9.46 (3.66) and 12.79 (5.32) μg/ml, respectively (p = 0.0517); AUMC(0-t), 77.64 (30.37) and 51.01 (15.76) μg h(2)/ml (p = 0.0046); AUC(0-inf), 41.61 (23.52) and 30.28 (9.74) μg h/ml (p = 0.0862); t(max), 1.68 (0.63) and 0.50 (0.25) h (p < 0001). The obtained C(max) and AUC values in patients after gastrectomy were reduced in comparison with healthy subjects. Total gastrectomy therefore affected the pharmacokinetics of paracetamol administered in tablets. In our patients, we also observed significant differences between the PK of paracetamol and two generic preparations. These two drugs can thus be used interchangeably, but with caution.

The pharmacokinetics of oral ketoprofen in patients after gastric resection

BACKGROUND Total and partial gastric resection may affect the pharmacokinetics of drugs, especially orally administered a few days after surgery. Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) broadly used to treat postoperative pain, including patients after gastric resection. The aim of the research was to analyse the pharmacokinetics (PK) of orally administered ketoprofen in patients after gastrectomy. METHODS The research was carried out on two groups of patients after total (TG; Roux-Y procedure) and partial (PG; Billroth II procedure) gastrectomy. The patients in group TG (n=15; mean [SD] age 61.86 [14.15] years; and BMI 24.20 [3.73] kg/m2) and group PG (n=5; mean [SD] age 62.40 [16.80] years; and BMI 23.98 [3.45] kg/m2) received ketoprofen in a single oral dose of 100mg. The measurement of ketoprofen plasma concentrations was made by means of the HPLC (high performance liquid chromatography) method. RESULTS The PK parameters in group TG and PG were as follows: maximum plasma concentration (Cmax), 3.42 [0.99] and 4.66 [0.81] mg/l (p=0.0220); area under the plasma concentration-time curve from zero to infinity (AUC0-∞), 9.12 [2.78] and 9.17 [2.87] mg×h/ml (p=0.9734); area under the first moment curve from zero to the time of infinity (AUMC0-∞), 25.95 [8.52] and 26.53 [11.43] mg×h2/l (p=0.9056); time to reach maximum concentration (tmax), 0.47 [0.25] and 0.55 [0.27] h (p=0.5327), respectively. CONCLUSIONS Lower concentrations of ketoprofen in patients after gastrectomy suggest that it might be necessary to apply higher dose of the analgesic.

Pharmacokinetic drug-drug interaction between erlotinib and paracetamol: A potential risk for clinical practice

Background: Erlotinib is a tyrosine kinase inhibitor available for the treatment of non‐small cell lung cancer. Paracetamol is an analgesic agent, commonly used in cancer patients. Because these drugs are often co‐administered, there is an increasing issue of interaction between them. Objective: The aim of the study was to investigate the effect of paracetamol on the pharmacokinetic parameters of erlotinib, as well as the influence of erlotinib on the pharmacokinetics of paracetamol. Methods: The rabbits were divided into three groups: the rabbits receiving erlotinib (IER), the group receiving paracetamol (IIPR), and the rabbits receiving erlotinib + paracetamol (IIIER + PR). A single dose of erlotinib was administered orally (25 mg) and was administered intravenously (35 mg/kg). Plasma concentrations of erlotinib, its metabolite (OSI420), paracetamol and its metabolites – glucuronide and sulphate were measured with the validated method. Results: During paracetamol co‐administration we observed increased erlotinib maximum concentration (Cmax) and area under the plasma concentration‐time curve from time zero to infinity (AUC0‐∞) by 87.7% and 31.1%, respectively. In turn, erlotinib lead to decreased paracetamol AUC0‐∞ by 35.5% and Cmax by 18.9%. The mean values of paracetamol glucuronide/paracetamol ratios for Cmax were 32.2% higher, whereas paracetamol sulphate/paracetamol ratios for Cmax and AUC0‐∞ were 37.1% and 57.1% lower in the IIPR group, when compared to the IIIER + PR group. Conclusions: Paracetamol had significant effect on the enhanced plasma exposure of erlotinib. Additionally, erlotinib contributed to the lower concentrations of paracetamol. Decreased glucuronidation and increased sulphation of paracetamol after co‐administration of erlotinib were also observed.

The pharmacokinetic interaction between levofloxacin and sunitinib

BACKGROUND The aim of this study was to evaluate the impact of sunitinib on pharmacokinetics of levofloxacin. The previous study proved that levofloxacin co-administered with sunitib changes the following pharmacokinetic parameters i.e. Cmax and AUC for both sunitinib and SU012662 (sunitinib metabolite). We will also investigate if the limited sample strategy can be applied for levofloxacin. METHODS Rabbits were divided into two groups. In both groups there were six animals. In the control group levofloxacin was administered and in investigated group levofloxacin and sunitinib were co-administered. The dose of levofloxacin was 20mg/kg and the dose of sunitinib was 25mg. The concentration in plasma was determined by HPLC-FLD. The pharmacokinetic parameters were evaluated by WinNonLin software. The results were evaluated by the following statistical tests: Shapiro-Wilk, t-Student and Mann-Whitney test. RESULTS Pharmacokinetics of levofloxacin obeys the two-compartment model. Sunitinib influences the following pharmacokinetic parameters of levofloxacin: half-life, elimination constant and volume of distribution. Statistical analysis proved that there is a correlation between AUC and the following five time-points: 0.25 h, 4h, 6h, 10h and 12h. CONCLUSIONS The study proved that there is a potential pharmacokinetic interaction between sunitinib and levofloxacin. The statistical analysis proved that the limited sample strategy can be applied for levofloxacin.