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Abstract

J. Stöbe¹, A. Siegemund², H. Achenbach³, C. Preiss¹ and R. Preiss¹

¹Institute of Clinical Pharmacology, ²Department of Clinical Medicine I, and ³Department of Clinical Medicine III, University of Leipzig, Leipzig, Germany
The pharmacokinetics of the low-molecular weight heparin (LMWH), dalteparin, was evaluated after a single intravenous bolus injection of 50 IU anti-Xa/kg in 8 healthy volunteers, 8 patients with moderate/severe renal failure (Clcrea 13.1 – 56.5 ml/min) and 8 hemodialysis patients. Venous blood samples were taken over a 1-day period to determine anti-Xa activity, anti-IIa activity and plasma levels of free tissue factor pathway inhibitor (free TFPI). Plasma anti-Xa and anti-IIa activities were measured using chromogenic assays and free TFPI levels using an ELISA technique. The anti-Xa clearance was significantly decreased (p < 0.05) in both groups with renal insufficiency when compared with healthy volunteers. There was a positive correlation between creatinine clearance and anti-Xa clearance in the healthy volunteers and patients with moderate/severe renal failure. The anti-IIa activity was characterized by 3- to 4-fold lower plasma concentrations and faster elimination compared with the anti-Xa activity. In patients with moderate/severe renal failure the elimination of anti-IIa was only slightly decreased, whereas in hemodialysis patients anti-IIa clearance was significantly decreased (p < 0.01). There was no correlation between creatinine clearance and anti-IIa clearance. The baseline mean free TFPI plasma levels in the two groups with renal insufficiency were significantly higher (p < 0.01) than in healthy volunteers. Dalteparin administration induced a transient, 6.0- to 8.1-fold increase in the free TFPI values in the three study groups. Dalteparin induced an increase in Cmax and AUC0–¥ values of free TFPI in the two groups with renal insufficiency that was higher than in healthy volunteers. No bleeding complications occurred during the study. In conclusion, this is the first report showing retarded elimination of dalteparin and enhanced free TFPI plasma levels induced by a LMWH in patients with renal insufficiency.Correspondence to:
J. Stöbe
Institute of Clinical Pharmacology
University of Leipzig
Härtelstraße 16 – 18
04107 Leipzig, Germany
Email: joergstoebe@aol.com

Abstract

M. de Wit¹, A.M. Best², S.K. Epstein³ and D.J. Greenblatt⁴

¹Division of Pulmonary and Critical Care Medicine, ²Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, ³Caritas St. Elizabeth Medical Center, and ⁴Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA
Objectives: To evaluate plasma concentrations, pharmacokinetics and pharmacodynamics of lorazepam in a cohort of mechanically ventilated patients. Interventions: Patients underwent simultaneous measurement of lorazepam concentration and sedation assessments using the Sedation-Agitation Scale (SAS) and Bispectral Index (BIS). Lorazepam administration was classified as either continuous intravenous infusion (CIVS) or bolus. Main results: A total of 124 observations were made in 13 patients. The median concentration was 59 ng/ml, interquartile range 23 – 93 ng/ml, range 0 – 1,072 ng/ml. Clearance was preserved at 92 ± 71 ml/min. Higher concentrations were associated with deeper sedation determined by both SAS and BIS. Two patients were managed with CIVS and received more lorazepam than those managed without (288 ± 53.5 versus 55 ± 25.2 mg, p-value < 0.005). CIVS administration was associated with higher concentrations (629 ± 36 versus 49 ± 15 ng/ml, p-value < 0.001) and deeper sedation by both SAS and BIS. Conclusions: Lorazepam clearance was preserved with a wide range of concentrations. Higher concentrations were associated with deeper sedation and use of CIVS. Elevated concentrations during CIVS were attributable to administration of larger doses.Correspondence to:
M. de Wit, MD
Division of Pulmonary and Critical Care Medicine
Virginia Commonwealth University
Medical College of Virginia Campus
Box 980050, Richmond, VA 23298-0050, USA
Email: mdewit@vcu.edu

Abstract

D. Czock

Medical Department, Division of Nephrology, University Hospital Ulm, Germany
Objective: The most commonly applied pharmacodynamic model is the sigmoid Emax model which can be applied for evaluation of dose adjustment schemes in renal failure. It is not known whether the Hill coefficient (H) is a shape factor that only improves the mathematical fit or whether the Hill coefficient is a pharmacodynamic parameter that independently affects drug effects and drug dosage adjustment. Methods: We performed simulations applying a mechanism-based mathematical pharmacokinetic-pharmacodynamic model for antimicrobial drugs. For the case of renal failure, two dose adjustment rules were evaluated. Results: Administering the drug as 3 dose fractions per day increased the predicted total effect in the case of H = 1 but decreased the predicted total effect in the case of H = 2 compared to once-daily dosing. In renal failure, administration of the normal dose and prolongation of the interval leads to an increased total effect for the simulated drugs for both cases, namely H = 1 and H = 2. However, reducing the dose in renal failure might produce underdosage for a drug with a high Hill coefficient. Conclusion: The predicted effects of once- versus thrice-daily dose fractions as well as the predicted effects of dose reduction versus interval prolongation in renal failure critically depend on the Hill coefficient. Methods to estimate the Hill coefficient more precisely should be explored.Correspondence to:
Dr. D. Czock
University Hospital Ulm
Medical Department, Division of Nephrology
Robert-Koch-Straße 8, 89081 Ulm, Germany
Email: david.czock@uniklinik-ulm.de

Abstract

U. Klotz

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
Worldwide a large number of patients suffer from severe chronic pain even after treatment with opioids following the 3-step analgesic ladder developed by the WHO. Intraspinal agents, including morphine, have been tried as a fourth step. However, approximately 20% of cases remain refractory. Ziconotide, an intrathecal analgesic with orphan drug status, is a novel alternative for the management of chronic intractable pain. Ziconotide is a synthetic peptide based on the toxin of the fish-hunting marine snail, Conus magus. It is the first therapeutic agent in a new pharmacological class of “topically” active analgesics that selectively target neuron-specific (N-type), voltage-gated calcium channels. Ziconotide produces potent analgesia by interruption of Ca-dependent primary afferent transmission of pain signals in the spinal cord. Ziconotide was significantly more effective than placebo in the treatment of chronic malignant (p < 0.001) and non-malignant pain (p < 0.001). In several clinical studies morphine dosages could be substituted by ziconotide. The drug has a lag-time for the onset and offset of analgesia and adverse effects. Initial doses should therefore be low (2.4 mg/day) and titrated slowly (increasing up to a maximum of 21.6 mg/day in increases of 2.4 mg/day no more than twice weekly). The gradual increase in dose helps to reduce the incidence and severity of adverse events which affect primarily the central nervous system (e.g. dizziness, nausea, confusion). Ziconotide maintains its analgesic efficacy over months and does not cause tolerance, dependence or respiratory depression. Following intrathecal infusion ziconotide is distributed within the cerebral spinal fluid (CSF) where its clearance (0.38 ml/min) corresponds to the rate of turnover of the CSF. Negligible amounts of ziconotide are present in the systemic circulation where it is rapidly degraded by proteolysis. In conclusion, ziconotide is a new and valuable alternative analgesic for the acute and long-term treatment of severe pain, especially in patients refractory to opioids.Correspondence to:
Prof. Dr. U. Klotz
Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie
Auerbachstraße 112
70376 Stuttgart, Germany
Email: ulrich.klotz@ikp-stuttgart.de

Abstract

C.W.R. Cheng¹, J.C.N. Chan², B. Tomlinson², K.S. Woo² and J.H.S. You¹

¹School of Pharmacy and ²Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, China
Background: Socio-economic status, comorbidities and adherence to statin therapy might affect the cost-effectiveness of statin therapy in hyperlipidemia. Objective: To examine the effects size of demographic factors, clinical factors and adherence to statin therapy on the direct medical costs for Chinese patients at high risk of coronary heart disease (CHD). Methods: This was a prospective, observational cohort study conducted in the outpatient departments of a public teaching hospital in Hong Kong. Patients at high risk of CHD who had been on statin monotherapy for < 12 months were recruited. Baseline demographic and clinical data were obtained. Statin adherence was monitored prospectively over 6 months using the Medication Event Monitoring System. Total direct medical costs per member per month (cPMPM), including cost for clinic visits, statin medication, laboratory tests on lipids and management of CHD events if any, were calculated from the perspective of a public healthcare organization. Results: 83 patients completed the study. Median cPMPM in 80 patients (96% of 83 patients) without a new CHD event (USD 42) and for 3 (4%) patients who experienced CHD events (USD 444) were significantly different (p = 0.003). History of congestive heart failure (b = 1,957, 95% CI = 1,006 – 2,909), male gender (b = 584, 95% CI = 215 – 952), coronary atherosclerosis (b = 1,436, 95% CI = 538 – 2,334) and diabetes mellitus (b = 604, 95% CI = 136 – 1,071) were positive predictors for cPMPM. Conclusion: In this pilot study male gender, diabetes mellitus, congestive heart failure and coronary atherosclerosis appear to be significantly associated with higher costs for Chinese patients at high risk of CHD.Correspondence to:
J.H.S. You, PharmD, BCPS
School of Pharmacy, Faculty of Medicine
The Chinese University of Hong Kong
Shatin, N.T., Hong Kong, China
Email: joyceyou@cuhk.edu.hk

Abstract

H. Modesto Rigato², G. Duarte Mendes², N. Carter do Carmo Borges¹,² and R.A. Moreno¹,²

¹Synchrophar Assessoria e Desenvolvimento de Projetos Clínicos, and ²Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil
Objective: In this study, the bioavailability of 2 meloxicam 15 mg tablet formulations was compared. A single dose of each formulation was administered to 24 healthy volunteers (12 males and 12 females). Material and methods: The study was conducted using an open, randomized and crossover design with a 2-week washout interval. The plasma samples were obtained over a 96-hour interval and meloxicam concentrations were analyzed by high-performance liquid chromatography (an agilent) coupled to an API 2000 turboionspray tandem mass spectrometry (LC-MS-MS). An electrospray ionization (ESI) source operating in the positive ion mode, using a cross flow counter electrode and set for the multiple reaction monitoring (MRM) was employed. The plasma protein precipitate was reconstituted with acetonitrile/water + 10 mM acetic acid (20/80, v/v) and injected in a Prevail C8 5 mm (150 mm × 4.6 mm i.d.) analytical column with reverse-phase liquid chromatography. The retention time observed for meloxicam and tenoxicam (internal standard) was 1.8 and 1.4 minutes, respectively. The mean recovery of meloxicam was 95.9% and the limit of quantification was 0.02 mg/ml. Results: The geometric mean of meloxicam/movatec 15 mg individual % ratio was 101.3% for AUClast, 99.9% for AUC0-¥ and 107.7% for Cmax. The 90% confidence intervals were 97.3 – 105.4%, 96.0 – 104.0% and 98.8 – 117.4%, respectively. Conclusion: Since the 90% CI for both AUClast, AUC0-¥ and Cmax, ratios were all inside the 80 – 125% interval proposed by the US Food and Drug Administration Agency and accepted by Brazilian ANVISA (Sanitary Surveillance Agency), it was concluded that the meloxicam formulation produced by Merck S.A. Indústrias Químicas is bioequivalent to the movatec formulation regarding both the rate and extent of absorption. This assay method was faster, more simple, specific, precise and accurate in determining the bioequivalence of meloxicam than any method previously described.Correspondence to:
R.A. Moreno
38 Dr. Candido Gomide Street
13070-200 Campinas, SP, Brazil
Email: synchrophar@synchrophar.com

Abstract

Chairman: K. Bestehorn, Bad Krozingen

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Volume 44, No. 10/2006(October)