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Editorial

E. von Stebut and K. Steinbrink

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International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 1/2011 (3-13)

The pharmacokinetics and safety of desvenlafaxine in subjects with chronic renal impairment

A.I. Nichols¹, L.S. Richards, J.A. Behrle², J.A. Posener¹, S.B. McGrory¹ and J. Paul¹

¹Pfizer Inc., formerly Wyeth Research, Collegeville, PA, and ²Centocor R&D, Horsham, PA, USA
Background: Desvenlafaxine (administered as desvenlafaxine succinate), the major active metabolite of venlafaxine, is a new serotonin-norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD). Objective: To assess the pharmacokinetics, safety, and tolerability of desvenlafaxine in healthy volunteers vs. those with renal impairment. Materials and methods: A single, oral, 100 mg dose of desvenlafaxine was administered to healthy subjects (n = 8) and subjects with mild (n = 9), moderate (n = 9), or severe (n = 7) renal impairment (24-h creatinine clearance, ml/min: 50 – 80, 30 – 50, or < 30 ml/min, respectively) or end-stage renal disease (ESRD; on dialysis <= 30 days, n = 10). Disposition of (R)-, (S)-, and (R+S)-desvenlafaxine was examined in plasma and urine for 72 h postdosing in healthy patients and 144 h postdosing in patients with renal impairment. For renally impaired subjects, geometric least squares mean (GLSM) ratios (vs. healthy controls as reference) and 90% confidence intervals (CIs) were calculated for area under the plasma concentration-versus-time curve (AUC), peak plasma concentration (C_max), and apparent oral-dose clearance (Cl/F). Safety was evaluated based on adverse events (AEs), physical examination, 12-lead electrocardiograms, vital signs, and laboratory assessments. Results: GLSM ratios (90% CIs) for AUC were 142% (94.4 – 213%), 156% (103 – 237%), 208% (135 – 322%), and 216% (143 – 324%) among those with mild, moderate, or severe renal impairment, or ESRD, respectively. GLSM ratios (90% CIs) for Cl/F were 71.2% (48.8 – 104%), 61.1% (41.4 – 90.2%), 48.8% (32.6 – 73.0%) and 42.2% (28.9 – 61.6%) for mild, moderate, severe renal impairment and ESRD, respectively. C_max and time to C_max were not significantly different among the groups; elimination half-life was prolonged in those with renal impairment. Pharmacokinetic parameters were similar between (R)- and (S)-desvenlafaxine, regardless of renal function. Urinary recovery of total desvenlafaxine was unchanged vs. healthy subjects. Desvenlafaxine was generally well tolerated. Conclusions: Desvenlafaxine 100 mg/d, twice the recommended therapeutic dose for MDD, was generally safe and well tolerated in healthy and renally impaired subjects. Dosage adjustment for desvenlafaxine is recommended in patients with severe renal impairment or ESRD.Correspondence to:
A.I. Nichols, PhD
Pfizer Inc.
500 Arcola Road
Collegeville, PA 19426, USA
Email: Alice.Nichols@pfizer.com

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International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 1/2011 (14-22)

An assessment of teicoplanin use and monitoring serum levels in a Chinese teaching hospital

Y.-L. Dong¹, H.-Y. Dong¹, S.-S. Hu¹, X. Wang², Y.-X. Wei¹, M.-Y. Wang¹, W.-H. Dong¹, H.-P. Yao¹, H.-S. You¹ and J.-F. Xing³

¹Department of Pharmacy, ²Department of Central ICU, The First Affiliated Hospital, Medical College, and ³Department of Pharmacy, Medical College, Xi’an JiaoTong University, Xi’an, China
Objective: To validate a high performance liquid chromatography (HPLC) method for serum teicoplanin measurement and use the method for clinical monitoring of teicoplanin levels to analyze the clinical application of teicoplanin. Methods: 55 patient profiles were collected and analyzed for the clinical teicoplanin application. 10 critically ill patients of the 55 cases were monitored for teicoplanin trough concentration using the HPLC method. Results: The modified HPLC method exhibited excellent linearity, with correlation coefficient r = 0.9995. The intra-day and inter-day coefficients of variation were less than 10%. The lower limit of detection of teicoplanin was 5.63 mg/l. The recovery of teicoplanin was above 90%. Of the 55 patients in this study, there were 42 patients without load-dosing. There were only 29 patients treated with teicoplanin documented Gram-positive infections by etiological diagnoses. In the 10 patients with teicoplanin serum trough concentration monitoring, all cases received a loading dose of 400 mg every 12 h for 3 doses, and the mean trough concentration of teicoplanin was 10.82 ± 4.51 mg/l. The mean trough levels were 13.04 ± 6.23 mg/l in 4 patients with microbiological eradication and improvement of symptoms of diseases and 9.34 ± 2.61 mg/l in 6 patients with persistence of previous clinical infectious symptoms, respectively. Conclusion: The modified HPLC method is robust, highly reproducible and suited to monitor the concentration of teicoplanin. In critically ill Chinese patients, we should consider more appropriate loading doses and evaluate the relationship between teicoplanin trough concentration and the efficacy using microbiological and clinical parameters.Correspondence to:
Y.-L. Dong, PhD
Department of Pharmacy
The First Affiliated Hospital
Medical College
Xi’an JiaoTong University, Xi’an, 710061, China
Email: dongyalin@medmail.com.cn

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International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 1/2011 (23-29)

Contribution of 1173C > T polymorphism in the VKORC1 gene to warfarin dose requirements in Han Chinese patients receiving anticoagulation

J. Yang¹, C. Huang², Z. Shen³ and L. Miao²

¹Institute of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ²Department of Clinical Pharmacology Research Lab, and ³Department of Cardiovascular Surgery, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
Objective: The objective was to assess 1173C > T polymorphism of the VKORC1 gene and its contribution to warfarin dose requirements in Han Chinese patients. Methods: Blood samples were collected from 178 patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range (1.5 – 3.0). Polymorphisms for VKORC1 (1173C > T), CYP2C9, venous INR, and plasma concentration and unbound concentration of warfarin were analyzed. Results: VKORC1 (1173C > T) genotyping showed that 154 patients were homozygous TT, 23 were heterozygous CT, and one was homozygous for the CC genotype. Patients with the VKORC1 (1173CC + CT) genotype required a significantly higher warfarin dose (3.33 ± 1.04 mg/day) than those with 1173TT (1.81 ± 0.63 mg/day; p < 0.001). The multiple linear regression model for warfarin dose indicated significant contributions from the VKORC1 (1173C > T) genotype (r² = 0.355; p < 0.001), and age, body weight, and CYP2C9 and VKORC1 genotype together (r² = 0.513; p < 0.001). The two SNPs (–1639 and 1173) were found to be in very strong linkage disequilibrium with estimated D’ = 0.96 (95%CI (0.83 – 0.99)). Conclusion: The VKORC1 (1173C > T) polymorphism might be very important, and its contribution can be equally explained by the VKORC1(–1639 G > A) polymorphism for warfarin dose requirements in Han Chinese patients.Correspondence to:
L. Miao
Department of Clinical Pharmacology Research Lab
First Affilated Hospital of Soochow University
Suzhou, Jiangsu, China
Email: miaolysuzhou@163.com

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International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 1/2011 (30-37)

The possibility of using the specific RIA method for the area-under-time-concentration curve sparse sampling calculation of cyclosporin A despite a large post-dose overestimation

M. Grundmann¹, B. Koristkova¹, H. Brozmanova¹, I. Perinova¹ and K. Safarcik²

¹Department of Clinical Pharmacology and ²Nuclear Medicine Clinic, Ostrava University Hospital and Medical Faculty, University of Ostrava, Ostrava, Czech Republic
Objective: To find limited sampling strategies (LSS) for prediction of the real AUC using the RIA analytical method. Method: Blood samples of 40 male renal transplant patients taken pre-dose and after 0.5, 1, 1.5, 2, 3, 5, 8, and 12 h in the steady-state were analyzed with HPLC and the specific RIA method. I. Eight equations for AUC_0–12 and one for AUC_0–8 obtained from the literature, that produced the mean percentage prediction error (%PE) < ± 15% and absolute %PE < 30% in 95% of predictions, were analyzed for possibility to predict the real AUC of CsA. II. Multiple regression analysis (MRA) was provided for the AUC equation proposal. Patients were divided into two groups according to the AUC_0–12. Group I was used for LSS : s proposals while Group II for validation. The bias and precision were expressed as %PE, r² and RMSE. The relationship of %PE interassay and with LSS:s was expressed as Pearson correlation r. GraphPad InStatt Software was used for MRA and Pearson r calculation. Results: None of the equations described in the literature predicts AUC of CsA proprietarily. Seven equations for AUC_0–12 and five for AUC_0–8 were proposed with MRA for prediction of real AUC from RIA values. Conclusions: LSS:s can moderate the interassay %PE in AUC of CsA. New patients should be tested with both RIA and HPLC for the level of overestimation. The conversion factors should be calculated for patients with an overestimation higher than 90%. Our equation 251.09 + 0.5195 × C_1h + 4.926 × C_3h or 196.13 + 4.526 × C_0h + 2.089 × C_1.5h for AUC_0–12, and 171.80 + 0.4759 × C_1h + 4.132 × C_3h for AUC_0–8 may be used in patients with medium or low RIA and HPLC differences. Repeated analysis with HPLC is thus suggested in cases with AUC:s results close to the lower or upper margin of the therapeutic window.Correspondence to:
M. Grundmann, AssocProf, MD, PhD
Department of Clinical Pharmacology
Ostrava University Hospital and Medical Faculty
University of Ostrava
17. listopadu 1790
CZ 708 52 Ostrava, Czech Republic
Email: milan.grundmann@fnspo.cz

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International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 1/2011 (38-40)

Subacute liver failure induced by adalimumab

S. Hagel¹, T. Bruns¹, B. Theis², A. Herrmann¹ and A. Stallmach¹

¹Division of Gastroenterology, Hepatology and Infectious Disease, Department of Internal Medicine II, and ²Department of Pathology, Friedrich-Schiller-University, Jena, Germany
Most cases of liver toxicity associated with TNF-antagonists have been linked to infliximab and to a lesser extent to etanercept. So far only mild elevations of liver enzymes during therapy with adalimumab have been reported. In general, patients who developed ALT and AST elevations were asymptomatic and the abnormalities decreased or resolved with either continuation or discontinuation of adalimumab, or modification of concomitant medications. In this case report, we are presenting the first case of a patient without previous history of liver disease or concomitant risk factors for liver disease who developed subacute liver failure during therapy with adalimumab for psoriatic arthritis.Correspondence to:
Dr. S. Hagel
Department of Internal Medicine II
Division of Gastroenterology, Hepatology and
Infectious Disease
Friedrich-Schiller-University
Erlanger Allee 101, 07740 Jena, Germany
Email: Stefan.hagel@med.uni-jena.de

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International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 1/2011 (41-45)

Erdosteine affects eicosanoid production in COPD

R.W. Dal Negro, M. Visconti, S. Tognella and C. Micheletto

Lung Department, Orlandi General Hospital, Bussolengo, Verona, Italy
Oxidant-antioxidant imbalance and lipid peroxidation are known to activate the 5-LO pathway with increased expression of inflammatory eicosanoids. Erdosteine has recently shown important anti-oxidant properties, including the ability to reduce 8-isoprostane in COPD patients. Aim: To assess the effects of erdosteine (E) on eicosanoids, and to compare the time-course of effect with that of E anti-oxidant activity. Methods: 12 moderate COPD patients (9 males, 60 – 78 y) randomly received E 300 mg b.i.d. or placebo (P) for 10 days in a double-blind, controlled design. Blood ROS (Fort/Units); serum LTB₄ and urine LTE₄ (pg/ml) were measured at baseline and after 1, 3, 5 and 10 days of treatment. Analysis of covariance (ANCOVA) was performed. Results: In COPD patients, both LTB₄ and LTE₄ dropped significantly during the 10-day treatment with E: s-LTB₄ from 136.0 ± 35.4 SD to 54.5 ± 31.2 SD; u-LTE₄ from 267.0 ± 91.5 SD to 84.0 ± 64.7 SD, p < 0.001 vs. p from Days 5 and 3, respectively. Moreover, a significant decrease of blood ROS was confirmed in patients using E. FEV₁ values slightly increased during erdosteine treatment, whereas a trend to decrease was observed in the placebo group, with a significant difference in favor of erdosteine after 10 days of treatment (p = 0.0088). Conclusions: 1) The scavenging and anti-inflammatory effects of Erdosteine were both confirmed; 2) erdosteine proved to affect eicosanoids significantly; 3) this novel effect underlines the important anti-inflammatory potentialities of the drug in COPD; 4) further investigation is needed in order to assess the capability of Erdosteine in controlling ongoing inflammation in chronic respiratory diseases.Correspondence to:
R.W. Dal Negro
Orlandi General Hospital
Via Ospedale, 37012 Bussolengo, Italy
Email: rdalnegro@ulss22.ven.it

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International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 1/2011 (46-48)

Toxic dermatitis in patients treated with Taxotere® (docetaxel): three case reports

B. van Oijen¹, M. Pleunis², F. Erdkamp², R. Prevoo³ and H. van der Kuy¹

¹Department of Pharmacology and Toxicology, ²Department of Hematology and Oncology, and ³Department of Dermatology, Orbis Medical Center, Sittard, The Netherlands
Three out of 25 patients receiving the same batch docetaxel, developed toxic dermatitis within 5 days after administration. Timing of occurrence was equal and symptoms were similar. Two patients continued with docetaxel without any problems. There is no assignable cause found that could explain the toxic dermatitis.Correspondence to:
B. van Oijen
Department of Pharmacology and Toxicology
Orbis Medical Center
Dr. H. van der Hoffplein 1
6162 BG Sittard – Geleen, The Netherlands
Email: b.vanoijen@orbisconcern.nl

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International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 1/2011 (49-50)

Minocycline-induced chemical pneumonitis and its successful treatment: a case report

H.-W. Shih¹, S.-L. Cheng¹, S.-C. Chang² and C.-Y. Chang¹

¹Department of Chest Medicine, Far Eastern Memorial Hospital, and ²Internal Medicine, National Yang-Ming University Hospital, Taipei, Taiwan
Chemical pleurodesis is an effective treatment for persistent air leakage and secondary pneumothorax. We report the case of a 57-year-old man who presented with pneumothorax and was treated by tube thoracostomy. Because of malpositioning of the chest tube, the minocycline that was administered for pleurodesis was injected into the lung parenchyma instead, which induced chemical pneumonitis. A review of literature indicated that this is the first report of minocycline-associated chemical pneumonitis and its successful treatment.Correspondence to:
Dr. C.-Y. Chang
Department of Chest Medicine
Far Eastern Memorial Hospital
21, Nan-Ya S. Rd., Sec.2
Pan-Chiao, Taipei, Taiwan
Email: koala2716@hotmail.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 1/2011 (51-57)

High absolute bioavailability of the new oral phosphodiesterase-4 inhibitor roflumilast

T.D. Bethke and G. Lahu

Nycomed GmbH, Konstanz, Germany
Objective: To establish basic intravenous (IV) pharmacokinetics of roflumilast (ROF) and its pharmacologically active metabolite roflumilast N-oxide (R-NO) and to determine the absolute bioavailability of ROF in humans. Materials: In a randomized, open-label, 2-period, 2-sequence crossover study 12 healthy male subjects were randomized to receive ROF either orally (PO) 500 µg (immediate release tablets) or single IV (150 µg over 15 min). Plasma concentrations were determined. Dose-adjusted point estimates and 90% confidence intervals (CI) were calculated for the ratio of the AUC time curves using a multiplicative model and parametric analysis. Results: After IV administration, clearance of ROF was 0.14 l/h/kg, volume of distribution (V_{d area}) 2.92 l/kg, and the terminal t_1/2 was 14.8 h. After PO administration, ROF was rapidly absorbed; the absolute bioavailability was 79%. The AUC of the R-NO metabolite generally exceeded that of ROF. After IV and PO administration, the metabolic ratios were 7.4 and 12.4, respectively. Dose-adjusted analysis of the R-NO AUC values indicate a 21% higher R-NO formation seen with PO vs. IV, suggesting entire first-pass conversion of ROF is to the active R-NO. Formation/clearance processes of the R-NO appear to be slow with an observed tmax of 6.9 – 8.8 h, and corresponding to apparent t_1/2 values of 22.7 h and 20.6 h, after IV and PO administration, respectively. Conclusion: ROF is rapidly absorbed after PO administration and exhibits high absolute bioavailability and low clearance pharmacokinetics. The total exposure of R-NO exceeds that of ROF by a factor of 12 after oral administration.Correspondence to:
Dr. T.D. Bethke
Medical Department
Nycomed Germany GmbH
Byk-Gulden-Straße 2
78467 Konstanz, Germany
Email: Thomas.Bethke@nycomed.com

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The 8th Annual Meeting of CESAR in St. Gallen – Novel therapeutic concepts in hemato-oncology

R. Morant, D. Sehrt and U. Jaehde

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Cytotoxic effects of opioids on cancer cell lines

C. Friesen, S. Bacher, I. Hormann, M. Roscher and E. Miltner

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Integrating predictive biomarkers and classifiers into oncology clinical development programs: an adaptive, evidence-based approach

R.A. Beckman

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MRI Molecular imaging with albumin nanoparticles: achievements and challenges

G.C. Thurner, A.A. Abdelmoez, E.A. Wallnoefer, I. Rohr, N. Klammsteiner, H. Talasz, C. Kremser, W. Jaschke and P. Debbage

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Relevance of microRNA modulation in chemoresistant colon cancer in vitro

R.M. Mader, M. Wieser, W. Berger, M. Kalipciyan, M. Hackl, G.G. Steger and J. Grillari

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Suicide activation in a 5-fluorouracil resistant colon cancer model in vitro

R.M. Mader, M. Kalipciyan, P. Ohana, A. Hochberg and G.G. Steger

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Stable combretastatin A-4 analogues with sub-nanomolar efficacy against chemoresistant HT-29 cells

R. Schobert, K. Effenberger-Neidnicht and B. Biersack

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MRI molecular imaging with nanoparticles: a technical platform for early diagnosis of cancer

E.A. Wallnöfer, G.C. Thurner, A.A. Abdelmoez, I. Rohr, N. Klammsteiner, H. Talasz, C. Kremser, W. Jaschke and P. Debbage

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Lysophosphatidylcholine (LPC) as a pharmacological molecule for the reduction of tumor cell adhesion and metastasis

M. Alexander, M. Schlesinger, P. Jantscheff, U. Massing and G. Bendas

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Chemosensitivity of conjunctival melanoma cell lines to chemotherapeutic agents

H. Westekemper, M. Freistuehler, G. Anastassiou, G. Nareyeck, M. Zeschnigk, N. Bornfeld, K.-P. Steuhl, M.E. Scheulen and R.A. Hilger

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Cross-resistance of 5-fluorouracil-resistant colon carcinoma in vitro

I.E. Ratzenboeck, B. Bartl, B. Forstner, M. Kalipciyan, G.G. Steger and R.M. Mader

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Measurement of 5-FU plasma levels in patients with advanced cancer: correct approach to practical procedures is essential

M. Blaschke, S. Cameron, K. Emami, J. Blumberg, U. Wegner, M. Nischwitz and G. Ramadori

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Comparison of seminal vesicle, non-malignant and malignant prostate tissues with gene expression patterns using quantitative real-time PCR

R. Morant, V. Vuaroqueaux, P.A. Diener, G. Fürstenberger, C. Horica, T. Németh, M. Sulmoni, U. Eppenberger and S. Eppenberger-Castori

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Biomarker response on exposure to sunitinib and its primary metabolite (SU12662) in metastatic colorectal cancer patients

F. Kanefendt, A. Lindauer, M. Kinzig, D. Strumberg, M.E. Scheulen, K. Mross, R. Fischer, B. Moritz, F. Sörgel and U. Jaehde

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Choice and simulation of the randomization procedure for clinical trials

D. Schrimpf, L. Plotnicki and L.R. Pilz

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Anti-inflammatory and anti-cancer activities of essential oils and their biological constituents

A. Torres Salazar, J. Hoheisel, M. Youns and M. Wink

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A preliminary report of a Phase II study of folinic acid, 5-fluorouracil, irinotecan (FOLFIRI) plus sunitinib with toxicity, efficacy, pharmacokinetics, biomarker, imaging data in patients with colorectal cancer with liver metastases as 1st line treatment

K. Mross, M. Büchert, U. Fasol, U. Jaehde, F. Kanefendt, D. Strumberg, J. Arends, J. Hense, B. Moritz, R. Fischer and M.E. Scheulen

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Volume 49, No. 1/2011(January)