Dustri Online Services

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 2/2010 (87-92)

Significant discrepancy in cyclosporin A post-dose concentrations when analyzed with specific RIA and HPLC method

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

¹Department of Clinical Pharmacology and ²Nuclear Medicine Clinic, Ostrava University Hospital and Faculty of Health Studies, University of Ostrava, Czech Republic
C₂ or AUC sparse sampling methods are widely recommended for therapeutic monitoring of cyclosporin A (CsA). One additional reason for promoting the C₂ sampling time in place of commonly used C₀ is that the C₂ level may actually provide more accurate measurement of parent drug concentration by immunoassays, as lower portion of metabolites has been formed 2 hours post-dose than at the steady-state trough time point. HPLC and RIA whole blood levels of CsA and its main metabolites AM1, AM9 and AM4N were compared during 12 hours profile after chronic administration. 40 stable renal transplant male patients (age 49 ± 6 years, body weight 76 ± 7 kg) were treated with CsA (Sandimmun Neoral^®, Novartis s.r.o, Prague, Czech Republic) in doses 198 ± 56 mg twice daily. Samples were collected in steady state (after 2 weeks of regular treatment regimen) as follows: pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8 and 12 hours after dose. CsA concentrations were determined both specific RIA assay (Cyclo-Trac SP Whole, Dia Sorin) and HPLC method, where concentrations of metabolites AM1, AM9 and AM4N were simultaneously analyzed. The AUC_0-12 was calculated by the linear trapezoidal rule. The percentage prediction error defined as [(RIA value-HPLC value)/HPLC value] × 100 was used for estimation of differences. C_max, t_max, and C_avg were compared using Student’s t-test. RIA produced significantly higher CsA levels than HPLC method in the period of 0.5 – 5 hours after application. The greatest differences (43 – 56%) occurred between 1 and 3 hours after dose. AUC_0-12, C_max a C_avg calculated from RIA results were consequently significantly higher. Only t_max remained unchanged. The ratio of metabolites/parent drug after CsA intake is decreasing but their absolute concentrations are significantly increasing. Mean levels at C₀/C₂ were CsA-RIA 82/612, CsA-HPLC 89/425, AM1 121/179, AM9 4.1/81.4, AM4N 9.5/21.0 ng/ml. TDM using C₂ and AUC sparse sampling may cause misleading interpretation using both methods alternately for the same patient.Correspondence to:
M. Grundmann,
Assoc. Prof, MD, PhD
Department of Clinical Pharmacology
Ostrava University Hospital and Faculty of Health Studies
University of Ostrava
17. listopadu 1790
708 52 Ostrava, Czech Republic
Email: milan.grundmann@fnspo.cz

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 2/2010 (93-102)

Effect of cilostazol on platelet aggregation in patients with non-ST elevation acute coronary syndrome

S. Pattanaik¹, S. Malhotra¹, Y.P. Sharma², J. Ahluwalia³, A. Bhalla⁴ and P. Pandhi¹

¹Department of Pharmacology, ²Department of Cardiology, ³Department of Hematology and ⁴Department of Internal Medicine, Post Graduate Institute of Medical Education and Research Chandigarh, India
Aims: The optimal antithrombotic regimen for non-ST elevation acute coronary syndrome(NSTEACS) has not yet been defined and the risk of ischemic events remains high in these patients. We aimed to evaluate the effect of cilostazol on agonist induced platelet aggregation and serum plasminogen activator inhibitor-1(PAI-1) in the patients with NSTEACS administered along with the standard antiplatelet regimen. Patients and methods: 40 patients of NSTEACS presenting within 72 h of onset of symptoms were randomized to cilostazol or placebo in 1 : 1 ratio, in whom a conservative treatment strategy was adopted. Cilostazol 100 mg b.i.d was administered within 12 h of hospital admission for 7 days along with standard doses of aspirin and clopidogrel. The primary end points were effect on agonist-induced platelet aggregation and serum PAI-1 levels after 7 days of treatment. Safety and clinical outcome assessment were also done at 7 and 30 days. Results: Patients in the triple therapy group showed significant decrease in the ADP (25.5 ± 27.4 vs. 5.6 ± 8.4; p = 0.003) and collagen (24.9 ± 25.5 vs. 11.7 ± 11; p = 0.04) induced percentage platelet aggregation after 7 days of treatment compared to the dual therapy group. There was no significant change in levels of serum PAI-1 (50.30 ± 10.17 ng/ml vs. 53.47 ± 14.08 ng/ml; p = 0.42). The composite of recurrent ischemia, myocardial infarction, need for intervention and death occurred in 4 patients in the cilostazol group compared to 7 in the placebo group at the end of 30 days of follow-up (p = 0.48). Conclusion: Cilostazol has additional platelet aggregation inhibition action in patients with NSTEACS along with aspirin and clopidogrel.Correspondence to:
Prof. P. Pandhi
Professor and Head, Department of Pharmacology
Postgraduate Institute of Medical Education and Research
Chandigarh-160 012, India
Email: ppandhi17@hotmail.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 2/2010 (103-108)

Sotrastaurin and everolimus pharmacokinetics after single-dose coadministration

J.M. Kovarik¹, M. Bartlett¹, C. Rordorf¹, M.C. Antunes¹, S. Winter¹, P. Marbach¹ and S. van Marle²

¹Novartis Pharmaceuticals, Basel, Switzerland and East Hanover, NJ, USA and ²Pharma Bio-Research Group, Zuidlaren, The Netherlands
Introduction: Sotrastaurin is an immunosuppressant that blocks T-lymphocyte activation via protein kinase C inhibition. The authors determined whether a pharmacokinetic interaction occurs between sotrastaurin and everolimus, both of which are substrates and inhibitors of CYP3A4. Methods: This was a randomized, three-period, crossover study in 18 healthy subjects. They received single oral doses of (1) 100 mg sotrastaurin, (2) 2 mg everolimus, and (3) the drug combination. Clinical and pharmacokinetic data were collected to Day 5 after each treatment. Results: Coadministration of everolimus decreased sotrastaurin C_max from 638 ± 295 to 539 ± 211 ng/ml yielding a combination/ monotherapy ratio (90% confidence interval) of 0.87 (0.76 – 1.00). Sotrastaurin total AUC was not altered by everolimus with values of 3660 ± 1853 versus 3630 ± 2006 ng.h/ml and a ratio of 1.00 (0.88 – 1.13). Sotrastaurin increased everolimus C_max from 15 ± 6 to 16 ± 6 ng/ml yielding a ratio of 1.15 (0.99 – 1.33) and increased everolimus total AUC from 114 ± 50 to 137 ± 56 ng.h/ml yielding a ratio of 1.20 (1.05 – 1.37). The possibility that a higher dose of sotrastaurin than used in this study might further increase everolimus blood levels cannot be excluded. Conclusions: Coadministration of a single 100 mg dose sotrastaurin with a single 2 mg dose everolimus did not alter sotrastaurin pharmacokinetics to a clinically relevant extent. Everolimus AUC was increased 20% by sotrastaurin.Correspondence to:
J.M. Kovarik
Novartis Pharma
Building WSJ 210.427
4002 Basel, Switzerland
Email: john.kovarik@ novartis.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 2/2010 (109-119)

A novel microsatellite polymorphism of sodium channel beta1-subunit gene (SCN1B) may underlie abnormal cardiac excitation manifested by coved-type ST-elevation compatible with Brugada syndrome in Japanese

R. Ogawa¹, R. Kishi², A. Takagi², I. Sakaue⁴, H. Takahashi¹, N. Matsumoto³, K. Masuhara⁴, K. Nakazawa², S. Kobayashi³, F. Miyake² and H. Echizen¹

¹Department of Pharmacotherapy, Meiji Pharmaceutical University, Tokyo, Departments of ²Cardiology, ³Pharmacology and ⁴Hospital Pharmacy, St. Marianna University School of Medicine, Kanagawa, Japan
Objective: Brugada syndrome (BrS) is a rare sodium channelopathy typically seen in middle-aged, Southeast Asian males conferring high risks of cardiac sudden death. Loss-of-function mutations in SCN5A encoding the α-subunit of cardiac sodium channels may account partially for its etiology. We aimed to study whether mutations in the β-subunits of sodium channel (SCN1B and SCN2B) would also be associated with abnormal cardiac excitation in BrS. Methods: 85 Japanese patients suspected to have BrS undertook a diagnostic challenge test with a sodium channel blocker, pilsicainide. Genetic screenings were performed for SCN5A, SCN1B and SCN2B by PCR-SSCP and direct sequence of amplicons in the patients and 50 healthy controls. Results: 30 patients exhibited BrS-like ECG pattern (i.e., a coved-type ST-segment elevation) either at baseline or after the drug challenge. Genetic screenings revealed a sequence variation (p.R190Q) and 3 polymorphisms (p.H558R, p.R1193Q, IVS24+53T > C) in SCN5A, a sequence variation (g.-26G > T) and 2 polymorphisms (IVS1+53G > T and IVS3 +2996(TTA)8-15) in SCN1B and 2 polymorphisms (IVS2+27A > G, IVS2+76G > A) in SCN2B. A logistic analysis revealed that male, middle age (40 – 59 years of age) and IVS3+2996(TTA)8 of SCN1B were significantly (p < 0.05) associated with the development of BrS-like ECG pattern with odds ratios (95% confidence intervals) of 5.9 (1.8 – 19.6), 2.9 (1.4 – 6.1) and 2.3 (1.1 – 4.9), respectively. While the IVS3+2996(TTA)8 allele has not been reported in Caucasians previously, its allelic frequency in the patients exhibiting the BrS-like ECG pattern (0.250) was comparable to that in the healthy controls (0.260). Conclusion: The IVS3+ 2996(TTA)8 allele commonly seen in Japanese would not be pathogenic itself but may render male, middle-aged Japanese more susceptible to BrS.Correspondence to:
R. Ogawa, MSc
Department of Pharmacotherapy
Meiji Pharmaceutical University
2-522-1 Noshio, Kiyose-shi
Tokyo, 204-8588, Japan
Email: smridron@my-pharm.ac.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 2/2010 (120-128)

The effect of food with varying fat content on the clinical pharmacokinetics of gabapentin after oral administration of gabapentin enacarbil

R. Lal, J. Sukbuntherng, W. Luo, F.J. Huff, J. Zou and K.C. Cundy

XenoPort, Inc., Santa Clara, CA, USA
Gabapentin enacarbil, an actively transported prodrug of gabapentin, provides sustained and dose-proportional exposure to gabapentin. Objective: To evaluate the effect of food of varying fat content on the pharmacokinetics and tolerability of gabapentin enacarbil. Methods, materials and subjects: A randomized, open-label, crossover study of 1,200 mg gabapentin enacarbil was conducted in 12 healthy adults, under four conditions: fasted, or following low-fat (200 – 300 kcal total, ~6% from fat), moderate-fat (500 – 600 kcal total, ~30% from fat) or high-fat meals (1,000 kcal total, ~50% from fat), separated by a washout period of ≥ 5 days. Results: Ten subjects completed treatment under all four conditions. Data from all subjects were used for pharmacokinetic and safety analyses unless stated otherwise. Mean (standard deviation) bioavailability (based on urinary recovery) of gabapentin from gabapentin enacarbil was 42.0 (6.1)% (fasted), 64.3 (13.2)% (low-fat meal), 64.9 (16.9)% (moderate-fat meal), and 76.1 (14.4)% (high-fat meal). Gabapentin exposures (AUC_inf) in fed conditions were 23% (low-fat meal), 31% (moderate-fat meal), and 40% (high-fat meal) greater than the exposure under fasted condition. Fed conditions did not significantly delay median t_max, but a trend for delayed gabapentin enacarbil absorption was seen in t_max ranges following moderate- and high-fat meals compared with the fasted state or low-fat meal. The most commonly reported treatment-emergent adverse events (TEAEs) were dizziness (4 subjects), balance disorder (4 subjects) and somnolence (3 subjects). All TEAEs were rated as mild in intensity. Conclusion: Administration of gabapentin enacarbil with food enhanced gabapentin exposure compared with fasted conditions, regardless of the fat or caloric content, and gabapentin enacarbil was generally well tolerated.Correspondence to:
R. Lal, PhD
XenoPort, Inc.
3410 Central Expressway
Santa Clara, CA 95051, USA
Email: ritu.lal@xenoport.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 2/2010 (129-137)

Comparison of one-year costs of Type 2 diabetes treatment with insulin glargine or insulin detemir in a basal supported oral therapy (BOT) in Germany

S. Pscherer¹, E.S. Dietrich², F.-W. Dippel³ and A.R. Neilson²

¹Klinikum Traunstein, Germany, ²HealthEcon AG, Basel, Switzerland, and ³Sanofi-Aventis Deutschland GmbH, Berlin, Germany
Objective: A one-year cost analysis comparing basal insulin analogues glargine (IG, Lantus^®) versus detemir (ID, Levemir^®) in combination with oral antidiabetic drugs (basal supported oral therapy; BOT) in insulin naive Type 2 diabetes patients in Germany based on the results of a randomized controlled clinical trial (RCT). The trial demonstrated equivalent treatment efficacy. Materials and methods: Total direct diabetes treatment costs were estimated from the perspective of the German statutory health insurance (SHI) for the time horizon of one-year. Simulated resources included medication (insulin, oral antidiabetic drugs) and consumable items (needles, blood glucose test strips and lancets). Initial and final insulin doses per kg body weight and proportion of patients with once/twice daily insulin injection were taken from the above mentioned RCT. Unit costs were taken from official German price lists and sources. Deterministic-(DTA) and probabilistic sensitivity analyses (PSA) on resource use and unit costs were performed to test robustness of the results. Results: Average annual treatment costs per patient (base case) were € 849 for glargine and € 1,334 for detemir resulting in cost savings of € 486 per patient per year (36%). Costs of insulins were € 469 (IG) and € 746 (ID). Costs of consumable items amounted at € 380 (IG) and € 588 (ID) respectively. Sensitivity analyses confirmed the findings in favor of insulin glargine. PSA results found cost savings ranging from € 429 to € 608 (5th/95th percentiles). Conclusions: The current model estimated that insulin glargine was associated with lower annual treatment costs of € 486 (36%) compared to the use of insulin detemir while the same glycemic control is expected to be achieved.Correspondence to:
A.R. Neilson
HealthEcon AG
Steinentorstr. 19, Postfach 1510
4001 Basel, Switzerland
Email: aneilson@healthecon.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 2/2010 (138-145)

Pharmacokinetic comparisons of three nasal fentanyl formulations; pectin, chitosan and chitosan-poloxamer 188

A. Fisher¹, M. Watling¹, A. Smith¹ and A. Knight²

¹Archimedes Development Limited, Albert Einstein Centre, Nottingham Science and Technology Park, University Boulevard, Nottingham, and ²Evicom Limited, Somerset House, Teddington, UK
Objectives: To optimize the absorption profile and reduce C_max, three new fentanyl nasal spray formulations have been developed: fentanyl pectin (FPNS), fentanyl chitosan (FChNS) and fentanyl in chitosan-poloxamer 188 (FChPNS). The venous pharmacokinetic profiles and tolerability of these formulations were assessed and compared with oral transmucosal fentanyl citrate (OTFC) lozenge. Subjects and methods: This randomized, open-label, crossover study was conducted in opioid-naïve, healthy adult volunteers. Subjects were dosed under naltrexone blockade on four occasions with three nasal sprays (100 µg in 100 µl) and OTFC 200 µg. Fentanyl venous plasma concentrations were measured up to 24 h post-dose. Tolerability was assessed by clinical nasal assessments and a nasal reactogenicity questionnaire. Results: 18 subjects were enrolled and completed the study. The mean dose-normalized AUC_0-∞ for each nasal formulation was significantly higher (p < 0.05) compared with OTFC. Bioavailability compared with OTFC was significantly greater for all nasal fentanyl formulations (FPNS 132.4%, FChNS 154.1%, FChPNS 122.3%). Median t_max (FPNS 0.33 h, FChNS 0.17 h, FChPNS 0.26 h) were significantly (p < 0.001) reduced (OTFC 1.5 h) and mean C_max significantly increased with all nasal formulations compared with OTFC. Nasal reactogenicity symptom incidence was lowest for the FPNS formulation (FPNS 2, FChNS 28 and FChPNS 45). Conclusions: All nasal formulations demonstrated significantly increased systemic exposure and reduced times to peak plasma values compared with OTFC. The FPNS formulation exhibited the most favorable nasal and general tolerability profiles. It appears suitable for further investigation in breakthrough cancer pain management.Correspondence to:
A. Fisher, PhD
Archimedes Development Limited
Albert Einstein Center
Nottingham Science and Technology Park
University Boulevard
Nottingham, NG7 2TN, UK
Email: tonyfisher@archimedespharma.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 2/2010 (146-157)

Comparative bioavailability of two once-daily tramadol HCl 200 mg extended-release products in healthy volunteers

G. Groenewoud¹, T. Cronje¹, M.A. Potgieter¹ and D. Karhu²

¹Farmovs Parexel (Pty) Ltd., Brandhof, Bloemfontein, South Africa, and ²Labopharm Inc., Laval, Québec, Canada
An open-label, randomized, 2-way crossover study was conducted to compare the pharmacokinetics of Tramadol Contramid^® OAD 200 mg tablets and Monocrixo^® L.P. 200 mg capsules following single-dose administration under fasting conditions in 30 healthy adult volunteers. Serial blood samples were collected at predefined time points over 48 hours post-dose and racemic tramadol and O-desmethyltramadol concentrations in plasma were determined using a validated LC-MS/MS method. Pharmacokinetic parameters were derived using noncompartmental methods. Results were compared using an analysis of variance (ANOVA) and the bioequivalence determination was based on the 90% confidence intervals for C_max, AUC_0-t and AUC_0-∞. Although the two products were determined to be bioequivalent with respect to C_max and AUC, the time to reach peak tramadol concentrations was significantly earlier for Tramadol Contramid^® OAD (6 hours vs. 10 hours). A mean tramadol concentration of 100 ng/ml was attained within 1 hour for Tramadol Contramid^® OAD compared with > 4 hours for Monocrixo^® L.P. Both products were well tolerated.Correspondence to:
D. Karhu, BSc
Labopharm Inc.
480 Boul. Armand-Frappier
Laval, Québec, H7V 4B4, Canada
Email: dkarhu@labopharm.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 48 – No. 2/2010 (158-170)

Differences in bioavailability between 60 mg of nifedipine osmotic push-pull systems after fasted and fed administration

M. Anschütz¹, M. Wonnemann², B. Schug¹, C. Toal³, F. Donath¹, A. Pontius⁵, K. Pauli⁵, E. Brendel⁴ and H. Blume¹

¹SocraTec R&D, Oberursel, ²SocraMetrics, Erfurt, Germany, ³Bayer Inc., Toronto, Canada, ⁴Bayer HealthCare, Elberfeld, and ⁵Bayer HealthCare, Berlin, Germany
Objectives: This study was designed to evaluate and compare the bioavailability of two osmotically active formulations of 60 mg nifedipine, Gen-Nifedipine extended release Test tablets (Genpharm ULC, Etobicoke, ON, Canada) and Adalat XL Reference tablets (Bayer Healthcare AG, Leverkusen, Germany) after single dose fasted and fed administration. Materials and methods: The study was performed following a 4-period crossover design with both investigational products obtained from marketed batches. The complete pharmacokinetic evaluation was carried out in 26 healthy male subjects with a median age of 29.5 years (range 18 – 44 years), mean weight of 79.7 kg (range 66.0 – 97.5 kg), and a mean body mass index (BMI) of 24.1 kg/m² (range 22.1 – 26.9 kg/m²). Tablets were administered with tap water either under fasting conditions or immediately following a high-fat, high-calorie breakfast. Blood samples were taken predose and at pre-defined time points until 48 h post dosing. Samples were protected from light during handling and frozen until analysis. A validated LC-MS/MS method was used for the quantification of nifedipine in plasma samples. All kinetic parameters were determined model-independently for each treatment directly from measured concentrations. Monitoring of subject safety was accomplished by routine monitoring of blood pressure, heart rate and probing for adverse events. Results: In-vitro dissolution curves show later onset and considerably lower quantity of nifedipine release from Test compared to Reference tablets. Under fasting conditions total and maximum exposure, represented by geometric mean AUC_0-tlast- and C_max-values, respectively were 466.7 h·ng/ml (AUC_0-tlast) and 21.9 ng/ml (C_max) for Test and 507.8 h·ng/ml (AUC_0-tlast) and 22.0 ng/ml (C_max) for Reference tablets. However, the Test product exhibited a notably longer lag-time and less rapid onset of absorption than the Reference tablets. Moreover, the plateau phase is maintained for about 14 hours on Test but for almost 20 hours on Reference. Point estimates (PE) and associated 90% confidence intervals (CI) were determined as 91.8% and 79.9 – 105.5% for AUC_0-tlast, as well as 99.8% and 88.6 – 112.4% for C_max. Larger differences were found for AUC_0-9h (PE: 54.8%; CI: 45.8 – 65.5%) determined as parameter for early exposure. Under fed conditions, although the mean plasma concentration time curves look similar in shape, concentrations of Test compared to Reference tablets are considerably lower at all time points until 36 hours after dosing. Again the lag time in onset of drug absorption is notably longer for the Test product. Both, total and maximum exposure, represented by geometric mean values for AUC_0-tlast and C_max, were considerably lower (differences also statistically significant) after administration of Test with 481.8 h·ng/ml for AUC_0-tlast and 25.3 ng/ml for C_max in comparison to Reference tablets with 595.9 h·ng/ml for AUC_0-tlast and 31.9 ng/ml for C_max. Test/Reference point estimates (PE) and associated 90% confidence intervals (CI) were determined as 80.7% and 73.7 – 88.5% for AUC_0-tlast, as well as 79.6% and 70.3 – 90.0% for C_max. Differences were also even more expressed for AUC_0-9h (PE: 54.9%; CI: 47.4 – 63.5%) determined as parameter for early exposure. Conclusion: The results indicate that although both products are osmotic release systems they are not bioequivalent according to the accepted standards. This difference between both osmotic delivery systems might be substantiated by the fact that the core of the Test product is designed as a monolayer system (containing both, the active ingredient and the osmotic component) while Reference tablets consist of two separate layers. The observed pharmacokinetic differences may have an impact on blood pressure control in patients and thus, should be kept in mind when switching during treatment.Correspondence to:
Prof. Dr. H. Blume
SocraTec R&D GmbH
Im Setzling 35
61440 Oberursel, Germany
Email: henning.blume@socratec-pharma.de

Abstract

Is 1-methylxanthine an ideal model substrate for establishing the renal tubular transport of organic ions?

N.R. Srinivas

Warenkorb Übersicht
Type	Qtty	Price
Der Warenkorb ist leer

Int. Journal of Clinical Pharmacology and Therapeutics Die Online-Versionen der Zeitschriften werden jeweils vor Erscheinen der Print-Ausgabe aktualisiert. Alle Inhalte dieser Website stehen Abonnenten der Zeitschrift nach einmaliger Registrierung ohne Mehrkosten zur Verfügung. Um die Artikel im PDF-Format betrachten zu können, benötigen Sie die Adobe Reader® Software.
Preis für gesamte Ausgabe: 30.00$

Benutzername:
Passwort:

Volume 48, No. 2/2010(February)