Volume 50, No. 2/2012(February)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Original Research
Self-medication of upper gastrointestinal symptoms with hydrotalcite: a noninterventional community pharmacy study on drug usage and patient satisfaction
Franziska Häcker and Hartmut Morck
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 2/2012 (87-99)
Self-medication of upper gastrointestinal symptoms with hydrotalcite: a noninterventional community pharmacy study on drug usage and patient satisfaction
Franziska Häcker1 and Hartmut Morck1,2
1Pharmazeutisches Institut, Philipps-Universität Marburg, Marburg and 2Cuibono Health Consulting GmbH, Berlin, Germany
Objective: Acid-related gastrointestinal symptoms are widely prevalent. These complaints are often self-medicated with antacids. For the community pharmacy setting little is known about how patients’ perceptions of self-treating symptoms are met, e.g., via patient satisfaction. Such outcomes are difficult to determine in clinical trials, therefore, non-interventional studies (NIS) are one applicable method for gaining data under real-world conditions. This study was conducted to investigate: (1) characteristics of gastrointestinal symptoms and patients’ global health status, (2) drug usage and symptom relief, and (3) patient satisfaction with the medication. Methods: This prospective, cross-sectional NIS was performed in cooperation with 137 community pharmacies in Germany. Participants were recruited from customers, after they had purchased the antacid, and were asked to complete a self-administered questionnaire. Patient satisfaction with hydrotalcite was assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM) on the scales effectiveness, side effects, convenience, and global satisfaction. Results: 548 patients answered the questionnaire. The following symptoms were reported most frequently: heartburn (65%) and acid regurgitation (37%). In comparison to the general population, more participants rated their global health in lower categories, e.g., satisfying (35% vs. 23%) or poor (12% vs. 5%). Drug usage patterns were found to be in accordance with the principles of self-medication. The majority of patients reported a noticeable symptom relief within 15 min after drug intake. TSQM mean scores were high in all four scales; an excellent score was achieved in the scale side effects. Study results also revealed that the self-perceived global health status of the patients had an impact on their global satisfaction with the medication. Conclusions: This NIS shows that patients (1) are often affected in their global health when suffering from acid-related symptoms, (2) observed a fast symptom relief after drug intake, and (3) are highly satisfied with the antacid hydrotalcite.Correspondence to:
Prof. Dr. Hartmut Morck
Cuibono Health Consulting GmbH
Grolmanstraße 44
10623 Berlin, Germany
Email: hartmut.morck@cuibonohealthconsulting.com
Original Research
Bioavailability and pharmacodynamics of two 10-mg estradiol valerate depot formulations following IM single dose administration in healthy postmenopausal volunteers
Barbara S. Schug, Frank Donath and Henning H. Blume
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 2/2012 (100-117)
Bioavailability and pharmacodynamics of two 10-mg estradiol valerate depot formulations following IM single dose administration in healthy postmenopausal volunteers
Barbara S. Schug, Frank Donath and Henning H. Blume
SocraTec R&D, Oberursel, Germany
Objective: To establish the bioequivalence (BE) between two i.m. estradiol valerate (E2V) depot formulations, i.e., Estradiol-Depot 10 mg® (test) and Progynon Depot-10® (reference). To compare the effect of both treatments on the vaginal maturation index and on the increase of the endometrial thickness after administration of both formulations. Methods: A total of 24 postmenopausal females aged 54.7 ± 5.35 year (BMI 25.84 ± 1.98 kg/m2) completed this BE assessment. The investigation was planned and designed as a single center, openlabel, single dose, cross-over study including 2 periods with 2 treatments and 2 sequences. Baseline levels were obtained for all subjects. Single doses of 10-mg E2V of each product were administered and pharmacokinetics and pharmacodynamics were assessed over 2 weeks with a washout period of 4 weeks. A gas chromatographic-mass spectrometric method with negative chemical ionization and selected ion monitoring was applied, after validation, for the determination of estradiol (E2), estrone (E1) and internal standard estradiol-D4 derivatives. The cytology of the vaginal smear (parabasal, intermediate and superficial cells from lateral wall opposite tip of cervix) was assessed by investigation of ~ 200 cells. The vaginal maturation index (VMI) was calculated by the equation: VMI (%) = (superficial cells × 1) (%) + (intermediate cells × 0.5) (%). Endometrial thickness was measured by transvaginal ultrasonic scans and recorded in mm. Results: The geometric means (Gmeans) of the measured values of Cmax and AUC0–t for E2 were 543.5 pg/ ml and 84,734 pg × h/ml for test and 505.7 pg/ml and 82,660 pg × h/ml for reference, whereas those for E1 were 219.0 pg/ml and 38,950 pg × h/ml for test and 204.9 pg/ml and 37,159 pg × h/ml for reference, respectively. The point estimates (PEs) of the Test/ Reference (T/R) mean ratios of the variables Cmax and AUC0–t for E2 (measured values) were 107.3% and 102.5%, respectively. The PEs of the T/R mean ratios of the variables Cmax and AUC0–t for E1 (measured values) were 106.9% and 105.0%, respectively. Median endometrial thickness increased in Period I from baseline levels of ~ 3 mm (Day –2) to ~ 7 mm (Day 21) after administration of both products without returning completely to baseline prior to the next administration. In Period II, median values of 7 mm were also reached (Day 21) after administration of both products. Median vaginal maturation indices increased in Period I from baseline levels of ranging from 45 – 60% (Day -2) to 86 – 94.5% (Day 21). In Period II maturation indices of ≥ 90% were calculated as baselines (Day -2) and these levels remained constant until the end of the assessment (Day 21) independently from the products. After 21 days of treatment, test and reference presented practically no differences in terms of their effects on endometrial thickness and vaginal maturation index. Conclusions: The 95% CIs for the T/R mean ratios of AUC0–t and Cmax for E2 and E1 fell within the acceptance limits of 80 – 125% and therefore bioequivalence could be demonstrated for both formulations. The changes in endometrial thickness and the vaginal maturation index indicated that the pharmacodynamic effect is pronounced already after the first administration and that the effect continued notably for longer time compared to the presence of E2 and E1 in plasma. A 4-week washout phase was insufficient to avoid residual pharmacological effects after the administration of both preparations.Correspondence to:
Barbara S. Schug, PhD
SocraTec R&D
Im Setzling 35
61440 Oberursel, Germany
Email: Barbara.Schug@ socratec-pharma.de
Original Research
Pharmacokinetics of multiple inhaled NVA237 doses in patients with chronic obstructive pulmonary disease (COPD)
Romain Sechaud, Didier Renard, Lixin Zhang- uberson, Stephan de la Motte, Anton Drollmann and Guenther Kaiser
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 2/2012 (118-128)
Pharmacokinetics of multiple inhaled NVA237 doses in patients with chronic obstructive pulmonary disease (COPD)
Romain Sechaud1, Didier Renard2, Lixin Zhang-Auberson2, Stephan de la Motte3, Anton Drollmann1 and Guenther Kaiser1
1Novartis Institutes for Biomedical Research, 2Novartis Pharma AG, Basel, Switzerland and 3Harrison Clinical Research GmbH, Munich, Germany
Objective: NVA237 (glycopyrronium bromide) is a once-daily longacting muscarinic antagonist (LAMA) in development for the treatment of chronic obstructive pulmonary disease (COPD). This study investigated the pharmacokinetics (PK) of NVA237 following single and repeated once-daily inhalation in mild-tomoderate COPD patients. Methods: In this double-blind, parallel-group study, COPD patients were randomized to a 14-day treatment with NVA237 (25, 50, 100 or 200 μg) or placebo. Plasma concentration-time profiles and urinary excretion of NVA237 were determined on Days 1 and 14. Results: The median time to reach maximal plasma concentration (tmax) was 5 or 6.5 min postinhalation. At steady state (Day 14), total and maximum systemic exposure (AUC0–24, Cmax) to NVA237 and urinary excretion of unchanged drug (Ae0–24) was approximately dose proportional over the 50 – 200 μg dose range. The average exposure was 1.4- to 1.7- fold higher on Day 14 compared with Day 1. The mean terminal elimination half-life (t1/2) of NVA237 ranged between 13 and 22 h. Steady-state plasma concentrations were reached within 1 week of treatment. Renal clearance (CLR) was similar across doses both after single and repeated dosing, ranging between 17.4 and 20.6 l/h. Urinary excretion of NVA237 enantiomers ([3S,2R]- and [3R,2S]-stereoisomers) was similar with respect to the amount excreted within 24 h and the excretion rate. Conclusions: The pharmacokinetics of NVA237 were consistent between doses with limited systemic accumulation at steady state after repeated once-daily inhalation.Correspondence to:
Dr. Romain Sechaud, PhD
Novartis Institutes for BioMedical Research
Translational Sciences, WSJ-210.4.20
Novartis Campus, 4056 Basel, Switzerland
Email: romain.sechaud@novartis.com
Original Research
Clinical research: benefits of Bhattacharya modeling
Manuel C. Solis and Ton J. Cleophas
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 2/2012 (129-135)
Clinical research: benefits of Bhattacharya modeling
Manuel C. Solis1 and Ton J. Cleophas2
1Hospital San Carlos, Playa del Carmen, Mexico and 2European College of Pharmaceutical Medicine Lyon France and Albert Schweitzer Hospital, Dordrecht, The Netherlands
Background: Bhattacharya modeling is a Gaussian method recommended by the Food and Agricultural Organization of the United Nations Guidelines for analyzing the eco-system. It is rarely used in clinical research. Objective: To investigate the performance of Bhattacharya modeling for clinical data analysis. Methods: Using as examples simulated vascular lab scores we assessed the performance of the Bhattacharya method. SPSS statistical software is used. Results: 1. The Bhattacharya method better fitted the data from a single sample than did the usual Gaussian curve derived from the mean and standard deviation with 15 vs. 9 cuts. 2. Bhattacharya models demonstrated a significant difference at p < 0.0001 between the data from two parallel-groups, while the usual t-test and Mann-Whitney test were insignificant at p = 0.051 and 0.085. 3. Bhattacharya modeling of a histogram suggestive of certain subsets identified three Gaussian curves. Conclusions: We recommend that Bhattacharya modeling be more often considered in clinical research for the purpose of (1) unmasking normal values of diagnostic tests, (2) improving the p-values of data testing and (3) objectively searching subsets in the data.Correspondence to:
Ton J. Cleophas, MD, PhD
c/o Dept Medicine Albert Schweitzer Hospital
Box 444, 3300 AK, Dordrecht, The Netherlands
Email: a.j.m.cleophas@asz.nl
Original Research
Clinical and economic impact of a pharmacistmanaged i.v.-to-p.o. conversion service for levofloxacin in Taiwan
Yu-Hsuan Yen, Hsiang-Yin Chen, Leu Wuan-Jin, You-Meei Lin, Wan C. Shen and Kuei-Ju Cheng
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 2/2012 (136-141)
Clinical and economic impact of a pharmacistmanaged i.v.-to-p.o. conversion service for levofloxacin in Taiwan
Yu-Hsuan Yen1,2, Hsiang-Yin Chen1,2, Leu Wuan-Jin2,3, You-Meei Lin2,3, Wan C. Shen1,2 and Kuei-Ju Cheng1,2
1Department of Pharmacy, Taipei Medical University, Wan Fang Hospital, 2School of Pharmacy, Taipei Medical University and 3Department of Pharmacy, Taipei Medical University, Shuang Ho Hospital, Taipei, Taiwan
Objective: A pharmacist-managed antibiotic intravenous to oral (i.v.-top. o.) conversion program has been incorporated to minimize unnecessary i.v. antibiotic usage. This study evaluated the clinical and economical impacts of a pharmacist-directed i.v.-to-p.o. conversion program for levofloxacin in Taiwan. Methods: Data was retrospectively collected by chart review during the pre-intervention period (PIP). During the intervention proactive conversion period (PCP), pharmacists reviewed and intervened on all levofloxacin orders. The detailed reimbursements for medications and inpatient expenses from the Bureau of National Health Insurance (NHI), Taiwan were calculated. The clinical impacts during the PIP and PCP were compared with the duration of the i.v. levofloxacin therapy, total used i.v./p.o. ratio levofloxacin, and total length of hospital stay. The financial impact was compared with medication costs and total inpatient expenditures. Results: The mean length of hospital stay was significantly decreased from 27.2 days to 16.1 days (p = 0.001) after the conversion program was implemented. The i.v. over p.o. ratio for DDD was 3.0 ± 0.6 vs. 2.1 ± 0.6 for PIP vs. PCP group (p = 0.032). The cost of the levofloxacin was significantly decreased ($ 568.9 ± 262.9 vs. $ 449.0 ± 266.4, PIP vs. PCP, p = 0.044). The total inpatient expenditures were also significantly reduced ($ 6,096 ± 5,164.0 vs. $ 3,649.6 ± 3, 740.4, PIP vs. PCP, p = 0.017). Conclusions: The pharmacist-managed i.v.-to-p.o. conversion service not only decreased the length of hospital stays, but also produced significant cost savings, both on medication costs and the total inpatient expenditures. This represents strong evidence for implementing the i.v.-to-p.o. conversion service in Taiwan.Correspondence to:
Kuei-Ju Cheng, MS, PhD
Department of Pharmacy
Taipei Medical University-Wanfang Hospital, No. 111
Hsing Long Road, Section 3
Taipei 116, Taiwan
Email: 97525@wanfang.gov.tw
Original Research
Pharmacokinetics of a fixed-dose glimepiride/sustained-release metformin combination
Kyu-pyo Kim, Kyoung Soo Lim, Bo-Hyung Kim, Hyun-Suk Shin, Joo-Youn Cho, Sang-Goo Shin, In-Jin Jang and Kyung-Sang Yu
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 2/2012 (142-149)
Pharmacokinetics of a fixed-dose glimepiride/sustained-release metformin combination
Kyu-pyo Kim1*, Kyoung Soo Lim*, Bo-Hyung Kim, Hyun-Suk Shin, Joo-Youn Cho, Sang-Goo Shin, In-Jin Jang and Kyung-Sang Yu
Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea
*Both authors contributed equally to this work.
1Current affiliation: Department of Internal Medicine, Ulsan University College of Medicine and Asan Medical Center, Seoul, Korea
Objective: Pharmacokinetic (PK) profiles of glimepiride and metformin have been established for the combination drug as well as each agent individually. However, the PK profiles of a combination drug containing glimepiride and sustainedrelease (SR) metformin have not been reported. To compare the pharmacokinetic profiles of glimepiride/SR metformin (2 mg/500 mg) with the PK of immediate-release (IR) formulations, an open-label, randomized, 3-period, 3-sequence, 3-treatment, crossover study was conducted in 12 healthy subjects. Methods: After a single administration of glimepiride/SR metformin 2 mg/500 mg (Treatment) or glimepiride/metformin IR 2 mg/500 mg (Reference 1), or administration of 2 doses of glimepiride/metformin IR 1 mg/250 mg 12 h apart (Reference 2), serial blood samples were collected and drug concentrations determined by liquid chromatography/ tandem mass spectrometry. PK parameters (Cmax and AUC24) for glimepiride and metformin were log-transformed and compared using a mixed-effects model analysis of variance (ANOVA). The mean differences and 95% confidence intervals (CIs) were back-transformed to obtain geometric mean ratios along with the CIs for the ratios. Results: Treatment demonstrated similar systemic exposures for glimepiride; the geometric mean ratio (95% CIs) for glimepiride AUC24 was 1.05 (0.97 – 1.13) for Treatment relative to Reference 1 and 1.08 (1.00 – 1.17) for Treatment relative to Reference 2. The SR formulation showed a delay in the time to reach maximum concentration for metformin from 1.0 – 4.0 h to 4.0 – 8.0 h and a decreased AUC24 value; the geometric mean ratio for metformin AUC24 was 0.87 (0.74 – 1.03) for Treatment relative to Reference 1 and 0.75 (0.63 – 0.88) for Treatment relative to Reference 2. Conclusions: This study demonstrates for the first time that fixed-dose glimepiride and SR metformin 2 mg/500 mg shows a PK profile similar to that of glimepiride, but with a delayed time to maximum concentration and slightly decreased bioavailability for metformin compared with the IR fixed-dose combination, in healthy volunteers. PK profiles from this exploratory study will be helpful in designing and conducting further studies in diabetic patients.Correspondence to:
Kyung-Sang Yu, MD, PhD
Department of Pharmacology and Clinical Pharmacology
National University College of Medicine and Hospital
101 Daehangno, Jongno-gu, Seoul 110-744, Korea
Email: ksyu@snu.ac.kr
Bioavailability Section
Absolute bioavailability of tolvaptan and determination of minimally effective concentrations in healthy subjects
Susan E. Shoaf, Patricia Bricmont and Suresh Mallikaarjun
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 2/2012 (150-156)
Absolute bioavailability of tolvaptan and determination of minimally effective concentrations in healthy subjects
Susan E. Shoaf, Patricia Bricmont and Suresh Mallikaarjun
Clinical Pharmacology, Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA
Tolvaptan is a selective vasopressin V2 receptor antagonist that can be given orally once daily for treatment of clinically significant hypervolemic and euvolemic hyponatremia (US) or cardiac edema (Japan). Tolvaptan absolute bioavailability was determined in a single-center, open-label, sequential administration trial in which intravenous (i.v.) placebo (Day –2), i.v. 1 mg tolvaptan (Day 1) and an oral 30 mg tablet (Day 8) were administered to 14 healthy subjects. Urine volume and osmolality were determined on Days –2, 1 and 8 at multiple intervals postdose; 24-h fluid balance was also assessed. On Days 1 and 8, blood samples for tolvaptan were collected for 48 h postdose. Mean absolute bioavailability was determined to be 56% (range 42 – 80). Mean peak tolvaptan concentration at 1 h (end-of-infusion) was 32.7 (range 18 – 45) ng/ml compared to 231 (range 87 – 410) ng/ml for the oral dose. In the 4-h period from start of the 1 mg tolvaptan i.v. infusion, 12 of 14 subjects experienced increased urine volume and decreased urine osmolality; both parameters were affected for 24 h postdose following the 30 mg oral dose. Minimally effective concentrations are rapidly achieved after oral dosing as all subjects had tolvaptan concentrations > 20 ng/ml at 1 h postdose.Correspondence to:
Susan E. Shoaf, PhD
2440 Research Blvd.
Rockville, MD 20850, USA
Email: susan.shoaf@otsuka-us. com
