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Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 2/2011 (99-108)

Exenatide – pharmacokinetics, pharmacodynamics, safety and tolerability in patients ≥ 75 years of age with Type 2 diabetes

H. Linnebjerg¹, P.A. Kothare², M. Seger², A.M. Wolka² and M.I. Mitchell¹

¹Lilly Research Centre, Eli Lilly and Company Limited, Erl Wood Manor, Surrey, UK, and ²Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA
Objective: This study evaluated pharmacokinetics, pharmacodynamics, safety, and tolerability of single doses of exenatide in elderly Type 2 diabetes (T2D) patients. Methods: This placebo-controlled, patient-blind, crossover study compared elderly patients (>= 75 y, n = 15) to controls (>= 45 to <= 65y, n = 15) with T2D. Patients were randomized to single subcutaneous doses of exenatide 5µg, placebo or exenatide 10 µg (Sequence 1) or placebo, exenatide 5 µg or exenatide 10 µg (Sequence 2) before a standardized breakfast over three consecutive days. Serial blood samples were collected for plasma exenatide and serum glucose concentrations. Pharmacokinetic data from this study were also integrated with those from six other clinical pharmacology studies to further evaluate the impact of age on plasma exenatide apparent clearance (CL/F) (139 controls (<= 65 y); 28 elderly patients (> 65 y)). Results: Mean ± SD ages for control and elderly patients were 57 ± 6 y and 78 ± 3 y, respectively. All elderly patients had renal impairment at baseline, as compared with one-third of controls. Dose-normalized plasma exenatide maximum concentration and exposure were greater in elderly patients, but between-age group differences were neither statistically significant nor considered clinically relevant. The integrated pharmacokinetic analysis showed a significant linear relationship between plasma exenatide CL/F and renal clearance (test of slope = 0, p < 0.001), with no additional effect from age. Exenatide dose-dependently blunted postprandial serum glucose excursions in both age groups. No hypoglycemia or serious adverse events were reported, and exenatide was generally well tolerated in both age groups. Conclusions: Exenatide dose adjustments should be determined by renal function rather than age in elderly T2D patients.Correspondence to:
H. Linnebjerg, MSc, PhD
Lilly Research Centre
Eli Lilly and Company Limited
Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK
Email: linnebjerg_helle@lilly.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 2/2011 (109-115)

A phase I, single-dose study of the disposition of ¹⁴C-radiolabeled gabapentin enacarbil in healthy male volunteers

R. Lal, J. Sukbuntherng, J. Ho and K.C. Cundy

XenoPort, Inc., Santa Clara, CA, USA
Gabapentin enacarbil (GEn) is a prodrug of gabapentin that is effective in restless legs syndrome (RLS) and has dose-proportional gabapentin exposure. Objective: This Phase I, open-label, non-randomized, single-center study of ¹⁴C-GEn in healthy male volunteers (XenoPort, Inc. protocol: XP065) characterized the mass balance, absorption, metabolism, and elimination pathways of GEn after oral administration of ¹⁴C-GEn. Methods: Subjects received GEn 600 mg as two gelatin capsules containing 300 mg immediate release GEn solution each with approximately 50 µCi of ¹⁴C-GEn. Pharmacokinetic assessments included total radioactivity excreted in urine (A_eu(0–t)) and feces (A_ef(0–t)), mean maximum concentration (C_max), ¹⁴C-GEn-derived radioactivity in plasma and whole blood, and gabapentin area under the concentration-time curve extrapolated to infinity (AUC_0–inf). Tolerability was assessed using adverse events (AEs), vital signs, clinical laboratory tests, and ECGs. Six male subjects aged 24 – 46 years were recruited to the study. Results: Mean total recovery of ¹⁴C-GEn-derived radioactivity was 99.3% (94.1% in urine and 5.2% in feces). Mean Cmax and AUC for GEn-derived total radioactivity were similar in whole blood and plasma; the blood to plasma ratio for ¹⁴C-GEn-derived total radioactivity was 0.91. ¹⁴C-gabapentin was the only radioactive species present in blood. More than 85% of the radioactive dose was recovered in urine within 24 h of dosing. Eight treatment-emergent AEs were reported by 3 subjects; all were mild in intensity. There were no clinically relevant changes in vital signs, laboratory values, or ECGs. Conclusions: GEn was extensively absorbed and rapidly eliminated from plasma and whole blood.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. 49 – No. 2/2011 (116-127)

Controlling pain in the post-operative setting

R. Costantini¹, G. Affaitati², A. Fabrizio² and M.A. Giamberardino²

¹Institute of Surgical Pathology, University of Chieti, and ²Pathophysiology of Pain Laboratory, Ce.S.I., “G. D’Annunzio” Foundation, Chieti, Italy
Background and aims: Post-operative pain (POP) is a form of acute, intense pain experienced in the period following surgery, whose adequate control is often problematic. This paper reviews determinants and characteristics of POP, together with rationale and current protocols for its management. Determinants/consequences of POP: Main determinants of POP are the type of intervention and the disease motivating surgery, though other factors related to patient (age, pain threshold, socio-cultural factors, personality) and setting (pre-operative information, relationship with medical staff) may also influence its perception. POP control is essential to relieve suffering but also to prevent dangerous consequences on organ systems, e.g., reduced cough, atelectasis, increased myocardial oxygen consumption and ischemia, constipation, urinary retention, reduced musculoskeletal mobility and increased risk of deep venous thrombosis. Management of POP: Constant assessment of pain intensity is recommended for optimal POP control. This is mostly achieved pharmacologically with monitoring of side-effects. Multi-modal analgesia is recommended, combining different drug classes, e.g., an opioid (morphine, pethidine, fentanyl, tramadol, codeine) with a non-opioid (NSAID; Cox-2 inhibitor), delivered through various routes, and including neuraxial use of local anesthetics (bupivacaine, ropivacaine) alone or in combination with other drugs, nerve blocks, antihyperalgesics (ketamine, dextromethorphan) and techniques such as patient-controlled analgesia (PCA) and pre-emptive analgesia. An efficient organization of pain services is also recommended. Conclusion: Acute post-surgical pain represents a crucial problem, but the multimodal therapeutic approach has enhanced the efficacy of pain-control while minimizing side-effects of each modality. Further improvement of POP control will necessarily involve better organization of pain services.Correspondence to:
M.A. Giamberardino, MD
via Carlo de Tocco n. 3, 66100 Chieti, Italy
Email: mag@unich.it

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 2/2011 (128-136)

Steady state pharmacokinetics and dose equivalents of oral clodronate in renal failure

S. Mäkelä¹, H. Saha¹, I. Ala-Houhala¹, S. Liukko-Sipi² and P. Ylitalo³,⁴

¹Departments of Internal Medicine, ³Clinical Chemistry, Tampere University Hospital, Tampere, ²Schering OY, Turku, and ⁴Department of Pharmacological Sciences, University of Tampere, Tampere, Finland
Objective: Clodronate is used in the treatment of osteoporosis, and malignancy-associated bone disease. The steady state pharmacokinetics and the dose equivalents of oral clodronate were assessed in subjects with various degrees of renal failure. Materials and methods: 1,600 mg of clodronate was given orally mornings for 11 days to 14 healthy volunteers (creatinine clearance, CL_Cr, > 80 ml/min), and 18, 12 and 16 subjects with mild (50 – 80 ml/min), moderate (30 – 50 ml/min) and severe (< 30 ml/min) renal failure, respectively. Trough drug levels at 4, 7 and 11 days, and concentration-time curves for 72 h after the last dose were followed. Results: In all study groups, the trough drug levels achieved the kinetic steady state within 11 days. The area under the 24-h concentration-time curve (AUC_0–24) enlarged and the elimination half-life (t_1/2elim) prolonged progressively when the renal function was impaired. The maximum drug level and the time to maximum were not changed significantly in the renal failure. In the steady state phase, the diurnal drug excretion (E_0–24) was not changed by the kidney function, but the renal drug clearance (CL_D) decreased in close correlation with CL_Cr. The normal-to-failed AUC_0–24 ratios in mild, moderate, and severe renal failure were 0.53, 0.43 and 0.31, respectively, when the ideally-matched counterpart was assumed as the normal reference to each renal failure group. Conclusions: In mild, moderate and severe renal failure, 53%, 43% and 31% oral clodronate doses, respectively, resulted in drug AUCs similar to those in controls with normal (> 80 ml/min) CL_CR.Correspondence to:
S. Mäkelä, MD, PhD
Department of Internal Medicine
Tampere University Hospital
P.O. Box 2000, 33521 Tampere, Finland
Email: satu.marjo.makela@uta.fi

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 2/2011 (137-144)

Pharmacoepidemiological profiles of prescriptions for antihypertensive agents among ethnic Chinese patients

M.C.S. Wong¹ and J.Y. Jiang²

¹School of Public Health and Primary Care, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, and ²Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
Objective: We compared the short- and long-term cumulative incidences of add-on therapy across the major anti-hypertensive drug classes among Chinese patients who had newly received an antihypertensive agent. Materials and methods: We analyzed 16,154 adult patients with uncomplicated hypertension who had newly received an antihypertensive monotherapy in one large territory of Hong Kong during January 2004 to June 2007. We compared the cumulative incidences of and factors associated with add-on therapy by drug classes at 180 days and 360 days using binary logistic regression analyses. Results: The crude cumulative incidences of add-on therapy at 180 days were not statistically significantly different among those receiving thiazide diuretics (6.26%), b-blockers (5.99%), calcium channel blockers (CCB) (5.95%) or drugs acting on the renin angiotensin system (RAS) (4.41%), and these figures were similar at 360 days (both p = 0.213). The odds ratios of add-on therapy for RAS (0.72, 95% CI 0.49 – 1.06), thiazide diuretics (1.08, 95% CI 0.85 – 1.37) and beta-blockers (1.02, 95% CI 0.86 – 1.22) were not statistically significant compared to CCB at 180 days and 360 days. Male patients and younger subjects were more likely to receive an add-on therapy in both time frames. Conclusions: This study suggested that the major antihypertensive drug classes had similar add-on rates in real-life clinical practice.Correspondence to:
J.Y. Jiang, MD, PhD
Chinese Academy of Medical Sciences &
Peking Union Medical College
Dongdan Santiao 9, DongCheng District
100730 Beijing, China

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 2/2011 (145-152)

Correlation between the pharmacological efficacy of cyclosporine and tacrolimus as evaluated by the lymphocyte immunosuppressant sensitivity test (LIST) and the MTT assay procedure in patients before and after renal transplantation

K. Sugiyama¹, K. Isogai¹, A. Toyama¹, H. Satoh¹, K. Saito¹, Y. Nakagawa¹, M. Tasaki², K. Takahashi² and T. Hirano³

¹Division of Pharmacy, Niigata University Medical and Dental Hospital, ²Division of Urology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, and ³Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Japan
Objectives: Cyclosporine and tacrolimus are calcineurin inhibitors that are used to prevent acute rejection in renal transplant recipients. The lymphocyte immunosuppressant sensitivity test (LIST) can predict the pharmacological efficacy of these immunosuppressive agents for renal transplant recipients. There is a correlation between cyclosporine and tacrolimus pharmacological efficacy as evaluated by LIST by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay procedure prior to renal transplantation. However, the LIST can also evaluate patients before and after the transplantation. Materials and methods: The present study examined the relationship between cyclosporine and tacrolimus pharmacological efficacy by LIST using the MTT assay in 16 renal transplant recipients at 1, 3 and 12 months after transplantation, as well as before the operation. Results: The relationship of cyclosporine and tacrolimus pharmacological efficacy gave a significant Kendall and Spearman’s coefficient correlation in these transplant recipients by the LIST using the MTT assay procedure immediately prior to renal transplantation (r_k = 0.711, r_s = 0.877, p < 0.01). Furthermore, correlations between the cyclosporine and tacrolimus IC50 values were also observed with a significant Kendall and Spearman’s coefficient correlation at 1 and 12 months after transplantation (r_k1month = 0.65, r_s1month = 0.829, p < 0.01, and k_12month = 0.433, r_s12month = 0.603, p < 0.01, respectively). However, no statistically significant relationship was observed between the pharmacological efficacies of the calcineurin inhibitors at 3 months after transplantation (r_k3month = 0.117, r_s3month = 0.1, p > 0.05). Conclusions: Both cyclosporine and tacrolimus exhibit pharmacological efficacy by the inhibition of calcineurin. However, the correlation between cyclosporine and tacrolimus pharmacological efficacies may be altered, due to immunosuppressive therapy or clinical events at 3 months after renal transplantation.Correspondence to:
Dr. K Sugiyama
Division of Pharmacy
Niigata University Medical and Dental Hospital
754 Asahimachi-dori 1-bancho Chuo-ku Niigata City
Niigata 951-8520, Japan
Email: sugiyama-nii@umin.ac.jp

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 2/2011 (153-161)

Safety, tolerability and pharmacokinetics of single escalating doses of indacaterol, a once-daily β₂-agonist bronchodilator, in subjects with COPD

S. Pascoe¹, C. Reynolds², W. Pleskow³, S. Perry⁴, A. Hmissi¹, G. Kaiser¹ and L. Brookman⁴

¹Novartis Pharma AG, Basel, Switzerland, ²Novartis Pharmaceuticals Corporation, East Hanover, NJ, ³Radiant Research, San Diego, CA, USA, and ⁴Novartis Horsham Research Center, Horsham, UK
Objectives: To assess the safety and tolerability of 4 doses of indacaterol, a once-daily beta₂-agonist, in subjects with chronic obstructive pulmonary disease (COPD). The 24-h bronchodilator effect and pharmacokinetics of indacaterol were also investigated. Methods: 16 subjects aged 43 – 72 years with mild/moderate COPD were each given single doses of indacaterol of 400, 1,000, 2,000 and 3,000 µg, via a single-dose dry powder inhaler. Results: Changes from predose (400, 1,000, 2,000, 3,000 µg doses, respectively) were as follows. Maximum mean decreases in fasting (up to 2 h post-dose) serum potassium were 0.12, 0.30, 0.38, 0.26 mmol/l; maximum mean increases (up to 2 h post-dose) in fasting serum glucose were 0.12, 0.40, 0.87, 1.01 mmol/l. The maximum increase in heart rate (by 3, 6, 12, 13 beats/min, respectively) was within 1 h post-dose. No clinically significant electrocardiogram abnormalities were reported. Most adverse events were mild or moderate, with none considered serious or leading to withdrawal. Indacaterol was rapidly absorbed and displayed multiphasic disposition kinetics. The terminal elimination phase with a half-life of 50 – 63 h could only be seen for doses of 1,000 µg or higher. Mean systemic exposure to indacaterol (AUC_0–24) increased by ~ 9-fold from 400 to 3,000 µg. Conclusion: Even at doses far in excess of the therapeutic range, indacaterol had minimal systemic effects; such changes would be considered within safe limits for a single dose.Correspondence to:
S. Pascoe, MD, MSc
Respiratory Clinical Franchise Head
Novartis Campus, Forum 1
4056 Basel, Switzerland
Email: pascoesteve@yahoo.co.uk

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 2/2011 (162-168)

Pharmacokinetic interaction between efavirenz and rifampicin in healthy volunteers

Yenny*¹, Nafrialdi*², Z. Djoerban³ and R. Setiabudy²

¹Department of Pharmacology and Therapy, School of Medicine, Trisakti University, Jakarta, ²Department of Pharmacology and Therapy, and ³Department of Internal Medicine, School of Medicine, University of Indonesia, Jakarta, Indonesia

*These authors use a single name.
Objective: Rifampicin induces the metabolism of efavirenz in humans. This study evaluated efavirenz bioavailability after rifampicin administration to healthy volunteers. Methods: A 3-week, before-and-after trial was performed on 8 healthy volunteers. The pharmacokinetic parameters were: plasma drug concentration-time profile from 0 to 72 h (AUC_0–72), plasma drug concentration-time profile from 0 h to infinity (AUC_0–inf), maximal drug concentration (C_max), time to reach maximal drug concentration (t_max), and time to reach half the initial drug concentration in elimination phase (t_1/2). After an overnight fast, the volunteers ingested one efavirenz 600 mg tablet, then blood samples were drawn to evaluate plasma efavirenz levels at 0, 2, 3, 4, 5, 6, 24, 72, 120, and 168 h. The procedure was repeated after a 1-week induction period of 450 mg/day. Paired-t test and Wilcoxon matched-pairs test were used for differences between mean concentrations. Results: Baseline mean AUC_0–72 was 46.80 ± 9.27 µg/ml.h, AUC_0–inf was 96.38 ± 38.10 µg/ml.h, C_max 2.19 ± 0.68 µg/ml.h, t_max 4.50 ± 0.93 h, and t_1/2 96.60 ± 42.38 h. Post-induction values were significantly increased: AUC_0–72 9.53 ± 11.26 µg/ml.h (p < 0.05; CI95% = 0.112 – 18.940), AUC_0–inf 37.24 ± 42.43 (p < 0.05; CI95% = 0.021 – 0.406) µg/ml.h, and t_max 1.13 ± 0.99 h (p < 0.05; CI95% = 0.296 – 1.953). No significant reduction occurred in post-rifampicin induction means of C_max and t_1/2. Conclusion: Co-administration of a single dose of efavirenz 600 mg/day with 1-week rifampicin 450 mg/day significantly reduced efavirenz bioavailability in healthy volunteers. Correspondence to:
Dr. Yenny
jl. Kyai Tapa (grogol)
1140 Jakarta Barat, Indonesia
Email: Stasia_mk@yahoo.com

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 2/2011 (169-176)

Evaluation of bioequivalence between a single-capsule formulation of esomeprazole 40 mg and acetylsalicylic acid 325 mg and the monotherapies given separately in healthy volunteers

M. Niazi, T. Andersson, E. Nauclér and J. Næsdal

AstraZeneca R&D, Mölndal, Sweden
Objective: The aim of this study was to investigate the bioequivalence of a single oral dose of esomeprazole 40 mg and acetylsalicylic acid 325 mg when formulated as a single capsule, relative to the components given as separate monotherapies. Methods: This was an open, randomized, single-center, single-dose, 2-stage group sequential design, 2-way crossover study (NCT00688428) in 49 healthy adult volunteers (29 women). In each treatment period, subjects received a single dose of esomeprazole 40 mg and ASA 325 mg formulated as a single capsule or as separate monotherapies given in combination. Treatment periods were separated by a washout period of at least 6 days. The bioequivalence of a single-capsule formulation of esomeprazole 40 mg and ASA 325 mg relative to the monotherapies given individually was assessed by the geometric mean ratios of the area under the plasma concentration-time curve (AUC) and observed maximum plasma concentration (C_max). If the 94% confidence interval (CI) of the geometric mean ratios of AUC and C_max were within 0.80 – 1.25, bioequivalence would be established. A 94% CI was used to compensate for the multiple analyses of the study design, and to assure that the actual overall confidence level was 90%. Results: The geometric mean ratios of the AUC for esomeprazole 40 mg and ASA 325 mg when administered in the single capsule formulation, relative to the monotherapies were 0.97 (94% CI, 0.90 – 1.04) and 1.04 (94% CI, 1.00 – 1.08). The corresponding mean geometric ratios for C_max were 0.99 (94% CI, 0.90 – 1.09) and 1.02 (94% CI, 0.92 – 1.13). Conclusions: Treatment with esomeprazole 40 mg and ASA 325 mg formulated as a single capsule is bioequivalent to the separate monotherapies of esomeprazole 40 mg and ASA 325 mg when given in combination as separately-administered drugs in healthy adult subjects.Correspondence to:
M. Niazi, MSc, Pharm
AstraZeneca R&D
431 83, Mölndal, Sweden
Email: Mohammad.Niazi@astrazeneca.com

Abstract

Tolerability of quetiapine in children and adolescents with Tourette’s syndrome

M. Copur, S. Hergüner and B. Arpaci

Abstract

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Volume 49, No. 2/2011(February)