Glucagon-like Peptide-1: Broadening the Incretin Concept to Involve Gut Motility; a New Target for Treament of IBS
HELLSTRÖM PM1, KRISTENSEN J2, BJÖRNSSON E3, BYTZER P4, HEIN J5, SCHAMBYE H2 1Gastrocenter Medicine, Karolinska University Hospital Solna, Stockholm, Sweden, 2Gastrotech Pharma A/S, Copenhagen, Denmark, 3Department of Medicine, Sahl-grenska University Hospital, Gothenburg, Sweden, 4Department of Medical Gastro-enterology, Køge University Hospital, Køge, Denmark and 5Gastroenterology Clinic, Marburg, Hessen, Germany.
Background: Glucagon-like peptide-1, GLP-1, is an incretin, that is a peptide hormone released from the gut and enhances insulin release from the pancreatic islets after food intake. In addition to that GLP-1 is also considered to have smooth muscle relaxing properties and causes a profound slowing of gastric emptying rate, making it ideal for the treatment of diabetes type 2. We have previously shown in rat and man that GLP-1 also inhibits small bowel motility. This has led further to evaluate this endogenous peptide for use in irritable bowel syndrome (IBS), where symptoms most likely are due to pressure build-up in the gut lumen. Therapies are needed for IBS as the impact of this disease is considerable in terms of individual suffering and economic cost. By causing relaxation of gastrointestinal smooth muscle, it is thought that the GLP-1 analog, ROSE 010, should be capable of alleviating pressure build-up in the gut, so reducing IBS-associated pain.
Methods: This phase IIA, prospective, randomized, cross-over, double-blind, placebo controlled, multicenter study enrolled 166 subjects with irritable bowel syndrome. Subjects received single subcutaneous injections at each clinic visit (placebo, 100 μg or 300 μg ROSE-010) within 1 hour of a pain attack. The primary efficacy endpoint was total pain relief response as evaluated by visual analog scales for pain with a reduction of pain of more than 50% in two hours. Secondary endpoints reflected different aspects of IBS pain relief such as meaningful and cumulative pain relief.
Results: ROSE-010 was superior to placebo (response rate 24.2% in total pain relief response compared with 12.0% for placebo [P=0.0053]) with regards to the primary endpoint. ROSE 010 was also more efficacious than placebo as assessed by maximum total pain relief, area under curve for pain relief and summed pain intensity, intensity of pain and summed pain intensity. In addition, the effect of ROSE 010 displayed a clear relationship to food intake. No hypoglycemia or other safety concerns were identified for ROSE-010.
Conclusions: The GLP-1 analog, ROSE-010 (100 μg or 300 μg), was superior to placebo in relieving acute abdominal pain in irritable bowel syndrome. ROSE 010 was safe and well tolerated. These results show that ROSE 010 is a potential treatment for pain in subjects with IBS.
Authors disclosure statement: HS and JK were supported by the sponsor during the study. Other authors have no disclosures.
Which gliclazide (GLC) formulation tablets, immediate (IR) or modified release (MR), are better therapeutic choice? RESZTAK M1, HERMANN TW1, MIKOŁAJCZAK P1, PASZUN S1, SAWICKI W2 1Univ. Med. Sci., Poznań, Poland; 2Medcal Academy, Gdańsk, Poland.
Background: IR and MR formulation tablets are available on the market. New formulation tablets (MR) allowing once-daily administration in patients with type 2 diabetes are supposed to improve patients compliance and enhance the long-term maintenance of blood glucose control. Aims: 1) To follow kinetics of GLC dissolution from commercial (CM) and home-made (HM) IR and MR formulation tablets. 2) To perform bioavailability (BA) studies on CM IR and MR formulation tablets in healthy volunteers. 3) To monitor GLC, fasting glucose (FPG), fasting insulin (FI), glycated hemoglobin (HbA1c) plasma levels in patients with type 2 diabetes. 4) To perform pharmacokinetic and pharmacodynamic experiments on GLC from CMIR and HMMR formulation tablets in normoglycaemia and streptozotocine (STZ)-induced hyperglycaemia rats.
Methods: A BP 2001 dissolution test was used for selected GLC formulation tablets. BA investigations included 10 each normal adult volunteers who received single 80 mg formulation tablet either CMIR or CMMR in a crossover design. Their serum samples were quantified for GLC and FPG. 37 type 2 diabetes outpatients were treated with a CMMR GLC formulation tablet once daily at the dose 30-120 mg, and their plasma levels were monitored for GLC, FPG, FI, and HbA1c. Wistar rats aged 7-8 weeks were also used. They were divided into 3 groups each of 8 rats: 3 normoglycaemia groups and 3 STZ-induced hyperglycaemia groups. The group 1 received a methylcellulose solution as a placebo, and the other groups received a suitable single dose of GLC mini-tablets, either CMIR or HMMR. HMMR mini-tablets consisted of GLC 3.0 mg, lactose 7.5 mg, maltodextrin 200 1.5 mg, and Kollidon SR 10.0 mg. TopFit 2.0 software was used for calculation of pharmacokinetic parameters.
Results: CM IR and MR tablets released GLC in vitro either very rapidly (approx. 99% at 100 min) or very slowly (67% at 8 h), respectively. The above tablets produced also significantly different serum concentration-time profiles whose mean Cmax values in healthy volunteers were equal either 3.8 or 0.7 mg/L for CM IR and MR tablets, respectively. GLC outpatients’ serum concentrations ranged from 0.38 to 9.43 mg/L and their FPG, HbA1c, and FI mean levels were equal 95-368 mg/L, 4.6-12%, and 8.0-25.5 μU/mL, respectively. MR tablets can be administered at lower GLC doses, because 24 h drug steady-state concentration at 24 h is greater (0.6±0.1 mg/L) if compared to 80 mg CMFR GLC tablets. Any case of hypoglycaemia was not observed in the above patients, because their FPG was never lower than 75 mg/dL. 7 patients produced less FI than required (5.6 μU/mL). It can be also distinguished a group of high FI level (≥15.6 μU/mL) patients who received higher GLC doses. GLC Cmax serum levels after administration CMIR mini-tablets were as it follows: 31.60±9.11 and 38.84±11.48 mg/L for healthy and diabetic rats, respectively. These values were over 8-fold greater than for HMMR mini-tablets. However, mean residence time (MRT) of HMMR tablets was approximately 2 h longer if compared to CMIR tablets. A greater decrease in FPG was observed for healthy rats (47%) as a result perhaps of diminished number of islet cells in STZ-induced hyperglycaemia rats.
Conclusions: 1) The dissolution process of CMIR GLC formulation tablets follows the first-order kinetics, and for MR tablets it proceeds according to a zero-order equation. 2) MR GLC resides in the human body longer at a lower level. 3) It is efficient with respect to HbA1c and FPG levels and safe to avoid hypoglycaemia. 4) Pharmacokinetic profiles of GLC are also remarkably different for IR and MR its formulation tablets in healthy and diabetic rats. 5) Pharmacokinetic profiles of CMMR and HMMR mini-tablets are comparable. 6) MR GLC formulation tablets are of benefit if a mild and an extended effect is desired.
Pharmacokinetic interactions of drugs and fruit juices with carbamazepine in Rat HIDAKA M1, NAGATA M1, AIMORI K2 1School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshinocho, 882-8508, Miyazaki, Japan; 2Department of Pharmacy, University of Miyazaki Hospital, 5200 Kihara, Kiyotake-cho, Miyazaki-gun, 889-1692, Miyazaki, Japan.
Background: Carbamazepine is an antiepireptic agent metabolized by CYP3A; hence CYP3A inhibitors or substrates may interact with carbamazepine. There are, however, only limited data on how to predict drug interactions in humans. Therefore, in this study, we investigated the CYP3A-mediated drug interaction in rat.
Methods:Male Wistar rats, weighing 280 to 300 g, were used in the study. The effects of simvastatin, pomegranate juice, and star fruit juice on carbamazepine pharmacokinetics in rats were evaluated. Simvastatin (10 mg/kg) or 2 ml of juice or water was orally administered to rats (N = 6). Carbamazepine at a dose of 50 mg/kg was orally administered through gastric intubation at 1 h after the pretreatment. Blood samples (approximately 0.2 ml) were collected through the carotid artery at 15 and 30 min and 1, 2, 4, 6, 8, 10, 12, and 24 h after the oral administration of carbamazepine. Analysis of carbamazepine and carbamazepine 10,11-epoxide was performed by high perfomrance liquid chromatography.
Results: In comparison with water, the area under the concentration-time curve (AUC) of carbamazepine was approximately 1.5-fold higher when pomegranate juice was administrated. On the other hand, the elimination half-life of carbamazepine and the AUC ratio of carbamazepine 10,11-epoxide to carbamazepine were not altered by the injection of pomegranate juice. Carbamazepine AUC were increased approximately 1.3-fold when simvastatin or starfruit juice administration. Carbamazepine pharmacokinetic parameters are shown in the table (average ± SEM, *: p<0.05).
Conclusions: Pomegranate juice, starfruit juice and simvastatin influenced the pharmacokinetics of carbamazepine in rat. These treatment did not affect the t1/2 values of carbamazepine and metabolite formation in the systemic circulation. These results suggest that the interacitons would be caused by enteric CYP3A inhibition.
Cost Implications of Oral Treatment of Colorectal Cancer in Germany
Background: Fluoropyrimidine-based therapies are standard in the treatment of metastatic colorectal cancer. Intravenously administered 5-fluorouracil was the only option before Capecitabine, an oral fluoropyrimidine, became available. As the drug acquisition costs of Capecitabine are considerably higher than those of 5-fluorouracil it was the objective of this study evaluate cost implications of oral chemotherapy with Capecitabine vs. standard fluoropyrimidine-therapies (Mayo Clinic and AIO/Ardalan-regimen), in different treatment settings in Germany.
Methods:Costs of fluoropyrimidine-therapies were evaluated for the office-based setting. Physician’s fees (89 quarterly fee-listings, 26 patients, 6 office-based oncologists), drug and pharmacy costs and costs for venous port systems and single-use pumps were included. Capecitabine treatment costs were assumed to be identical to the cost of the Mayo Clinic-regimen, except drug administration and acquisition. Based on the frequency of administration of active drugs by office-based oncologists costs were modelled for the hospital sector, i.e. day-case and inpatient treatment. A third-party payer perspective was adopted. Market research data on frequency and setting of use of the evaluated regimens were used to estimate potential overall cost implications.
Results: Treatment costs for a 6-months course in the office-based setting was most expensive with the AIO/Ardalan regimen (€ 18'600) and cheapest with Capecitabine (€ 3'870). Treatment costs in the hospital setting ranged from € 7’070 (Mayo) to € 22’790 (Ardalan, inpatient treatment).
Conclusions: Higher drug acquisition costs of Capecitabine compared to 5-fluorouracil are more than compensated by lower costs for drug administration, resulting in net cost savings for Capecitabine. The most expensive treatment options were the AIO/Ardalan-protocol in both, the office-based and the hospital setting. Capecitabine emerged as the cheapest option in the office-based setting (NA for hospital due to oral administration). Transferring patients to oral capecitabine is likely to result in substantial cost savings. Savings are likely to be even higher if combination therapies with irinotecan or oxaliplatin are considered.
