Exposure-response relationship of certolizumab pegol induction and maintenance therapy in patients with Crohn's disease.

BACKGROUND: Therapeutic drug monitoring may optimize therapy for Crohn's disease (CD). AIM: To use a population pharmacokinetic model that accounts for the time-varying nature of covariates to simulate certolizumab pegol (CZP) concentrations to evaluate the exposure-response relationship for CZP in Crohn's disease. METHODS: Adults (N = 2157) with Crohn's disease were treated with CZP in nine clinical trials. Simulated CZP concentrations were compared to outcomes at weeks 6 and 26, including Crohn's disease activity index (CDAI) response (decrease from baseline ≥ 100 points), remission (CDAI ≤ 150), C-reactive protein (CRP) ≤ 5 mg/L, faecal calprotectin (FC) ≤ 250 µg/g, and a composite endpoint of CDAI ≤ 150 and FC ≤ 250 µg/g. Multivariable analyses identified covariates associated with outcomes and receiver operating characteristic analyses determined optimal CZP concentrations. RESULTS: CZP concentrations at weeks 2, 4 and 6 were higher in patients with clinical response, remission, CRP ≤ 5 mg/L or FC ≤ 250 µg/g at week 6 than without. In multivariable analyses, higher CZP concentrations at week 6 were associated with the composite outcome at weeks 6 and 26 (P < .001). Although the exposure-response relationship varied among patients, approximate CZP concentrations of at least 36.1 µg/mL (positive predictive value [PPV] 22.8% and negative predictive value [NPV] 92.7%) and at least 14.8 µg/mL (PPV 28.0% and NPV 90.4%) at weeks 6 and 12 were associated with weeks 6 and 26 outcomes. CONCLUSIONS: An exposure-response relationship was apparent for CZP in Crohn's disease and achieving higher CZP concentrations may increase the likelihood of attaining efficacy outcomes, but this remains to be evaluated prospectively.

Clinical and demographic characteristics predictive of treatment outcomes for certolizumab pegol in moderate to severe Crohn's disease: analyses from the 7-year PRECiSE 3 study.

BACKGROUND: Clinical factors were previously identified as predictors of short-term treatment efficacy in Crohn's disease (CD). The PRECiSE 3 (P3) 7-year trial provides an opportunity to study predictors of short- and long-term clinical remission among CD patients treated with certolizumab pegol (CZP). AIM: To identify factors that influence long-term remission of CD with CZP treatment. METHODS: Patients who had completed placebo-controlled studies (PRECiSE 1/PRECiSE 2, P1/P2) enrolled in P3 and received open-label CZP 400 mg every 4 weeks up to 7 years. Baseline predictors included, but were not limited to, smoking status, disease duration, prior inflammatory bowel disease (IBD) surgery, Harvey-Bradshaw Index (HBI), albumin, haematocrit and CZP exposure; association with time to initial remission (HBI ≤4) was tested for patients who received CZP in P1/P2; time to loss of remission/frequency of maintenance of remission was also tested. Univariate analyses and multivariate Cox or logistic regression models were used. RESULTS: Predictors for initial remission (N = 377) included age, haematocrit, prior IBD surgery and entry HBI (P < 0.05 for all). Predictors for loss of remission (N = 437) included HBI, serum albumin concentration, haematocrit, smoking status and exposure. Predictors of maintenance of remission (N = 437) included haematocrit, IBD surgery, HBI, disease duration, serum albumin concentration and exposure. Significant predictors were confirmed with stepwise multivariate regression models. CONCLUSIONS: These analyses identified several influential parameters for short-and long-term remission of Crohn's disease with certolizumab pegol treatment. The data yield valuable hypotheses regarding factors that influence certolizumab pegol treatment. More investigation is needed. (ClinicalTrials.gov identifier NCT00552058).

Randomised clinical trial: ghrelin agonist TZP-101 relieves gastroparesis associated with severe nausea and vomiting--randomised clinical study subset data.

BACKGROUND: Limited therapeutic options exist for severe gastroparesis, where severe nausea and vomiting can lead to weight loss, dehydration and malnutrition due to inadequate caloric and fluid intake. TZP-101 (ulimorelin) is a ghrelin receptor agonist that accelerates gastric emptying and improves upper gastrointestinal symptoms in diabetic patients with gastroparesis. AIM: To assess effects of TZP-101 in diabetic gastroparesis patients with severe nausea/vomiting and baseline severity scores of ≥3.5 (range: 0-5) on the Gastroparesis Cardinal Symptom Index (GCSI) Nausea/Vomiting subscale. METHODS: Patients were hospitalised and received four single daily 30-min infusions of one of six TZP-101 doses (range 20-600 µg/kg) or placebo. Efficacy was assessed by symptom improvement. RESULTS: At baseline, 23 patients had a mean severity score for GCSI Nausea/Vomiting of 4.45±0.44. Statistically significant improvements over placebo occurred in the 80 µg/kg group for end of treatment changes from baseline in GCSI Nausea/Vomiting subscale (reduction in score of -3.82±0.76, P=0.011) and the GCSI Total score (-3.14±0.78, P=0.016) and were maintained at the 30-day follow-up assessment (-2.02±1.63, P=0.073 and -1.99±1.33, P=0.032 respectively). The proportion of days with vomiting was reduced significantly (P=0.05) in the 80 µg/kg group (mean of 1.2 days of vomiting for four treatment days) compared with placebo (mean of 3.2 days of vomiting across 4 treatment days). CONCLUSIONS: TZP-101 substantially reduced the frequency and severity of nausea and vomiting as well as overall gastroparesis symptoms. The results are consistent with gastrointestinal motility effects of TZP-101, supporting further investigation of TZP-101 in the management of severe gastroparesis.

Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study.

BACKGROUND: Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP-101, is in clinical development for treatment of gastroparesis. This double-blind, randomized, placebo-controlled study evaluated the safety and efficacy of multiple TZP-101 doses in patients with moderate to severe symptomatic diabetic gastroparesis. METHODS: Patients were admitted to the hospital and adaptively randomized to receive a single 30-min intravenous infusion of 20, 40, 80, 160, 320, or 600 µg kg(-1) TZP-101, (n = 57) or placebo, (n = 19) for four consecutive days. Symptoms were evaluated daily with the patient-rated Gastroparesis Cardinal Symptom Index (GCSI) and Gastroparesis Symptom Assessment (GSA). Clinicians rated gastroparesis symptoms on treatment day 4. KEY RESULTS: The 80 µg kg(-1) dose was identified as the most effective dose. On day 4, there was statistically significant improvement compared with placebo in the severity of GCSI Loss of Appetite and Vomiting scores for that dose group (P = 0.034 and P = 0.006). In addition, at the 80 µg kg(-1) dose, the proportion of patients with at least 50% improvement in vomiting score was significantly different (P = 0.019) compared with placebo. Meal-related GSA scores for Postprandial fullness were significantly improved in the 80 µg kg(-1) TZP-101 group compared with placebo (P = 0.012). Clinicians rated the 80 µg kg(-1) group better improved than placebo for overall symptom assessment (P = 0.047). Safety profiles were similar in the placebo and TZP-101 groups and all doses were well-tolerated. CONCLUSIONS & INFERENCES: TZP-101 appears to be safe, well-tolerated, and effective at acutely addressing several gastroparesis symptoms.

Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis.

BACKGROUND: TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis. AIM: To assess safety and effects of TZP-101 in diabetes patients with symptomatic gastroparesis. METHODS: Adults with type 1 or type 2 diabetes mellitus received placebo and TZP-101 (80, 160, 320 or 600 microg/kg) infusions in a cross-over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic-euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses. RESULTS: Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate-to-severe gastroparesis symptoms and > or =29% retention 4 h after a radiolabelled solid meal were enrolled. TZP-101 produced significant reductions in solid meal half-emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP-101 infusion were not statistically significant. Most adverse events were mild and self-limiting and there were no identifiable differences in numbers or types of adverse events between TZP-101 and placebo. CONCLUSIONS: This proof-of-concept study demonstrates that the ghrelin agonist TZP-101 is well-tolerated in diabetes patients with moderate-to-severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.

Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty.

BACKGROUND: Unfractionated heparin (UFH) is safe and effective for thromboprophylaxis, but its use is limited to parenteral administration. A novel drug delivery agent (SNAC) has been developed to accomplish the oral delivery of heparin. OBJECTIVE: This report describes the foundation for dose selection and use of oral heparin/SNAC in patients undergoing elective total hip arthroplasty (THA). PATIENTS AND METHODS: To develop a treatment regimen for clinical study, a multiple dose Phase I pharmacokinetic (PK) study in healthy volunteers compared oral heparin/SNAC (90 000 U heparin) with subcutaneous UFH (5000 U). On this basis, we carried out a double-blind, randomized, multicenter study comparing subcutaneous UFH (5000 U) with oral heparin/SNAC at either 60 000 or 90 000 U heparin in 123 patients undergoing elective THA. Patients received, postoperatively, one of the three treatments every 8 h for a total of 12 doses and were followed for 35 days post surgery. RESULTS: In the Phase I study, anti-factor Xa activity peaked at 45-60 min following oral heparin/SNAC, returning to baseline at 4 h. RESULTS of the randomized trial in THA patients showed that venous thromboembolic events (n = 6), major bleeding events (n = 5) and need for transfusion (n = 23) were distributed evenly among the three treatment groups, UFH and both doses of oral heparin/SNAC. CONCLUSION: This is the first demonstration that oral heparin/SNAC can be safely delivered to the postoperative THA patient, and provides the basis for a larger clinical trial to assess the prophylactic efficacy of heparin/SNAC.