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1.
Diabetes Obes Metab ; 16(8): 748-56, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24762094

ABSTRACT

AIMS: AWARD-5 was an adaptive, seamless, double-blind study comparing dulaglutide, a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist, with placebo at 26 weeks and sitagliptin up to 104 weeks. The study also included a dose-finding portion whose results are presented here. METHODS: Type 2 diabetes (T2D) patients on metformin were randomized 3 : 1 : 1 to seven dulaglutide doses, sitagliptin (100 mg), or placebo. A Bayesian algorithm was used for randomization and dose selection. Patients were adaptively randomized to dulaglutide doses using available data on the basis of a clinical utility index (CUI) of glycosylated haemoglobin A1c (HbA1c) versus sitagliptin at 52 weeks and weight, pulse rate (PR) and diastolic blood pressure (DBP) versus placebo at 26 weeks. The algorithm randomly assigned patients until two doses were selected. RESULTS: Dulaglutide 1.5 mg was determined to be the optimal dose. Dulaglutide 0.75 mg met criteria for the second dose. Dulaglutide 1.5 mg showed the greatest Bayesian mean change from baseline (95% credible interval) in HbA1c versus sitagliptin at 52 weeks -0.63 (-0.98 to -0.20)%. Dulaglutide 2.0 mg showed the greatest placebo-adjusted mean change in weight [-1.99 (-2.88 to -1.20) kg] and in PR [0.78 (-2.10 to 3.80) bpm]. Dulaglutide 1.5 mg showed the greatest placebo-adjusted mean change in DBP [-0.62 (-3.40 to 2.30) mmHg]. CONCLUSIONS: The Bayesian algorithm allowed for an efficient exploration of a large number of doses and selected dulaglutide doses of 1.5 and 0.75 mg for further investigation in this trial.


Subject(s)
Anti-Obesity Agents/administration & dosage , Diabetes Mellitus, Type 2/drug therapy , Glucagon-Like Peptides/analogs & derivatives , Hyperglycemia/prevention & control , Hypoglycemic Agents/administration & dosage , Immunoglobulin Fc Fragments/administration & dosage , Metformin/therapeutic use , Receptors, Glucagon/agonists , Recombinant Fusion Proteins/administration & dosage , Adolescent , Adult , Aged , Anti-Obesity Agents/adverse effects , Anti-Obesity Agents/therapeutic use , Combined Modality Therapy/adverse effects , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/therapy , Diet, Diabetic , Diet, Reducing , Dose-Response Relationship, Drug , Drug Therapy, Combination/adverse effects , Exercise , Female , Glucagon-Like Peptide-1 Receptor , Glucagon-Like Peptides/administration & dosage , Glucagon-Like Peptides/adverse effects , Glucagon-Like Peptides/therapeutic use , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Immunoglobulin Fc Fragments/adverse effects , Immunoglobulin Fc Fragments/therapeutic use , Injections, Subcutaneous , Male , Middle Aged , Overweight/complications , Overweight/drug therapy , Overweight/therapy , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/therapeutic use , Young Adult
2.
Pharm Res ; 17(12): 1531-6, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11303964

ABSTRACT

PURPOSE: To determine the enzyme kinetics (EK) and identify the human cytochrome(s) P450 (CYP) involved in the deethylation of phenacetin to acetaminophen using a population-based method. METHODS: A sparse data set was generated from incubations containing human liver microsomes (n = 19) with phenacetin. Estimates of the EK parameters were obtained by fitting the concentration-velocity data to Michaelis-Menten models by using nonlinear mixed effects modeling. Relationships between the EK parameters and the CYP activities determined for these liver microsomes were examined. RESULTS: A two-enzyme kinetic model with a saturated, low KM enzyme and an unsaturated, high KM enzyme capable of forming acetaminophen best fit the data. The population estimates of the EK parameters were Vmax1, 911 pmol/min/mg protein; KM1, 11.3 microM; and Cl(int2), 0.4 microl/min/mg. The coefficients of variation for interliver variability in Vmax1 and residual error of the model were 39% and 15%, respectively. When the selective catalytic activities were examined as potential covariates, 7-ethoxyresorufin O-deethylation (CYP1A2) activity was found to be associated with the low KM enzyme, however, the high KM enzyme(s) could not be identified. CONCLUSIONS: The population approach characterized the EK parameters and identified the low KM enzyme responsible for phenacetin O-deethylation as CYP1A2. Population modeling of EK provides valuable information on inter- and intraliver variability in CYP dependent activities.


Subject(s)
Analgesics, Non-Narcotic/metabolism , Phenacetin/metabolism , Algorithms , Biotransformation , Cytochrome P-450 Enzyme System/metabolism , Dealkylation , Humans , In Vitro Techniques , Microsomes, Liver/metabolism , Models, Biological , Population
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