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Aims Exenatide is an incretin mimetic whose effect on glycaemic control in patients with Type 2 diabetes is currently under investigation. This study assessed the effect of injection time relative to a standardized meal on postprandial pharmacodynamics of exenatide in patients with Type 2 diabetes. Methods Eighteen patients participated in this single-centre, open-label, placebo-controlled, randomized, six-way crossover study. Patients received subcutaneous injections of either placebo (−15 min) or 10 µg of exenatide at −60, −15, 0, +30 or +60 min relative to a standardized breakfast meal on six consecutive days. Serial blood samples were assayed for plasma glucose and insulin concentrations. Results For all exenatide treatments, incremental postprandial glucose area under the postprandial plasma glucose curve from zero to 6 h (AUC0−6 h) was significantly reduced compared with placebo. When exenatide was administered before (−60, −15 min) or with the meal (0 min), peak postprandial glucose concentrations were significantly decreased ( P < 0.0001 for all treatments) compared with placebo. Post-meal exenatide administration (+30, P < 0.05; +60 min, P = 0.21) resulted in smaller peak glucose reductions and in some patients transient low plasma glucose concentrations were reported. Peak plasma insulin concentrations in the pre-meal treatments were significantly lower than placebo ( P < 0.05 for all treatments), while post-meal dosing groups exhibited a trend towards higher insulin peaks compared with placebo. The most common adverse events related to exenatide were headache, nausea, dyspepsia and vomiting, and were generally of mild-to-moderate intensity. Conclusions In this study, all exenatide treatments demonstrated reductions in postprandial plasma glucose excursions compared with placebo. Pre-meal and with meal administration of exenatide produced greater reduction of postprandial glucose excursions compared with post-meal administration. These data support flexible dosing of exenatide at any time within 60 min before a meal. [ABSTRACT FROM AUTHOR]

Background: The purpose of this analysis was to describe pharmacokinetics of fluoxetine (FLX) and norfluoxetine (NFLX, the active metabolite), identify and explain the sources of variability in patients.Methods: Five studies were pooled (n=1137), including adult, Japanese and pediatric patients. FLX and NFLX models were sequentially built using NONMEM. Covariates were screened. Final models were validated using external/internal validation and visual predictive checks.Results: A one compartment open model with first order absorption and elimination was used to describe the pharmacokinetics of FLX. Body weight was the only covariate retained in the model. CL/F and V/F of FLX were 13.0 L/hr and 3420 L; the between-subject variability (BSV) was 53% and 45%, respectively. A general linear model (ADVAN5) with first order absorption and complete conversion of parent to metabolite was used to fit the FLX and NFLX data simultaneously with FLX final estimates fixed. Similar to the FLX, weight was the only covariate retained in the NFLX model. CL/F of NFLX was 7.9 L/hr with a BSV of 41%. Preadolescent's (n=11, 6-12 years) had lower clearances compared with other patient populations. Sex and ethnicity were not significant covariates.Conclusions: FLX and NFLX blood concentrations were highly variable among patients. The lower clearance observed in preadolescent patients could be partially explained by lower body weights in these patients. A significant fraction of BSV remains unexplained.Clinical Pharmacology & Therapeutics (2005) 79, P27–P27; doi: 10.1016/j.clpt.2005.12.100 [ABSTRACT FROM AUTHOR]

Background: In a warfarin interaction study, Asian Indian and Chinese subjects received racaemic warfarin to establish baseline pharmacokinetics (PK) and anticoagulation. Previous data have suggested ethnic differences in INR response to warfarin, thus INR and PK were compared post-hoc.Methods: 8 Asian Indians (31±7 yrs, 70±10 kg) and 8 Chinese (28±3 yrs, 70±7 kg) healthy male subjects initially received a 25mg oral dose of warfarin, with serial sampling for R- and S-warfarin plasma concentrations and INR for up to 144 hr post dose. Subjects were genotyped for CYP2C9.Results: All Chinese subjects were wild-type homozygous for CYP2C9, whilst 3 Indians subjects were heterozygous for *2 or *3. Overall, there were no significant differences between Indian and Chinese subjects for R- or S-warfarin PK (Table 1). Baseline Vitamin K1 levels (Table 1) were also similar. Chinese subjects, however, were found to be more sensitive to warfarin anticoagulant effect, with higher INRAUC and INRmax (Table 1). The 3 CYP2C9 heterozygotes appeared to have higher S-warfarin exposures as compared to wild-type subjects.Conclusions: Despite similar PK profiles and baseline Vitamin K1 levels, Chinese subjects appeared more sensitive to the anticoagulant effect of warfarin. This does not appear to be related to differences in drug metabolism.Clinical Pharmacology & Therapeutics (2005) 79, P32–P32; doi: 10.1016/j.clpt.2005.12.117 [ABSTRACT FROM AUTHOR]

Background/aims: Exenatide, a novel therapy for type 2 diabetes, among other glucoregulatory actions, slows gastric emptying and may alter the rate of absorption of concomitant oral drugs. As statins are commonly used in patients with type 2 diabetes, the potential interaction between exenatide and statins was evaluated.Methods: [A] PK study: open-label, fixed-sequence study in 21 healthy subjects. Lovastatin PK was evaluated after a single dose of lovastatin (40 mg) administered alone and in combination with concomitant exenatide (10 μg BID). [B] Long-term clinical trials: Data from statin users in three 30-week, placebo-controlled trials for exenatide were combined and stratified based on concomitant placebo (n=168) or exenatide (n=180) use. Lipid profiles and statin dosage were compared between the active and placebo arms.Results: [A] PK study: Exenatide decreased mean lovastatin Cmax and AUC 0-∞ by 28% and 40% respectively and increased median tmax by about 4 hours. [B] Long-term trials: Changes for fasting HDL-C, LDL-C, total cholesterol, triglycerides and the subjects (6 total) that increased their statin dose were not significantly different between the exenatide and placebo groups (see table).Conclusions: Despite changes in lovastatin PK observed in an acute study, long-term exenatide treatment did not alter HDL-C, LDL-C, total cholesterol, or triglycerides or require increases in statin dose. These data indicate that no change in statin dose is required during use with exenatide.Clinical Pharmacology & Therapeutics (2005) 79, P46–P46; doi: 10.1016/j.clpt.2005.12.164 [ABSTRACT FROM AUTHOR]

Background/aims: Exenatide, a new therapy for the treatment of type 2 diabetes, slows gastric emptying as one of its actions and therefore may alter the absorption of concomitant oral drugs. This study evaluated the influence of exenatide co-administration on the PK and PD of warfarin.Methods: 15 healthy male subjects (22-50 yr, BMI 19.0-27.5 kg/m2) participated in this open-label, two-period, fixed-sequence study. Each subject received a single, 25-mg, oral dose of warfarin in Period 1 and concomitantly with 10 μg exenatide SC BID in Period 2. Serial sampling for plasma warfarin concentrations and coagulation index (INR) were conducted up to 144 hr post dose.Results: Exenatide did not produce statistically significant changes in R- or S-warfarin AUC0-∞ or Cmax. For R-warfarin, the ratios (exenatide/no exenatide) of AUC0-∞ and Cmax geometric means (90% CI) were 1.11 (1.06-1.17) and 1.05 (1.00-1.09) respectively and for S-warfarin, 1.06 (1.01-1.11) and 0.97 (0.93-1.01). Exenatide also produced no significant changes in INRAUC or INRmax; the ratios of geometric means were 0.94 (0.93-0.96) and 0.88 (0.84-0.92) respectively. The most frequent adverse events were mild to moderate nausea, somnolence, and headache; no hypoglycemic events occurred.Conclusions: Co-administration of warfarin with exenatide was generally well tolerated and resulted in no significant changes in warfarin PK or in INR. These results indicate that no adjustment in INR monitoring or warfarin dosage is required with exenatide.Clinical Pharmacology & Therapeutics (2005) 79, P75–P75; doi: 10.1016/j.clpt.2005.12.269 [ABSTRACT FROM AUTHOR]

Background: While several drugs are commercially available as the pamoate salts, information on the systemic exposure of pamoic acid (PA) from such drug products is not available in the literature. This study was conducted to determine the pharmacokinetics of PA from a marketed formulation, hydroxyzine pamoate.Methods: The study was conducted as open-label in 6 healthy Caucasian male subjects (25 to 37 years). Each subject received 100 mg hydroxyzine pamoate once on Day 1 and every 6 hours from Days 2 to 4 (9 oral doses). Blood samples were obtained on Days 1 and 4 at 0, 1, 2, 3, 4, 5, 6, 7, 8, 12, and 24 hr after the dose. PA concentrations were measured using a validated HPLC method with fluorescence detection and analyzed using non-compartmental method.Results: Plasma concentration-time profile of PA showed biphasic elimination. PA was rapidly absorbed with time to maximal concentration of 3 hr on Day 1 and 3.5 hr on Day 4. Mean apparent half-life on Days 1 and 4 were 5.7 and 7.0 hr, respectively. Upon multiple dosing, oral clearance ranged from 12 to 115 L/hr and oral volume of distribution ranged from 99 to 1200 L. Maximum average steady state concentrations of PA were 715 ng/mL.Conclusions: PA is rapidly absorbed and eliminated from the systemic circulation on oral administration of hydroxyzine pamoate. The concentrations of PA reported in this study provide information on the systemic exposure of PA. Further studies are warranted to evaluate the pharmacokinetics of PA from other pamoate salts.Clinical Pharmacology & Therapeutics (2005) 79, P79–P79; doi: 10.1016/j.clpt.2005.12.284 [ABSTRACT FROM AUTHOR]