The objective of this work was to demonstrate that clinical OAT1-mediated DDIs can be predicted using physiologically based pharmacokinetic (PBPK) modeling. LY404039 is a metabotropic glutamate receptor 2/3 agonist and the active moiety of the prodrug pomaglumetad methionil (LY2140023). After oral administration, pomaglumetad methionil is rapidly taken up by enterocytes via PEPT1 and once absorbed, converted to LY404039 via membrane dehydropeptidase 1 (DPEP1). LY404039 is renally excreted by both glomerular filtration and active secretion and in vitro studies showed that the active secretion of LY404039 was mediated by the organic anion transporter 1 (OAT1). Both clinical and in vitro data were used to build a PBPK model to predict OAT1-mediated DDIs. In vitro inhibitory potencies (IC50) of the known OAT inhibitors, probenecid and ibuprofen, were determined to be 4.00 and 2.63 µM, respectively. Subsequently, clinical drug-drug interaction (DDI) study showed probenecid reduced the renal clearance of LY404039 by 30 to 40

OBJECTIVE:Galunisertib (LY2157299 monohydrate), an inhibitor of the transforming growth factor β (TGFβ) pathway, is currently under investigation in several clinical trials involving multiple tumor types. The primary objective of this study was to assess relative bioavailability of two new galunisertib formulations developed using the roller compaction (RC) dry-milled (RCD) and RC slurry-milled (RCS) processes, compared with the existing formulation developed using the high-sheer wet granulation (HSWG) process. The secondary objective was to report the safety profile after a single dose of the three formulations.METHODS:Patients with advanced or metastatic cancer were enrolled into this single-center, 3-period, 6-sequence crossover study. Patients were assigned sequentially to 1 of 6 sequences in blocks of 6 to ensure that all 6 sequences have the same number of completers. A patient entering a sequence received a different galunisertib formulation as a single 150 mg dose orally during each of the 3 periods. Each period was separated from the next by a washout interval of at least 48 hours. Pharmacokinetic (PK) parameters, including area under curve (AUC) and Cmax, were computed using standard non-compartmentalized methods of analysis. For comparison of exposures between formulations, log-transformed AUC and Cmax values were analyzed using a linear mixed-effects model. Safety assessments included adverse event monitoring, physical examinations, and laboratory tests.RESULTS:Of the 14 patients who entered and completed the study, 13 patients were included in the final statistical analysis. AUC(0-tlast), AUC(0-48 h), and AUC(0-∞) for the RC formulations and the HSWG formulation were similar. Cmax was reduced by approximately 22% and tmax was longer by at least 1.00 h for the RCD and RCS formulations compared with the HSWG formulation. The RC formulations demonstrated a safety profile after a single dose similar to the HSWG formulation.CONCLUSIONS:In this relative bioavailability study comparing galunisertib formulations after a single dose, RCD and RCS formulations had similar exposure and safety profile compared with the HSWG formulation.

Despite peptide transporter 1 (PEPT1) being responsible for the bioavailability for a variety of drugs, there has been little study of its potential involvement in drug-drug interactions. Pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist prodrug, utilizes PEPT1 to enhance absorption and bioavailability. In vitro studies were conducted to guide the decision to conduct a clinical drug interaction study and to inform the clinical study design. In vitro investigations determined the prodrug (LY2140023 monohydrate) is a substrate of PEPT1 with Km value of approximately 30 µM, whereas the active moiety (LY404039) is not a PEPT1 substrate. In addition, among the eight known PEPT1 substrates evaluated in vitro, valacyclovir was the most potent inhibitor (IC50 = 0.46 mM) of PEPT1-mediated uptake of the prodrug. Therefore, a clinical drug interaction study was conducted to evaluate the potential interaction between the prodrug and valacyclovir in healthy subjects. No effect of coadministration was observed on the pharmacokinetics of the prodrug, valacyclovir, or either of their active moieties. Although in vitro studies showed potential for the prodrug and valacyclovir interaction via PEPT1, an in vivo study showed no interaction between these two drugs. PEPT1 does not appear to easily saturate because of its high capacity and expression in the intestine. Thus, a clinical interaction at PEPT1 is unlikely even with a compound with high affinity for the transporter.

Introduction: Testosterone 2% solution (Axiron) applied to armpit(s) is used for replacement therapy in men with a deficiency of endogenous testosterone.Aim: To determine the amount of testosterone on subjects' T-shirts 12 hours after applying testosterone solution, the residual testosterone on subjects' T-shirts after laundering, and the testosterone transferred to unworn textile items during laundering with worn T-shirts.Methods: Healthy males >= 18 years old applied 2 x 1.5 mL of testosterone 2% solution to both axillae (total testosterone dose: 120 mg) and dressed in cotton long-sleeved T-shirts after a >= 3-minute waiting period. T-shirts were worn 12 hours before being removed and cut into halves, after which a 10 x 10 cm sample of each armpit area was excised for testosterone quantification before or after laundering with samples of unworn textiles.Main Outcome Measures: Testosterone on worn T-shirts before and after laundering, and on unworn textiles laundered with the worn T-shirts.Results: Twelve subjects enrolled and completed, with only minor adverse events. Mean testosterone in unwashed worn T-shirts was 7603 mg, with high between-subject variability (3359 mg to 13,069 mg), representing 13% of the dose to 1 armpit. Mean testosterone in worn, laundered T-shirts was 260 mg (7.55 mg to 1343 mg), representing 3% of the dose to 1 armpit. Mean transferred testosterone to other textiles during laundering ranged from 69 mg on texturized Dacron 56T Double to 10,402 mg on 87/13 nylon/Lycra knit, representing 0.0382% to 5.78% of the dose to 1 armpit.Conclusion: Thirteen percent of the testosterone applied to axillae was transferred to T-shirts during wear. Ninety-seven percent of the transferred testosterone was removed from the T-shirts during washing, some of which was then absorbed to various degrees by other textiles. Clinical implications of these findings and biological activity of the remaining/transferred testosterone are unknown. Copyright (C) 2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Necitumumab is a second-generation, recombinant, human immunoglobulin G1 monoclonal antibody that blocks the ligand binding site of the epidermal growth factor receptor. The primary objective of this phase 2 study, conducted in accordance with International Conference on Harmonisation E14 guidance, was to determine the effect of necitumumab treatment on QT/QTc interval in patients with advanced solid tumors.

Thorough QT studies conducted according to the International Council on Harmonisation E14 guideline are required for new nonantiarrhythmic drugs to assess the potential to prolong ventricular repolarization. Special considerations may be needed for conducting such studies with antidiabetes drugs as changes in blood glucose and other physiologic parameters affected by antidiabetes drugs may prolong the QT interval and thus confound QT/corrected QT assessments. This review discusses potential mechanisms for QT/corrected QT interval prolongation with antidiabetes drugs and offers practical considerations for assessing antidiabetes drugs in thorough QT studies. This article represents collaborative discussions among key stakeholders from academia, industry, and regulatory agencies participating in the Cardiac Safety Research Consortium. It does not represent regulatory policy.

OBJECTIVE This thorough QT/QTc (TQT) study assessed the effects of a supratherapeutic dose of pomaglumetad methionil, a potential treatment for schizophrenia, compared to placebo on the QT interval in subjects with schizophrenia. METHODS This double-blind, 3-period crossover study enrolled 86 subjects aged 22 - 63 years, who met Diagnostic and Statistical Manual, Fourth Edition, Test Revision (DSM-IV-TR) criteria for schizophrenia; 78 subjects completed the study. Subjects were randomly assigned to sequences of 3 treatment periods of single oral doses of pomaglumetad methionil 400 mg, moxifloxacin 400 mg, and placebo. Quadruplicate electrocardiograms (ECGs) were extracted from 2 hours predose to 12 hours postdose and were overread by a blinded central reader. Time-matched pharmacokinetic (PK) parameters were assessed. RESULTS At all-time points, the upper bound of the 90% 2-sided confidence interval (CI) for the least squares (LS) mean difference in changes from baseline in Fridericia's corrected QT interval (ΔQTcF) between pomaglumetad methionil and placebo was < 10 milliseconds (msec). Sufficient assay sensitivity was not achieved, likely due to food effect; although the maximum observed drug concentration (Cmax) with moxifloxacin (1,410 ng/mL) was lower than expected, the slope of the regression line of moxifloxacin plasma concentrations versus placebo-subtracted ΔQTcF was similar to that reported in the literature. CONCLUSIONS A single supratherapeutic dose of 400 mg pomaglumetad methionil did not prolong QTcF to a clinically significant degree and, importantly, did not result in any absolute QTcF > 450 msec or increase in QTcF from predose > 30 msec.

INTRODUCTION Testosterone 2% solution is applied to axillae and is indicated for testosterone replacement therapy in males deficient in endogenous testosterone. AIM This open-label crossover study evaluated the effect of deodorant/antiperspirant use and presence or absence of axillary hair on absorption of testosterone solution. METHODS Healthy males (N = 30; ≥50 years of age with baseline testosterone <400 ng/dL) were randomized to one of four treatment sequences involving six treatments. Each treatment consisted of one 1.5-mL dose of testosterone 2% solution (30 mg of testosterone) applied to each axilla. Axillae were unshaved or shaved, and were untreated or pretreated with deodorant/antiperspirant. MAIN OUTCOME MEASURES Blood samples were taken over 72 hours after each dose for measuring serum testosterone concentrations. RESULTS Profiles of mean testosterone concentrations were similar across treatments. For all treatments, area under the concentration-time curve through 24 hours (AUC[0-24] ) and 72 hours (AUC[0-72] ), and maximum total testosterone concentration (Cmax ) were similar except for 15% lower Cmax when treatment was applied after deodorant/antiperspirant to shaved vs. unshaved axillae (least squares mean, 531 ng/dL vs. 626 ng/dL, respectively; P = 0.011). This difference is not considered clinically significant. The 95% confidence intervals for AUC(0-24) , AUC(0-72) , and Cmax fell within the traditional bioequivalence limits of 0.8 to 1.25. Incidence of treatment-emergent adverse events (TEAEs) was low (<15%) in each treatment arm, and most TEAEs were mild. CONCLUSIONS Absorption of testosterone 2% solution was unaffected by use of deodorant/antiperspirant or by the presence or absence of axillary hair. Testosterone solution was generally well tolerated.

Pomaglumetad methionil (LY2140023) is the prodrug of a novel metabotropic glutamate 2/3 receptor agonist (LY404039) being investigated for the treatment of schizophrenia. Using accelerator mass spectrometry (AMS) and an intravenous (i.v.) radiolabeled tracer approach, the absolute bioavailability of the prodrug and the extent of its conversion to active moiety (LY404039) were estimated at presystemic (intestinal/first pass) and systemic sites after simultaneous oral and i.v. dosing in healthy subjects. The mean absolute bioavailability of prodrug (80 mg oral) was 0.68. On the basis of these data and a previous radiolabeled mass balance study in which no prodrug was recovered in feces, we concluded that 0.32 of the dose is converted to active drug in the intestinal tract. The fraction of prodrug converted to active moiety was approximately 1, indicating complete conversion of the prodrug that reaches the systemic circulation to the active moiety. Prodrug (80 mg oral and 100 μg i.v.) and active moiety (100 μg i.v.) were well tolerated in healthy subjects. Thus, the absolute bioavailability of prodrug LY2140023 and the fraction converted presystemically and systemically to active moiety LY404039 were estimated simultaneously using radiolabeled tracer microdosing and AMS.

OBJECTIVESA modified insulin tolerance test (ITT) can be used to simulate a physiological stress state through the induction of controlled hypoglycemia in healthy volunteers. This allows for evaluation of hypothalamic-pituitary-adrenocortical axis response to stress via a surge in cortical release. However, a consequence of severe, prolonged hypoglycemia is QT interval prolongation. The aim of this analysis was to confirm that blood glucose lowering to 60 mg/dL (previously identified as adequate for inducing stress) has low risk of inducing clinically significant QT prolongation.MATERIALS AND METHODSContinuous ECG monitoring was conducted as a planned sub study of an open-label, 2-period study involving 18 healthy male subjects. The QTcF response to hypoglycemia was measured over 2 identical periods, ~ 7 days apart.RESULTSAn indirect- response model adequately described the pharmacological relationship between blood glucose and QTcF intervals over the time-course of the ITT. The model correctly identified the steep glucose-QT relationship as an on-off response with a large Hill coefficient of 59 and the threshold glucose, EC50, as ~ 57 mg/dL with narrow between-subject variability of 10%. Simulated QTcF profiles over the course of an ITT did not demonstrate any QTcF interval changes of clinical concern, defined as QTcF observation > 500 ms, if hypoglycemia did not reach below 60 mg/dL. The statistical prediction that the chance of a mean QTcF observation > 500 ms was < 0.0001.CONCLUSIONSResults support that an ITT maintained at or above 60 mg/dL is unlikely to cause QT prolongation in healthy volunteers and does not warrant continuous ECG monitoring in this group of subjects.

Duloxetine selectively inhibits the serotonin (5-HT) and norepinephrine (NE) transporters (5-HTT and NET, respectively), as demonstrated in vitro and in preclinical studies; however, transporter inhibition has not been fully assessed in vivo at the approved dose of 60 mg/d. Here, the in vivo effects of dosing with duloxetine 60 mg once daily for 11 days in healthy subjects were assessed in 2 studies: (1) centrally (n = 11), by measuring concentrations of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylglycol (DHPG), and NE in cerebrospinal fluid, and (2) versus escitalopram 20 mg/d (n = 32) in a 2-period crossover study by assessing the ΔDHPG/ΔNE ratio in plasma during orthostatic testing and by pharmacokinetic/pharmacodynamic modeling of reuptake inhibition using subjects' serum in cell lines expressing cloned human 5-HTT or NET. At steady state, duloxetine significantly reduced concentrations of DHPG and 5-hydroxyindoleacetic acid (P < 0.05), but not NE, in cerebrospinal fluid; DHPG was also decreased in plasma and urine. The ΔDHPG/ΔNE ratio in plasma decreased significantly more with duloxetine than escitalopram (65% and 21%, respectively; P < 0.0001). Ex vivo reuptake inhibition of 5-HTT was comparable (EC50 = 44.5 nM) for duloxetine and escitalopram, but duloxetine inhibited NET more potently (EC50 = 116 nM and 1044 nM, respectively). Maximal predicted reuptake inhibition for 5-HTT was 84% for duloxetine and 80% for escitalopram, and that for NET was 67% and 14%, respectively. In summary, duloxetine significantly affected 5-HT and NE turnover in the central nervous system and periphery; these effects presumably occurred via inhibition of reuptake by the 5-HTT and NET, as indicated by effects on functional reuptake inhibition ex vivo.

1. The disposition and metabolism of a Chk-1 inhibitor (LY2603618) was characterized following a 1-h intravenous administration of a single 250-mg dose of [C-14]LY2603618 (50 mu Ci) to patients with advanced or metastatic solid tumors.2. LY2603618 was well tolerated with no clinically significant adverse events. Study was limited to three patients due to challenges of conducting ADME studies in patients with advanced cancer. Plasma, urine and feces were analyzed for radioactivity, LY2603618 and metabolites. LY2603618 had a half-life of 10.5 h and was the most abundant entity in plasma, accounting for approximately 69% of total plasma radioactivity. The second most abundant metabolites, H2 and H5, accounted for <10% of total circulating radioactivity. The major route of clearance was via CYP450 metabolism. The mean total recovery of radioactivity was 83%, with approximately 72% of the radioactivity recovered in the feces and approximately 11% in the urine. LY2603618 represented approximately 6% and 3% of the administered dose in feces and urine, respectively.3. A total of 12 metabolites were identified. In vitro phenotyping indicated that CYP3A4 was predominantly responsible for the metabolic clearance of LY2603618. Additionally, aldehyde oxidase was involved in the formation of a unique human and non-human primate metabolite, H5.

Background: This was the first study, to our knowledge, in patients with schizophrenia in which olanzapine long-acting injection (LAI) was used to attempt delivery of depot formulation in multiple therapeutic doses.Objective: This study assessed the safety profile, tolerability, and pharmacokinetic (PK) properties of olanzapine after single and multiple administrations of olanzapine LAI and evaluated maintenance of symptom control.Methods: This was an open-label, multicenter, non-randomized study of olanzapine LAI in patients with schizophrenia stabilized with oral olanzapine. Key inclusion criteria included well-tolerated and efficacious treatment with daily olanzapine. Patients were required to be receiving a stable oral dose for 4 weeks before study entry with no requirement for as-needed additional antipsychotic medication within 2 weeks before entry. Exclusion criteria included serious unstable illnesses, unresolved seizures, pregnancy or breast-feeding, hypothyroidism, hyperthyroidism, narrow-angle glaucoma, or serious suicidal risk. Initially, 34 patients received olanzapine LAI as a single injection of 50 to 450 mg, and as the study progressed, 247 patients received consecutive injections of 100 to 405 mg olanzapine LAI administered every 2, 3, or 4 weeks for 3 to 6 months. Spontaneously reported adverse events were recorded at each visit. Analyses of efficacy and safety profile parameters were performed on an intent-to-treat basis. All hypotheses were tested at a 2-sided significance leyel of P < 0.05.Results: Study participants had a mean age of 39 years and were primarily white men. The PK properties suggested prolonged release providing sustained olanzapine plasma concentrations and supporting a dosing interval <= 4 weeks. Olanzapine LAI doses of 150 or 300 mg every 2 weeks and 210 or 405 mg every 4 weeks provide mean steady-state olanzapine concentrations similar to those after oral administration of 5 to 20 mg/d. The mean baseline Brief Psychiatric Rating Scale score of 17.27 decreased by 2.68 points, and the mean baseline Clinical Global Impression Severity score of 3.39 decreased by 0.23 points, indicating that patients' psychiatric health was maintained or slightly improved. Significant mean weight gain (P < 0.001) and treatment-emergent changes in nonfasting glucose were observed. Incidence of weight gain >= 7% of baseline was observed in 17.8% of patients. The common adverse events were injection site pain, anxiety, sedation, insomnia, somnolence, and headache, and the safety profile for olanzapine LAI was comparable to that of oral olanzapine, except for injection site related adverse events.Conclusion: The safety profile and PK data from this study support continued clinical development of olanzapine LAI in controlled efficacy studies at doses <= 300 mg every 2 weeks or 405 mg every 4 weeks. (C) 2013 Elsevier HS Journals, Inc. All rights reserved.

Aim The effects of atomoxetine (20 and 60?mg twice daily), 400?mg moxifloxacin and placebo on QTc in 131 healthy CYP2D6 poor metabolizer males were compared. Methods Atomoxetine doses were selected to result in plasma concentrations that approximated expected plasma concentrations at both the maximum recommended dose and at a supratherapeutic dose in CYP2D6 extensive metabolizers. Ten second electrocardiograms were obtained for time-matched baseline on days -2 and -1, three time points after dosing on day 1 for moxifloxacin and five time points on day 7 for atomoxetine and placebo. Maximum mean placebo-subtracted change from baseline model-corrected QT (QTcM) on day 7 was the primary endpoint. Results QTcM differences for atomoxetine 20 and 60?mg twice daily were 0.5?ms (upper bound of the one-sided 95% confidence interval 2.2?ms) and 4.2?ms (upper bound of the one-sided 95% confidence interval 6.0?ms), respectively. As plasma concentration of atomoxetine increased, a statistically significant increase in QTc was observed. The moxifloxacin difference from placebo met the a priori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QTcM for moxifloxacin was 4.8?ms and this difference was statistically significant. Moxifloxacin plasma concentrations were below the concentrations expected from the literature. However, the slope of the plasma concentration-QTc change observed was consistent with the literature. Conclusion Atomoxetine was not associated with a clinically significant change in QTc. However, a statistically significant increase in QTc was associated with increasing plasma concentrations.

To assess the impact of hepatic or renal impairment on the pharmacokinetics (PK) of edivoxetine.

AimsExenatide has been demonstrated to improve glycaemic control in patients with type 2 diabetes, with no effect on heart rate corrected QT (QTc) at therapeutic concentrations. This randomized, placebo‐ and positive‐controlled, crossover, thorough QT study evaluated the effects of therapeutic and supratherapeutic exenatide concentrations on QTc.MethodsIntravenous infusion was employed to achieve steady‐state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e. days). Subjects received exenatide, placebo and moxifloxacin, with ECGs recorded pre‐therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice daily or once weekly formulations. To assure proper heart rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction.ResultsTargeted steady‐state plasma exenatide concentrations were exceeded (geometric mean ± SEM 253 ± 8.5 pg ml−1, 399 ± 11.9 pg ml−1 and 627 ± 21.2 pg ml−1). QTcP, a population‐based method, was identified as the most appropriate heart rate correction and was prespecified for primary analysis. The upper bound of the two‐sided 90% confidence interval for placebo‐corrected, baseline‐adjusted QTcP (ΔΔQTcP) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady‐state plasma exenatide concentration of ∼500 pg ml−1 (ΔΔQTcPavg) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔQTcP and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin.ConclusionsThese results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QTc and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect.

A decrease in heart rate variability (HRV) can indicate increased sympathetic nervous system activity and possibly increased norepinephrine levels. In this randomized, placebo- and escitalopram (ESC)-controlled, subject-blind, 2-period, crossover study, 26 healthy subjects 50 to 65 years old received duloxetine (DLX) 60 mg once daily or ESC 20 mg once daily for 11 days, each in sequential study periods separated by a 10-day or more washout period. Continuous electrocardiogram recordings were obtained by Holter monitoring (baseline, day 9, and day 10 of treatment). Duloxetine and ESC did not produce any clinically significant effects on standard measures of HRV, which included SD of normal R-R intervals and the root mean square difference among successive R-R normal intervals index values, mean change in SD of normal R-R intervals, and frequency domain analysis. However, treatment with DLX was associated with significantly less change from baseline in total beats per 24 hours than ESC, which was an unexpected finding compared with previous observations in which vital signs were measured at a specific time point while awake. In conclusion, in healthy adults exposed to DLX or ESC, no clinically significant effects on HRV were observed.

BACKGROUND:Consistent with its effect on gastric emptying, exenatide, an injectable treatment for type 2 diabetes, may slow the absorption rate of concomitantly administered oral drugs resulting in a decrease in maximum concentration (Cmax). This study evaluated the drug interaction potential of exenatide when administered adjunctively with oral contraceptives, given their potential concomitant use.METHODS:This trial evaluated the effect of exenatide co-administration on single- and multiple-dose pharmacokinetics of a combination oral contraceptive (ethinyl estradiol [EE] 30 μg, levonorgestrel [LV] 150 μg [Microgynon 30®]). Thirty-two healthy female subjects participated in an open-label, randomised, crossover trial with 3 treatment periods (oral contraceptive alone, 1 hour before exenatide, 30 minutes after exenatide). Subjects received a single dose of oral contraceptive on Day 8 of each period and QD doses on Days 10 through 28. During treatment periods of concomitant usage, exenatide was administered subcutaneously prior to morning and evening meals at 5 μg BID from Days 1 through 4 and at 10 μg BID from Days 5 through 22. Single- (Day 8) and multiple-dose (Day 22) pharmacokinetic profiles were assessed for each treatment period.RESULTS:Exenatide did not alter the bioavailability nor decrease daily trough concentrations for either oral contraceptive component. No substantive changes in oral contraceptive pharmacokinetics occurred when oral contraceptive was administered 1 hour before exenatide. Single-dose oral contraceptive administration 30 minutes after exenatide resulted in mean (90% CI) Cmax reductions of 46% (42-51%) and 41% (35-47%) for EE and LV, respectively. Repeated daily oral contraceptive administration 30 minutes after exenatide resulted in Cmax reductions of 45% (40-50%) and 27% (21-33%) for EE and LV, respectively. Peak oral contraceptive concentrations were delayed approximately 3 to 4 hours. Mild-to-moderate nausea and vomiting were the most common adverse events observed during the trial.CONCLUSIONS:The observed reduction in Cmax is likely of limited importance given the unaltered oral contraceptive bioavailability and trough concentrations; however, for oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before exenatide injection.TRIAL REGISTRATION:ClinicalTrials.gov: NCT00254800.