In Vitro and Clinical Evaluations of the Drug-Drug Interaction Potential of a Metabotropic Glutamate 2/3 Receptor Agonist Prodrug with Intestinal Peptide Transporter 1.

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.

Relative bioavailability of three formulations of galunisertib administered as monotherapy in patients with advanced or metastatic cancer.

OBJECTIVE: Galunisertib (LY2157299 monohydrate), an inhibitor of the transforming growth factor ß (TGFß) 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.

Evaluation of the effect of necitumumab on the corrected QT interval in patients with advanced solid tumors.

PURPOSE: 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. METHODS: Patients received necitumumab monotherapy at an absolute dose of 800 mg, once per week for each 6-week cycle. Triplicate electrocardiogram readings were taken at pretreatment (baseline) and then weekly at multiple timepoints that were time-matched with blood samples to determine necitumumab concentrations. RESULTS: Seventy-five patients received treatment. Overall, the upper bound of the two-sided 90 % confidence interval for mean change from baseline in QTc in cycle 1 did not exceed 10 ms. No patients had a mean QTcF interval >500 ms, and no patients had an increase of >60 ms. Necitumumab concentration-QTc analysis also showed that necitumumab is unlikely to cause QTc prolongation. CONCLUSIONS: The results demonstrate lack of effect of necitumumab on the QTc interval in heavily pretreated patients with advanced solid tumors, suggesting that QT prolongation is not a major safety concern for necitumumab at the recommended therapeutic dose. The safety profile was consistent with the known safety profile of necitumumab.

Amount of Testosterone on Laundered Clothing After Use of Testosterone Topical 2% Solution by Healthy Male Volunteers.

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 × 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 × 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 µg, with high between-subject variability (3359 µg to 13,069 µg), representing 13% of the dose to 1 armpit. Mean testosterone in worn, laundered T-shirts was 260 µg (7.55 µg to 1343 µg), representing 3% of the dose to 1 armpit. Mean transferred testosterone to other textiles during laundering ranged from 69 µg on texturized Dacron 56T Double to 10,402 µg 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.

Considerations for assessing the potential effects of antidiabetes drugs on cardiac ventricular repolarization: A report from the Cardiac Safety Research Consortium.

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.

Effect of pomaglumetad methionil on the QT interval in subjects with schizophrenia.

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.

Relative contributions of presystemic and systemic peptidases to oral exposure of a novel metabotropic glutamate 2/3 receptor agonist (LY404039) after oral administration of prodrug pomaglumetad methionil (LY2140023).

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.

Effect of deodorant and antiperspirant use and presence or absence of axillary hair on absorption of testosterone 2% solution applied to men's axillae.

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.

Modeling and simulations to confirm a controlled hypoglycemic stress test in healthy subjects is not associated with clinically significant QT prolongations.

OBJECTIVES: A 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 METHODS: Continuous 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. RESULTS: An 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. CONCLUSIONS: Results 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.

Disposition and metabolism of LY2603618, a Chk-1 inhibitor following intravenous administration in patients with advanced and/or metastatic solid tumors.

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 [14C]LY2603618 (50 µCi) to patients with advanced or metastatic solid tumors. 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. 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.

Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy 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.

The effect of hepatic or renal impairment on the pharmacokinetics of edivoxetine, a selective norepinephrine transporter reuptake inhibitor.

PURPOSE: To assess the impact of hepatic or renal impairment on the pharmacokinetics (PK) of edivoxetine. METHODS: Two separate multi-center, open-label studies with males and females were conducted. Subjects were categorized according to their hepatic function, determined by the Child-Pugh classification, or renal function, determined by creatinine clearance using the Cockcroft-Gault equation. Subjects received a single dose of 18 mg in the hepatic impairment study or 6 mg in the renal impairment study. Noncompartmental PK parameters were computed from the edivoxetine plasma concentration-time data. RESULTS: In the hepatic study, the geometric least squares mean (GLSM) and 90 % confidence interval (CI) of the ratio [impaired : normal] of area under the concentration versus time curve from time zero to infinity (AUC0-∞; h × ng/mL) was 1.24 (0.93, 1.64) in the mild, 1.60 (1.21, 2.12) in the moderate, and 1.70 (1.28, 2.24) in the severe group. In the renal impairment study, the GLSM (90 % CI) of the ratio [impaired : normal] of AUC0-∞ was 1.13 (0.73, 1.73) in mild, 1.90 (1.28, 2.82) in moderate, 1.55 (0.94, 2.55) in severe, and 1.03 (0.66, 1.59) in ESRD groups. Overall, the GLSM of the ratio [impaired : normal] of Cmax was slightly less than or approximately 1 across the hepatic and renal impairment groups. Across both studies, there were no clinically significant changes in vital signs and laboratory values, the adverse events were mild in severity and mostly related to nervous system and gastrointestinal disorder-related events. CONCLUSIONS: PK changes in subjects with hepatic or renal impairment were of small magnitude and did not appear to impact overall subject tolerability. Daily dosing of edivoxetine in a larger population of impaired subjects, including those with dual impairment, would aid in establishing edivoxetine tolerability and PK in a clinical practice scenario.

Evaluation of the effects of duloxetine and escitalopram on 24-hour heart rate variability: a mechanistic study using heart rate variability as a pharmacodynamic measure.

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.

Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers.

AIM: The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QT(c) 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 (QT(c)M) on day 7 was the primary endpoint. RESULTS: QT(c)M 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 QT(c) was observed. The moxifloxacin difference from placebo met the a priori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QT(c)M 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-QT(c) change observed was consistent with the literature. CONCLUSION: Atomoxetine was not associated with a clinically significant change in QT(c). However, a statistically significant increase in QT(c) was associated with increasing plasma concentrations.

Effect of exenatide on the pharmacokinetics of a combination oral contraceptive in healthy women: an open-label, randomised, crossover trial.

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.

Evaluation of methods for achieving stable INR in healthy subjects during a multiple-dose warfarin study.

PURPOSE: No consistent method is available for finding stable warfarin maintenance doses and fast stabilization of international normalized ratio (INR) values among healthy subjects in experimental warfarin interaction studies. Using data from an earlier study that targeted a stable INR of 1.5-2.0 to test an interaction, we retrospectively evaluated potential dosing algorithms using all methods available to us to decrease the time needed for INR stabilization, which could be useful for future interaction studies in healthy subjects. METHODS: Published pharmacogenetic and clinical dosing algorithms used to initiate pharmacotherapy with warfarin were applied, predicted doses and actual doses were compared by regression analysis, and concentration-time profiles of S-warfarin were simulated using SimCYP® software. RESULTS: No demographic variables were significantly associated with time to reach a stable, low-intensity INR in this population of relatively young, healthy subjects. Predicted and actual doses were positively correlated for the pharmacogenetic algorithm, but not for the clinical algorithm. INR levels and S-warfarin concentrations were associated with CYP2C9 and VKORC1 genotypes. CONCLUSIONS: Induction to a pharmacodynamic steady state for warfarin for future multiple-dose warfarin drug-interaction studies in healthy volunteers may be predicted using a pharmacogenetic-based dosing algorithm. Simulations revealed that the desired subtherapeutic INR level may be achieved by reducing the predicted dose by approximately 15%. Further study is needed to assess the applicability of this approach to decrease attrition rates and the time needed to reach INR stabilization.

Systematic decrements in QTc between the first and second day of contiguous daily ECG recordings under controlled conditions.

BACKGROUND: Many thorough QT (TQT) studies use a baseline day and double delta analysis to account for potential diurnal variation in QTc. However, little is known about systematic changes in the QTc across contiguous days when normal volunteers are brought into a controlled inpatient environment. METHODS: Two separate crossover TQT studies included 2 days of no treatment lead-in days with ECG collection preceding periods of drug treatment . In the first study, there were two pairs of such contiguous days with 10 replicate electrocardiograms (ECGs) collected at six time points, and in the second study, there were four pairs of contiguous days with nine replicate ECGs collected at five time points. These lead-in day pairs provided the opportunity to evaluate any systematic changes across contiguous first and second days of an inpatient environment. Within-patient consistency of change across pairs of days as well as within day, diurnal variation could also be evaluated. RESULTS: Modest (4.2 ms [range 1.9-6.5 ms]) but consistent decreases (significant [P < 0.05] for all 32 comparisons) were observed (probability: ≤5.4 × 10(-16)). Although group behavior with respect to QTc was consistent, individual subjects demonstrated substantial variability across pairs of days. Evidence of diurnal variation was weak and inconsistent. Magnitude of any diurnal variation was less than magnitude of change across days. CONCLUSIONS: Subjects show a systematic decrease in QTc from first day to second day of inpatient status and do not demonstrate a significant diurnal pattern. The magnitude of this systematic change is sufficient to influence QTc study interpretation.

Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, II: investigations of mechanism.

BACKGROUND: Olanzapine long-acting injection (LAI) is a salt-based depot antipsychotic combining olanzapine and pamoic acid. The slow intramuscular dissolution of this practically insoluble salt produces an extended release of olanzapine lasting up to 4 weeks. However, in a small number of injections (< 0.1%), patients experienced symptoms suggestive of olanzapine overdose, a phenomenon that has been termed "post-injection delirium/sedation syndrome" (PDSS). The authors conducted a series of parallel investigations into the possible reasons PDSS events occur. METHODS: Healthcare providers involved in the PDSS cases were queried for clinical information around the events. Plasma samples from patients experiencing PDSS were collected when possible (12/30 cases) and olanzapine concentrations compared with the known pharmacokinetic profile for olanzapine LAI. Product batches and used vials from the PDSS cases were evaluated for compliance with established manufacturing standards and/or possible user error. Because this depot formulation depends upon slow dissolution at the intramuscular injection site, in-vitro experiments were conducted to assess solubility of olanzapine pamoate in various media. RESULTS: Injection administrators reported no unusual occurrences during the injection. No anomalies were found with the product batches or the remaining suspension in the used vials. Olanzapine concentrations during PDSS events were higher than the expected 5-73 ng/mL range, with concentrations exceeding 100 ng/mL and in some cases reaching >600 ng/mL during the first hours after injection but then returning to the expected therapeutic range within 24 to 72 hours. Solubility and dissolution rate of olanzapine pamoate were also found to be substantially greater in plasma than in other media such as those approximating the environment in muscle tissue. CONCLUSIONS: Manufacturing irregularities, improper drug reconstitution, and inappropriate dosing were ruled out as possible causes of PDSS. In-vitro solubility and in-vivo pharmacokinetic investigations suggest that PDSS is related to exposure of the injected product to a substantial volume of blood. This exposure is most likely the result of unintended partial intravascular injection or blood vessel injury during the injection (occurring even with proper injection technique) with subsequent seepage of the medication into the vasculature, which would produce higher than intended olanzapine concentrations and symptoms consistent with PDSS. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects.

Tadalafil, an oral phosphodiesterase 5 (PDE5) inhibitor, is being investigated as a treatment for pulmonary arterial hypertension. Bosentan is an oral endothelin receptor antagonist widely used in the treatment of pulmonary arterial hypertension. Tadalafil is mainly metabolized by cytochrome P450 (CYP) 3A4, and as bosentan induces CYP2C9 and CYP3A4, a pharmacokinetic interaction is possible between these agents. This open-label, randomized study investigated whether any pharmacokinetic interaction exists between tadalafil and bosentan. Healthy adult men (n = 15; 19-52 years of age) received 10 consecutive days of tadalafil 40 mg once daily, bosentan 125 mg twice daily, and a combination of both in a 3-period, crossover design. Following 10 days of multiple-dose coadministration of bosentan and tadalafil, compared with tadalafil alone, tadalafil geometric mean ratios (90% confidence interval [CI]) for AUCtau and Cmax were 0.59 (0.55, 0.62) and 0.73 (0.68, 0.79), respectively, with no observed change in tmax. Following coadministration of bosentan with tadalafil, bosentan ratios (90% CI) for AUCtau and Cmax were 1.13 (1.02, 1.24) and 1.20 (1.05, 1.36), respectively. Tadalafil alone and combined with bosentan was generally well tolerated. In conclusion, after 10 days of coadministration, bosentan decreased tadalafil exposure by 41.5% with minimal and clinically irrelevant differences (<20%) in bosentan exposure.

Design and analysis considerations for thorough QT studies employing conventional (10 s, 12-lead) ECG recordings.

The QT interval from the ECG cannot be measured precisely. The relationship of the QT interval to the RR interval within individuals across time and different RR values, and across individuals eludes complete understanding. Intrinsic beat-to-beat variability in QT interval corrected for heart rate (QTc interval) is not trivial. Therefore, it is difficult to determine a valid and reliable estimate of the time for ventricular repolarization based on the QTc interval. Yet, it must be demonstrated that a drug does not result in an increase in the QTc interval that exceeds 5 ms with some reasonable degree of certainty to be quite confident that the drug does not convey some risk of ventricular tachydysrhythmia due to delayed ventricular repolarization. This demonstration can be a Herculean task due to the magnitude of variability in the QTc interval. Design features and analytical methods that might be used in the thorough QT study to improve the chances of demonstrating the true relationship between a drug and QTc interval are reviewed.