Malcolm I. Mitchell

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 AUCτ 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 AUCτ 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.

Effect of Tadalafil on Cytochrome P450 3A4–mediated Clearance: Studies in Vitro and in Vivo

Tadalafil was examined in vitro and in vivo for its ability to affect human cytochrome P450 (CYP) 3A‐mediated metabolism.

A thorough QT study to evaluate the effects of singledose exenatide 10 μg on cardiac repolarization in healthy subjects.

OBJECTIVE This was a singledose, randomized, positive- and placebo-controlled, double-dummy, double-blinded, 3-period crossover thorough QT study of exenatide, a glucagon-like peptide-1 receptor agonist for the treatment of Type 2 diabetes that enhances insulin secretion in a glucose- dependent fashion. METHODS Healthy subjects (n = 70) underwent an initial tolerability screening, receiving subcutaneous exenatide 10 μg daily for 3 consecutive days. Subjects who passed tolerability screening (n = 62) received exenatide 10 μg, placebo, and moxifloxacin (400 mg orally; positive control) separated by washout periods of approximately 5 days. Twelve-lead electrocardiograms and blood samples for plasma exenatide, glucose, and insulin were collected. QT intervals were heart rate-corrected using Fridericias correction (QTcF) and an individual correction (QTcI) and were analyzed as change from predose (ΔQTcF, or ΔQTcI). The relationships between the QTc interval and plasma exenatide, glucose, and insulin concentrations were also explored. RESULTS Based on ΔQTcF and ΔQTcI assessments, exenatide 10 μg did not show a clinically significant prolongation of QT compared with placebo; the upper bound of the 2-sided 90% confidence interval (CI) for the largest mean difference from placebo was < 10 msec with both corrections. A positive slope was observed between plasma exenatide and ΔΔQTcF (0.02 (95% CI 0.01, 0.03), p < 0.001); no significant slope was observed between plasma exenatide concentrations and ΔΔQTcI (0.01 (95% CI 0.00, 0.02), p = 0.064). The plasma exenatide versus QTc analyses may be confounded by exenatides glucose-lowering effect. A negative slope was observed between plasma glucose and [delta]QTcF (-1.5 (95% CI -2.2, -0.7), p < 0.001) and between plasma glucose and ΔQTcI (-1.6 (95% CI -2.3, -0.9), p < 0.0001). Plasma insulin and ΔQTcF were not correlated. CONCLUSION This study demonstrated that single-dose exenatide 10 μg was not associated with clinically meaningful prolongation of the QTc interval.

The effects of supratherapeutic doses of duloxetine on blood pressure and pulse rate.

The effects of supratherapeutic dosages of duloxetine, a serotonin and norepinephrine reuptake inhibitor, on blood pressure and pulse rate were assessed in a multicenter, double-blind, randomized, placebo-controlled, crossover study in 117 healthy women aged 19 to 74 years. Dosages were escalated from 60 mg twice daily (BID) to 200 mg BID over 16 days. Vital signs were monitored at baseline, before morning dosing, and sequentially at steady state. Duloxetine produced increases in supine systolic and diastolic blood pressures, which reached maximums of ~12 mm Hg and ~7 mm Hg above baseline, respectively, during dosing at 120 mg BID and then stabilized. Supine pulse rate increased gradually with dose, reaching 10 to 12 bpm above baseline after 4 days of dosing at 200 mg BID. Duloxetine caused changes in orthostatic blood pressures and pulse rate that reached plateau values after 3 to 4 days of dosing at 160 mg BID and were generally not associated with subjectively reported orthostatic-related adverse events. All vital signs normalized by 1 to 2 days after study drug discontinuation. Prehypertensive subjects may become hypertensive upon initial duloxetine dosing, but this can be predicted from predose blood pressure. Short-term supratherapeutic duloxetine dosages up to 200 mg BID are not well tolerated but are generally not associated with severe, clinically important adverse events. Overall, the types of adverse events reported in this study were similar to those in other studies of duloxetine in healthy subjects.

Exenatide - pharmacokinetics, pharmacodynamics, safety and tolerability in patients ≥ 75 years of age with Type 2 diabetes.

OBJECTIVE This study evaluated pharmacokinetics, pharmacodynamics,safety, and tolerability of single doses of exenatide in elderly Type 2 diabetes (T2D)patients. METHODS This placebo-controlled,patient-blind, crossover study compared elderly patients (≥ 75 y, n = 15) to controls( ≥ 45 to ≤ 65y, n = 15) with T2D. Patients were randomized to single subcutaneous doses of exenatide 5μg, placebo or exenatide 10 μg (Sequence 1) or placebo, exenatide 5 μg or exenatide 10 μg (Sequence 2) before a standardized breakfast over three consecutive days. Serial blood samples were collected for plasma exenatide and serum glucose concentrations.Pharmacokinetic data from this study were also integrated with those from six other clinical pharmacology studies to further evaluate the impact of age on plasma exenatide apparent clearance (CL/F) (139 controls ( ≤ 65 y); 28 elderly patients (> 65 y)). RESULTS Mean ± SD ages for control and elderly patients were 57 ± 6 y and 78 ± 3 y, respectively.All elderly patients had renal impairment at baseline, as compared with one third of controls. Dose-normalized plasma exenatide maximum concentration and exposure were greater in elderly patients, but between-age group differences were neither statistically significant nor considered clinically relevant. The integrated pharmacokinetic analysis showed a significant linear relationship between plasma exenatide CL/F and renal clearance (test of slope = 0, p < 0.001),with no additional effect from age. Exenatide dose-dependently blunted postprandial serum glucose excursions in both age groups. No hypoglycemia or serious adverse events were reported, and exenatide was generally well tolerated in both age groups. CONCLUSIONS Exenatide dose adjustments should be determined by renal function rather than age in elderly T2D patients.

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

BackgroundConsistent 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.MethodsThis 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.ResultsExenatide 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.ConclusionsThe 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 registrationClinicalTrials.gov: NCT00254800.

Current Status of the Ventak® PRx Pulse Generator and Endotak™ Nonthoracotomy Lead System

Recent advances in the electrical management of tachyarrhythmias include the development and clinical evaluation of multifunction implantable pacemaker defibrillators (MIPD) and nonthoracotomy lead systems. For selected patients, these devices, alone or in combination, offer certain diagnostic, therapeutic, and cost benefits compared with standard systems. The MIPD and nonthoracotomy leads are available in Europe and currently are undergoing clinical investigation in the United States in accordance with the Food and Drug Administration (FDA) regulations.

Hemodynamic Interaction Between a Daily Dosed Phosphodiesterase 5 Inhibitor, Tadalafil, and the α‐Adrenergic Blockers, Doxazosin and Tamsulosin, in Middle‐Aged Healthy Male Subjects

The hemodynamic interaction between tadalafil (5 mg/d) and doxazosin or tamsulosin was investigated in 2 randomized, double‐blind, crossover phase 1 studies. Healthy men (n = 45) received tadalafil or placebo for 28 days and increasing doses of doxazosin (1, 2, and 4 mg/d) for the last 21 days of treatment. In the second study, participants (n = 39) received tadalafil or placebo for 14 days and tamsulosin (0.4 mg/d) for the last 7 days of treatment. Similar mean maximum postbaseline changes in standing systolic blood pressure were observed in subjects given tadalafil or placebo with 4 mg of doxazosin (−0.5 mm Hg; 95% confidence interval, −4 to 3.1 mm Hg) or with tamsulosin (0.9 mm Hg; 95% confidence interval, −1.4 to 3.2 mm Hg). Standing systolic blood pressure less than 85 mm Hg (blood pressure outlier) occurred in 1 subject treated with 4 mg of doxazosin plus tadalafil but was not reported in subjects treated with tamsulosin and tadalafil. Three subjects experienced moderate hypotensive events lasting less than 2 hours, 2 with syncope (after tadalafil alone or with 4 mg of doxazosin) and 1 without (after 4 mg of doxazosin with placebo). The incidence of hypotension was low in healthy men given increasing doses of doxazosin with chronically dosed tadalafil or placebo. Administration of tadalafil with tamsulosin was well tolerated in healthy men.

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

Abstract 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 &Dgr;DHPG/&Dgr;NE 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 &Dgr;DHPG/&Dgr;NE 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 exenatide on lisinopril pharmacodynamics and pharmacokinetics in patients with hypertension.

OBJECTIVES This study evaluated the potential effect of exenatide on the pharmacokinetics and pharmacodynamics of lisinopril in patients with mild-to-moderate hypertension. METHODS 22 patients with mild-to-moderate primary hypertension participated in a double-blind, randomized, placebo-controlled, 2-period, 2-sequence crossover study. Patients on stable lisinopril therapy were randomly assigned to receive subcutaneous exenatide (10 microg b.i.d.) and placebo b.i.d. separated by at least 2 days washout period. The primary pharmacodynamic parameters were baseline-adjusted 24-hour mean systolic and diastolic blood pressure. Steady state plasma lisinopril concentration-time profiles were also assessed. RESULTS Mean blood pressure changes were not significantly different between exenatide and placebo coadministered with lisinopril. The least squares mean differences (95% CI) between treatments were +1.38 mmHg (-1.41, 4.17) for diastolic and +1.38 mmHg (-1.95, 4.71) for systolic blood pressure. Exenatide delayed the time to attain maximum lisinopril concentration (tmax,ss) by 2 hours but did not significantly alter maximum lisinopril concentration (Cmax,ss) or area under the concentration-time profile (AUCtau,ss) over the 24-hour steady-state dosing interval. CONCLUSIONS This study demonstrated that concurrent administration of exenatide did not produce clinically relevant changes in blood pressure and did not significantly alter lisinopril pharmacokinetics in patients with mild-to-moderate hypertension.