Malcolm Mitchell

Effect of renal impairment on the pharmacokinetics of exenatide.

What is already known about this subject Nonclinical studies have shown that exenatide is primarily cleared by the renal system. It was not known to what degree the clinical pharmacokinetics and tolerability would be affected by increasing renal impairment (RI). What this study adds Patients with mild to moderate RI adequately tolerate current therapeutic doses of exenatide. However, exenatide is not recommended in patients with severe RI or end-stage renal disease. Aims To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI). Methods Exenatide (5 or 10 µg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft–Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min−1, n = 8), mild RI (51–80 ml min−1, n = 8), moderate RI (31–50 ml min−1, n = 7) or end-stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single-dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL. Results Mean half-life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h−1, respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 µg q.d.). Conclusions Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 µg) unsuitable in severe RI or ESRD.

Cardiovascular effects of tadalafil

To determine the effects of tadalafil on the cardiovascular system, safety assessments were performed on a database of >4000 subjects who received tadalafil in >60 clinical pharmacology, phase 2, phase 3, and open-label studies. In healthy subjects, tadalafil resulted in small changes in blood pressure, which are not believed to be clinically relevant. Daily administration of tadalafil 20 mg for 26 weeks in healthy male subjects or patients with mild erectile dysfunction resulted in blood pressure changes similar to those observed after placebo administration. In patients with coronary artery disease (CAD), tadalafil administration before nitrate administration resulted in small decreases in blood pressure. The resulting mean maximal change in standing systolic blood pressure (SBP) after coadministration of sublingual nitroglycerin in patients with chronic stable angina was -36 mm Hg for tadalafil 5 mg, -31 mm Hg for tadalafil 10 mg, and -28 mm Hg for placebo. In addition, a larger number of men had a standing SBP <85 mm Hg after coadministration of sublingual nitroglycerin and tadalafil 5 mg (p <0.001 vs placebo) or tadalafil 10 mg (p <0.01 vs placebo) compared with coadministration with placebo. In patients with chronic stable angina taking doses of isosorbide mononitrate on a long-term basis, the mean maximal change in standing SBP was -23 mm Hg for placebo, -23 mm Hg for tadalafil 5 mg, and -26 mm Hg for tadalafil 10 mg. In a study of older subjects (>or=55 years of age) with no overt evidence of CAD, the resulting mean maximal change in standing SBP after coadministration of sublingual nitroglycerin was -25 mm Hg for tadalafil 10 mg, -29 mm Hg for sildenafil 50 mg, and -25 mm Hg for placebo. Cardiac mortality rates in tadalafil studies are consistent with the expected rate in this male population. Across all studies, the incidence rate of myocardial infarction was low in tadalafil-treated patients (0.43 per 100 patient-years) compared with patients who received placebo (0.6 per 100 patient-years), and the incidence rate was comparable to that observed in the age-standardized male population (0.60 per 100 patient-years). The incidence rate of presumed thrombotic strokes in tadalafil studies (0.27 per 100 patient-years) is comparable to the expected rate in this patient population. The data presented herein suggest that tadalafil can be safely used by healthy subjects and by patients with cardiovascular diseases. As with sildenafil, the use of tadalafil is contraindicated in patients receiving nitrate therapy because of the potential for significant hypotensive effects.

Cardiovascular effects of tadalafil in patients on common antihypertensive therapies

Tadalafil is a potent, selective, reversible phosphodiesterase 5 inhibitor under investigation for the treatment of erectile dysfunction (ED). Because some oral agents for ED have vasodilator properties, interaction studies were performed between tadalafil and commonly prescribed antihypertensive agents. In addition, cardiovascular safety assessments were made from a safety database of phase 3 studies comparing patients who were and who were not receiving antihypertensives. In patients receiving concomitant antihypertensive therapy, tadalafil administration may result in a reduction in blood pressure, which is, in general, mild and not likely to be of clinical concern. In the phase 3 studies, no statistically significant differences were observed between tadalafil and placebo in the mean changes in blood pressure from baseline in patients taking >or=2 antihypertensive agents. The incidence rates of cardiovascular events were comparable between patients who were and were not treated with concomitant antihypertensive therapy, with the exception of events recorded as hypertension, which would be expected to occur periodically in this patient population despite treatment. Hypotension or postural hypotension was not reported in any tadalafil-treated patient, compared with 1 report of each in the placebo-treated patients. Syncope was reported in 1 tadalafil-treated patient (0.1%) who was not on concomitant antihypertensive medication and in 2 patients (1.9%) who received placebo with concomitant antihypertensive agents. The data presented herein suggest that tadalafil is safe in patients receiving >or=1 concomitant antihypertensive agent.

Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects

Aims Exenatide 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. Methods Intravenous 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. Results Targeted 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. Conclusions These 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.

Effects of Duloxetine on the Pharmacodynamics and Pharmacokinetics of Warfarin at Steady State in Healthy Subjects

This study evaluated the pharmacodynamics and pharmacokinetics of once‐daily dosing of warfarin at steady state when taken concomitantly with once‐daily doses of duloxetine. Healthy subjects with a stable international normalized ratio (INR) of 1.5 to 2.0 on an individualized fixed dose of warfarin (2–9 mg) in period 1 received daily warfarin and duloxetine (60 mg for 14 days [n = 15] or 60 mg for 4 days, then 120 mg for 10 days [n = 15]) in period 2. Across the 14‐day period when warfarin was coadministered with duloxetine, the least squares mean INR changes from baseline (warfarin alone) ranged from −0.05 to +0.07, and the 90% confidence intervals ranged from −0.12 to +0.14. Following coadministration of warfarin with 60 mg duloxetine, but not with 120 mg duloxetine, there was a statistically significant prolongation in bleeding time compared to warfarin alone. For both R‐ and S‐warfarin, the 90% confidence interval for the geometric mean ratios of area under the curve (AUCτ,ss) and maximum plasma concentrations (Cmax, ss) between warfarin administered alone and with 60 or 120 mg duloxetine were contained within the bioequivalence limits of 0.8 to 1.25. In conclusion, duloxetine had no clinically or statistically significant effect on the pharmacodynamics or pharmacokinetics of warfarin at steady state.

Comparison of manual versus ambulatory blood pressure measurements with pharmacokinetic-pharmacodynamic modeling of antihypertensive compounds: Application to moxonidine

To compare the results of the pharmacokinetic‐pharmacodynamic analyses of 24‐hour ambulatory blood pressure measurements and manual blood pressure data in patients receiving moxonidine.

Effect of exenatide on lisinopril pharmacodynamics in patients treated for hypertension

Exenatides antihyperglycemic actions under investigation include slowing gastric emptying, which may affect absorption of co‐administered oral drugs. This study evaluated that potential effect with lisinopril, an ACE inhibitor.

Evaluation of the likelihood of a selective CHK1 inhibitor (LY2603618) to inhibit CYP2D6 with desipramine as a probe substrate in cancer patients

LY2603618 is a selective inhibitor of deoxyribonucleic acid damage checkpoint kinase 1 (CHK1) and has been in development for the enhancement of chemotherapeutic agents. The study described was to assess the potential interaction between LY2603618 and cytochrome P450 isoform 2D6 (CYP2D6) substrate desipramine in patients with cancer. Before clinical investigation, in silico simulations (using Simcyp®) were conducted. An open‐label, two‐period, fixed‐sequence study was planned in 30 patients with advanced or metastatic cancers, in which a 50 mg oral dose of desipramine was administered alone and in combination with 275 mg of LY2603618 (i.v. infusion). An interim analysis was planned after 15 patients completed both periods. Ratios of geometric least squares means (LSMs) of primary pharmacokinetic (PK) parameters and 90% repeated confidence intervals (RCIs) between desipramine plus LY2603618 and desipramine alone were calculated. Lack of an interaction was declared if the 90% RCI fell between 0.8 and 1.25. The LSM ratios (90% RCI) for areas under the plasma concentration–time curve from time zero to tlast (AUC[0‐tlast]) and to infinity (AUC[0‐∞]) and maximum plasma concentration (Cmax) were 1.14 (1.04, 1.25), 1.09 (0.99, 1.21) and 1.16 (1.05, 1.29). In silico simulations were predictive of clinical results. Single doses of 275 mg LY2603618 administered with 50 mg desipramine were generally well tolerated. In conclusion, no clinically significant interaction was observed between LY2603618 and desipramine in patients with cancer. In silico predictions of clinical results demonstrated that mechanistic and physiologically based PK approaches may inform clinical study design in cancer patients. Copyright