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Taspoglutide, a glucagon-like peptide-1 agonist, like native glucagon-like peptide-1, delays gastric emptying time and prolongs intestinal transit time, which may alter the pharmacokinetics of concomitantly administered oral drugs. The effect of taspoglutide on the pharmacokinetics of five oral drugs commonly used in patients with type 2 diabetes mellitus was assessed in healthy subjects. Five clinical pharmacology studies evaluated the potential drug–drug interaction between multiple subcutaneous taspoglutide doses and a single dose of lisinopril, warfarin, and simvastatin and multiple doses of digoxin and an oral contraceptive containing ethinylestradiol and levonorgestrel. The extent of interaction was quantified using geometric mean ratios and 90% confidence intervals for the maximum plasma concentration and area under the plasma concentration–time curve. In addition to pharmacokinetics, pharmacodynamic effects were assessed for warfarin and the oral contraceptive. Among the tested drugs, the effect of taspoglutide on the pharmacokinetics of simvastatin was most pronounced, on the day of taspoglutide administration, the average exposure to simvastatin was decreased by − 26% and − 58% for the area under the plasma concentration–time curve and maximum plasma concentration, respectively, accompanied by an increase in average exposure to its active metabolite, simvastatin β-hydroxy acid (+ 74% and + 23% for area under the plasma concentration–time curve and maximum plasma concentration, respectively). Although statistically significant changes in exposure were observed for other test drugs, the 90% confidence intervals for the geometric mean ratio for maximum plasma concentration and area under the plasma concentration–time curve were within the 0.7–1.3 interval. No clinically relevant changes on coagulation (for warfarin) and ovulation-suppressing activity (for the oral contraceptive) were apparent. Overall, multiple doses of taspoglutide did not result in changes in the pharmacokinetics of digoxin, an oral contraceptive containing ethinylestradiol and levonorgestrel, lisinopril, warfarin, and simvastatin that would be considered of clinical relevance. Therefore, no dose adjustments are warranted upon co-administration.

To evaluate single-dose pharmacokinetics and tolerability of taspoglutide in people with varying degrees of renal impairment and matched healthy participants.Participants in the present study were people with mild renal impairment (n = 10), moderate impairment (n = 10), severe impairment (n = 9), and a matched healthy control group (n = 10). Participants received a single subcutaneous injection of taspoglutide (10 mg) on day 1. Plasma and urine drug concentration, antibody formation, vital signs, ECGs and routine laboratory variables were measured frequently and adverse events (AEs) were monitored for 9 weeks.Taspoglutide exposure was higher among participants with moderate and severe renal impairment compared with participants with normal renal function. Mean AUCRenal impairment altered the pharmacokinetics of taspoglutide. The degree of renal impairment was associated with an increased exposure to taspoglutide and an increased risk of GI AEs.

Two open-label studies assessed the pharmacokinetics of single orally administered doses of 40 mg of stavudine in subjects with renal impairment. In one study (study I), 15 subjects with selected degrees of renal impairment, but not requiring hemodialysis, were stratified into three groups of five subjects each according to creatinine clearance (CL CR ) normalized by body surface area (ml/min/1.73 m 2 ): mild (CL CR , 60 to 80), moderate (30 to 50), and severe (≤20) renal impairment. Five healthy subjects (CL CR ≥ 90) were also enrolled. The stavudine area under the curve from 0 h to infinity (AUC 0–∞ ) increased nonlinearly with declining renal function: 1,864, 2,215, 3,609, and 5,928 ng · h/ml for normal renal function and for mild, moderate, and severe renal impairment, respectively ( P = 0.0001 between renal impairment groups). The following stavudine dosage recommendations for renal impairment were proposed for subjects weighing ≥60 kg: CL CR of >50 ml/min/1.73 m 2 , 40 mg every 12 h; CL CR of 21 to 50 ml/min/1.73 m 2 , 20 mg every 12 h; and CL CR of 10 to 20 ml/min/1.73 m 2 , 20 mg every 24 h. For subjects weighing 0–∞ , AUC 2–6 , time to maximum concentration of drug in serum, half-life, or apparent oral clearance when the two treatment dosage regimens were compared. As a result of study II, the recommended dosing rate for subjects requiring hemodialysis was the same as that proposed for those with severe renal impairment not requiring hemodialysis; however, dosing was recommended to follow hemodialysis and to occur at the same time each day.

Item does not contain fulltext The aim of the study was to evaluate the analgesic/antihyperalgesic efficacy and to establish the dose-response relationship of morphine immediate release (IR) and oxycodone IR in a human experimental algesimetric model. Calculated effect ratios for peak-to-peak (PtP) amplitudes of laser-evoked potentials (LEPs) and visual analog scales (VAS) postlaser pain on UVB-irradiated skin (main target variables) were 1.68 and 1.18 respectively for oxycodone 10mg/morphine 20mg, 3.00 and 1.63 respectively for oxycodone 15mg/morphine 30mg, and 1.12 and 1.25 respectively for oxycodone 20mg/morphine 40mg. The effect on the laser-PtP amplitude of morphine at the highest dose (40mg) and of oxycodone at all doses (10, 15, 20mg) was considered to be clinically relevant based on a difference from placebo of >/=2.5muV. For both compounds, a statistically significant linear trend was observed between dose groups in at least 1 of the 2 main target variables (adjusted P value for both end points

Study Objective. To evaluate the effects of acetaminophen, naproxen, and acetylsalicylic acid on the pharmacokinetics of the centrally acting analgesic tapentadol in healthy subjects. Design. Two randomized, open-label, crossover, drug-drug interaction studies. Setting. Clinical research facilities in the United States and Belgium. Participants. Twenty-four healthy adults (2-way crossover study) and 38 healthy adults (3-way crossover study). Interventions. In both studies, tapentadol immediate release (IR) 80 mg was administered as a single oral dose alone. In the 2-way crossover study, tapentadol IR was also given with the fifth of seven doses of acetaminophen 1000 mg; in the 3-way crossover study, tapentadol IR was also given with the third of four doses of naproxen 500 mg and the second of two doses of acetylsalicylic acid 325 mg. All treatments were separated by a washout period of 7–14 days. Measurements and Main Results. Overall, mean serum concentrations were similar after administration of tapentadol IR alone and after coadministration with acetaminophen or acetylsalicylic acid, and the 90% confidence intervals (CIs) for the ratios of the mean area under the serum concentration-time curve (AUC) from time zero to time of the last measurable concentration (AUC0-t) and from time zero extrapolated to infinity (AUC0-$iF) and the maximum serum concentration (Cmax) of the combined treatments to those parameters of tapentadol alone were well within 80–125%, representing the accepted range for bioequivalence. Coadministration of naproxen did not significantly alter the Cmax of tapentadol, although a slightly higher serum tapentadol exposure relative to tapentadol alone was observed. Coadministration of naproxen resulted in a mean increase of 17% in AUCs, and the upper limits of the 90% CIs for the ratios of the mean AUC0-t and AUCo-$iF were slightly outside the upper limit of bioequivalence range of 80–125% (126.47% AUC0-t and 126.14% AUC0-$iF). Conclusion. No clinically relevant changes were noted in the serum concentrations of tapentadol, and accordingly, no dosage adjustments with respect to the investigated pharmacokinetic mechanism of interaction are warranted for the administration of tapentadol given concomitantly with acetaminophen, naproxen, or acetylsalicylic acid.

Background There is currently no clear evidence that dual neutral endopeptidase–angiotensin-converting enzyme inhibitors have effects on angiotensin-converting enzyme, renin, or blood pressure that are different from specific angiotensin-converting enzyme inhibitors in humans. Methods and results In a double-blind, placebo-controlled crossover study, single oral doses of the dual neutral endopeptidase–angiotensin-converting enzyme inhibitor, 10 mg BMS-186716 and the angiotensinconverting enzyme inhibitor fosinopril (20 mg) were administered to 9 normotensive subjects with induced mild sodium depletion. Values for area under the time curve from 0 to 24 hours [AUC(0-24)] for the plasma angiotensin II/angiotensin I ratio and for angiotensin II were similar for 10 mg BMS-186716 and 20 mg fosinopril. Plasma atrial natriuretic peptide decreased significantly after 20 mg fosinopril (9 ± 3 pg/mL; P < .05 versus 10 mg BMS-186716 and placebo) compared with 10 mg BMS-186716 (16 ± 5 pg/mL) and placebo (16 ± 5 pg/mL). BMS-186716, 10 mg, significantly increased urinary atrial natriuretic peptide from baseline by 2 ± 1.3–fold (P < .05 versus placebo and 20 mg fosinopril). AUC(0-24) of plasma active renin did not differ significantly between 10 mg BMS-186716 (3898 ± 333 pg · h · mL−1) and 20 mg fosinopril (4383 ± 302 pg · h · mL−1; difference not significant). Both drugs decreased blood pressure, but the AUC(0-24) of the changes in mean blood pressure differed significantly from placebo (79 ± 84 mm Hg · h) only for 20 mg fosinopril (181 ± 6 mm Hg · h; P < .05) but not for 10 mg BMS-186716 (118 ± 7 mmHg · h). Conclusions In this model, single oral doses of 10 mg BMS-186716 and 20 mg fosinopril induced similar 24-hour in vivo angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, increased urinary atrial natriuretic peptide and blunted the expected decrease in plasma atrial natriuretic peptide caused by angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, did not inhibit plasma active renin rise compared with 20 mg fosinopril. A single oral dose of 10 mg BMS-186716 had a shorter blood pressure–lowering effect than 20 mg fosinopril. Clinical Pharmacology & Therapeutics (1999) 65, 448–459; doi

Objectives To study pravastatin and lovastatin pharmacokinetic and pharmacodynamic effects and their interactions with cyclosporine (INN, ciclosporin) in kidney transplant patients after single and multiple doses. Subjects and methods The pharmacokinetic and pharmacodynamic effects of administration of 20 mg/day oral pravastatin and lovastatin for 28 days and their interactions with cyclosporine (2 to 6 mg/kg/day) were studied in a double-blind, double-dummy, randomized, parallel-group multicenter trial in 44 stable kidney graft recipients. Results The median area under the curve [AUC(0–24)] of pravastatin was 249 μg · hr/L (range, 104 to 1026 μg · hr/L) after a single dose (day 1) and 241 μg · hr/L (114 to 969 μg · hr/L) after multiple doses (day 28) and was fivefold higher than values reported in the absence of cyclosporine. The median AUC(0–24) of lovastatin was 243 μg · hr/L (105 to 858 μg · hr/L) on day 1 and 459 μg · hr/L (140 to 1508 μg · hr/L) on day 28. Besides a significant accumulation during the study period (p < 0.001), the lovastatin AUC(0–24) values were twentyfold higher than values reported without cyclosporine. Coadministration of pravastatin or lovastatin did not alter cyclosporine pharmacokinetics. In this study, 20 mg/day doses of both drugs resulted in a significant improvement of the lipid profile and were well tolerated. Conclusions In contrast to lovastatin, pravastatin did not accumulate over the study period, which is probably one of the reasons rhabdomyolysis has been reported in lovastatin-treated but not pravastatin-treated transplant patients receiving cyclosporine immunosuppression. Clinical Pharmacology & Therapeutics (1997) 62, 311–321; doi