The effect of sitagliptin, a dipeptidyl peptidase‐4 inhibitor, on ambulatory blood pressure was assessed in nondiabetic patients with mild to moderate hypertension in a randomized, double‐blind, ...placebo‐controlled, 3‐period crossover study. Nineteen patients on stable treatment with antihypertensive agent(s) received sitagliptin 100 mg b.i.d., 50 mg b.i.d., or placebo for 5 days, with at least a 7‐day washout interval between periods. Twenty‐four‐hour ambulatory blood pressure, including systolic blood pressure, diastolic blood pressure, and mean arterial pressure, were monitored on days 1 and 5. Relative to placebo on day 1, the mean difference in 24‐hour systolic blood pressure was −0.9 mm Hg (90% confidence interval: −2.9 to 1.1; P = .46) with sitagliptin 50 mg b.i.d. and −2.8 mm Hg (90% confidence interval: −4.9 to −0.8; P < .05) with 100 mg b.i.d. On day 5, the mean difference in 24‐hour systolic blood pressure was −2.0 mm Hg (90% confidence interval: −3.5 to −0.4; P < .05) with 50 mg b.i.d. and −2.2 mm Hg (90% confidence interval: −3.7 to −0.6; P < .05) with 100 mg b.i.d. relative to placebo. For 24‐hour diastolic blood pressure, there were no between‐group differences in mean 24‐hour diastolic blood pressure on day 1. On day 5, sitagliptin 50 mg and 100 mg b.i.d significantly (P < .05) lowered mean 24‐hour diastolic blood pressure by −1.8 mm Hg (90% confidence interval: −2.8 to −0.8) and −1.6 mm Hg (90% confidence interval: −2.6 to −0.7), respectively, relative to placebo. Sitagliptin produced small but statistically significant reductions of 2 mm Hg to 3 mm Hg in 24‐hour ambulatory blood pressure measurements acutely (day 1) and at steady state (day 5), and was generally well tolerated in nondiabetic patients with mild to moderate hypertension.
Raltegravir is an HIV integrase inhibitor that is metabolized through glucuronidation by uridine diphosphate glucuronosyltransferase 1A1, and its use is anticipated in combination with atazanavir (a ...uridine diphosphate glucuronosyltransferase 1A1 inhibitor). Two pharmacokinetic studies of healthy subjects assessed the effect of multiple-dose atazanavir or ritonavir-boosted atazanavir on raltegravir levels in plasma. Atazanavir and atazanavir plus ritonavir modestly increase plasma levels of raltegravir.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Sitagliptin is an oral antihyperglycaemic agent that improves glycaemic control by inhibiting dipeptidyl peptidase‐4 (DPP‐4), the enzyme that is principally ...responsible for inactivation of incretins. Incretins are endogenous peptide hormones that support glycaemic homeostasis through glucose‐dependent stimulation of insulin secretion by pancreatic β‐cells and suppression of glucagon secretion by α‐cells.
• Pharmacokinetic properties of sitagliptin and inhibition of plasma DDP‐4 by sitagliptin have been characterized previously in young, normoglycaemic, non‐Japanese adult males and in other non‐Japanese subjects. It was found in these studies that doses of at least 100 mg once daily produced nearly complete inhibition of DPP‐4 over 24 h.
WHAT THIS STUDY ADDS
• The findings from this study suggest that the pharmacokinetic and pharmacodynamic (i.e. plasma DPP‐4 inhibition) properties of sitagliptin in Japanese subjects are not substantially different from responses in non‐Japanese subjects.
• Consumption of a standardized traditional Japanese breakfast prior to dose ingestion did not alter plasma sitagliptin concentrations to a clinically meaningful extent.
• Oral administration of sitagliptin at approved doses provided nearly complete inhibition of DPP‐4 over an interval of 24 h. The findings support once daily dosing with sitagliptin in Japanese patients with type 2 diabetes.
AIMS Sitagliptin is a selective inhibitor of dipeptidyl peptidase‐4 (DPP‐4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males.
METHODS In this alternating two‐panel, randomized, controlled double‐blind study, six healthy Japanese male subjects (aged 20–46 years) in each panel received single oral doses of 5–400 mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0–48 h post dose and plasma DPP‐4 inhibition from 0–24 h post dose. The results were compared with historical data from young, healthy non‐Japanese males.
RESULTS Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2–6 h post‐dose. The mean apparent terminal half‐life for plasma sitagliptin was 9–14 h, with the half‐life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73–1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin ≥50 mg resulted in weighted average DPP‐4 inhibition from 0–24 h post‐dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP‐4 inhibition parameters were found between Japanese and non‐Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia.
CONCLUSIONS The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes.
This report investigated safety and dosing recommendations of intravenous caspofungin in hepatic insufficiency. In the single‐dose study, 8 patients each with mild and moderate hepatic insufficiency ...received 70 mg of caspofungin. In the multiple‐dose study, 8 patients with mild hepatic insufficiency and 13 healthy matched controls received 70 mg on day 1 and 50 mg daily on days 2 through 14. Eight patients with moderate hepatic insufficiency received 70 mg on day 1 and 35 mg daily on days 2 through 14. Caspofungin was generally well tolerated with no discontinuations due to serious or nonserious adverse experiences. The area under the concentration‐time profile over the interval of last quantifiable point to infinity (AUC0‐∞) geometric mean ratio (GMR) (90% confidence interval CI) for mild hepatic insufficiency/historical controls was 1.55 (1.32–1.86) in the single‐dose study and for mild hepatic insufficiency/concurrent controls was 1.21 (1.04–1.39) for day 14 area under the concentration– time profile calculated over the interval 0 to 24 hours (AUC0‐24h) following multidose. The AUC0‐∞ GMR (90% CI) for moderate hepatic insufficiency/historical controls was 1.76 (1.51–2.06) following 70 mg; AUC0‐24h GMR (90% CI) for moderate hepatic insufficiency/concurrent controls was 1.07 (0.90–1.28) on day 14 after 35 mg daily. No dosage adjustment is recommended for patients with mild hepatic insufficiency. A dosage reduction to 35 mg daily following the 70‐mg loading dose is recommended for patients with moderate hepatic insufficiency.
Caspofungin was the first in a new class of antifungal agents (echinocandins) indicated for the treatment of primary and refractory fungal infections. Higher doses of caspofungin may provide another ...option for patients who have failed caspofungin or other antifungal therapy. This study evaluated the safety, tolerability, and pharmacokinetics of single 150‐ and 210‐mg doses of caspofungin in 16 healthy participants and 100 mg/d for 21 days in 20 healthy participants. Other than infusion site reactions and 1 reversible elevation in alanine aminotransferase (≥2× and <4× upper limit of normal), caspofungin was generally well tolerated. Geometric mean AUC0‐∞ after single 150‐ and 210‐mg doses was 279.7 and 374.9 μg·h/mL, respectively; peak concentrations were 29.4 and 33.5 μg/mL, respectively; and 24‐hour postdose concentrations were 2.8 and 4.2 μg/mL, respectively. Steady state was achieved in the third week of dosing. Following multiple 100‐mg doses of caspofungin, day 21 geometric mean AUC0–24 was 227.4 μg·h/mL, peak concentration was 20.9 μg/mL, and trough concentration was 4.7 μg/mL. Beta‐phase t1/2 was ∼8 to ∼13 hours. Caspofungin pharmacokinetics at these higher doses were dose proportional to and consistent with those observed at lower doses, suggesting a modest nonlinearity of increased accumulation with dose, which was considered not clinically meaningful.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• No data are available on the potential drug interaction of sitagliptin and glyburide.
• Sitagliptin belongs to a new class of drugs called DPP‐4 inhibitors ...recently approved for the treatment of Type 2 diabetes.
WHAT THIS STUDY ADDS
• Glyburide is a commonly used sulphonylurea medication to treat Type 2 diabetes.
• Combination therapy is often required to achieve adequate glucose control in Type 2 diabetes.
• Sitagliptin does not appear to interfere with glyburide pharmacokinetics and therefore may be potentially co‐administered with glyburide for the treatment of Type 2 diabetes.
AIMS
Sitagliptin, a dipeptidyl peptidase‐4 inhibitor, is an incretin enhancer that is approved for the treatment of Type 2 diabetes. Sitagliptin is mainly renally eliminated and not an inhibitor of CYP450 enzymes in vitro. Glyburide, a sulphonylurea, is an insulin sensitizer and mainly metabolized by CYP2C9. Since both agents may potentially be co‐administered, the purpose of this study was to examine the effects of sitagliptin on glyburide pharmacokinetics.
METHODS
In this open‐label, randomized, two‐period crossover study, eight healthy normoglycaemic subjects, 22–44 years old, received single 1.25‐mg doses of glyburide alone in one period and co‐administered with sitagliptin on day 5 following a multiple‐dose regimen for sitagliptin (200‐mg q.d. ×6 days) in the other period.
RESULTS
The geometric mean ratios and 90% confidence intervals (glyburide + sitagliptin)/glyburide for AUC0–∞ and Cmax were 1.09 (0.96, 1.24) and 1.01 (0.84, 1.23), respectively.
CONCLUSION
Sitagliptin does not alter the pharmacokinetics of glyburide in healthy subjects.
Ertapenem is a parenteral β‐lactam carbapenem antibiotic. This open‐label study examined the pharmacokinetics of single 1‐g intravenous doses of ertapenem, administered over 30 minutes, in patients ...with mild, moderate, and advanced renal insufficiency (RI) and in patients with end‐stage renal disease (ESRD) requiring hemodialysis. Pharmacokinetics were compared with historical controls pooled across healthy young and elderly subjects. Area under the concentration‐time curve from time zero to infinity increased 7% in mild, 53% in moderate, 158% in advanced RI, and 192% in ESRD; end of infusion concentration changed minimally; half‐life was 4.5 hours in the historical control group and 4.4, 6.1, 10.6, and 14.1 hours in mild RI, moderate RI, advanced RI, and ESRD, respectively. Hemodialysis cleared ∼30% of the dose. The recommended dose in mild to moderate RI and after hemodialysis is unchanged at 1 g daily; and in advanced RI and ESRD is reduced to 0.5 g daily. If the daily dose is given 6 hours prior to hemodialysis, a supplementary 150‐mg dose (30% of the daily dose) is recommended postdialysis.
Ertapenem is a carbapenem antibiotic with broad spectrum activity and a pharmacokinetic profile that favors once-daily administration in adults.
This investigation was designed to evaluate the ...dose-exposure profile of ertapenem in children from infancy through adolescence.
Eighty-four children (3 months-16 years) requiring antibiotic therapy were enrolled in this multicenter trial. Children received a single intravenous dose of ertapenem at 15, 20, or 40 mg/kg followed by repeated blood sampling for 24 hours. Free and total plasma ertapenem concentrations were quantitated by high-performance liquid chromatography, and the pharmacokinetics were determined using a model-independent approach.
Ertapenem exposure increased proportionally with increasing dose; however, achievable concentrations were influenced by age. Children older than 12 years attained higher dose-normalized concentrations at the end of the infusion (concentration at the end of the infusion Ceoi: 8.7 ± 1.9 mg/L per mg/kg dose) and total body exposure (area under the curve area under the plasma concentration-time curve AUC0-∞: 34.7 ± 14.7 mg hr/L per mg/kg dose) as compared with children 2 to 12 years (Ceoi: 6.9 ± 2.4 mg/L per mg/kg dose, AUC0-∞: 18.4 ± 8.0 mg hr/L per mg/kg dose) and children younger than 2 years (Ceoi: 6.1 ± 2.2 mg/L per mg/kg dose, AUC0-∞: 17.0 ± 5.4 mg hr/L per mg/kg dose). These findings were accounted for by age-dependent changes in ertapenem clearance and distribution volume. In 3 children adverse events (nausea, n = 2; injection site reaction, n = 1) were considered related to study drug administration.
Children younger than 12 years require dosing more frequently than once daily to achieve optimal efficacy when treating organisms with a minimum inhibitory concentration near the susceptibility breakpoint.
Sitagliptin, a dipeptidyl peptidase‐4 inhibitor, is an incretin enhancer that is approved for the treatment of type 2 diabetes. Sitagliptin is mainly renally eliminated and not a potent inhibitor of ...CYP450 enzymes in vitro. Rosiglitazone, a thiazolidenedione, is an insulin sensitizer and mainly metabolized by CYP2C8. Since both agents may potentially be coadministered, the purpose of this study was to examine the effects of sitagliptin on rosiglitazone pharmacokinetics. In this open‐label, randomized, 2‐period, crossover study, 12 healthy normoglycemic subjects, 21 to 44 years, received single 4‐mg doses of rosiglitazone alone in one period and coadministered with sitagliptin on day 5 following a multiple‐dose regimen for sitagliptin (200 mg once daily × 5 days) in the other period. The geometric mean ratios and 90% confidence intervals (rosiglitazone + sitagliptin/rosiglitazone) for rosiglitazone AUC0‐∞ and Cmax were 0.98 (0.93, 1.02) and 0.99 (0.88, 1.12), respectively. In conclusion, sitagliptin did not alter the pharmacokinetics of rosiglitazone in healthy subjects.
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