Goutam C. Mistry

Effect of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, on Blood Pressure in Nondiabetic Patients With Mild to Moderate Hypertension

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.

Pharmacokinetics of Ertapenem in Healthy Young Volunteers

ABSTRACT Ertapenem (INVANZ) is a new once-a-day parenteral β-lactam antimicrobial shown to be effective as a single agent for treatment of various community-acquired and mixed infections. The single- and multiple-dose pharmacokinetics of ertapenem at doses up to 3 g were examined in healthy young men and women volunteers. Plasma and urine samples collected were analyzed using reversed-phase high-performance liquid chromatography with UV detection. Ertapenem is highly bound to plasma protein. The protein binding changes from ∼95% bound at concentrations of <50 μg/ml to ∼92% bound at concentrations of 150 μg/ml (concentration at the end of a 30-min infusion following the 1-g dose). The nonlinear protein binding of ertapenem resulted in a slightly less than dose proportional increase in the area under the curve from 0 h to infinity (AUC0-∞) of total ertapenem. The single-dose AUC0-∞ of unbound ertapenem was nearly dose proportional over the dose range of 0.5 to 2 g. The mean concentration of ertapenem in plasma ranged from ∼145 to 175 μg/ml at the end of a 30-min infusion, from ∼30 to 34 μg/ml at 6 h, and from ∼9 to 11 μg/ml at 12 h. The mean plasma t1/2 ranged from 3.8 to 4.4 h. About 45% of the plasma clearance (CLP) was via renal clearance. The remainder of the CLP was primarily via the formation of the β-lactam ring-opened metabolite that was excreted in urine. There were no clinically significant differences between the pharmacokinetics of ertapenem in men and women. Ertapenem does not accumulate after multiple once-daily dosing.

Disposition of Caspofungin: Role of Distribution in Determining Pharmacokinetics in Plasma

ABSTRACT The disposition of caspofungin, a parenteral antifungal drug, was investigated. Following a single, 1-h, intravenous infusion of 70 mg (200 μCi) of [3H]caspofungin to healthy men, plasma, urine, and feces were collected over 27 days in study A (n = 6) and plasma was collected over 26 weeks in study B (n = 7). Supportive data were obtained from a single-dose [3H]caspofungin tissue distribution study in rats (n = 3 animals/time point). Over 27 days in humans, 75.4% of radioactivity was recovered in urine (40.7%) and feces (34.4%). A long terminal phase (t1/2 = 14.6 days) characterized much of the plasma drug profile of radioactivity, which remained quantifiable to 22.3 weeks. Mass balance calculations indicated that radioactivity in tissues peaked at 1.5 to 2 days at ∼92% of the dose, and the rate of radioactivity excretion peaked at 6 to 7 days. Metabolism and excretion of caspofungin were very slow processes, and very little excretion or biotransformation occurred in the first 24 to 30 h postdose. Most of the area under the concentration-time curve of caspofungin was accounted for during this period, consistent with distribution-controlled clearance. The apparent distribution volume during this period indicated that this distribution process is uptake into tissue cells. Radioactivity was widely distributed in rats, with the highest concentrations in liver, kidney, lung, and spleen. Liver exhibited an extended uptake phase, peaking at 24 h with 35% of total dose in liver. The plasma profile of caspofungin is determined primarily by the rate of distribution of caspofungin from plasma into tissues.

Atazanavir Modestly Increases Plasma Levels of Raltegravir in Healthy Subjects

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.

A Phase I/II Study of the Protease Inhibitor Indinavir in Children With HIV Infection

Background. Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose. Methods. Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/m2, 350 mg/m2, and 500 mg/m2 per dose given orally every 8 h) were evaluated in 2 age groups (<12 years and ≥12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks. Results. Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median CD4 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/mm3, and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy. Conclusions. Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine.

Sitagliptin, an dipeptidyl peptidase‐4 inhibitor, does not alter the pharmacokinetics of the sulphonylurea, glyburide, in healthy subjects

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. x 6 days) in the other period. RESULTS The geometric mean ratios and 90% confidence intervals [(glyburide + sitagliptin)/glyburide] for AUC(0-infinity) and C(max) 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.

Single- and multiple-dose administration of caspofungin in patients with hepatic insufficiency: implications for safety and dosing recommendations.

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.

Multiple‐Dose Administration of Sitagliptin, a Dipeptidyl Peptidase‐4 Inhibitor, Does Not Alter the Single‐Dose Pharmacokinetics of Rosiglitazone in Healthy Subjects

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.

Pharmacokinetics of Total and Unbound Ertapenem in Healthy Elderly Subjects

ABSTRACT Ertapenem is a new once-a-day parenteral carbapenem antimicrobial agent. The pharmacokinetics of unbound and total concentrations of ertapenem in plasma were investigated in elderly subjects and compared with historical data from young adults. In a single- and multiple-dose study, healthy elderly males and females (n = 14) 65 years old or older were given a 1-g intravenous (i.v.) dose once daily for 7 days. Plasma and urine samples collected for 24 h on days 1 and 7 following administration of the 1-g doses were analyzed by reversed-phase high-performance liquid chromatography. Areas under the concentration-time curve from 0 h to infinity (AUC0-∞) for elderly females and males were similar following administration of 1-g single i.v. doses, and thus, the genders were pooled in subsequent analyses. Concentrations in plasma and the half-life of ertapenem were generally higher and longer, respectively, in elderly subjects than in young adults. The mean AUC0-∞ of total ertapenem in the elderly was 39% higher than that in young subjects following administration of a 1-g dose. The differences were slightly greater for the mean AUC0-∞ of unbound ertapenem (71%). The unbound fraction of ertapenem in elderly subjects (∼5 to 11%) was generally greater than that in young adults (∼5 to 8%). As in young adults, ertapenem did not accumulate upon multiple dosing in the elderly. The pharmacokinetics of ertapenem in elderly subjects, while slightly different from those in young adults, do not require a dosage adjustment for elderly patients.

Safety and pharmacokinetics of higher doses of caspofungin in healthy adult participants.

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.