Nimish N. Vachharajani

Dapagliflozin, a Novel, Selective SGLT2 Inhibitor, Improved Glycemic Control Over 2 Weeks in Patients With Type 2 Diabetes Mellitus

Dapagliflozin, administered to patients in once‐daily oral doses, is a sodium–glucose cotransporter 2 (SGLT2) inhibitor that blocks the reabsorption of glucose from urine into the blood. This 14‐day study randomized patients with type 2 diabetes mellitus (T2DM) to four treatment groups receiving daily oral doses of 5‐, 25‐, or 100‐mg doses of dapagliflozin or placebo, in order to evaluate glucosuria and glycemic parameters. Significant reductions in fasting serum glucose (FSG) were observed on day 2 with 100 mg dapagliflozin (−9.3%, P < 0.001), and dose‐dependent reductions were observed on day 13 with the 5‐mg (−11.7%; P < 0.05), 25‐mg (−13.3%; P < 0.05), and 100‐mg (−21.8%; P < 0.0001) doses as compared with placebo. Significant improvements in oral glucose tolerance test (OGTT) were observed with all doses on days 2 and 13 (P < 0.001 as compared with placebo). On day 14, urine glucose values were 36.6, 70.1, and 69.9 g/day for the 5‐, 25‐, and 100‐mg doses (as compared with no change for placebo), which were slightly lower than those on day 1. This was attributed to the decrease in filtered glucose load following improved glycemic control. Dapagliflozin produced dose‐dependent increases in glucosuria and clinically meaningful changes in glycemic parameters in T2DM patients.

Dapagliflozin, a Novel SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects

Dapagliflozin selectively inhibits renal glucose reabsorption by inhibiting sodium–glucose cotransporter‐2 (SGLT2). It was developed as an insulin‐independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug were evaluated in single‐ascending‐dose (SAD; 2.5–500 mg) and multiple‐ascending‐dose (MAD; 2.5–100 mg daily for 14 days) studies in healthy subjects. Dapagliflozin exhibited dose‐proportional plasma concentrations with a half‐life of ~17 h. The amount of glucosuria was also dose‐dependent. Cumulative amounts of glucose excreted on day 1, relating to doses from 2.5–100 mg (MAD), ranged from 18 to 62 g; day 14 values were comparable to day 1 values, with no apparent changes in glycemic parameters. Doses of ~20–50 mg provided close‐to‐maximal SGLT2 inhibition for at least 24 h. Dapagliflozin demonstrates pharmacokinetic (PK) characteristics and dose‐dependent glucosuria that are sustained over 24 h, which indicates that it is suitable for administration in once‐daily doses and suggests that further investigation of its efficacy in T2DM patients is warranted.

Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin.

Background and ObjectivePatients with type 2 diabetes mellitus often have impaired renal function or may have impaired hepatic function, which can pose significant safety and tolerability issues for anti-hyperglycaemic pharmacotherapies. Therefore, the pharmacokinetics and tolerability of saxagliptin and its pharmacologically active metabolite, 5-hydroxy saxagliptin, in nondiabetic subjects with mild, moderate or severe renal or hepatic impairment, or end-stage renal disease (ESRD) were compared with saxagliptin and metabolite pharmacokinetics and tolerability in healthy adult subjects.MethodsTwo open-label, parallel-group, single-dose studies were conducted. Subjects received a single oral dose of saxagliptin 10 mg (Onglyza™).ResultsCompared with healthy subjects, the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC∞) for saxagliptin was 16%, 41% and 108% (2.1-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. AUC∞ values for 5-hydroxy saxagliptin were 67%, 192% (2.9-fold) and 347% (4.5-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. As creatinine clearance (CLCR) values decreased, saxagliptin and 5-hydroxy saxagliptin AUC∞ generally increased or became more variable. Twenty-three percent of the saxagliptin dose (measured as the sum of saxagliptin and 5-hydroxy saxagliptin) was cleared by haemodialysis in a 4-hour dialysis session.In the hepatic impairment study, the differences in exposure to saxagliptin and 5-hydroxy saxagliptin were less than 2-fold across all groups. As compared with healthy subjects matched for age, bodyweight, sex and smoking status, the AUC∞ values for saxagliptin were 10%, 38% and 77% higher in subjects with mild, moderate or severe hepatic impairment, respectively. These values were 22%, 7% and 33% lower, respectively, for 5-hydroxy saxagliptin compared with matched healthy subjects.ConclusionsOne-half the usual dose of saxagliptin 5mg (i.e. 2.5 mg orally once daily) is recommended for patients with moderate (CLCR 30–50 mL/min) or severe (CLCR <30 mL/min not on dialysis) renal impairment or ESRD, but no dose adjustment is recommended for those with mild renal impairment or any degree of hepatic impairment.

The Pharmacokinetics of Irbesartan in Hypertensive Children and Adolescents

An open‐label study was conducted to characterize the pharmacokinetics and antihypertensive response to irbesartan in children (1–12 years) and adolescents (13–16 years) with hypertension. Patients received single once‐daily oral doses of irbesartan 2 mg/kg (maximum of 150 mg once daily) for 2 to 4 weeks (nifedipine or hydrochlorothiazide). Plasma irbesartan concentrations were determined by a validated high‐performance liquid chromatography/fluorescence method from blood samples taken predose, up to 24 hours after dosing on Day1, and up to 48 hours after the final dose. The plasma concentration‐time profiles were similar between the 6‐ to 12‐year and the 13‐ to 16‐year age groups and to that previously determined from a study of adult subjects receiving 2 mg/kg (i.e., 150 mg) oral irbesartan once daily. Mean reductions in systolic/diastolic blood pressure were 16/10 mmHg at Day 28 with irbesartan monotherapy (n = 8). Irbesartan was well tolerated and maybe a treatment option for pediatric hypertensive patients.

An open-label study of aripiprazole: Pharmacokinetics, tolerability, and effectiveness in children and adolescents with conduct disorder

OBJECTIVES This study evaluated flexible-dose pharmacokinetics, safety, and effectiveness of aripiprazole in children and adolescents with conduct disorder (CD). METHODS This open-label, 15-day, three-center study with an optional 36-month extension enrolled a total of 23 patients: 12 children (6-12 years) and 11 adolescents (13-17 years) with CD and a score of 2-3 on the Rating of Aggression Against People and/or Property (RAAPP). Initially, the protocol used the following dosing: subjects <25 kg, 2 mg/day; subjects 25-50 kg, 5 mg/day; subjects >50-70 kg, 10 mg/day; and subjects >70 kg, 15 mg/day. Due to vomiting and sedation, this schedule was revised to: <25 kg, 1 mg/day; 25-50 kg, 2 mg/day; >50-70 kg, 5 mg/day; and >70 kg, 10 mg/day. RESULTS Aripiprazole pharmacokinetics were linear, and steady state appeared to be attained within 14 days. Both groups demonstrated improvements in RAAPP scores and Clinical Global Impressions-Severity (CGI-S) scores. Adverse events were similar to the known profile for aripiprazole in adults. CONCLUSION The pharmacokinetics of aripiprazole in children and adolescents are linear and comparable with those in adults. Aripiprazole was generally well-tolerated in patients with CD, particularly after protocol adjustments, with improvements in aggressive behavior.

Oral bioavailability and disposition characteristics of irbesartan, an angiotensin antagonist, in healthy volunteers

Absolute oral bioavailability and disposition characteristics of irbesartan, an angiotensin II receptor antagonist, were investigated in 18 healthy young male volunteers. Subjects received [14C] irbesartan as a 30‐minute intravenous infusion (50 mg), [14C] irbesartan orally as a solution (50 mg or 150 mg), or irbesartan capsule (50 mg). Irbesartan was rapidly and almost completely absorbed after oral administration, and exhibited a mean absolute oral bioavailability of 60% to 80%. Mean total body clearance was approximately 157 mL/min, and renal clearance was 3.0 mL/min. Volume of distribution at steady state was 53 L to 93 L, and terminal elimination half‐life was approximately 13 to 16 hours. Hepatic extraction ratio was low (0.2). There were no major circulating metabolites, and approximately 80% of total plasma radioactivity was attributable to unchanged irbesartan. Regardless of route of administration, approximately 20% of dose was recovered in urine and the remainder in feces.

Drug interactions with irbesartan.

AbstractIrbesartan is an angiotensin II receptor antagonist indicated for the treatment of patients with hypertension. Although irbesartan does not require biotransformation for its pharmacological activity, it does undergo metabolism via the cytochrome P450 (CYP) 2C9 isoenzyme and negligible metabolism by the CYP3A4 isoenzyme. The long term treatment of patients with hypertension is generally required for effective management of the disease, and the use of concurrent medications is usually inevitable. This paper reviews the drug and food interaction trials involving irbesartan that have been conducted to date.Based on the available literature, no significant interactions have been identified between irbesartan and hydrochlorothiazide, nifedipine, simvastatin, tolbutamide, warfarin, magnesium and aluminum hydroxides, digoxin or food. Fluconazole did increase the steady-state peak plasma concentration (by 19%) and area under the concentration-time curve (by 63%) of irbesartan, but these increases are not likely to be clinically significant. In summary, irbesartan has demonstrated minimal potential for drug or food interactions in trials conducted to date.

A pharmacokinetic interaction study between butorphanol and sumatriptan nasal sprays in healthy subjects: importance of the timing of butorphanol administration

Sumatriptan and butorphanol nasal sprays are commonly used agents for the management of migraine headaches. Under certain circumstances, these two agents may be administered closely in time. However, the possibility of a pharmacokinetic interaction and the safety of this regime have not been examined. In this crossover design study, 24 healthy subjects received the following four treatments, each separated by at least 7 days: 1 mg butorphanol (Stadol NS7®); 20 mg sumatriptan (Imitrex® Nasal Spray); or both formulations together with butorphanol administered either 1 or 30 min after sumatriptan. Serial plasma samples were collected for 24 h post-dose and analysed for butorphanol and/or sumatriptan by HPLC-MS/MS. Butorphanol plasma concentrations were reduced when it was administered 1 min (mean 28.6% decrease in AUC0-∞) , but not 30 min, after sumatriptan. The pharmacokinetics of sumatriptan were not substantially altered by butorphanol. The combination of nasally administered sumatriptan and butorphanol appeared safe. However, if butorphanol nasal spray is administered < 30 min after sumatriptan nasal spray, the analgesic effect of butorphanol may be diminished due to reduced nasal absorption resulting from probable transient vasoconstriction of nasal blood vessels by sumatriptan.

Lack of Effect of Food on the Oral Bioavailability of Irbesartan in Healthy Male Volunteers

This study was conducted to evaluate the effects of a high‐fat meal on the oral bioavailability of an 300‐mg irbesartan tablet in healthy male volunteers. Sixteen healthy young male volunteers participated in this single‐center, open‐label, single‐dose, crossover study. Each volunteer received a single 300‐mg irbesartan tablet under fasted conditions and 5 minutes after a high‐fat breakfast, with administrations separated by a 7‐day washout period. Serial blood samples were collected over a 72‐hour period, and plasma samples were analyzed for irbesartan using a validated high‐performance liquid chromatography/fluorescence procedure. Food had no statistically significant effects on the peak concentration (Cmax) and area under the concentration‐time curve (AUC) of irbesartan. The presence of food was associated with a slightly prolonged time to maximum concentration (tmax) and half‐life (t1/2), but the differences were not statistically significant. The results of this study indicate that food does not affect the bioavailability of irbesartan. Thus, irbesartan can be administered without regard to meals.

Pharmacokinetics of Irbesartan are not altered in special populations

Summary:Studies were conducted to determine whether pharmacokinetics of irbesartan (IRBE), a potent, long-acting angiotensin (AT)-II receptor antagonist selective for AT-II type 1 receptor subtype, are altered in patients with renal impairment (RI), hepatic impairment (HI), or heart failure (HF) or