Marc Pfister

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.

Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight

Aim: Dapagliflozin is a stable, competitive, reversible, and highly selective inhibitor of sodium‐glucose co‐transporter 2, the major transporter responsible for renal glucose reabsorption. With an insulin‐independent mechanism of action, dapagliflozin is currently being developed for the treatment of type 2 diabetes mellitus (T2DM). This work aims to compare the efficacy of dapagliflozin, as measured by the change in hemoglobin A1c concentration (A1c) and body weight, and to determine the pharmacodynamic effects of dapagliflozin, as measured by urinary glucose excretion in early‐stage and late‐stage T2DM patient populations.

Additive antiproteinuric effect of combined Ace inhibition and angiotensin Ii receptor blockade

Background Limitation of systemic and glomerular hypertension reduces urinary protein excretion and prevents renal function deterioration. Objective To investigate whether, in hypertensive patients with glomerulonephritis, a combination of an angiotensin converting enzyme inhibitor (ACEI, fosinopril 20 mg/day) with an angiotensin receptor blocker (ARB, irbesartan 150 mg/day) produces a more profound antiproteinuric effect than either drug alone. Methods Ten non-diabetic patients with glomerulonephritis, normal or slightly reduced but stable renal function (creatinine clearance 40–106 ml/min) without immunosuppression were studied. Clinical evaluations, 24 h blood pressure measurements and laboratory tests were performed as follows: (1) without medication (baseline) and in random sequence; (2) ACEI alone; (3) ARB alone; and (4) combination of ACEI + ARB. Each period lasted for 6 weeks, separated by three washout periods of 4 weeks each without therapy. Results ACEI and ARB alone reduced proteinuria from 7.9 ± 7.1 to 5.3 ± 5.2 and 5.0 ± 4.9 g/24 h (mean ± SD), respectively. The combination of ACEI + ARB induced a more remarkable reduction of proteinuria in every patient (to 3.3 ± 3.7 g/24 h) than either drug alone (P = 0.039 by ANOVA). The enhanced antiproteinuric effect of the combined therapy could not be attributed to a more pronounced reduction of 24 h mean arterial pressure (basal, 106 ± 8; ACEI, 97 ± 5; ARB, 98 ± 5; ACEI + ARB, 95 ± 5 mmHg) or creatinine clearance (basal, 77 ± 27; ACEI, 73 ± 31; ARB 80 ± 30; ACEI + ARB, 73 ± 32 ml/min). Conclusions A combination of ACEI and ARB in patients with glomerulonephritis produces a more profound decrease in proteinuria than either drug alone. This additive antiproteinuric effect is not dependent on changes in blood pressure or creatinine clearance. A long-term controlled study is required to confirm the positive effect of this treatment on the progression of renal function loss.

Population Pharmacokinetics and Pharmacodynamics of Efavirenz, Nelfinavir, and Indinavir: Adult AIDS Clinical Trial Group Study 398

ABSTRACT The present population pharmacokinetic (PK) and pharmacodynamic (PD) study modeled the effects of covariates including drug adherence and the coadministration of protease inhibitors (PIs) on the pharmacokinetics of efavirenz (EFV) and the relationship between EFV exposure and virological failure in patients who failed initial PI treatment in Adult AIDS Clinical Trial Group (AACTG) study 398. We also report on the population PKs of the PIs nelfinavir (NFV) and indinavir (IDV). AACTG study 398 patients received EFV, amprenavir, adefovir dipivoxil, and abacavir and were randomized to take, in addition, one of the following: NFV, IDV, saquinavir (SQV), or placebo. The PK databases consisted of 531 EFV concentrations (139 patients), 219 NFV concentrations (75 patients), and 66 IDV concentrations (11 patients). Time to virological failure was ascertained for all patients in the PK databases. PK data were fit with a population PK model that assumed exclusive hepatic elimination (the well-stirred model). Notable findings with respect to EFV PK and PD are as follows. (i) The hepatic clearance of EFV is unaltered by NFV, IDV, or SQV coadministration. (ii) The hepatic clearance of EFV appears to be 28% higher in white non-Hispanics than in African Americans and Hispanics (P = 0.03). (iii) Higher adherence scores (as measured with the Medication Event Monitoring System) are associated with marginally increased levels of exposure to EFV. (iv) In patients with no prior experience with nonnucleoside reverse transcriptase inhibitors (NNRTIs), a given percent increase in the oral clearance (CL/F) of EFV is associated with a greater percent increase in the hazard of virological failure (P < 0.0003). Among NNRTI-experienced patients, however, hazard is relatively uncorrelated with EFV CL/F.

Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects With Type 2 Diabetes

OBJECTIVE To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique. RESEARCH DESIGN AND METHODS Subjects with type 2 diabetes (n = 12) and matched healthy subjects (n = 12) underwent pancreatic/SHC (plasma glucose range 5.5–30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves. RESULTS At baseline, type 2 diabetic subjects had elevated TmG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the TmG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects. CONCLUSIONS The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine.

Daptomycin Is Highly Efficacious against Penicillin-Resistant and Penicillin- and Quinolone-Resistant Pneumococci in Experimental Meningitis

ABSTRACT The penetration of daptomycin, a new lipopeptide antibiotic, into inflamed meninges ranged between 4.37 and 7.53% (mean, 5.97%). Daptomycin was very efficacious in the treatment of experimental pneumococcal meningitis, producing a decrease of −1.20 ± 0.32 Δlog10 CFU/ml · h in the bacterial titer of Streptococcus pneumoniae against a penicillin-resistant strain and of −0.97 ± 0.32 Δlog10 CFU/ml · h against a penicillin- and quinolone-resistant strain found in cerebrospinal fluid (CSF). For both strains, daptomycin was significantly superior to the standard regimen of a combination of ceftriaxone with vancomycin, sterilizing 9 of 10 CSF samples after 4 h. In vitro, daptomycin produced highly bactericidal activity in concentrations above the MIC.

Concepts and challenges in quantitative pharmacology and model-based drug development.

Model-based drug development (MBDD) has been recognized as a concept to improve the efficiency of drug development. The acceptance of MBDD from regulatory agencies, industry, and academia has been growing, yet today’s drug development practice is still distinctly distant from MBDD. This manuscript is aimed at clarifying the concept of MBDD and proposing practical approaches for implementing MBDD in the pharmaceutical industry. The following concepts are defined and distinguished: PK–PD modeling, exposure–response modeling, pharmacometrics, quantitative pharmacology, and MBDD. MBDD is viewed as a paradigm and a mindset in which models constitute the instruments and aims of drug development efforts. MBDD covers the whole spectrum of the drug development process instead of being limited to a certain type of modeling technique or application area. The implementation of MBDD requires pharmaceutical companies to foster innovation and make changes at three levels: (1) to establish mindsets that are willing to get acquainted with MBDD, (2) to align processes that are adaptive to the requirements of MBDD, and (3) to create a closely collaborating organization in which all members play a role in MBDD. Pharmaceutical companies that are able to embrace the changes MBDD poses will likely be able to improve their success rate in drug development, and the beneficiaries will ultimately be the patients in need.

Quantification of Apixaban's Therapeutic Utility in Prevention of Venous Thromboembolism: Selection of Phase III Trial Dose

A model‐based approach was used to integrate data from a phase II study in order to provide a quantitative rationale for selecting the apixaban dosage regimen for a phase III trial. The exposure–response models demonstrated that an increase in daily steady‐state area under the plasma concentration‐vs.‐time curve (AUCss) of 1 µg·h/ml would increase the odds ratio for major bleeding by 0.118 and decrease the odds ratio for venous thromboembolism (VTE) by 0.0499. The therapeutic utility index (TUI) was used to integrate the efficacy and safety predictions to quantify apixabans efficacy/safety balance as a function of AUCss. Of the apixaban dosage regimens tested in phase II, the 2.5 mg twice‐daily (b.i.d.) dosage regimen had the highest TUI (86.2%). This was also higher than the TUI for either 30 mg b.i.d. enoxaparin (82.5%) or for warfarin (71.8%). Subjects with moderate renal impairment are expected to have a 43% increase in apixaban exposure; however, apixabans TUI suggests that dose adjustment is not needed in these subjects with renal impairment.

Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium–glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects

Aims: Dapagliflozin increases urinary glucose excretion by selectively inhibiting renal sodium–glucose transporter 2, an insulin‐independent mechanism of action that may be complementary to that of other oral antidiabetes drugs. The current studies assessed the potential for pharmacokinetic (PK) interaction between dapagliflozin and pioglitazone, metformin, glimepiride or sitagliptin in healthy subjects following single‐dose administration.