Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor.
in Clinical pharmacokinetics (2014), 53(3), 213-25
Empagliflozin is an orally active, potent and selective inhibitor of sodium glucose co-transporter 2 (SGLT2), currently in clinical development to improve glycaemic control in adults with type 2 diabetes ... [more ▼]
Empagliflozin is an orally active, potent and selective inhibitor of sodium glucose co-transporter 2 (SGLT2), currently in clinical development to improve glycaemic control in adults with type 2 diabetes mellitus (T2DM). SGLT2 inhibitors, including empagliflozin, are the first pharmacological class of antidiabetes agents to target the kidney in order to remove excess glucose from the body and, thus, offer new options for T2DM management. SGLT2 inhibitors exert their effects independently of insulin. Following single and multiple oral doses (0.5-800 mg), empagliflozin was rapidly absorbed and reached peak plasma concentrations after approximately 1.33-3.0 h, before showing a biphasic decline. The mean terminal half-life ranged from 5.6 to 13.1 h in single rising-dose studies, and from 10.3 to 18.8 h in multiple-dose studies. Following multiple oral doses, increases in exposure were dose-proportional and trough concentrations remained constant after day 6, indicating a steady state had been reached. Oral clearance at steady state was similar to corresponding single-dose values, suggesting linear pharmacokinetics with respect to time. No clinically relevant alterations in pharmacokinetics were observed in mild to severe hepatic impairment, or in mild to severe renal impairment and end-stage renal disease. Clinical studies did not reveal any relevant drug-drug interactions with several other drugs commonly prescribed to patients with T2DM, including warfarin. Urinary glucose excretion (UGE) rates were higher with empagliflozin versus placebo and increased with dose, but no relevant impact on 24-h urine volume was observed. Increased UGE resulted in proportional reductions in fasting plasma glucose and mean daily glucose concentrations. [less ▲]Detailed reference viewed: 20 (2 ULg)
Pharmacokinetic and toxicological considerations for the treatment of diabetes in patients with liver disease.
in Expert opinion on drug metabolism & toxicology (2014)
Introduction: Patients with type 2 diabetes have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis and about one-third of cirrhotic patients ... [more ▼]
Introduction: Patients with type 2 diabetes have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents may be a cause for concern in the case of hepatic impairment (HI). Areas covered: An extensive literature search was performed to analyze the influence of HI on the pharmacokinetics (PK) of glucose-lowering agents and the potential consequences for clinical practice as far as the efficacy/safety balance of their use in diabetic patients with CLD is concerned. Expert opinion: Almost no PK studies have been published regarding metformin, sulfonylureas, thiazolidinediones and alpha-glucosidase inhibitors in patients with HI. Only mild changes in PK of glinides, dipeptidyl peptidase-4 inhibitors and sodium glucose cotransporters type 2 inhibitors were observed in dedicated PK studies in patients with various degrees of HI, presumably without major clinical relevance although large clinical experience is lacking. Glucagon-like peptide-1 receptor agonists have a renal excretion rather than liver metabolism. Rare anecdotal case reports of hepatotoxicity have been described with various glucose-lowering agents contrasting with numerous reassuring data. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, including with the use of metformin. [less ▲]Detailed reference viewed: 8 (2 ULg)
Pharmacokinetic considerations for the treatment of diabetes in patients with chronic kidney disease.
in Expert Opinion on Drug Metabolism & Toxicology (2013)
Introduction: People with chronic kidney disease (CKD) of stages 3 - 5 (creatinine clearance < 60 ml/min) represent approximately 25% of patients with type 2 diabetes mellitus (T2DM), but the problem is ... [more ▼]
Introduction: People with chronic kidney disease (CKD) of stages 3 - 5 (creatinine clearance < 60 ml/min) represent approximately 25% of patients with type 2 diabetes mellitus (T2DM), but the problem is underrecognized or neglected in clinical practice. However, most oral antidiabetic agents have limitations in case of renal impairment (RI), either because they require a dose adjustment or because they are contraindicated for safety reasons. Areas covered: The author performed an extensive literature search to analyze the influence of RI on the pharmacokinetics (PK) of glucose-lowering agents and the potential consequences for clinical practice. Expert opinion: As a result of PK interferences and for safety reasons, the daily dose should be reduced according to glomerular filtration rate (GFR) or even the drug is contraindicated in presence of severe CKD. This is the case for metformin (risk of lactic acidosis) and for many sulfonylureas (risk of hypoglycemia). At present, however, the exact GFR cutoff for metformin use is controversial. New antidiabetic agents are better tolerated in case of CKD, although clinical experience remains quite limited for most of them. The dose of DPP-4 inhibitors should be reduced (except for linagliptin), whereas both the efficacy and safety of SGLT2 inhibitors are questionable in presence of CKD. [less ▲]Detailed reference viewed: 47 (3 ULg)
Pharmacokinetic evaluation of a long-acting sulfamethazine bolus for lambs
Evrard, Brigitte ; ; Delattre, Luc
in Proceedings of 21th International Symposium on controlled release of Bioactive Materials (1994)Detailed reference viewed: 8 (0 ULg)
Pharmacokinetic evaluation of atorvastatin and sitagliptin in combination for the treatment of type 2 diabetes.
in Expert Opinion on Drug Metabolism & Toxicology (2012), 8(6), 745-58
INTRODUCTION: Patients with type 2 diabetes (T2DM) are exposed to a high risk of cardiovascular disease (CVD) requiring a global therapeutic approach. Statin therapy has proven its efficacy in reducing ... [more ▼]
INTRODUCTION: Patients with type 2 diabetes (T2DM) are exposed to a high risk of cardiovascular disease (CVD) requiring a global therapeutic approach. Statin therapy has proven its efficacy in reducing CVD events in T2DM patients. Dipeptidylpeptidase-4 inhibitors (gliptins), which are increasingly used to target hyperglycemia, also offer promising preliminary results regarding a possible reduction in CVD events. As most patients with T2DM may be treated with both a statin and a gliptin, dual pharmacological therapy, possibly as a fixed-dose combination (FDC), deserves further consideration. AREAS COVERED: The reader is provided with an update of information on the pharmacokinetics (PK) and pharmacodynamics (PD) of atorvastatin and sitagliptin . The article provides an analysis of the potential PK/PD interactions between the two compounds and puts into perspective the potential cardiovascular protection that such a dual therapy may offer in patients with T2DM. EXPERT OPINION: Atorvastatin and sitagliptin are not prone to PK drug-drug interactions. Their coadministration, either separately or in an FDC, improves both blood glucose levels and cholesterol concentrations, without clinically relevant adverse events. The atorvastatin plus sitagliptin combination may be used to reduce LDL cholesterol and hyperglycemia in patients with T2DM, with the aim to improve CVD prognosis and adherence to therapy. [less ▲]Detailed reference viewed: 20 (1 ULg)
Pharmacokinetic parameters estimation using adaptive Bayesian P-splines models
; Lambert, Philippe ; et al
in Pharmaceutical Statistics (2009), 8
In preclinical and clinical experiments, pharmacokinetic (PK) studies are designed to analyse the evolution of drug concentration in plasma over time i.e. the PK profile. Some PK parameters are estimated ... [more ▼]
In preclinical and clinical experiments, pharmacokinetic (PK) studies are designed to analyse the evolution of drug concentration in plasma over time i.e. the PK profile. Some PK parameters are estimated in order to summarize the complete drug’s kinetic profile: area under the curve (AUC), maximal concentration (Cmax), time at which the maximal concentration occurs (tmax) and half-life time (t1/2). Several methods have been proposed to estimate these PK parameters. A first method relies on interpolating between observed concentrations. The interpolation method is often chosen linear. This method is simple and fast. Another method relies on compartmental modelling. In this case, nonlinear methods are used to estimate parameters of a chosen compartmental model. This method provides generally good results. However, if the data are sparse and noisy, two difficulties can arise with this method. The first one is related to the choice of the suitable compartmental model given the small number of data available in preclinical experiment for instance. Second, nonlinear methods can fail to converge. Much work has been done recently to circumvent these problems (J. Pharmacokinet. Pharmacodyn. 2007; 34:229–249, Stat. Comput., to appear, Biometrical J., to appear, ESAIM P&S 2004; 8:115–131). In this paper, we propose a Bayesian nonparametric model based on P-splines. This method provides good PK parameters estimation, whatever be the number of available observations and the level of noise in the data. Simulations show that the proposed method provides better PK parameters estimations than the interpolation method, both in terms of bias and precision. The Bayesian nonparametric method provides also better AUC and t1/2 estimations than a correctly specified compartmental model, whereas this last method performs better in tmax and Cmax estimations. We extend the basic model to a hierarchical one that treats the case where we have concentrations from different subjects. We are then able to get individual PK parameter estimations. Finally, with Bayesian methods, we can get easily some uncertainty measures by obtaining credibility sets for each PK parameter. [less ▲]Detailed reference viewed: 77 (8 ULg)
Pharmacokinetic study of a new synthetic MMP inhibitor (Ro 28-2653) after IV and oral administration of cyclodextrin solutions
Piette, Marie ; Evrard, Brigitte ; et al
in European Journal of Pharmaceutical Sciences (2006), 28(3), 189-195
Ro 28-2653 (5-biphenyl-4-yl-5-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione) is a new synthetic inhibitor of matrix metalloproteinases (MMPs) with a high selectivity towards MMP2, MMP9 and ... [more ▼]
Ro 28-2653 (5-biphenyl-4-yl-5-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione) is a new synthetic inhibitor of matrix metalloproteinases (MMPs) with a high selectivity towards MMP2, MMP9 and membrane type 1-MMP. It has been shown that cyclodextrins (CDs) are able to form inclusion complexes with Ro 28-2653 and to increase its aqueous solubility. The aim of this study is to demonstrate that an increase in Ro 28-2653 solubility, via ternary complex formation, can lead to an increase in the oral bioavailability of this drug. This study shows that a synergistic effect exists between hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and L-lysine. The use of this multicomponent system enabled the preparation of oral and intravenous solutions of Ro 28-2653. In vivo evaluation of the oral solution of the inclusion complex of Ro 28-2653 in comparison with a suspension of the same uncomplexed drug showed a significant (p < 0.05) increase in absolute bioavailability. The area under curve (AUC) and the peak serum concentration (C-max) were approximately 10 times higher than those obtained with the suspension, while the time (T-max) to reach C-max was reduced. Moreover, in vivo administration of Ro 28-2653 solutions highlighted some information about the pharmacokinetic behavior of Ro 28-2653: a long biologic half-life (about 15.5 h) and a small overall volume of distribution (81). (c) 2006 Elsevier B.V. All rights reserved. [less ▲]Detailed reference viewed: 86 (17 ULg)
Pharmacokinetic study of a new syntheyic MMP inhibitor (Ro 28-2653) after IV and oral administration of solutions containing hydroxypropyl-b-cyclodextrin
Piette, Marie ; Evrard, Brigitte ; et al
Poster (2005, June)Detailed reference viewed: 11 (4 ULg)
Pharmacokinetic study of a new testosteron in-Adhesive Matrix patch applied every two days to hypogonadal men
; ; et al
in The Endocrine society ENDO 2005 - Abstract book (2005)Detailed reference viewed: 4 (0 ULg)
Pharmacokinetic study of a new testosterone-in-adhesive matrix patch applied every 2 days to hypogonadal men.
; ; et al
in Journal of Steroid Biochemistry & Molecular Biology (2008), 109(1-2), 177-184
The present study assessed pharmacokinetic testosterone time profile and dose proportionality after application of a new matrix testosterone patch (30, 45, and 60 cm2 containing 0.5mg of testosterone per ... [more ▼]
The present study assessed pharmacokinetic testosterone time profile and dose proportionality after application of a new matrix testosterone patch (30, 45, and 60 cm2 containing 0.5mg of testosterone per cm2). This open study was a single dose, three-period, crossover trial with a randomised treatment sequence in 24 hypogonadal men, consisting in a single 48-h application of two patches of 2x 30 cm2, 2x 45 cm2, 2x 60 cm2, separated by a 5-day wash-out. Testosterone concentrations were determined during patch application and after patch removal. Dose proportionality was assessed on baseline corrected, dose normalised parameters for C av,corr/D, C max,corr/D and AUC(0-48),corr/D. Testosterone concentrations rose during the first 9h following patch application, remained relatively sustained until 48 h and then decreased abruptly after patch removal, with a half-life of 1.3h. Testosterone levels were maintained above 3 ng/mL for 42-45 h with all patches. C av were 3.39, 4.03 and 4.58 ng/mL and Cmax were 4.33, 5.29 and 6.18 ng/mL according to the doses. AUC 0-48), C av and Cmax were dose dependent with mean ratios within the acceptance range (0.70-1.43). In conclusion, dose linearity was demonstrated between the different strengths of testosterone patches. Application resulted in dose proportional increases in serum T levels in hypogonadal men into the low to mid-normal range within the first hours and achieved steady state for 48 h. During this short term study with three consecutive patch applications, this patch was shown to be efficient, convenient and safe with excellent adhesiveness and skin tolerability, and with no cross-contamination to partner or to environment. [less ▲]Detailed reference viewed: 32 (0 ULg)
Pharmacokinetics and clinical evaluation of the alogliptin plus pioglitazone combination for type 2 diabetes.
in Expert opinion on drug metabolism & toxicology (2015), 11(6), 1005-20
INTRODUCTION: Type 2 diabetes is a complex disease with multiple defects, which generally requires a combination of several pharmacological approaches to reach glucose control targets. A unique fixed-dose ... [more ▼]
INTRODUCTION: Type 2 diabetes is a complex disease with multiple defects, which generally requires a combination of several pharmacological approaches to reach glucose control targets. A unique fixed-dose combination combines a thiazolidinedione (pioglitazone) and a dipeptidyl peptidase-4 inhibitor (alogliptin). Area covered: An extensive literature search was performed to analyze the pharmacokinetics of pioglitazone and alogliptin when used separately and in combination as well as to summarize clinical and toxicological considerations about the combined therapy. Expert opinion: Pioglitazone, a potent insulin sensitizer, and alogliptin, an incretin-based agent that potentiates post-meal insulin secretion and reduces glucagon secretion, have complementary mechanisms of action. The clinical efficacy of a combined therapy is superior to any single therapy in patients treated with diet or with metformin (with or without sulphonylurea). These two drugs can be administered once daily, with or without a meal. No clinically relevant pharmacokinetic interactions between the two agents have been described and the fixed-dose combination has shown bioequivalence with alogliptin and pioglitazone given separately. Combining alogliptin with pioglitazone does not alter the safety profile of each compound. Weight gain observed with pioglitazone may be limited with the addition of alogliptin. The concern of an increased risk of heart failure remains to be better investigated. [less ▲]Detailed reference viewed: 14 (2 ULg)
Pharmacokinetics and Clinical Use of Incretin-Based Therapies in Patients with Chronic Kidney Disease and Type 2 Diabetes.
in Clinical pharmacokinetics (2014)
The prevalence of chronic kidney disease (CKD) of stages 3-5 (glomerular filtration rate [GFR] <60 mL/min) is about 25-30 % in patients with type 2 diabetes mellitus (T2DM). While most oral antidiabetic ... [more ▼]
The prevalence of chronic kidney disease (CKD) of stages 3-5 (glomerular filtration rate [GFR] <60 mL/min) is about 25-30 % in patients with type 2 diabetes mellitus (T2DM). While most oral antidiabetic agents have limitations in patients with CKD, incretin-based therapies are increasingly used for the management of T2DM. This review analyses (1) the influence of CKD on the pharmacokinetics of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists; and (2) the efficacy/safety profile of these agents in clinical practice when prescribed in patients with both T2DM and CKD. Most DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin) are predominantly excreted by the kidneys. Thereby, pharmacokinetic studies showed that total exposure to the drug is increased in proportion to the decline of GFR, leading to recommendations for appropriate dose reductions according to the severity of CKD. In these conditions, clinical studies reported a good efficacy and safety profile in patients with CKD. In contrast, linagliptin is eliminated by a predominantly hepatobiliary route. As a pharmacokinetic study showed only minimal influence of decreased GFR on total exposure, no dose adjustment of linagliptin is required in the case of CKD. The experience with GLP-1 receptor agonists in patients with CKD is more limited. Exenatide is eliminated by renal mechanisms and should not be given in patients with severe CKD. Liraglutide is not eliminated by the kidney, but it should be used with caution because of the limited experience in patients with CKD. Only limited pharmacokinetic data are also available for lixisenatide, exenatide long-acting release (LAR) and other once-weekly GLP-1 receptor agonists in current development. Several case reports of acute renal failure have been described with GLP-1 receptor agonists, probably triggered by dehydration resulting from gastrointestinal adverse events. However, increasing GLP-1 may also exert favourable renal effects that could contribute to reducing the risk of diabetic nephropathy. In conclusion, the already large reassuring experience with DPP-4 inhibitors in patients with CKD offers new opportunities to the clinician, whereas more caution is required with GLP-1 receptor agonists because of the limited experience in this population. [less ▲]Detailed reference viewed: 19 (1 ULg)
Pharmacokinetics and pharmacological properties of two galenical preparations of glibenclamide, HB419 and HB420, in non insulin-dependent (type 2) diabetes.
Scheen, André ; ; et al
in International Journal of Clinical Pharmacology, Therapy, and Toxicology (1987), 25(2), 70-6
The pharmacokinetics and pharmacological properties of a new micronized preparation of glibenclamide (HB420, 3.5 mg/tablet) were compared to those of the classical formulation (HB419, 5 mg/tablet) in non ... [more ▼]
The pharmacokinetics and pharmacological properties of a new micronized preparation of glibenclamide (HB420, 3.5 mg/tablet) were compared to those of the classical formulation (HB419, 5 mg/tablet) in non insulin-dependent diabetics. In a double-blind cross-over randomized acute study, blood glucose, plasma insulin, C-peptide and glibenclamide levels were determined in 10 patients after a standardized breakfast taken 15 min following the ingestion of 1.1 +/- 0.2 tablets of HB419 or HB420. Plasma glibenclamide levels rose faster, the peak value was higher (637 +/- 154 versus 411 +/- 76 nmol/l, p less than 0.05) and the area under the curve from 0 to 240 min was 35% greater (p less than 0.05) on HB420 than on HB419. Nevertheless, the post-breakfast hormonal and metabolic changes were similar with both preparations. In a single-blind cross-over chronic study, 12 patients were treated during 3 successive 6 to 8-week periods--HB419, HB420, HB419--with glibenclamide at a dose of 1.8 +/- 0.3 tablets/day. While fasting blood glucose concentrations remained unchanged throughout the study, postprandial levels decreased from 10.9 +/- 0.8 mmol/l during the HB419 pre-period to 9.2 +/- 0.6 mmol/l during HB420 (p less than 0.02) and rose again up to 10.4 +/- 0.8 mmol/l during the last HB419 period (p less than 0.05). Similarly HbA1c decreased slightly from 7.4 +/- 0.3 to 7.2 +/- 0.4% (NS) and increased again up to 7.8 +/- 0.4% (p less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS) [less ▲]Detailed reference viewed: 37 (0 ULg)
Pharmacokinetics for once- versus twice-daily tacrolimus formulations in de novo kidney transplantation: a randomized, open-label trial.
; Squifflet, Jean-Paul ; et al
in American Journal of Transplantation (2009), 9(11), 2505-13
Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice-daily formulation (Tacrolimus BID). A once-daily prolonged-release formulation (Tacrolimus QD) has been developed that may ... [more ▼]
Tacrolimus, a cornerstone immunosuppressant, is widely available as a twice-daily formulation (Tacrolimus BID). A once-daily prolonged-release formulation (Tacrolimus QD) has been developed that may improve adherence and impart long-lasting graft protection. This study compared the pharmacokinetics (PK) of tacrolimus in de novo kidney transplant patients treated with Tacrolimus QD or Tacrolimus BID. A 6-week, open-label, randomized comparative study was conducted in centers in Europe and Australia. Eligible patients received Tacrolimus QD or Tacrolimus BID. PK profiles were obtained following the first tacrolimus dose (day 1), and twice under steady-state conditions. As secondary objectives, efficacy and safety parameters were also evaluated. Sixty-six patients completed all PK profiles (34 Tacrolimus QD, 32 Tacrolimus BID). Mean AUC(0-24) of tacrolimus on day 1 was approximately 30% lower for Tacrolimus QD than Tacrolimus BID (232 and 361 ng.h/mL, respectively), but was comparable by day 4. There was a good correlation and a similar relationship between AUC(0-24) and C(min) for both formulations. Efficacy and safety data were also comparable over the 6-week period. Tacrolimus QD can be administered once daily in the morning on the basis of the same systemic exposure and therapeutic drug monitoring concept as Tacrolimus BID. [less ▲]Detailed reference viewed: 73 (9 ULg)
Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type 2 diabetes mellitus.
in Clinical pharmacokinetics (2014), 53(9), 773-85
Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have ... [more ▼]
Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2 years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients. [less ▲]Detailed reference viewed: 22 (8 ULg)
Pharmacokinetics of dipeptidylpeptidase-4 inhibitors.
in Diabetes, Obesity & Metabolism (2010), 12(8), 648-58
Type 2 diabetes (T2DM) is a complex disease combining defects in insulin secretion and insulin action. New compounds have been developed for improving glucose-induced insulin secretion and glucose control ... [more ▼]
Type 2 diabetes (T2DM) is a complex disease combining defects in insulin secretion and insulin action. New compounds have been developed for improving glucose-induced insulin secretion and glucose control, without inducing hypoglycaemia or weight gain. Dipeptidylpeptidase-4 (DPP-4) inhibitors are new oral glucose-lowering agents, so-called incretin enhancers, which may be used as monotherapy or in combination with other antidiabetic compounds. Sitagliptin, vildaglipin and saxagliptin are already on the market in many countries, either as single agents or in fixed-dose combined formulations with metformin. Other DPP-4 inhibitors, such as alogliptin and linagliptin, are currently in late phase of development. The present paper summarizes and compares the main pharmacokinetics (PK) properties, that is, absorption, distribution, metabolism and elimination, of these five DPP-4 inhibitors. Available data were obtained in clinical trials performed in healthy young male subjects, patients with T2DM, and patients with either renal insufficiency or hepatic impairment. PK characteristics were generally similar in young healthy subjects and in middle-aged overweight patients with diabetes. All together gliptins have a good oral bioavailability which is not significantly influenced by food intake. PK/pharmacodynamics characteristics, that is, sufficiently prolonged half-life and sustained DPP-4 enzyme inactivation, generally allow one single oral administration per day for the management of T2DM; the only exception is vildagliptin for which a twice-daily administration is recommended because of a shorter half-life. DPP-4 inhibitors are in general not substrates for cytochrome P450 (except saxagliptin that is metabolized via CYP 3A4/A5) and do not act as inducers or inhibitors of this system. Several metabolites have been documented but most of them are inactive; however, the main metabolite of saxagliptin also exerts a significant DPP-4 inhibition and is half as potent as the parent compound. Renal excretion is the most important elimination pathway, except for linagliptin whose metabolism in the liver appears to be predominant. PK properties of gliptins, combined with their good safety profile, explain why no dose adjustment is necessary in elderly patients or in patients with mild to moderate hepatic impairment. As far as patients with renal impairment are concerned, significant increases in drug exposure for sitagliptin and saxagliptin have been reported so that appropriate reductions in daily dosages are recommended according to estimated glomerular filtration rate. The PK characteristics of DPP-4 inhibitors suggest that these compounds are not exposed to a high risk of drug-drug interactions. However, the daily dose of saxagliptin should be reduced when coadministered with potent CYP 3A4 inhibitors. In conclusion, besides their pharmacodynamic properties leading to effective glucose-lowering effect without inducing hypoglycaemia or weight gain, DPP-4 inhibitors show favourable PK properties, which contribute to a good efficacy/safety ratio for the management of T2DM in clinical practice. [less ▲]Detailed reference viewed: 39 (0 ULg)
Pharmacokinetics of imipramine in narcoleptic horses
Conference given outside the academic context (2007)Detailed reference viewed: 24 (0 ULg)
Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease.
in Clinical pharmacokinetics (2015), 54
Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of ... [more ▼]
Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of the glucose filtered by the kidney. The glucuretic effect resulting from SGLT2 inhibition contributes to reduce hyperglycaemia and also assists weight loss and blood pressure reduction. Several SGLT2 inhibitors are already available in many countries (dapagliflozin, canagliflozin, empagliflozin) and in Japan (ipragliflozin, tofogliflozin). These SGLT2 inhibitors share similar pharmacokinetic characteristics with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites and a low renal elimination as a parent drug. Pharmacokinetic parameters are slightly altered in the case of chronic kidney disease (CKD). While no dose adjustment is required in the case of mild CKD, SGLT2 inhibitors may not be used or only at a lower daily dose in patients with moderate CKD. Furthermore, the pharmacodynamic response to SGLT2 inhibitors as assessed by urinary glucose excretion declines with increasing severity of renal impairment as assessed by a reduction in the estimated glomerular filtration rate. Nevertheless, the glucose-lowering efficacy and safety of SGLT2 inhibitors are almost comparable in patients with mild CKD as in patients with normal kidney function. In patients with moderate CKD, the efficacy tends to be dampened and safety concerns may occur. In patients with severe CKD, the use of SGLT2 inhibitors is contraindicated. Thus, prescribing information should be consulted regarding dosage adjustments or restrictions in the case of renal dysfunction for each SGLT2 inhibitor. The clinical impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy deserve attention because of preliminary favourable results in animal models. [less ▲]Detailed reference viewed: 13 (3 ULg)
Pharmacokinetics, pharmacodynamics, and safety of pasireotide LAR in patients with acromegaly: A randomized, multicenter, open-label, phase I study.
; ; et al
in Journal of Clinical Pharmacology (2014), 54(11), 1308-1317
Pasireotide (SOM230), a multireceptor-targeted somatostatin analogue, has exhibited favorable safety/tolerability in several clinical studies. A long-acting-release (LAR) formulation of pasireotide may ... [more ▼]
Pasireotide (SOM230), a multireceptor-targeted somatostatin analogue, has exhibited favorable safety/tolerability in several clinical studies. A long-acting-release (LAR) formulation of pasireotide may offer advantages over the subcutaneous formulation. This randomized, open-label, Phase I study evaluated the safety, PK, and PD of pasireotide LAR 20, 40, or 60 mg/month in patients with acromegaly. Safety assessments and blood samples for PK and PD were taken at designated time points. Thirty-five patients were randomized and completed the study. Steady-state pasireotide concentrations were achieved following three monthly injections. Trough pasireotide concentrations (ng/mL) 28 days after each injection were: 2.48, 4.16, and 3.10 (20 mg group); 6.42, 6.62, and 7.12 (40 mg group); and 9.51, 11.7, and 13.0 (60 mg group). At study end, 51% and 57% of patients achieved GH levels </=2.5 mug/L and IGF-1 levels below ULN, respectively. Compared with baseline, fasting blood glucose and HbA1c levels increased, whereas fasting blood insulin levels decreased. Acromegaly symptoms were generally improved. Adverse events were mostly gastrointestinal and mild/moderate. Pasireotide LAR was generally well tolerated. Steady-state PK was achieved after three monthly doses; exposures were approximately dose proportional. Control of GH, IGF-1, and symptoms improved, suggesting that pasireotide LAR may be an effective treatment for acromegaly. [less ▲]Detailed reference viewed: 33 (1 ULg)
Pharmacologic treatment of inner ear: from basic science to the patient.
Lefèbvre, Philippe ; ; et al
in Acta Oto-Rhino-Laryngologica Belgica (2002), 56(1), 45-9
Most of the deafness are of sensorineural origin and are characterized by a loss of hair cells and of spiral ganglion neurons. At the present time, hearing aids are the only treatment. However, in some ... [more ▼]
Most of the deafness are of sensorineural origin and are characterized by a loss of hair cells and of spiral ganglion neurons. At the present time, hearing aids are the only treatment. However, in some diseases of the inner ear, pharmacological treatment have been proposed and used successfully. In this paper, we will review some basic science aspects of the biology of the neurosensory structures of the inner ear, in particular of the auditory neurons, that lead to the rationale of some treatments for the inner ear diseases. Developmental studies, neuronal cell culture experiments, and analyses of gene knockout animals reveal a number of growth factors which are important for the rescue and repair of injured auditory neurons in the inner ear. These factors rescue the injured auditory neurons in vivo. Furthermore, perfusion of antioxydant to the cochlea prevented the hearing loss induced by cisplatin. These in vitro and in vivo experiments demonstrate that it is possible to manipulate the neurosensory structures of the inner ear and provide an effective treatment to prevent the degeneration of the neurons. The molecules or drugs can be administered locally to the inner ear through a direct perilymphatic perfusion or through the round window membrane. As an example, we will discuss the treatment of patients suffering from idiopathic sensorineural hearing loss which can be treated successfully by a perfusion through the round window membrane, improving their hearing threshold and their speech discrimination. [less ▲]Detailed reference viewed: 33 (7 ULg)