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ABSTRACT: Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily nonrenal route of excretion. Consequently, renal impairment should not substantially affect drug exposure. This analysis was undertaken to compare steady-state trough concentrations of linagliptin among patients with type-2 diabetes receiving linagliptin 5 mg in phase 3 studies. Data were pooled from 3 randomized studies from the global phase 3 program of linagliptin (5 mg daily in each) in patients with type-2 diabetes. These studies were selected for their inclusion of pharmacokinetic data. Linagliptin plasma concentrations were available for 969 patients who were determined by estimated glomerular filtration rate to have normal renal function (n = 438), mild renal impairment (RI) (n = 429), moderate RI (n = 44), or severe RI (n = 58). In patients with normal renal function, the geometric mean linagliptin trough concentration (coefficient of variation) was 5.93 nmol/L (56.3%); in patients with mild, moderate, or severe RI, geometric mean concentrations were 6.07 nmol/L (62.9%), 7.34 nmol/L (58.6%), and 8.13 nmol/L (49.8%), respectively. In patients with type-2 diabetes, RI had a minor effect on linagliptin exposure. Therefore, neither dose-adjustment nor drug-related monitoring of estimated glomerular filtration rate is necessary for patients with RI.
American journal of therapeutics 02/2013;
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ABSTRACT: AIM: This was an open-label, multicenter phase I trial to study the pharmacokinetics and pharmacodynamics of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin in African American patients with type 2 diabetes mellitus (T2DM). METHODS: Forty-one African American patients with type 2 diabetes mellitus were included in this study. Patients were admitted to a study clinic and administered 5 mg linagliptin once-daily for 7 days, followed by 7 days of outpatient evaluation. RESULTS: Primary endpoints were area under the plasma concentration-time curve (AUC), maximum plasma concentration (C(max) ), and plasma DPP-4 trough inhibition at steady state. Linagliptin geometric mean AUC was 194 nmol/L·h (geometric coefficient of variation, 26%), with a C(max) of 16.4 nmol/L (41%). Urinary excretion was low (0.5% and 4.4% of the dose excreted over 24 hours, days 1 and 7). The geometric mean DPP-4 inhibition at steady state was 84.2% at trough and 91.9% at maximum. The exposure range and overall pharmacokinetic/pharmacodynamic profile of linagliptin in this study of African Americans with T2DM was comparable with that in other populations. Laboratory data, vital signs, and physical exams did not show any relevant findings. No safety concerns were identified. CONCLUSIONS: The results of this study in African American patients with T2DM support the use of the standard 5 mg dose recommended in all populations.
British Journal of Clinical Pharmacology 01/2013; · 2.96 Impact Factor
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ABSTRACT: To develop a longitudinal statistical model to indirectly estimate the comparative efficacies of two drugs, using model-based meta-analysis (MBMA). Comparison of two oral dipeptidyl peptidase (DPP)-4 inhibitors, sitagliptin and linagliptin, for type 2 diabetes mellitus (T2DM) treatment was used as an example.
Systematic review with MBMA.
MEDLINE, EMBASE, http://www.ClinicalTrials.gov, Cochrane review of DPP-4 inhibitors for T2DM, sitagliptin trials on Food and Drug Administration website to December 2011 and linagliptin data from the manufacturer. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Double-blind, randomised controlled clinical trials, ≥12 weeks' duration, that analysed sitagliptin or linagliptin efficacies as changes in glycated haemoglobin (HbA1c) levels, in adults with T2DM and HbA1c >7%, irrespective of background medication. MODEL DEVELOPMENT AND APPLICATION: A Bayesian model was fitted (Markov Chain Monte Carlo method). The final model described HbA1c levels as function of time, dose, baseline HbA1c, washout status/duration and ethnicity. Other covariates showed no major impact on model parameters and were not included. For the indirect comparison, a population of 1000 patients was simulated from the model with a racial composition reflecting the average racial distribution of the linagliptin trials, and baseline HbA1c of 8%.
The model was developed using longitudinal data from 11 234 patients (10 linagliptin, 15 sitagliptin trials), and assessed by internal evaluation techniques, demonstrating that the model adequately described the observations. Simulations showed both linagliptin 5 mg and sitagliptin 100 mg reduced HbA1c by 0.81% (placebo-adjusted) at week 24. Credible intervals for participants without washout were -0.88 to -0.75 (linagliptin) and -0.89 to -0.73 (sitagliptin), and for those with washout, -0.91 to -0.76 (linagliptin) and -0.91 to -0.75 (sitagliptin).
This study demonstrates the use of longitudinal MBMA in the field of diabetes treatment. Based on an example evaluating HbA1c reduction with linagliptin versus sitagliptin, the model used seems a valid approach for indirect drug comparisons.
BMJ open. 01/2013; 3(3).
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ABSTRACT: Objective: To investigate the pharmacokinetic and safety profile of linagliptin after single and multiple doses in healthy Chinese volunteers. Methods: Men and women (n = 12) aged 18 - 45 years with body mass index 19 - 24 kg/m2 received a single 5-mg dose of linagliptin on Day 1, followed by 7-day washout and 6 consecutive days of once-daily administration. Vital signs, electrocardiogram, routine laboratory tests, urinalysis, and adverse events were recorded. Blood and urine analytes were measured by HPLC/MS/MS. Results: Linagliptin was rapidly absorbed; median time to maximum concentration was 1.75 h for single dose and 1.5 h at steady-state. Maximum plasma drug concentration (Cmax) after single dose was 4.9 ng/ml (10.4 nM), with a geometric coefficient of variation (gCV) 46%. The corresponding geometric mean area under the plasma concentrationtime curve (AUC) was 71 ng×h ml-1 (150 nmol×h l-1, gCV 25%). At steady-state, Cmax and AUC were 6.7 ng/ml (14.1 nM, gCV 49%) and 96 nmol×h l-1 (204 nmol×h l-1, gCV 25%). An accumulation half-life of ~ 11.5 h (gCV 46.9%) was calculated. Renal excretion of linagliptin was low and < 8% of administered dose at steady-state (< 2% at Day 1). Single and multiple daily oral doses of 5 mg linagliptin were safe and well tolerated. No adverse events or clinically significant changes in laboratory tests, vital signs, or physical examination were reported. Conclusions: Linagliptin demonstrated a favorable safety profile in healthy Chinese volunteers, with a pharmacokinetic profile that was similar to that observed previously in subjects of Japanese, Caucasian, or African American origin.
International journal of clinical pharmacology and therapeutics 10/2012; · 1.18 Impact Factor
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ABSTRACT: Linagliptin is an orally active small-molecule inhibitor of dipeptidyl peptidase (DPP)-4, which was first licensed in the US, Europe, Japan and other territories in 2011 to improve glycaemic control in adults with type 2 diabetes mellitus. Linagliptin is the first and thus far the only DPP-4 inhibitor, and oral antihyperglycaemic drug in general, to be approved as a single-strength once-daily dose (5 mg). Compared with other available DPP-4 inhibitors, linagliptin has a unique pharmacokinetic/pharmacodynamic profile that is characterized by target-mediated nonlinear pharmacokinetics, concentration-dependent protein binding, minimal renal clearance and no requirements for dose adjustment for any intrinsic or extrinsic factor. After single or multiple oral doses of 1-10 mg, linagliptin displays less than dose-proportional increases in maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC). Linagliptin is rapidly absorbed after oral administration, with C(max) occurring after approximately 90 minutes, and reaches steady-state concentrations within 4 days. With the therapeutic dose, steady-state C(max) (11-12 nmol/L) and AUC (∼150 nmol · h/L) are approximately 1.3-fold greater than after a single dose, indicating little drug accumulation with repeat dosing. Linagliptin exhibits concentration-dependent protein binding in human plasma in vitro (99% at 1 nmol/L to 75-89% at >30 nmol/L) and has a large apparent volume of distribution, demonstrating extensive distribution into tissues. The nonlinear pharmacokinetics of linagliptin are best described by a two-compartmental model that incorporates target-mediated drug disposition resulting from high-affinity, saturable binding to DPP-4. The oral bioavailability of linagliptin estimated with this model is approximately 30%. Linagliptin has a long terminal half-life (>100 hours); however, its accumulation half-life is much shorter (approximately 10 hours), accounting for the rapid attainment of steady state. The majority of linagliptin is eliminated as parent compound, demonstrating that metabolism plays a minor role in the overall pharmacokinetics in humans. The main, pharmacologically inactive S-3-hydroxypiperidinyl metabolite accounted for approximately 17% of the total drug-related compounds in plasma. Linagliptin is eliminated primarily in faeces, with only around 5% of the oral therapeutic dose excreted in the urine at steady state. Linagliptin potently inhibits DPP-4 (inhibition constant 1 nmol/L), and trough drug concentrations achieved with therapeutic dosing inhibit >80% of plasma DPP-4 activity, the threshold associated with maximal antihyperglycaemic effects in animal models. There are no clinically relevant alterations in linagliptin pharmacokinetics resulting from renal impairment, hepatic impairment, coadministration with food, race, body weight, sex or age. In vitro, linagliptin is a weak substrate and weak inhibitor of cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) but not of other CYP isozymes or ATP-binding cassette transporters. Clinical studies have revealed no relevant drug interactions when coadministered with other drugs commonly prescribed to patients with type 2 diabetes, including the narrow therapeutic index drugs warfarin and digoxin. Linagliptin plasma exposure is reduced by potent inducers of CYP3A4 or P-gp. Linagliptin has demonstrated a large safety window (>100-fold the recommended daily dose) and clinically relevant antihyperglycaemic effects in patients with type 2 diabetes.
Clinical Pharmacokinetics 05/2012; 51(7):411-27. · 5.40 Impact Factor
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ABSTRACT: Linagliptin is an oral dipeptidyl peptidase (DPP)-4 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. Microgynon® 30 is a combined oral contraceptive pill containing both ethinylestradiol 30 μg and levonorgestrel 150 μg (EE 30 μg/LNG 150 μg).
The objective of this study was to determine the effect of multiple doses of linagliptin (5 mg once daily) on the steady-state pharmacokinetics of EE and LNG following once-daily doses of EE 30 μg/LNG 150 μg.
This was an open-label, two-period, fixed-sequence, multiple-dose study, consisting of a run-in period, a 14-day reference treatment period and a 7-day test treatment period. The study recruited 18 healthy pre-menopausal female subjects aged 18-40 years with a body mass index of 18.5-27.0 kg/m2. Only women with regular menstrual cycles were included in this study. The treatment sequence was divided into three steps: an individually tailored run-in period with EE 30 μg/LNG 150 μg to synchronize the menstrual cycles of the subjects followed by a washout period of 7 days; the reference treatment period, during which EE 30 μg/LNG 150 μg alone was taken on days 1-14; and the test treatment period, during which EE 30 μg/LNG 150 μg plus linagliptin were taken on days 15-21. The pharmacokinetic parameters measured were maximum steady-state plasma concentration during a dosage interval (C(max,ss)), time to reach maximum plasma concentration following administration at steady state (t(max,ss)) and area under the plasma concentration-time curve during a dosage interval (τ) at steady state (AUC(τ,ss)).
The AUC(τ,ss) and C(max,ss) of EE and LNG were comparable when EE 30 μg/LNG 150 μg was given alone or combined with linagliptin. The adjusted geometric mean ratios for AUC(τ,ss) and C(max,ss) of EE following EE 30 μg/LNG 150 μg plus linagliptin versus EE 30 μg/LNG 150 μg alone were 101.4 (90% CI 97.2, 105.8) and 107.8 (90% CI 99.7, 116.6), respectively. The adjusted geometric mean ratios for AUC(τ,ss) and C(max,ss) of LNG following EE 30 μg/LNG 150 μg plus linagliptin versus EE 30 μg/LNG 150 μg alone were 108.8 (90% CI 104.5, 113.3) and 113.5 (90% CI 106.1, 121.3), respectively. The combination was well tolerated.
Linagliptin had no clinically relevant effect on the steady-state pharmacokinetics of EE and LNG in healthy female subjects, and the combination of EE 30 μg/LNG 150 μg and linagliptin was well tolerated in this study. Therefore, linagliptin has the potential to be used in the treatment of female patients with type 2 diabetes in combination with oral contraceptives containing these components, such as EE 30 μg/LNG 150 μg.
The EudraCT number for this study is 2008-000953-37.
Clinical Drug Investigation 06/2011; 31(9):643-53. · 1.82 Impact Factor
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ABSTRACT: The aim of this study was to determine whether administration of the prodrugs bisacodyl (Bisa) and sodium picosulfate (SPS) leads to excretion of their common active metabolite, bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM), in breast milk. Two groups of 8 healthy lactating women who had stopped breast feeding received multiple doses of Bisa or SPS. Plasma, urine, and breast milk were collected and concentrations of free and total BHPM were determined using validated liquid chromatography/mass spectrometry methods. BHPM remained below the limits of detection in breast milk following single- and multiple-dose administration of Bisa and SPS. First, BHPM plasma concentrations were observed after a lag time of about 3 to 4 h and 4 to 5 h following Bisa and SPS administration, respectively. C(max) was attained approximately 5 h after dosing of Bisa and 9 h after dosing of SPS. BHPM did not accumulate after multiple administrations of Bisa and only slightly accumulated following multiple doses of SPS. About 12% and 13% of Bisa and SPS was excreted as BHPM into urine at steady state. BHPM, the active moiety of Bisa and SPS, was not excreted into human breast milk. Hence, use of Bisa or SPS to treat constipation of breast-feeding women is considered well tolerated with regard to exposing infants to BHPM via breast milk.
Drug Metabolism and Pharmacokinetics 06/2011; 26(5):458-64. · 2.32 Impact Factor
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ABSTRACT: This study assessed the influence of various degrees of renal impairment on the exposure of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily non-renal route of excretion, in subjects with type 2 diabetes mellitus (T2DM).
Linagliptin pharmacokinetics was studied under single-dose and steady-state conditions in subjects with mild, moderate and severe renal impairment (with and without T2DM) and end-stage renal disease and compared with the pharmacokinetics in subjects with normal renal function (with and without T2DM).
Renal excretion of unchanged linagliptin was <7% in all groups. Under single-dose conditions, the degree of renal impairment did not affect mean plasma linagliptin concentration-time profiles. These showed a similar decline and almost identical plasma concentrations 24 h postdosing in subjects with mild, moderate or severe renal impairment and in subjects with T2DM with and without renal impairment. Although there was a tendency towards slightly higher (20-60%) exposure in renally impaired subjects (with and without T2DM) compared with subjects with normal renal function, the steady-state AUC and C(max) values showed a large overlap and were not affected by the degree of renal impairment. The accumulation half-life of linagliptin ranged from 14-15 h in subjects with normal renal function to 18 h in severe renal impairment. Only a weak correlation (r(2) = 0.18) was seen between creatinine clearance and steady-state exposure.
Renal impairment has only a minor effect on linagliptin pharmacokinetics. Consequently, there will be no need for adjusting the linagliptin dose in renally impaired patients with T2DM.
Diabetes Obesity and Metabolism 06/2011; 13(10):939-46. · 3.38 Impact Factor
