The Experts below are selected from a list of 270 Experts worldwide ranked by ideXlab platform
Gangadhar Sunkara - One of the best experts on this subject based on the ideXlab platform.
-
Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.
Clinical pharmacokinetics, 2017Co-Authors: Surya Ayalasomayajula, Thomas Langenickel, Sreedevi Boggarapu, Gangadhar SunkaraAbstract:Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum Plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a twofold increase in dose, an increase in the area under the Plasma Concentration-Time Curve was proportional for sacubitril, ~1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum Plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug-drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum Plasma concentration (~2.0-fold) and area under the Plasma Concentration-Time Curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the Plasma Concentration-Time Curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the Plasma Concentration-Time Curves, while the area under the Plasma Concentration-Time Curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the Plasma Concentration-Time Curves of valsartan and sacubitrilat ~2.1-fold.
-
Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.
Clinical Pharmacokinectics, 2017Co-Authors: Surya Ayalasomayajula, Thomas Langenickel, Sreedevi Boggarapu, Gangadhar SunkaraAbstract:Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum Plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5–2.0, and 2.0–3.0 h, respectively. With a two-fold increase in dose, an increase in the area under the Plasma concentration–time Curve was proportional for sacubitril, ~1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum Plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug–drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum Plasma concentration (~2.0-fold) and area under the Plasma concentration–time Curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the Plasma concentration–time Curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the Plasma concentration–time Curves, while the area under the Plasma concentration–time Curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the Plasma concentration–time Curves of valsartan and sacubitrilat ~2.1-fold.
-
Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor–Neprilysin Inhibitor
Clinical pharmacokinetics, 2017Co-Authors: Surya Ayalasomayajula, Thomas Langenickel, Sreedevi Boggarapu, Parasar Pal, Gangadhar SunkaraAbstract:Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum Plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5–2.0, and 2.0–3.0 h, respectively. With a two-fold increase in dose, an increase in the area under the Plasma concentration–time Curve was proportional for sacubitril, ~1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum Plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug–drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum Plasma concentration (~2.0-fold) and area under the Plasma concentration–time Curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the Plasma concentration–time Curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the Plasma concentration–time Curves, while the area under the Plasma concentration–time Curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the Plasma concentration–time Curves of valsartan and sacubitrilat ~2.1-fold.
Pertti J. Neuvonen - One of the best experts on this subject based on the ideXlab platform.
-
Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride.
Clinical Pharmacology & Therapeutics, 2001Co-Authors: Mikko Niemi, Pertti J. Neuvonen, Janne T. Backman, Mikko Neuvonen, Jouko Laitila, Kari T. KivistöAbstract:Objective Our objective was to study the effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride, a new sulfonylurea antidiabetic drug. Methods In this randomized, double-blind, three-phase crossover study, 12 healthy volunteers took 200 mg of fluconazole once daily (400 mg on day 1), 100 mg of fluvoxamine once daily, or placebo once daily for 4 days. On day 4, a single oral dose of 0.5 mg of glimepiride was administered. Plasma glimepiride and blood glucose concentrations were measured up to 12 hours. Results In the fluconazole phase, the mean total area under the Plasma Concentration-Time Curve of glimepiride was 238% (P < .0001) and the peak Plasma concentration was 151% (P < .0001) of the respective control value. The mean elimination half-life of glimepiride was prolonged from 2.0 to 3.3 hours (P < .0001) by fluconazole. In the fluvoxamine phase, the mean area under the Plasma Concentration-Time Curve of glimepiride was not significantly different from that in the placebo phase. However, the mean peak Plasma concentration of glimepiride was 143% (P < .05) of the control and the elimination half-life was prolonged from 2.0 to 2.3 hours (P < .01) by fluvoxamine. Fluconazole and fluvoxamine did not cause statistically significant changes in the effects of glimepiride on blood glucose concentrations. Conclusions Fluconazole considerably increased the area under the Plasma Concentration-Time Curve of glimepiride and prolonged its elimination half-life. This was probably caused by inhibition of the cytochrome P-450 2C9–mediated biotransformation of glimepiride by fluconazole. Concomitant use of fluconazole with glimepiride may increase the risk of hypoglycemia as much as would a 2- to 3-fold increase in the dose of glimepiride. Fluvoxamine moderately increased the Plasma concentrations and slightly prolonged the elimination half-life of glimepiride. Clinical Pharmacology & Therapeutics (2001) 69, 194–200; doi: 10.1067/mcp.2001.114229
-
Effect of rifampicin on the pharmacokinetics and pharmacodynamics of glimepiride
British Journal of Clinical Pharmacology, 2000Co-Authors: Mikko Niemi, Kari T. Kivistö, Janne T. Backman, Pertti J. NeuvonenAbstract:Aims To study the effects of rifampicin on the pharmacokinetics and pharmacodynamics of glimepiride, a new sulphonylurea antidiabetic drug. Methods In this randomised, two-phase cross-over study, 10 healthy volunteers were treated for 5 days with 600 mg rifampicin or placebo once daily. On day 6, a single oral dose of 1 mg glimepiride was administered. Plasma glimepiride and blood glucose concentrations were measured up to 12 h. Results Rifampicin decreased the mean area under the Plasma Concentration-Time Curve of glimepiride by 34% (P
-
The area under the Plasma concentration–time Curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin
European journal of clinical pharmacology, 1998Co-Authors: J. T. Backman, Kari T. Kivistö, Klaus T. Olkkola, Pertti J. NeuvonenAbstract:To determine the effects of treatment with itraconazole and rifampicin (rifampin) on the pharmacokinetics and pharmacodynamics of oral midazolam during and 4 days after the end of the treatment. Nine healthy volunteers received itraconazole (200 mg daily) for 4 days and, 2 weeks later, rifampicin (600 mg daily) for 5 days. In addition, they ingested 15 mg midazolam before the first treatment, 7.5 mg on the last day of itraconazole administration, and 4 days later, and 15 mg 1 day and 4 days after the last dose of rifampicin. The disposition of midazolam and its alpha-hydroxy metabolite was determined and its pharmacodynamic effects were measured. During itraconazole treatment, or 4 days after, alpha-hydroxymetabolite the dose-corrected area under the Plasma midazolam concentration time Curve (AUC0-infinity) was 8- or 2.6-fold larger than that before itraconazole (i.e. 1707 or 695 versus 277 ng x h x ml(-1)), respectively. One day after rifampicin treatment, the AUC0-infinity of midazolam was 2.3% (i.e. 4.4 ng x h x ml(-1)) of the before-treatment value and only 0.26% of its value during itraconazole treatment; 4 days after rifampicin, the AUC0-infinity was still only 13% (i.e. 27.1 ng x h x ml(-1)) of the before-treatment value. The peak concentration and elimination half-life of midazolam were also increased by itraconazole and decreased by rifampicin. The ratio of Plasma alpha-hydroxymidazolam to midazolam was greatly decreased by itraconazole and increased by rifampicin. In addition, the effects of midazolam were greater during itraconazole and smaller 1 day after rifampicin than without treatment. Switching from inhibition to induction of cytochrome P450 3A (CYP3A) enzymes causes a very great (400-fold) change in the AUC of oral midazolam. During oral administration of CYP3A substrates that undergo extensive first-pass metabolism, similar changes in pharmacokinetics are expected to occur when potent inhibitors or inducers of CYP3A are added to the treatment. After cessation of treatment with itraconazole or rifampicin, the risk of significant interaction continues up to at least 4 days, probably even longer.
-
The area under the Plasma concentration–time Curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin
European journal of clinical pharmacology, 1998Co-Authors: J. T. Backman, Kari T. Kivistö, Klaus T. Olkkola, Pertti J. NeuvonenAbstract:Objective: To determine the effects of treatment with itraconazole and rifampicin (rifampin) on the pharmacokinetics and pharmacodynamics of oral midazolam during and 4 days after the end of the treatment.
-
the area under the Plasma concentration time Curve for oral midazolam is 400 fold larger during treatment with itraconazole than with rifampicin
European Journal of Clinical Pharmacology, 1998Co-Authors: J. T. Backman, Kari T. Kivistö, Klaus T. Olkkola, Pertti J. NeuvonenAbstract:Objective: To determine the effects of treatment with itraconazole and rifampicin (rifampin) on the pharmacokinetics and pharmacodynamics of oral midazolam during and 4 days after the end of the treatment.
Surya Ayalasomayajula - One of the best experts on this subject based on the ideXlab platform.
-
Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.
Clinical pharmacokinetics, 2017Co-Authors: Surya Ayalasomayajula, Thomas Langenickel, Sreedevi Boggarapu, Gangadhar SunkaraAbstract:Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum Plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a twofold increase in dose, an increase in the area under the Plasma Concentration-Time Curve was proportional for sacubitril, ~1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum Plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug-drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum Plasma concentration (~2.0-fold) and area under the Plasma Concentration-Time Curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the Plasma Concentration-Time Curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the Plasma Concentration-Time Curves, while the area under the Plasma Concentration-Time Curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the Plasma Concentration-Time Curves of valsartan and sacubitrilat ~2.1-fold.
-
Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.
Clinical Pharmacokinectics, 2017Co-Authors: Surya Ayalasomayajula, Thomas Langenickel, Sreedevi Boggarapu, Gangadhar SunkaraAbstract:Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum Plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5–2.0, and 2.0–3.0 h, respectively. With a two-fold increase in dose, an increase in the area under the Plasma concentration–time Curve was proportional for sacubitril, ~1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum Plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug–drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum Plasma concentration (~2.0-fold) and area under the Plasma concentration–time Curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the Plasma concentration–time Curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the Plasma concentration–time Curves, while the area under the Plasma concentration–time Curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the Plasma concentration–time Curves of valsartan and sacubitrilat ~2.1-fold.
-
Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor–Neprilysin Inhibitor
Clinical pharmacokinetics, 2017Co-Authors: Surya Ayalasomayajula, Thomas Langenickel, Sreedevi Boggarapu, Parasar Pal, Gangadhar SunkaraAbstract:Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum Plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5–2.0, and 2.0–3.0 h, respectively. With a two-fold increase in dose, an increase in the area under the Plasma concentration–time Curve was proportional for sacubitril, ~1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum Plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug–drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum Plasma concentration (~2.0-fold) and area under the Plasma concentration–time Curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the Plasma concentration–time Curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the Plasma concentration–time Curves, while the area under the Plasma concentration–time Curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the Plasma concentration–time Curves of valsartan and sacubitrilat ~2.1-fold.
Rajesh Gandhi - One of the best experts on this subject based on the ideXlab platform.
-
effect of food on the pharmacokinetics of 2 formulations of drl 17822 a novel selective cholesteryl ester transfer protein cetp inhibitor in healthy males
Clinical pharmacology in drug development, 2019Co-Authors: Annelieke C Kruithof, Shanavas Alikunju, Rajeev Singh Raghuvanshi, Rajesh Gandhi, Jasper Stevens, Anirudh Gautam, Bijay Kumar Padhi, Swati Kulkarni, Rajinder Kumar, Jacobus BurggraafAbstract:: DRL-17822 is a novel selective cholesteryl ester transfer protein inhibitor that showed an increased exposure, including an increase of >20-fold of maximum concentration and area under the Plasma Concentration-Time Curve from time zero to the time of the last quantifiable concentration, following a high-fat breakfast using a nanocrystal formulation. To reduce this effect of food, we generated an amorphous solid dispersion formulation. In this study, we compared the food effect of both formulations of DRL-17822 in a 2-part randomized, open-label, 4-way crossover study involving healthy adult males 18-45 years of age. In both parts of the study, 12 subjects received both formulations of DRL-17822 in both the fasted and fed states; a low-fat breakfast was provided in the first part and a high-fat breakfast in the second part. Compared to the nanocrystal formulation, the amorphous solid dispersion formulation substantially increased DRL-17822 exposure in the fasted state, including increased maximum concentration, area under the Plasma Concentration-Time Curve from time zero to the time of the last quantifiable concentration, and area under Plasma Concentration-Time Curve from time zero to infinity. Following a high-fat breakfast, DRL-17822 exposure was increased to a lesser extent in the amorphous solid dispersion formulation compared to the nanocrystal formulation (P < .001). Moreover, compared to the nanocrystal formulation the amorphous solid dispersion formulation caused a more pronounced increase in high-density lipoprotein in the fasted state. Consuming breakfast increased the effect of DRL-17822 on high-density lipoprotein. Taken together, our results indicate that by improving its formulation, DRL-17822 has a favorable exposure profile and therefore a more predictable food effect profile.
-
Effect of Food on the Pharmacokinetics of 2 Formulations of DRL‐17822, a Novel Selective Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Males
Clinical pharmacology in drug development, 2019Co-Authors: Annelieke C Kruithof, Shanavas Alikunju, Rajeev Singh Raghuvanshi, Jasper Stevens, Anirudh Gautam, Bijay Kumar Padhi, Swati Kulkarni, Rajinder Kumar, Marieke L. De Kam, Rajesh GandhiAbstract:DRL-17822 is a novel selective cholesteryl ester transfer protein inhibitor that showed an increased exposure, including an increase of >20-fold of maximum concentration and area under the Plasma Concentration-Time Curve from time zero to the time of the last quantifiable concentration, following a high-fat breakfast using a nanocrystal formulation. To reduce this effect of food, we generated an amorphous solid dispersion formulation. In this study, we compared the food effect of both formulations of DRL-17822 in a 2-part randomized, open-label, 4-way crossover study involving healthy adult males 18-45 years of age. In both parts of the study, 12 subjects received both formulations of DRL-17822 in both the fasted and fed states; a low-fat breakfast was provided in the first part and a high-fat breakfast in the second part. Compared to the nanocrystal formulation, the amorphous solid dispersion formulation substantially increased DRL-17822 exposure in the fasted state, including increased maximum concentration, area under the Plasma Concentration-Time Curve from time zero to the time of the last quantifiable concentration, and area under Plasma Concentration-Time Curve from time zero to infinity. Following a high-fat breakfast, DRL-17822 exposure was increased to a lesser extent in the amorphous solid dispersion formulation compared to the nanocrystal formulation (P < .001). Moreover, compared to the nanocrystal formulation the amorphous solid dispersion formulation caused a more pronounced increase in high-density lipoprotein in the fasted state. Consuming breakfast increased the effect of DRL-17822 on high-density lipoprotein. Taken together, our results indicate that by improving its formulation, DRL-17822 has a favorable exposure profile and therefore a more predictable food effect profile.
Annelieke C Kruithof - One of the best experts on this subject based on the ideXlab platform.
-
effect of food on the pharmacokinetics of 2 formulations of drl 17822 a novel selective cholesteryl ester transfer protein cetp inhibitor in healthy males
Clinical pharmacology in drug development, 2019Co-Authors: Annelieke C Kruithof, Shanavas Alikunju, Rajeev Singh Raghuvanshi, Rajesh Gandhi, Jasper Stevens, Anirudh Gautam, Bijay Kumar Padhi, Swati Kulkarni, Rajinder Kumar, Jacobus BurggraafAbstract:: DRL-17822 is a novel selective cholesteryl ester transfer protein inhibitor that showed an increased exposure, including an increase of >20-fold of maximum concentration and area under the Plasma Concentration-Time Curve from time zero to the time of the last quantifiable concentration, following a high-fat breakfast using a nanocrystal formulation. To reduce this effect of food, we generated an amorphous solid dispersion formulation. In this study, we compared the food effect of both formulations of DRL-17822 in a 2-part randomized, open-label, 4-way crossover study involving healthy adult males 18-45 years of age. In both parts of the study, 12 subjects received both formulations of DRL-17822 in both the fasted and fed states; a low-fat breakfast was provided in the first part and a high-fat breakfast in the second part. Compared to the nanocrystal formulation, the amorphous solid dispersion formulation substantially increased DRL-17822 exposure in the fasted state, including increased maximum concentration, area under the Plasma Concentration-Time Curve from time zero to the time of the last quantifiable concentration, and area under Plasma Concentration-Time Curve from time zero to infinity. Following a high-fat breakfast, DRL-17822 exposure was increased to a lesser extent in the amorphous solid dispersion formulation compared to the nanocrystal formulation (P < .001). Moreover, compared to the nanocrystal formulation the amorphous solid dispersion formulation caused a more pronounced increase in high-density lipoprotein in the fasted state. Consuming breakfast increased the effect of DRL-17822 on high-density lipoprotein. Taken together, our results indicate that by improving its formulation, DRL-17822 has a favorable exposure profile and therefore a more predictable food effect profile.
-
Effect of Food on the Pharmacokinetics of 2 Formulations of DRL‐17822, a Novel Selective Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Males
Clinical pharmacology in drug development, 2019Co-Authors: Annelieke C Kruithof, Shanavas Alikunju, Rajeev Singh Raghuvanshi, Jasper Stevens, Anirudh Gautam, Bijay Kumar Padhi, Swati Kulkarni, Rajinder Kumar, Marieke L. De Kam, Rajesh GandhiAbstract:DRL-17822 is a novel selective cholesteryl ester transfer protein inhibitor that showed an increased exposure, including an increase of >20-fold of maximum concentration and area under the Plasma Concentration-Time Curve from time zero to the time of the last quantifiable concentration, following a high-fat breakfast using a nanocrystal formulation. To reduce this effect of food, we generated an amorphous solid dispersion formulation. In this study, we compared the food effect of both formulations of DRL-17822 in a 2-part randomized, open-label, 4-way crossover study involving healthy adult males 18-45 years of age. In both parts of the study, 12 subjects received both formulations of DRL-17822 in both the fasted and fed states; a low-fat breakfast was provided in the first part and a high-fat breakfast in the second part. Compared to the nanocrystal formulation, the amorphous solid dispersion formulation substantially increased DRL-17822 exposure in the fasted state, including increased maximum concentration, area under the Plasma Concentration-Time Curve from time zero to the time of the last quantifiable concentration, and area under Plasma Concentration-Time Curve from time zero to infinity. Following a high-fat breakfast, DRL-17822 exposure was increased to a lesser extent in the amorphous solid dispersion formulation compared to the nanocrystal formulation (P < .001). Moreover, compared to the nanocrystal formulation the amorphous solid dispersion formulation caused a more pronounced increase in high-density lipoprotein in the fasted state. Consuming breakfast increased the effect of DRL-17822 on high-density lipoprotein. Taken together, our results indicate that by improving its formulation, DRL-17822 has a favorable exposure profile and therefore a more predictable food effect profile.