One TEAE occurred when naldemedine was coadministered with rifampin (fatigue), which was not considered to be related to coadministration of naldemedine and rifampin
One TEAE occurred when naldemedine was coadministered with rifampin (fatigue), which was not considered to be related to coadministration of naldemedine and rifampin. Based on standard DDI study methodology, naldemedine was administered as a single dose because it was being evaluated as a substrate in these studies (either of CYP3A or the P-gp efflux transporter). (%)?White10 (71.4)005 (35.7)?Black/African American4 (28.6)008 (57.1)?Asian014 (100)14 (100)0?Multiple0001 (7.1)Ethnicity, (%)?Hispanic or Latino3 (21.4)NANA7 (50.0)?Not Hispanic or Latino11 (78.6)NANA7 (50.0)ALT, IU/L24.9 (15.3)15.2 (5.2)15.8 (8.1)21.2 (8.7)AST, IU/L21.6 (5.9)15.6 (3.1)17.2 (3.5)20.9 (3.7)Creatinine, mol/L85.2 (12.8)67.2 AZD-4635 (HTL1071) (13.3)68.1 (10.6)82.7 (11.8) Open in a separate window alanine aminotransferase, aspartate aminotransferase, body mass index, not applicable, standard deviation aValues are mean (SD) unless otherwise specified Pharmacokinetics and Safety Linear and semi-logarithmic plots show mean plasma concentrations of naldemedine over time when administered as a single oral dose with and without coadministration of cyclosporine (Fig.?1), itraconazole (Fig.?2), fluconazole (Fig.?3), and rifampin (Fig.?4). Table?2 shows the pharmacokinetic parameters of naldemedine alone and when coadministered with each other drug. Statistical comparisons of pharmacokinetic parameters are provided in Table?3. A forest plot illustrating the (1/h)(h)area under the concentration-time curve from 0 to infinity, area under the concentration-time curve from 0 to the last measurable concentration, apparent total clearance, maximum observed plasma concentration, cytochrome P450 3A, coefficient of variance, apparent elimination rate constant, P-glycoprotein, standard deviation, apparent terminal removal half-life, time to (h)???Naldemedine + itraconazole/Naldemedine2.1286 (1.9444, 2.3302)??CL/F (L/h)???Naldemedine + itraconazole/Naldemedine0.3431 (0.3109, 0.3785)?Cohort 2??Cmax (ng/mL)???Naldemedine + fluconazole/Naldemedine1.3831 (1.2316, 1.5532)??AUC0Clast (ngh/mL)???Naldemedine + fluconazole/Naldemedine1.8782 (1.7827, 1.9789)??AUC0Cinf (ngh/mL)???Naldemedine + fluconazole/Naldemedine1.8987 (1.8049, 1.9973)??area under the concentration-time curve from 0 to infinity, area under the concentration-time curve from 0 to the last measurable concentration, confidence interval, apparent total clearance, maximum observed plasma concentration, cytochrome P450 3A, coefficient of variance, P-glycoprotein, apparent terminal removal half-life Open in a separate windowpane Fig.?5 Forest plot of area under the concentration-time curve from 0 to infinity, confidence interval, maximum observed plasma concentration, least squares Effect of P-gp Inhibitor Coadministration on Naldemedine Pharmacokinetics and Safety The coadministration of cyclosporine increased naldemedine em C /em max by 1.45-fold, AUC0Clast by 1.79-fold, and AUC0Cinf by 1.78-fold, compared with administration of naldemedine alone (Table?3). Median naldemedine em T /em maximum was not notably affected by coadministration of cyclosporine (Table?2). The semi-logarithmic naldemedine plasma concentration-time profiles after em C /em maximum was reached have related slopes for both treatments (Fig.?1), suggesting the observed changes in em C /em maximum and AUC are mainly due to increased dental bioavailability of naldemedine when coadministered with cyclosporine. In this study, 7 (50.0 %) of 14 subjects experienced 20 TEAEs; 19 of these TEAEs were regarded as drug related. Most observed TEAEs occurred in subjects who received Rabbit Polyclonal to ACAD10 naldemedine 0.4 mg plus cyclosporine 600 mg (7 [53.8%] in 13) compared with naldemedine alone 1 (7.7%) of 13. The only TEAE AZD-4635 (HTL1071) reported in subjects who received naldemedine only was headache (1 [7.7%] of 13). TEAEs reported in subjects who received naldemedine plus cyclosporine included diarrhea (6 [46.2%] of 13), abdominal pain (3 [23.1%] of 13), nausea (3 [23.1%] of 13), flushing (3 [23.1%] of 13), frequent bowel movements (1 [7.7%] of 13), chills (1 [7.7%] of 13), hunger (1 [7.7%] of 13), and dizziness (1 [7.7%] of 13). All TEAEs except food cravings were considered drug related. No SAEs or AEs led to withdrawal. In addition, there were no clinically significant findings from medical laboratory, vital sign, ECG, or physical exam measurements. Effect of CYP3A Inhibitor Coadministration on AZD-4635 (HTL1071) Naldemedine Pharmacokinetics and Security The coadministration of a single oral dose of 0.2 mg naldemedine on Day time 9 after administration of 200-mg doses of itraconazole BID on Day time 5 and QD on Day time 6 to Day time 11 resulted in higher-plasma naldemedine concentrations and a slower rate of elimination compared with a single oral dose of 0.2 mg naldemedine administered alone on Day time 1 (Fig.?2). The coadministration of itraconazole improved naldemedine em C /em maximum by 1.12-fold, AUC0Clast by 2.65-fold, and AUC0Cinf by 2.91-fold compared with values after administration of naldemedine alone (Table?3). Naldemedine median em T /em maximum was not notably affected by coadministration of itraconazole (Table?2). The coadministration of a single oral dose of 0.2 mg naldemedine on Day time 9 after administration of fluconazole 400 mg QD on Day AZD-4635 (HTL1071) time 5 and 200 mg QD on Day time 6 to Day time 11 resulted in higher plasma naldemedine concentrations and a slightly slower rate of elimination compared with a single oral dose of 0.2 mg naldemedine administered alone on Day time 1 (Fig.?3). The coadministration of fluconazole improved naldemedine em C /em maximum by1.38-fold, AUC0Clast by 1.88-fold, and AUC0Cinf by 1.90-fold compared with values after administration of naldemedine alone (Table?3). Naldemedine median em T /em maximum was not notably affected by coadministration of fluconazole.The naldemedine 0.2 mg dose was determined in both the CYP3A inhibitors study and the CYP3A inducer study because 0.2 mg is the recommended therapeutic dose for naldemedine [11, 12]. each cohort). Cyclosporine improved naldemedine AUC0Cinf 1.78-fold and (%)?Male14 (100)10 (71.4)10 (71.4)12 (85.7)?Woman04 (28.6)4 (28.6)2 (14.3)Age, years34.4 (7.1)27.7 (4.2)27.5 (4.4)40.6 (7.9)Excess weight, kg81.77 (11.16)61.49 (9.43)59.77 (6.57)79.77 (9.61)BMI, kg/m226.18 (2.34)22.07 (1.83)20.70 (1.42)26.75 (2.28)Race, (%)?White colored10 (71.4)005 (35.7)?Black/African American4 (28.6)008 (57.1)?Asian014 (100)14 (100)0?Multiple0001 (7.1)Ethnicity, (%)?Hispanic or Latino3 (21.4)NANA7 (50.0)?Not Hispanic or Latino11 (78.6)NANA7 (50.0)ALT, IU/L24.9 (15.3)15.2 (5.2)15.8 (8.1)21.2 (8.7)AST, IU/L21.6 (5.9)15.6 (3.1)17.2 (3.5)20.9 (3.7)Creatinine, mol/L85.2 (12.8)67.2 (13.3)68.1 (10.6)82.7 (11.8) Open in a separate windowpane alanine aminotransferase, aspartate aminotransferase, body mass index, not applicable, standard deviation aValues are mean (SD) unless otherwise specified Pharmacokinetics and Security Linear and semi-logarithmic plots display mean plasma concentrations of naldemedine over time when administered while a single dental dose with and without coadministration of cyclosporine (Fig.?1), itraconazole (Fig.?2), fluconazole (Fig.?3), and rifampin (Fig.?4). Table?2 shows the pharmacokinetic guidelines of naldemedine alone and when coadministered with each other drug. Statistical comparisons of pharmacokinetic guidelines are provided in Table?3. A forest storyline illustrating the (1/h)(h)area under the concentration-time curve from 0 to infinity, area under the concentration-time curve from 0 to the last measurable concentration, apparent total clearance, maximum observed plasma concentration, cytochrome P450 3A, coefficient of variance, apparent elimination rate constant, P-glycoprotein, standard deviation, apparent terminal removal half-life, time to (h)???Naldemedine + itraconazole/Naldemedine2.1286 (1.9444, 2.3302)??CL/F (L/h)???Naldemedine + itraconazole/Naldemedine0.3431 (0.3109, 0.3785)?Cohort 2??Cmax (ng/mL)???Naldemedine + fluconazole/Naldemedine1.3831 (1.2316, 1.5532)??AUC0Clast (ngh/mL)???Naldemedine + fluconazole/Naldemedine1.8782 (1.7827, 1.9789)??AUC0Cinf (ngh/mL)???Naldemedine + fluconazole/Naldemedine1.8987 (1.8049, 1.9973)??area under the concentration-time curve from 0 to infinity, area under the concentration-time curve from 0 to the last measurable concentration, confidence interval, apparent total clearance, maximum observed plasma concentration, cytochrome P450 3A, coefficient of variance, P-glycoprotein, apparent terminal removal half-life Open in a separate windowpane Fig.?5 Forest plot of area under the concentration-time curve from 0 to infinity, confidence interval, maximum observed plasma concentration, least squares Effect of P-gp Inhibitor Coadministration on Naldemedine Pharmacokinetics and Safety The coadministration of cyclosporine increased naldemedine em C /em max by 1.45-fold, AUC0Clast by 1.79-fold, and AUC0Cinf by 1.78-fold, compared with administration of naldemedine alone (Table?3). Median naldemedine em T /em maximum was not notably affected by coadministration of cyclosporine (Table?2). The semi-logarithmic naldemedine plasma concentration-time profiles after em C /em maximum was reached have related slopes for both treatments (Fig.?1), suggesting the observed changes in em C /em maximum and AUC are mainly due to AZD-4635 (HTL1071) increased dental bioavailability of naldemedine when coadministered with cyclosporine. With this study, 7 (50.0 %) of 14 subjects experienced 20 TEAEs; 19 of these TEAEs were regarded as drug related. Most observed TEAEs occurred in subjects who received naldemedine 0.4 mg plus cyclosporine 600 mg (7 [53.8%] in 13) compared with naldemedine alone 1 (7.7%) of 13. The only TEAE reported in subjects who received naldemedine only was headache (1 [7.7%] of 13). TEAEs reported in subjects who received naldemedine plus cyclosporine included diarrhea (6 [46.2%] of 13), abdominal pain (3 [23.1%] of 13), nausea (3 [23.1%] of 13), flushing (3 [23.1%] of 13), frequent bowel movements (1 [7.7%] of 13), chills (1 [7.7%] of 13), hunger (1 [7.7%] of 13), and dizziness (1 [7.7%] of 13). All TEAEs except food cravings were considered drug related. No SAEs or AEs led to withdrawal. In addition, there were no clinically significant findings from clinical laboratory, vital sign, ECG, or physical exam measurements. Effect of CYP3A Inhibitor Coadministration on Naldemedine Pharmacokinetics and Security The coadministration of a single oral dose of 0.2 mg naldemedine on Day time 9 after administration of 200-mg doses of itraconazole BID on Day time 5 and.