Ching-Ming Yeh

Pharmacokinetics of the Oral Direct Renin Inhibitor Aliskiren in Combination With Digoxin, Atorvastatin, and Ketoconazole in Healthy Subjects: The Role of P-Glycoprotein in the Disposition of Aliskiren

This study investigated the potential pharmacokinetic interaction between the direct renin inhibitor aliskiren and modulators of P‐glycoprotein and cytochrome P450 3A4 (CYP3A4). Aliskiren stimulated in vitro P‐glycoprotein ATPase activity in recombinant baculovirus‐infected Sf9 cells with high affinity (Km 2.1 μmol/L) and was transported by organic anion‐transporting peptide OATP2B1‐expressing HEK293 cells with moderate affinity (Km 72 μmol/L). Three open‐label, multiple‐dose studies in healthy subjects investigated the pharmacokinetic interactions between aliskiren 300 mg and digoxin 0.25 mg (n = 22), atorvastatin 80 mg (n = 21), or ketoconazole 200 mg bid (n = 21). Coadministration with aliskiren resulted in changes of <30% in AUCτ and Cmax,ss of digoxin, atorvastatin, o‐hydroxy‐atorvastatin, and ρ‐hydroxy‐atorvastatin, indicating no clinically significant interaction with P‐glycoprotein or CYP3A4 substrates. Aliskiren AUCτwas significantly increased by coadministration with atorvastatin (by 47%, P < .001) or ketoconazole (by 76%, P < .001) through mechanisms most likely involving transporters such as P‐glycoprotein and organic anion‐transporting peptide and possibly through metabolic pathways such as CYP3A4 in the gut wall. These results indicate that aliskiren is a substrate for but not an inhibitor of P‐glycoprotein. On the basis of the small changes in exposure to digoxin and atorvastatin and the <2‐fold increase in exposure to aliskiren during coadministration with atorvastatin and ketoconazole, the authors conclude that the potential for clinically relevant drug interactions between aliskiren and these substrates and/or inhibitors of P‐glycoprotein/CPY3A4/OATP is low.

Pharmacokinetics, safety, and tolerability of the oral renin inhibitor aliskiren in patients with hepatic impairment

Aliskiren is the first in a new class of orally active, direct renin inhibitors for the treatment of hypertension. This open‐label, nonrandomized, single‐center, parallel‐group study compared the pharmacokinetics and safety of a single 300‐mg oral dose of aliskiren in patients with mild, moderate, or severe hepatic impairment to that in healthy subjects. When pooled across subgroups, there were no significant differences between patients with hepatic impairment and healthy subjects in aliskiren AUC0‐∞ (ratio of geometric means, 1.12; 90% confidence interval, 0.85, 1.48) or Cmax (mean ratio, 1.19; 90% confidence interval, 0.84, 1.68), and there was no correlation between severity of hepatic impairment and either AUC0‐∞ or Cmax. Aliskiren was well tolerated by healthy subjects and patients with hepatic impairment. In conclusion, hepatic impairment has no significant effect on the pharmacokinetics of aliskiren following single‐dose administration, and dosage adjustment is unlikely to be needed in patients with liver disease.

Pharmacokinetics, safety, and tolerability of the novel oral direct renin inhibitor aliskiren in elderly healthy subjects

This open‐label, multicenter study compared the pharmacokinetics and safety of the oral direct renin inhibitor aliskiren in 29 elderly (≤65 years) and 28 young (18–45 years) healthy subjects. Plasma drug concentrations were determined for up to 168 hours following a single 300‐mg oral dose of aliskiren. In elderly compared with young subjects, AUC0‐∞ was 57% higher (ratio of geometric means 1.57, 90% confidence interval: 1.19, 2.06; P = .008) and Cmax was 28% higher (1.28, 90% confidence interval: 0.91, 1.79; P = .233). Other parameters, including tmax and Vd/F, were similar between age groups. No differences in aliskiren exposure were observed between subjects ages 65 to 74 years (n = 16) and ≤75 years (n = 13). Aliskiren was well tolerated by all age groups, including the very elderly. In conclusion, aliskiren exposure is modestly increased in elderly subjects. Based on its wide therapeutic index and shallow dose response for blood pressure lowering, no initial dose adjustment should be needed for elderly patients.

A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with allopurinol, celecoxib and cimetidine in healthy subjects

ABSTRACT Objective: Aliskiren is the first in a new class of orally effective direct renin inhibitors approved for the treatment of hypertension. This multiple-dose study investigated the potential for pharmacokinetic interactions between aliskiren and three drugs, each predominantly eliminated by a different clearance/metabolic pathway: allopurinol (glomerular filtration), celecoxib (cytochrome P450 metabolism) and cimetidine (P-glycoprotein and organic anion/cation transporters). Research design and methods: Three open-label, multiple-dose studies in healthy subjects investigated possible pharmacokinetic interactions between aliskiren 300 mg od and allopurinol 300 mg od (n = 20), celecoxib 200 mg bid (n = 22), or cimetidine 800 mg od (n = 22). Subjects received aliskiren alone or co-administered with allopurinol, celecoxib or cimetidine. Allopurinol and celecoxib were also administered alone and in combination with aliskiren. Plasma drug concentrations were determined by LC/MS/MS. Results: Co-administration of aliskiren with allopurinol had no effect on allopurinol AUCτ (ratio of geometric means 0.93 [90 % CI, 0.88, 0.98]) or oxypurinol AUCτ (mean ratio 1.12 [90 % CI, 1.08, 1.16]) and Cmax (mean ratio 1.08 [90 % CI, 1.04, 1.13]), with 90 % CI within the bioequivalence range 0.80–1.25, and a minor effect on allopurinol Cmax (mean ratio 0.88 [90 % CI, 0.78, 1.00]). Aliskiren co-administration had no effect on AUCτ or Cmax of celecoxib (mean ratios and 90 % CI within range 0.80–1.25). Neither allopurinol nor celecoxib significantly altered aliskiren AUCτ or Cmax (geometric mean ratios 0.88–1.02 with 90 % CI including 1.00, but with some 90 % CI outside the 0.80–1.25 range due to high variability). Co-administration of aliskiren with cimetidine increased aliskiren AUCτ by 20 % (mean ratio 1.20 [90 % CI, 1.07, 1.34]) and Cmax by 25 % (mean ratio 1.25 [90 % CI, 0.98, 1.59]). Conclusions: In this multiple-dose study, aliskiren showed no clinically relevant pharmacokinetic interactions when co-administered with allopurinol, celecoxib or cimetidine in healthy subjects.

Aliskiren penetrates adipose and skeletal muscle tissue and reduces renin-angiotensin system activity in obese hypertensive patients

Objective: In animals, the direct renin inhibitor aliskiren showed extensive tissue binding in the kidney and long-lasting renal effects. Aliskiren provides prolonged blood pressure-lowering effects following treatment discontinuation in patients. Therefore, we investigated whether aliskiren attains tissue concentrations sufficient to inhibit local renin–angiotensin system (RAS) activity in patients. Methods: We included 10 hypertensive patients with abdominal adiposity in an open-label study. Following 1–2 weeks washout, patients received 2 weeks placebo, then 4 weeks aliskiren 300 mg once daily, followed by 4 weeks washout, and then 4 weeks amlodipine 5 mg once daily. Drug concentrations and RAS biomarkers were measured in interstitial fluid using microdialysis and in biopsies from abdominal subcutaneous adipose and skeletal muscle. Results: We detected aliskiren in all compartments. After 4 weeks of treatment, microdialysate aliskiren concentrations (ng/ml) were 2.4 ± 2.1 (adipose) and 7.1 ± 4.2 (skeletal muscle), similar to plasma concentrations (8.4 ± 4.4); tissue concentrations (ng/g) were 29.0 ± 16.7 (adipose) and 107.3 ± 68.6 (skeletal muscle). Eight weeks after discontinuation, aliskiren was measurable in tissue biopsies but not in plasma or in interstitial fluid. Pooled microdialysate samples from two sets of four patients suggested reduction in tissue angiotensin II with aliskiren but not with amlodipine. Conclusion: In obese hypertensive patients, aliskiren penetrates adipose and skeletal muscle tissue at levels that are apparently sufficient to reduce tissue RAS activity. Furthermore, tissue binding may contribute to aliskirens prolonged blood pressure-lowering effect following discontinuation.

Effects of Aliskiren, a Direct Renin Inhibitor, on Cardiac Repolarization and Conduction in Healthy Subjects

This multicenter, double‐blind study evaluated the effects of aliskiren, a direct renin inhibitor approved for hypertension, on cardiac repolarization and conduction. Healthy volunteers (n = 298) were randomized to aliskiren 300 mg, aliskiren 1200 mg, moxifloxacin 400 mg (positive control), or placebo once daily for 7 days. Digitized electrocardiograms were obtained at baseline and day 7 of treatment over 23 hours postdose. Placebo‐adjusted mean changes from baseline in QTcF (Fridericia corrected), QTcI (individualized correction), PR, and QRS intervals were compared at each time point (time‐matched analysis) and for values averaged across the dosing period (baseline‐averaged analysis). In time‐matched analysis, mean changes in QTcF with aliskiren were below predefined limits for QTc prolongation (mean increase <5 milliseconds; upper 90% confidence interval [CI] <1 0 milliseconds) except aliskiren 1200 mg at 23 hours (5.2 milliseconds; 90% CI 2.2, 8.1). With moxifloxacin, significant QTcF prolongation occurred at most time points, confirming the sensitivity of the assay. Baseline‐averaged analysis was consistent with time‐matched analysis. Instances of QTcF interval >450 milliseconds or a >30‐millisecond increase from baseline with aliskiren (≤1%) were similar or lower than placebo (≤4%). Results were similar for QTcI. Aliskiren had no effect on PR or QRS duration. In conclusion, aliskiren at the highest approved dose (300 mg) and a 4‐fold higher dose had no effect on cardiac repolarization or conduction in healthy volunteers.

A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with metformin, pioglitazone and fenofibrate in healthy subjects

ABSTRACT Objective: Hypertension and type 2 diabetes are common comorbidities, thus many patients receiving antihypertensive medication require concomitant therapy with hypoglycemic or lipid-lowering drugs. The aim of these three studies was to investigate the pharmacokinetics, safety and tolerability of aliskiren, a direct renin inhibitor for the treatment of hypertension, co-administered with the glucose-lowering agents metformin or pioglitazone or the lipid-lowering agent fenofibrate in healthy volunteers. Methods: In three open-label, multiple-dose studies, healthy volunteers (ages 18 to 45 years) received once-daily treatment with either metformin 1000 mg (n = 22), pioglitazone 45 mg (n = 30) or fenofibrate 200 mg (n = 21) and aliskiren 300 mg, administered alone or co-administered in a two-period study design. Blood samples were taken frequently on the last day of each treatment period to determine plasma drug concentrations. Results: Co-administration of aliskiren with metformin decreased aliskiren area under the plasma concentration–time curve during the dose interval (AUCτ) by 27% (geometric mean ratio [GMR] 0.73; 90% confidence interval [CI] 0.64, 0.84) and maximum observed plasma concentration (Cmax) by 29% (GMR 0.71; 90% CI 0.56, 0.89) but these changes were not considered clinically relevant. Co-administration of aliskiren with fenofibrate had no effect on aliskiren AUCτ (GMR 1.05; 90% CI 0.96, 1.16) or Cmax (GMR 1.05; 90% CI 0.80, 1.38); similarly, co-administration of aliskiren with pioglitazone had no effect on aliskiren AUCτ (GMR 1.05; 90% CI 0.98, 1.13) or Cmax (GMR 1.01; 90% CI 0.84, 1.20). All other AUCτ and Cmax GMRs for aliskiren, metformin, pioglitazone, ketopioglitazone, hydroxypioglitazone and fenofibrate were close to unity and the 90% CI were contained within the bioequivalence range of 0.80 to 1.25. Conclusion: Co-administration of aliskiren with metformin, pioglitazone or fenofibrate had no significant effect on the pharmacokinetics of these drugs in healthy volunteers. These findings indicate that aliskiren can be co-administered with metformin, pioglitazone or fenofibrate without the need for dose adjustment.

Influence of Body Weight and Gender on the Pharmacokinetics, Pharmacodynamics, and Antihypertensive Efficacy of Aliskiren

Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n = 392). A separate pooled analysis of 5 clinical studies in patients with hypertension (n = 2327) assessed the influence of gender and BMI on the effects of aliskiren on plasma renin activity and blood pressure. Area under the aliskiren plasma concentration‐time curve (AUCτ) was 22% lower and the peak aliskiren plasma concentration (Cmax) was 24% lower in men than women (P < .05). BMI was not significantly correlated with AUCτ (r = 0.005; P = .917); AUCτ was negatively correlated with body weight (r = −0.235; P < .0001) and LBW (r = −0.295; P < .0001). Results were similar for Cmax. Adjusting individual aliskiren AUCτ and Cmax values for overall mean body weight or LBW abolished gender differences. Based on r2 values, LBW variation accounted for 8.9% of aliskiren AUCτ variation. In patients with hypertension, gender and BMI did not significantly influence the effects of aliskiren on plasma renin activity or blood pressure. It was concluded that lower systemic exposure to aliskiren in men versus women relates to differences in body weight; neither gender nor body weight has clinically relevant effects on the pharmacokinetics or pharmacodynamics of aliskiren.

Lumiracoxib: Pharmacokinetic and Pharmacodynamic Profile When Coadministered with Fluconazole in Healthy Subjects

This two‐way crossover study evaluated the effect of fluconazole on the pharmacokinetics and selective COX‐2 inhibition of lumiracoxib. Thirteen healthy subjects were randomized to fluconazole (day 1: 400 mg; days 2–4: 200 mg) or no drug. On day 4, all subjects received a single dose of lumiracoxib (400 mg). Lumiracoxib pharmacokinetics were assessed during the following 48 hours. Thromboxane B2 (TxB2) inhibition was measured prior to lumiracoxib dosing and 2 hours afterwards. Fluconazole caused a small (18%) but not clinically relevant increase in lumiracoxib mean AUC0‐∞ but had no effect on lumiracoxib mean Cmax. The geometric mean ratio (lumiracoxib plus fluconazole/ lumiracoxib alone) for AUC0‐∞ was 1.19 (90% confidence interval [CI] = 1.12, 1.27) and for Cmax was 1.11 (90% CI = 0.98, 1.27). The decrease in TxB2 from predose was not significantly different for lumiracoxib (11.8%) or lumiracoxib plus fluconazole (7.1%); no correlation between lumiracoxib concentration and TxB2 decrease was seen. As fluconazole is a strong inhibitor of cytochrome P450 (CYP) 2C9, other CYP2C9 inhibitors are unlikely to affect lumiracoxib pharmacokinetics with clinical relevance, making dosage adjustment unnecessary.

Pharmacokinetic Interaction of the Direct Renin Inhibitor Aliskiren with Furosemide and Extended-Release Isosorbide-5-Mononitrate in Healthy Subjects

This study investigated the pharmacokinetics, safety, and tolerability of aliskiren administered alone or in combination with either the loop diuretic furosemide or an oral extended-release formulation of isosorbide-5-mononitrate (ISMN). In separate studies, 22 healthy subjects (ages 18-45 years) received either ISMN 40 mg or furosemide 20 mg once-daily for 3 days followed by a 3-day washout. Subjects then received aliskiren 300 mg once-daily for 7 days followed by combination therapy for 3 days. Pharmacokinetic assessments were taken at regular intervals over 24 h after dosing on the last day of each treatment period. At steady state, aliskiren AUC(tau) was decreased by 7% (geometric mean ratio [90% CI], 0.93 [0.84, 1.04]), and C(max) by 20% (0.80 [0.65, 0.97]) with furosemide coadministration compared with aliskiren administration alone. Aliskiren coadministration reduced furosemide AUC(tau) by 28% (0.72 [0.64, 0.81]) and C(max) by 49% (0.51 [0.39, 0.66]) compared with furosemide alone. Coadministration of aliskiren and ISMN was associated with only minor changes in the pharmacokinetic parameters of aliskiren (AUC(tau) 1.03 [0.90, 1.18]; C(max) 0.94 [0.69, 1.29]) and ISMN (AUC(tau) 0.88 [0.71, 1.10]; C(max) 0.94 [0.79, 1.13]). Headache and dizziness were the most common adverse events in both studies; dizziness and BP values below normal (SBP < 90 and/or DBP < 50 mmHg) were more frequent with aliskiren and ISMN coadministration than with either agent alone. Coadministration of aliskiren and ISMN had no clinically relevant effect on either aliskiren or ISMN pharmacokinetics. In conclusion, coadministration of aliskiren and furosemide reduced furosemide exposure and had a minor effect on aliskiren pharmacokinetics. The clinical significance of reduced systemic exposure to furosemide during coadministration of aliskiren is uncertain.