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 (K(m) 2.1 micromol/L) and was transported by organic anion-transporting peptide OATP2B1-expressing HEK293 cells with moderate affinity (K(m) 72 micromol/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 AUC(tau) and C(max,ss) of digoxin, atorvastatin, o-hydroxy-atorvastatin, and rho-hydroxy-atorvastatin, indicating no clinically significant interaction with P-glycoprotein or CYP3A4 substrates. Aliskiren AUC(tau) was 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.

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

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 AUC(tau) (ratio of geometric means 0.93 [90% CI, 0.88, 0.98]) or oxypurinol AUC(tau) (mean ratio 1.12 [90% CI, 1.08, 1.16]) and C(max) (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 C(max) (mean ratio 0.88 [90% CI, 0.78, 1.00]). Aliskiren co-administration had no effect on AUC(tau) or C(max) of celecoxib (mean ratios and 90% CI within range 0.80-1.25). Neither allopurinol nor celecoxib significantly altered aliskiren AUC(tau) or C(max) (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 AUC(tau) by 20% (mean ratio 1.20 [90% CI, 1.07, 1.34]) and C(max) 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.

Evaluation of pharmacokinetic interactions between vildagliptin and digoxin in healthy volunteers.

Vildagliptin is a novel antidiabetic agent that is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV, the enzyme responsible for degradation of the incretin hormones. This open-label, randomized, 3-period crossover study investigated the potential for pharmacokinetic interactions in 18 healthy subjects during coadministration of vildagliptin and digoxin. Subjects were randomized to receive each of 3 treatments: vildagliptin 100 mg qd, digoxin (0.5 mg, then 0.25 mg qd on days 2-7), and the combination vildagliptin/digoxin for 7 days. Coadministration of digoxin with vildagliptin had no effect on exposure to vildagliptin (geometric mean ratios [90% confidence interval]: AUC(0-24h), 0.99 [0.95-1.03]; C(max), 0.95 [0.85-1.06]) or to digoxin (AUC(0-24h), 1.02 [0.94-1.12]; C(max), 1.08 [0.97-1.20]). In addition, no changes in t(max), t((1/2)), and CL/F were observed for either drug. These results indicate that no dose adjustment is necessary when vildagliptin and digoxin are coadministered.

Pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in combination with irbesartan in renal impairment.

BACKGROUND: Aliskiren is an orally active direct renin inhibitor approved for the treatment of hypertension. This study assessed the effects of renal impairment on the pharmacokinetics and safety of aliskiren alone and in combination with the angiotensin receptor antagonist irbesartan. METHODS: This open-label study enrolled 17 males with mild, moderate or severe renal impairment (creatinine clearance [CL(CR)] 50-80, 30-49 and <30 mL/minute, respectively) and 17 healthy males matched for age and bodyweight. Subjects received oral aliskiren 300 mg once daily on days 1-7 and aliskiren coadministered with irbesartan 300 mg on days 8-14. Plasma aliskiren concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry at frequent intervals up to 24 hours after dosing on days 1, 7 and 14. RESULTS: Renal clearance of aliskiren averaged 1280 +/- 500 mL/hour (mean +/- SD) in healthy subjects and 559 +/- 220, 312 +/- 75 and 243 +/- 186 mL/hour in patients with mild, moderate and severe renal impairment, respectively. At steady state (day 7), the geometric mean ratios (renal impairment : matched healthy volunteers) ranged from 1.21 to 2.05 for the area under the plasma concentration-time curve (AUC) over the dosage interval tau (24h) [AUC(tau)]) and from 0.83 to 2.25 for the maximum observed plasma concentration of aliskiren at steady state. Changes in exposure did not correlate with CL(CR), consistent with an effect of renal impairment on non-renal drug disposition. The observed large intersubject variability in aliskiren pharmacokinetic parameters was unrelated to the degree of renal impairment. Accumulation of aliskiren at steady state (indicated by the AUC from 0 and 24 hours [AUC(24)] on day 7 vs day 1) was similar in healthy subjects (1.79 [95% CI 1.24, 2.60]) and those with renal impairment (range 1.39-1.99). Coadministration with irbesartan did not alter the pharmacokinetics of aliskiren. Aliskiren was well tolerated when administered alone or with irbesartan. CONCLUSIONS: Exposure to aliskiren is increased by renal impairment but does not correlate with the severity of renal impairment (CL(CR)). This is consistent with previous data indicating that renal clearance of aliskiren represents only a small fraction of total clearance. Initial dose adjustment of aliskiren is unlikely to be required in patients with renal impairment.

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 (>or=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, AUC(0-infinity) was 57% higher (ratio of geometric means 1.57, 90% confidence interval: 1.19, 2.06; P = .008) and C(max) was 28% higher (1.28, 90% confidence interval: 0.91, 1.79; P=.233). Other parameters, including t(max) 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 >or=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.

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 AUC(0-infinity) (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 AUC(0-infinity) 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.

Aliskiren, a novel orally effective renin inhibitor, exhibits similar pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects.

AIMS: Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study compared the pharmacokinetic and pharmacodynamic properties of aliskiren in Japanese and Caucasian subjects. METHODS: In this open-label, single-centre, parallel-group, single- and multiple-dose study, 19 Japanese and 19 Caucasian healthy young male subjects received a single 300-mg oral dose of aliskiren on day 1 and then aliskiren 300 mg once daily on days 4-10. Blood samples were collected for the measurement of plasma aliskiren concentration, plasma renin concentration (PRC) and plasma renin activity (PRA). RESULTS: Pharmacokinetic parameters were comparable in Japanese and Caucasian subjects following administration of a single dose of aliskiren {ratio of geometric means: C(max) 1.12 [90% confidence interval (CI) 0.88, 1.43]; AUC(0-72 h) 1.19 [90% CI 1.02, 1.39]} and at steady state [mean ratio: C(max) 1.30 (90% CI 1.00, 1.70); AUC(0-tau) 1.16 (90% CI 0.95, 1.41)]. There was no notable difference in the plasma half-life of aliskiren between Japanese and Caucasian groups (29.7 +/- 10.2 h and 32.0 +/- 6.6 h, respectively). At steady state, peak PRC level and AUC for the concentration-time plot were not significantly different between Japanese and Caucasian subjects (P = 0.64 and P = 0.80, respectively). A single oral dose of aliskiren significantly reduced PRA to a similar extent in Japanese and Caucasian subjects (by 87.5% and 85.7%, respectively, compared with baseline; P < 0.01). Aliskiren was well tolerated by both ethnic groups. CONCLUSIONS: The oral renin inhibitor aliskiren demonstrated similar pharmacokinetic and pharmacodynamic properties in Japanese and Caucasian subjects.

Everolimus therapeutic concentration range defined from a prospective trial with reduced-exposure cyclosporine in de novo kidney transplantation.

Prospective therapeutic drug monitoring of everolimus was performed in a 1-year multicenter trial in 237 de novo kidney transplant patients. Trough blood levels, rejection episodes, and safety parameters were evaluated to define an appropriate therapeutic concentration range for everolimus in this setting. Patients were randomized to everolimus starting doses of 0.75 mg bid (n = 112) or 1.5 mg bid (n = 125). Doses were then individualized based on everolimus trough blood levels (C0) in an attempt to maintain troughs > or = 3 ng/mL; no upper limit was specified. The regimen also contained corticosteroids and cyclosporine with an early dose reduction in months 2-3 posttransplant based on concentrations 2 hours postdose (C2). Cyclosporine C0 levels were also collected. Prospective therapeutic drug monitoring of everolimus C0 in patients starting at 0.75 mg bid led to dose adjustments in 52% of patients to an average long-term dose of 0.93 +/- 0.36 mg bid. This gave median (10th to 90th percentile) C0 levels of 5.3 (3.4-7.9) ng/mL. In patients starting at 1.5 mg bid, 55% had dose adjustments leading to an average long-term dose of 1.24 +/- 0.35 mg bid. This yielded C0 levels of 7.2 (4.4-11.6) ng/mL. Cyclosporine dosing began on average at 274 +/- 78 mg bid, was down-titrated in months 2-3 from 181 +/- 80 mg to 81 +/- 33 mg bid, and stabilized at 70 +/- 26 mg bid thereafter. This yielded median C2 levels of 1165 ng/mL in month 1, a down-titration with levels of 853 and 630 ng/mL in months 2 and 3, and a posttitration level of 472 ng/mL. The corresponding median cyclosporine C0 was 242 ng/mL initially and 70 ng/mL in the posttitration phase. In patients starting at 0.75 mg bid everolimus and an early down-titration of cyclosporine, everolimus C0 between 3 and 8 ng/mL was an effective and safe concentration range. Concentrations up to 12 ng/mL were tolerated over the first year posttransplant. This trial demonstrated that therapeutic monitoring of everolimus can be prospectively performed for dose individualization. Maintaining everolimus troughs in the range 3 to 8 ng/mL in the first posttransplant year with reduced-exposure cyclosporine is associated with good efficacy and safety profiles.