Marie-Noelle Bizot

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.

Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers.

Aliskiren is a novel, orally active direct renin inhibitor that lowers blood pressure alone and in combination with existing antihypertensive agents. As aliskiren does not affect cytochrome P450 enzyme activities, is minimally metabolised, and is not extensively protein bound, the potential for drug interactions is predicted to be low. Four open‐label studies investigated the pharmacokinetic interactions between aliskiren 300 mg and the antihypertensive drugs amlodipine 10 mg (n = 18), valsartan 320 mg (n = 18), hydrochlorothiazide 25 mg (HCTZ, n = 22) and ramipril 10 mg (n = 17) in healthy subjects. In each study, subjects received multiple once‐daily doses of aliskiren and the test antihypertensive drug alone or in combination in two dosing periods separated by a drug‐free washout period. Plasma concentrations of drugs were determined by liquid chromatography and mass spectrometry methods. At steady state, relatively small changes in exposure to aliskiren were observed when aliskiren was co‐administered with amlodipine (AUC increased by 29%, p = 0.032), ramipril (Cmax,ss increased by 31%, p = 0.043), valsartan (AUC decreased by 26%, p = 0.002) and HCTZ (Cmax,ss decreased by 22%, p = 0.039). Co‐administration with aliskiren resulted in small changes in exposure to ramipril (AUC increased by 22%, p = 0.002), valsartan (AUC decreased by 14%, p = 0.062) and HCTZ (AUC decreased by 10% and Cmax,ss by 26%, both p < 0.001). All other changes in pharmacokinetic parameters were also small, and not statistically significant. None of the observed pharmacokinetic changes was considered clinically relevant. Aliskiren inhibited plasma renin activity (PRA) and also prevented the reactive rise in PRA induced by valsartan. The most commonly reported adverse events were headache, dizziness and gastrointestinal symptoms (all mild in severity), which were similar in frequency during antihypertensive drug treatment alone and in combination with aliskiren except for an increase in dizziness during treatment with the combination of aliskiren and HCTZ. In conclusion, aliskiren shows no clinically relevant pharmacokinetic interactions and is generally well tolerated when administered in combination with amlodipine, valsartan, HCTZ or ramipril.

Pharmacokinetics of the Oral Direct Renin Inhibitor Aliskiren Alone and in Combination with Irbesartan in Renal Impairment

BackgroundAliskiren 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.MethodsThis open-label study enrolled 17 males with mild, moderate or severe renal impairment (creatinine clearance [CLCR] 50–80, 30–49 and <30 mL/minute, respectively) and 17 healthy males matched for age and bodyweight. Subjects received oral aliskiren 300mg once daily on days 1–7 and aliskiren coadministered with irbesartan 300mg 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.ResultsRenal 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 τ (24h) [AUCτ]) 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 CLCR, 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 [AUC24] 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.ConclusionsExposure to aliskiren is increased by renal impairment but does not correlate with the severity of renal impairment (CLCR). 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.

Blood Concentrations of Everolimus Are Markedly Increased by Ketoconazole

The authors sought to quantify the influence of the CYP3A and P‐glycoprotein inhibitor ketoconazole on the pharmacokinetics of everolimus in healthy subjects. This was a 2‐period, single‐sequence, crossover study in 12 healthy subjects. In period 1, subjects received the reference treatment of a single 2‐mg dose of everolimus. In period 2, they received the test treatment of ketoconazole 200 mg twice daily for a total of 8 days and a single dose of everolimus coadministered on the fourth day of ketoconazole therapy. The test/reference ratio and 90% confidence interval were derived for everolimus maximum concentration and area under the curve. During ketoconazole coadministration, everolimus maximum concentration increased 3.9‐fold (90% confidence interval, 3.4–4.6) from 15 ± 4 ng/mL to 59 ± 13 ng/mL. Everolimus area under the curve increased 15.0‐fold (90% confidence interval, 13.6–16.6) from 90 ± 23 ng•h/mL to 1324 ± 232 ng•h/mL. Everolimus half‐life was prolonged by 1.9‐fold from 30 ± 4 hours to 56 ± 5 hours. Everolimus did not appear to alter ketoconazole predose concentrations. Given the magnitude of this drug interaction, use of ketoconazole should be avoided if possible in everolimus‐treated 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 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.

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]: AUC0‐24h, 0.99 [0.95–1.03]; Cmax, 0.95 [0.85–1.06]) or to digoxin (AUC0‐24h, 1.02 [0.94–1.12]; Cmax, 1.08 [0.97–1.20]). In addition, no changes in tmax, t1/2, and CL/F were observed for either drug. These results indicate that no dose adjustment is necessary when vildagliptin and digoxin are coadministered.

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.

Effect of aliskiren, an oral direct renin inhibitor, on the pharmacokinetics and pharmacodynamics of a single dose of acenocoumarol in healthy volunteers

ABSTRACT Objective: Aliskiren is a direct renin inhibitor approved for the treatment of hypertension. This study investigated the effects of aliskiren on the pharmacokinetics and pharmacodynamics of a single dose of acenocoumarol in healthy volunteers. Methods: This two-sequence, two-period, randomized, double-blind crossover study recruited 18 healthy subjects (ages 18–45) to receive either aliskiren 300 mg or placebo once daily on days 1–10 of each treatment period and a single dose of acenocoumarol 10 mg on day 8. Treatment periods were separated by a 10-day washout. Blood samples were taken frequently for determination of steady-state plasma concentrations of aliskiren (LC-MS/MS) and of R (+)- and S (−)-acenocoumarol (HPLC-UV), prothrombin time (PT) and international normalized ratio (INR). Results: Co-administration with aliskiren had no effect on exposure to R (+)-acenocoumarol. Geometric mean ratios (GMR; aliskiren:placebo co-administration) for R (+)-acenocoumarol AUC0−t and Cmax were 1.08 and 1.04, respectively, with 90% CI within the range 0.80–1.25. Co-administration of aliskiren resulted in a 19% increase in S (−)-acenocoumarol AUC0−t (GMR 1.19; 90% CI 0.92, 1.54) and a 9% increase in Cmax (GMR 1.09; 90% CI 0.88, 1.34). The anticoagulant effect of acenocoumarol was not affected by co-administration of aliskiren. Geometric mean ratios were 1.01 for all pharmacodynamic parameters (AUCPT, PTmax, AUCINR and INRmax), with 90% CI within the range 0.97–1.05. Conclusion: Aliskiren has no clinically relevant effect on the pharmacokinetics or pharmacodynamic effects of a single dose of acenocoumarol in healthy volunteers, hence no dosage adjustment of acenocoumarol is likely to be required during co-administration with aliskiren.