Dan Howard

Clinical Pharmacokinetics and Pharmacodynamics of Aliskiren

Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. It acts at the point of activation of the renin-angiotensin-aldosterone system, or renin system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin-converting enzyme (ACE) and ACE-independent pathways. Aliskiren is a highly potent inhibitor of human renin in vitro (concentration of aliskiren that produces 50% inhibition of renin 0.6 nmol/L). Aliskiren is rapidly absorbed following oral administration, with maximum plasma concentrations reached within 1–3 hours. The absolute bioavailability of aliskiren is 2.6%. The binding of aliskiren to plasma proteins is moderate (47–51%) and is independent of the concentration. Once absorbed, aliskiren is eliminated through the hepatobiliary route as unchanged drug and, to a lesser extent, through oxidative metabolism by cytochrome P450 (CYP) 3A4. Unchanged aliskiren accounts for approximately 80% of the drug in the plasma following oral administration, indicating low exposure to metabolites. The two major oxidized metabolites of aliskiren account for less than 5% of the drug in the plasma at the time of the maximum concentration. Aliskiren excretion is almost completely via the biliary/faecal route; 0.6% of the dose is recovered in the urine. Steady-state plasma concentrations of aliskiren are reached after 7–8 days of once-daily dosing, and the accumulation factor for aliskiren is approximately 2. After reaching the peak, the aliskiren plasma concentration declines in a multiphasic fashion.No clinically relevant effects of gender or race on the pharmacokinetics of aliskiren are observed, and no adjustment of the initial aliskiren dose is required for elderly patients or for patients with renal or hepatic impairment. Aliskiren showed no clinically significant increases in exposure during coadministration with a wide range of potential concomitant medications, although increases in exposure were observed with P-glycoprotein inhibitors. Aliskiren does not inhibit or induce CYP isoenzyme or P-glycoprotein activity, although aliskiren is a substrate for P-glycoprotein, which contributes to its relatively low bioavailability.Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 mg and 300 mg. Phase II and III clinical studies involving over 12 000 patients with hypertension have demonstrated that aliskiren provides effective long-term blood pressure (BP) lowering with a good safety and tolerability profile at these doses. Aliskiren inhibits plasma renin activity (PRA) by up to 80% following both single and multiple oral-dose administration. Similar reductions in PRA are observed when aliskiren is administered in combination with agents that alone increase PRA, including diuretics (hydrochlorothiazide, furosemide [frusemide]), ACE inhibitors (ramipril) and angiotensin receptor blockers (valsartan), despite greater increases in the plasma renin concentration. Moreover, PRA inhibition and BP reductions persist for 2–4 weeks after stopping treatment, which is likely to be of benefit in patients with hypertension who occasionally miss a dose of medication.Preliminary data on the antiproteinuric effects of aliskiren in type 2 diabetes mellitus suggest that renoprotective effects beyond BP lowering may be possible. Further studies to evaluate the effects of aliskiren on cardiovascular outcomes and target organ protection are ongoing and will provide important new data on the role of direct renin inhibition in the management of hypertension and other cardiovascular disease.

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 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.

Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, Has No Pharmacokinetic Interactions With the Antihypertensive Agents Amlodipine, Valsartan, and Ramipril in Healthy Subjects

We conducted 3 open–label, multiple–dose, 3‐period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin‐converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration–time curve from time zero to 24 hours (AUC0–24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80–1.25). Valsartan AUC0–24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.

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.

Dose Proportionality and the Effect of Food on Vildagliptin, a Novel Dipeptidyl Peptidase IV Inhibitor, in Healthy Volunteers

Vildagliptin is a potent and selective dipeptidyl peptidase IV inhibitor in development for the treatment of type 2 diabetes that improves glycemic control by enhancing α‐ and β‐cell responsiveness to glucose. Two open‐label, single‐dose, randomized, crossover studies in healthy subjects (ages 18–45 years) investigated the dose proportionality of vildagliptin pharmacokinetics (n = 20) and the effect of food (n = 24) on vildagliptin pharmacokinetics. There was a linear relationship (r2 = 0.999) between vildagliptin doses of 25, 50, 100, and 200 mg and area under the plasma concentration‐time curve from time zero to infinity (AUC0–∞) and maximum plasma concentration (Cmax). Dose proportionality was assessed using a statistical power model [X = α·(dose)β]. The 90% confidence intervals of the proportionality coefficient, β, for AUC0–∞ (1.15–1.19) and Cmax (1.04–1.14) indicated that deviations from dose proportionality were small (<7.7%). Doubling of dose led to 2.1‐ to 2.3‐fold increases in AUC0–∞ and Cmax but no dose‐dependent changes in time to reach Cmax or terminal elimination half‐life. Administration of vildagliptin 100 mg following a high‐fat meal decreased Cmax by 19% and AUC0–∞ by 10%. Vildagliptin displays approximately dose‐proportional pharmacokinetics over the 25‐ to 200‐mg dose range, and administration with food has no clinically relevant effect on vildagliptin pharmacokinetics.

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.

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.

Pharmacokinetic and pharmacodynamic properties of canakinumab in patients with gouty arthritis

Pharmacokinetics and pharmacodynamics of the anti‐interleukin (IL)‐1β monoclonal antibody, canakinumab, in gouty arthritis patients from three studies are reported. Canakinumab has low serum clearance (0.214 L/day), low steady‐state volume of distribution (7.44 L), a 25.8‐day half‐life, and approximately 60% subcutaneous absolute bioavailability in a typical 93‐kg patient. Creatinine clearance had a small positive impact on serum canakinumab clearance that is not likely to be clinically relevant. Binding to circulating IL‐1β was demonstrated by increases in total serum IL‐1β following canakinumab dosing. Total IL‐1β kinetics and canakinumab pharmacokinetics were characterized by a population‐based pharmacokinetic‐binding model, where the estimated apparent in vivo dissociation constant (signifying binding affinity of canakinumab to circulating IL‐1β) was 0.99 nmol/L in gouty arthritis patients. Canakinumab treatment provided rapid, sustained decreases in C‐reactive protein and serum amyloid A, provided superior pain relief to triamcinolone acetonide, and increased time to first recurrent attack (P ≤ 0.01 favoring all canakinumab doses vs. triamcinolone acetonide).