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.

The effect of nateglinide on the pharmacokinetics and pharmacodynamics of acenocoumarol.

OBJECTIVE: The potential for a drug interaction was investigated between nateglinide, an oral antidiabetic agent, and acenocoumarol, an oral anticoagulant, as these drugs are primarily metabolized via CYP2C9. METHODS: A two-period, randomized, double-blind, two-way crossover study design was employed to evaluate the effect of nateglinide on the pharmacokinetics and pharmacodynamics of acenocoumarol in 11 healthy male or female subjects. All subjects received either nateglinide 120 mg t.i.d. or placebo for 5 days in a crossover fashion and a single 10-mg dose of acenocoumarol on day 3. Plasma concentrations of R- and S-acenocoumarol and the anticoagulation parameters [prothrombin time (PT) and international normalized ratio of PT (PTINR)] were determined for 72 h following acenocoumarol administration. The pharmacokinetic and pharmacodynamic parameters of acenocoumarol were determined by noncompartmental analysis. RESULTS: The mean (coefficient of variation (CV%)) area under the concentration-time curve (AUC(0-t)) of R-acenocoumarol in the presence and absence of nateglinide was 4217 (23%) and 3831 (24%) ng.h/ml, respectively. The corresponding values for S-acenocoumarol were 397 (20%) and 382 (23%), respectively. The mean (CV%) C(max) of R-acenocoumarol in the presence and absence of nateglinide was 304 (16%) and 316 (16%), respectively and the corresponding values for S-acenocoumarol were 142 (36%) and 141 (34%), respectively. The 90% confidence intervals indicated that exposure parameters, AUC(0-t) and C(max), of both R- and S-acenocoumarol were within the acceptable limits of 0.8-1.25. The mean (CV%) of area under the concentration-time curve of PT (AUC(PT)) following acenocoumarol administration in the presence and absence of nateglinide was 1170 (10%) and 1136 (8%), respectively. The corresponding AUC(INR) values were 104 (13%) and 99 (10%), respectively. Nateglinide co-administration has no influence on the PT or PTINR of acenocoumarol (p > 0.05). CONCLUSION: Co-administration of nateglinide does not influence either the pharmacokinetics or the anticoagulant activity of R- and S-acenocoumarol in healthy subjects. This suggests that no dosage adjustments will be required when nateglinide and acenocoumarol are coadministered in clinical practice.

Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to beta-thalassemia.

ICL670 is an orally active representative of a new class of tridentate iron chelator developed for the treatment of blood transfusion-dependent iron overload in chronic anemias. In this randomized, double-blind study, patients with transfusion-dependent beta-thalassemia received single oral doses of ICL670 ranging from 2.5 to 80 mg/kg to investigate its safety, tolerability, and pharmacokinetics and to obtain preliminary information on pharmacodynamic effects. ICL670 was well tolerated, and no safety problems occurred up to 80 mg/kg. A plasma half-life of 11 to 19 hours was found for ICL670, supporting once-daily oral administration. AUC0-24 h and Cmax of ICL670 increased nearly proportionally with the dose. The urinary excretion of ICL670 and its iron complex was less than 0.1% of the dose, and this was in accordance with the expected predominant iron fecal excretion induced by ICL670 (based on preclinical experiments). Notwithstanding, a positive trend toward increased amounts of urinary excreted iron was observed when the AUC0-24 h of ICL670 and the iron complex exceeded specific threshold values at the 40- and 80-mg/kg dose levels.