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.

Aliskiren showed a similar pharmacokinetic profile in healthy volunteers and patients with type 2 diabetes, and administration of a single oral 300 mg dose of aliskiren was well tolerated by both patients and healthy volunteers. The pharmacodynamic effects of aliskiren were also similar in healthy volunteers and diabetic patients, with sustained inhibition of renin system activity observed for at least 24 hours after dosing.

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.

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OctreoTher^TM (⁹⁰Y-DOTA-D-Phe¹-Tyr³-octreotide, a.k.a. ⁹⁰Y-SMT 487) consists of a somatostatin peptide analogue (Tyr³-octreotide), coupled with a complexing moiety (DOTA), and labeled with a tightly bound beta-emitter (yttrium-90). By targeting somatostatin receptor-positive tumors (as imaged by OctreaScan^®) it may deliver a tumoricidal dose of radiation. Phase I clinical trials, conducted in patients with neuroendocrine tumors, established the safety and tolerability of the dose selected for further study and demonstrated the capacity of OctreoTher to deliver radiation doses to tumors that resulted in significant neuroendocrine tumor shrinkage. Novartis-sponsored phase II studies will soon begin to test the efficacy of OctreoTher in breast and small cell lung cancer. A fixed-dose regimen of 120 mCi/cycle × 3 cycles administered with concomitant amino acid infusion has been chosen for the study. Phase I data and published literature support that this fixed dose regimen will be safely tolerated.

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.

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: Cmax 1.12 [90% confidence interval (CI) 0.88, 1.43]; AUC0−72 h 1.19 [90% CI 1.02, 1.39]} and at steady state [mean ratio: Cmax 1.30 (90% CI 1.00, 1.70); AUC0–τ 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.

BackgroundEfforts to ease administration and enhance acceptability of the oral anti-malarial artemether-lumefantrine (A-L) crushed tablet to infants and children triggered the development of a novel dispersible tablet of A-L. During early development of this new formulation, two studies were performed in healthy subjects, one to evaluate the palatability of three flavours of A-L, and a second one to compare the bioavailability of active principles between the dispersible tablet and the tablet (administered crushed and intact).MethodsStudy 1 was performed in 48 healthy schoolchildren in Tanzania. Within 1 day, all subjects tasted a strawberry-, orange- and cherry-flavoured oral A-L suspension for 10 seconds (without swallowing) in a randomized, single-blind, crossover fashion. The palatability of each formulation was rated using a visual analogue scale (VAS). Study 2 was an open, randomized crossover trial in 48 healthy adults given single doses of A-L (80 mg artemether + 480 mg lumefantrine) with food. The objectives were to compare the bioavailability of artemether, dihydroartemisinin (DHA) and lumefantrine between the dispersible tablet and the tablet administered crushed (primary objective) and intact (secondary objective).ResultsStudy 1 showed no statistically significant difference in VAS scores between the three flavours but cherry had the highest score in several ratings (particularly for overall liking). Study 2 demonstrated that the dispersible and crushed tablets delivered bioequivalent artemether, DHA and lumefantrine systemic exposure (area under the curve [AUC]); mean ± SD AUC0-tlast were 208 ± 113 vs 195 ± 93 h.ng/ml for artemether, 206 ± 81 vs 199 ± 84 h.ng/ml for DHA and 262 ± 107 vs 291 ± 106 h.μg/ml for lumefantrine. Bioequivalence was also shown for peak plasma concentrations (Cmax) of DHA and lumefantrine. Compared with the intact tablet, the dispersible tablet resulted in bioequivalent lumefantrine exposure, but AUC and Cmax values of artemether and DHA were 20-35% lower.ConclusionsConsidering that cherry was the preferred flavour, and that the novel A-L dispersible tablet demonstrated similar pharmacokinetic performances to the tablet administered crushed, a cherry-flavoured A-L dispersible tablet formulation was selected for further development and testing in a large efficacy and safety study in African children with malaria.