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.
The kinetics of distribution of lumiracoxib in synovial fluid are likely to extend the therapeutic action of the drug beyond that expected from plasma pharmacokinetics. These data support the use of lumiracoxib in a once-daily regimen for the treatment of rheumatoid arthritis.
The dose of everolimus should initially be reduced by half in patients with mild and moderate hepatic impairment on the basis of the Child-Pugh classification. Therapeutic monitoring would be a helpful adjunct to subsequent titration of everolimus exposure in this subpopulation. Everolimus has not been assessed in patients with severe hepatic impairment.
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.
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.
ABSTRACT:The metabolism, pharmacokinetics, and excretion of [ 14 C]indacaterol were investigated in healthy male subjects. Although indacaterol is administered to patients via inhalation, the dose in this study was administered orally. This was done to avoid the complications and concerns associated with the administration of a radiolabeled compound via the inhalation route. The submilligram doses administered in this study made metabolite identification and structural elucidation by mass spectrometry especially challenging. In serum, the mean t max , C max , and AUC 0-last values were 1.75 h, 0.47 ng/ml, and 1.81 ng ⅐ h/ml for indacaterol and 2.5 h, 1.4 ngEq/ml, and 27.2 ngEq ⅐ h/ml for total radioactivity. Unmodified indacaterol was the most abundant drug-related compound in the serum, contributing 30% to the total radioactivity in the AUC 0-24h pools, whereas monohydroxylated indacaterol (P26.9), the glucuronide conjugate of P26.9 (P19), and the 8-O-glucuronide conjugate of indacaterol (P37) were the most abundant metabolites, with each contributing 4 to 13%. In addition, the N-glucuronide (2-amino) conjugate (P37.7) and two metabolites (P38.2 and P39) that resulted from the cleavage about the aminoethanol group linking the hydroxyquinolinone and diethylindane moieties had a combined contribution of 12.5%. For all four subjects in the study, >90% of the radioactivity dose was recovered in the excreta (85% in feces and 10% in urine, mean values). In feces, unmodified indacaterol and metabolite P26.9 were the most abundant drugrelated compounds (54 and 17% of the dose, respectively). In urine, unmodified indacaterol accounted for ϳ0.3% of the dose, with no single metabolite accounting for >1.3%.
Based on the wide therapeutic dosage ranges of valsartan and simvastatin, and the highly variable pharmacokinetics of three analytes, the observed differences in the exposure and C(max) of valsartan, simvastatin beta-hydroxy acid and simvastatin in the combination treatment are unlikely to be of clinical relevance.
Aim:To determine the pharmacokinetic (PK) and pharmacodynamic (PD) comparability of a novel solution for injection (solution) and the reference lyophilized powder formulation (powder) of omalizumab. Methods:In this open-label, parallel-group study, adult atopic subjects (serum immunoglobulin [Ig] E 30−300 IU/ ml; body weight, 40−90 kg) received a single subcutaneous dose (150 or 300 mg) of solution or powder omalizumab. Serum concentrations of total omalizumab, free and total IgE and safety were determined up to 84 days post dose. Bioequivalence was examined for dose-normalized parameters of omalizumab in serum: maximum concentration (C max ), area under the concentration-time curve up to the last quantifiable concentration (AUC 0-tlast ) and up to infinity (AUC 0-inf ). Bioequivalence was concluded if the 90% confidence interval (CI) of the ratio of solution vs. powder geometric means was entirely contained within 0.8-1.25.Results: 155 subjects were randomized and dosed (62.6% female; mean age, 34.7 years). Systemic exposure to omalizumab was similar for the two formulations at both doses. PK bioequivalence was demonstrated (n = 153): C max , ratio of geometric means: 1.01 (90% CI: 0.95-1.08); AUC 0-tlast , 0.98 (0.92-1.05); AUC 0-inf , 0.98 (0.91-1.05). Omalizumab mean elimination half-life: 22.1 days for solution; 22.9 days for powder. PD parameters (n = 154) of free and total IgE in serum were comparable between formulations; each produced a 95% reduction from screening in free IgE. Most common adverse events (AEs): headache (23.9%), sinus congestion (8.4%). No serious AEs were reported. Conculsions:The novel, ready-to-use omalizumab solution formulation is bioequivalent to the reference lyophilized powder formulation.
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