Christine Reynolds

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.

Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment.

We assessed the influence of hepatic impairment on the pharmacokinetics of the immunosuppressant everolimus to provide dose recommendations for clinical use.

Pharmacokinetics of Lumiracoxib in plasma and synovial fluid

Backgroundumiracoxib is a new cyclo-oxygenase-2 (COX-2) selective inhibitor in development for the treatment of rheumatoid arthritis, osteoarthritis and acute pain.ObjectiveTo investigate the pharmacokinetics of lumiracoxib in plasma and knee joint synovial fluid from patients with rheumatoid arthritis.DesignOpen-label multiple-dose study evaluating the steady-state pharmacokinetics of lumiracoxib in plasma and synovial fluid after 7 days of treatment with lumiracoxib 400mg once daily.Patient populationMales and females aged 18–75 years with rheumatoid arthritis, having moderate to significant synovial fluid effusion of the knee.Outcome measuresFollowing a 7-day washout period for previous nonsteroidal anti-inflammatory drugs, 22 patients (17 female, 5 male) received lumiracoxib 400mg once daily for seven consecutive days. On day 7, following an overnight fast, a final dose of lumiracoxib was administered and serial blood and synovial fluid samples were collected for up to 28 hours. Lumiracoxib and its metabolites (4′-hydroxy-lumiracoxib and 5-carboxy-4′-hydroxy-lumiracoxib) were measured by validated high performance liquid chromatography-mass spectrometry methods. The steady-state pharmacokinetics of lumiracoxib were evaluated in plasma and synovial fluid by both a population pharmacokinetic model and noncompartmental analysis.ResultsLumiracoxib was rapidly absorbed (peak plasma concentration at 2 hours) and the terminal elimination half-life in plasma was short (6 hours). Lumiracoxib concentrations were initially higher in plasma than in synovial fluid; however, from 5 hours after administration until the end of the 28-hour assessment period, concentrations of lumiracoxib were higher in synovial fluid than in plasma. Peak drug concentration in synovial fluid occurred 3–4 hours later than the peak plasma concentration. The mean steady-state trough concentration of lumiracoxib in synovial fluid (454 μg/L) was approximately three times higher than the mean value in plasma (155 μg/L), and the area under the concentration-time curve from 12 to 24 hours after administration was 2.6-fold higher for synovial fluid than for plasma. Median lumiracoxib protein binding was similar in plasma and synovial fluid (range 97.9–98.3%). Concentrations of 4′-hydroxy-lumiracoxib, the active COX-2 selective metabolite, remained low in comparison with parent drug in both plasma and synovial fluid. The concentration of lumiracoxib in synovial fluid at 24 hours after administration would be expected to result in substantial inhibition of prostaglandin E2 formation.ConclusionThe 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.

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.

Early clinical development of artemether-lumefantrine dispersible tablet: palatability of three flavours and bioavailability in healthy 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.

Evaluation of a pharmacokinetic interaction between valsartan and simvastatin in healthy subjects

ABSTRACT Objective: The potential for a pharmacokinetic drug interaction between valsartan, an antihypertensive drug, and simvastatin, a lipid-lowering agent, was investigated in this study. This was an open-label, multiple-dose, randomized, three-period, cross over study in 18 healthy subjects. Each subject received one 160 mg valsartan tablet or one 40 mg simvastatin tablet or co-administration of valsartan (160 mg) and simvastatin (40 mg) tablets for 7 days, with a 7‑day inter-dose washout period. The steady-state pharmacokinetics of valsartan, simvastatin β‑hydroxy acid (active metabolite of simvastatin) and simvastatin (pro-drug) were determined on day 7 of each dosing period. Results: The results were interpreted based on the point estimates and the 90% confidence intervals.italic> These results indicated that the area under the curve of plasma concentration from 0 to 24 hours (AUC(0–24)) of valsartan, simvastatin β‑hydroxy acid and simvastatin was increased by 14%, 19%, and 23%, respectively, with the combination treatment. In addition, the maximum concentration (Cmax) of valsartan and simvastatin β‑hydroxy acid was increased by 10% and 22%, respectively, and the Cmax of simvastatin was decreased by 26% with the combination treatment. All treatments were safe and well tolerated. Conclusions: 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 Cmax of valsartan, simvastatin β‑hydroxy acid and simvastatin in the combination treatment are unlikely to be of clinical relevance.

Pharmacokinetics of vildagliptin in patients with varying degrees of renal impairment.

OBJECTIVE The kidney plays a key role in both the metabolism and excretion of vildagliptin. This study was designed to investigate the effects of varying degrees of renal impairment (RI) on the pharmacokinetics of vildagliptin. METHODS A total of 96 subjects were enrolled, and each subject received vildagliptin 50 mg dosed orally once daily for 14 days. Vildagliptin and metabolite concentrations in plasma and urine were measured on Days 1 and 14. RESULTS Compared to age-, gender-, BMI-matched subjects with normal renal function, the mean AUC of vildagliptin after 14 days in patients with mild, moderate, and severe RI increased by 40%, 71%, and 100%, respectively, and the Cmax of vildagliptin showed similar and minimal increases of 37%, 32% and 36%, respectively. CONCLUSIONS These pharmacokinetics results suggest that 50 mg once daily is an appropriate dose and recommended for patients with moderate and severe renal impairment.

Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects.

LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug‐drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co‐administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel‐ethinyl estradiol 150/30 μg single dose (n = 24) in three separate open‐label, single‐sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel‐ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co‐administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co‐administration of LCZ696 with levonorgestrel‐ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co‐administration of LCZ696 with omeprazole, metformin, or levonorgestrel‐ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions.

Metabolism and Pharmacokinetics of Indacaterol in Humans

The metabolism, pharmacokinetics, and excretion of [14C]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 tmax, Cmax, and AUC0-last values were 1.75 h, 0.47 ng/ml, and 1.81 ng · h/ml for indacaterol and 2.5 h, 1.4 ngEq/ml, and 27.2 ngEq · 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 AUC0–24h 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 drug-related compounds (54 and 17% of the dose, respectively). In urine, unmodified indacaterol accounted for ∼0.3% of the dose, with no single metabolite accounting for >1.3%.

Lack of Effect of Omeprazole or of an Aluminium Hydroxide/Magnesium Hydroxide Antacid on the Pharmacokinetics of Lumiracoxib

AbstractObjective: To evaluate the effects of multiple doses of omeprazole and of a single dose of an aluminium hydroxide/magnesium hydroxide (Al/Mg) antacid on the single-dose plasma pharmacokinetics of lumiracoxib. Study Design: Open-label, randomised, three-period, crossover study. Population Studied: Healthy subjects aged 18–65 years. Methods: Fourteen subjects who met eligibility criteria were each administered three treatments in random order: (A) lumiracoxib 400mg as a single oral dose; (B) oral omeprazole 20mg once daily for 4 consecutive days, then lumiracoxib 400mg as a single oral dose just prior to oral omeprazole 20mg on day 5; and (C) lumiracoxib 400mg as a single oral dose immediately prior to a 20mL dose of Al/Mg antacid (magnesium hydroxide 800mg and aluminium hydroxide 900mg). The interval between each lumiracoxib dose was 7 days. Analysis of variance was performed to determine whether lumiracoxib alone differed from lumiracoxib plus omeprazole or from lumiracoxib plus Al/Mg antacid for overall exposure (area under the concentration-time curve from zero to infinity [AUC∞]) and peak concentration (Cmax), with treatment sequence, subject, period and treatment as factors. Ratios of geometric means between lumiracoxib plus omeprazole and lumiracoxib plus Al/Mg antacid to lumiracoxib alone (reference) were calculated for AUC∞ and Cmax. If the mean ratios, with 90% CIs, fell within the interval 0.80–1.25, the treatments were considered equivalent. Results: Arithmetic mean plasma lumiracoxib concentration-time profiles were similar for all treatments, with a rapid rise in concentration after administration, reaching Cmax values (mean ± SD) of 9.24 ± 1.96, 8.81 ± 2.30, and 10.43 ± 3.24 mg/L within 2–3 hours for treatments A, B and C, respectively. AUC∞ was similar for the three treatments (36.75 ± 7.73, 34.88 ± 8.40 and 35.50 ± 5.72 mg • h/L). All ratios of geometric means with 90% CIs fell within the interval used for establishing bioequivalence, except for the Cmax comparison between lumiracoxib plus Al/Mg antacid and lumiracoxib alone, which was 1.11 (0.95, 1.31). Conclusion: Coadministration of lumiracoxib with omeprazole or with an Al/Mg antacid had no clinically significant effect on lumiracoxib single-dose plasma pharmacokinetics. Lumiracoxib can, therefore, be administered concurrently with either of these agents without need for lumiracoxib dosage alteration.