AUC Tau Research Articles

Biosimilarity of HX575 (human recombinant epoetin alfa) and epoetin beta after multiple subcutaneous administration

To compare the steady-state pharmacokinetics and pharmacodynamics following multiple subcutaneous administration of a new erythropoiesis stimulating agent (HX575, Binocrit, Sandoz GmbH, Holzkirchen, Germany) with that of epoetin beta (NeoRecormon, Roche Ltd., Welwyn Garden City, UK). An open, randomized, parallel group study was conducted in 80 healthy adult males. Subjects were randomized to multiple subcutaneous doses of 100 IU/kg body weight of HX575 or epoetin beta three-times-weekly for 4 weeks. Serum epoetin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) and pharmacokinetic parameters for the two treatments were compared. The time course and area under the effect curve ratios of hematological characteristics were used as surrogate parameters for efficacy evaluation. The pharmacokinetic profiles after multiple doses were similar for both treatments. HX575 was bioequivalent to epoetin beta with respect to the rate and extent of exposure of exogenous epoetin, as indicated by the ratios (90% confidence intervals) of AUC(tau) (96.1 (86.4 - 106.9)) and C(max,ss) (98.5 (85.2 - 113.9)). The hematological profiles of both treatments were similar as determined from the population mean curves and the AUEC(Hb) ratio (90% confidence interval] (99.2 (97.7 - 100.7)), the primary endpoint of this study. Study medication was well tolerated with no clinically relevant differences between safety profiles of the treatments. Anti-epoetin antibodies were not detected at any time. HX575 and epoetin beta were bioequivalent with respect to their steady-state pharmacokinetic profile and pharmacodynamic action. These results support the conclusion that HX575 and epoetin beta will be equally efficacious and may be interchangeable as therapy.

Effects of smoking on the pharmacokinetics and pharmacodynamics of a nicotine patch

The effect of smoking on the pharmacokinetics and pharmacodynamics of a nicotine transdermal delivery system, administered as a single dose or multiple doses, was examined in smokers (n=12) and nonsmokers (n=12). The study was a two-period, parallel trial. In the first period, a single dose of the Nicotinell TTS 20 patch was administered, followed by a 1-week washout period. Then, in the second period, multiple doses of the Nicotinell TTS 20 patch were administered over 4 days. Regarding the pharmacokinetics of nicotine, the AUC(36 h) and AUC(tau) of smokers were about 20% and 40% greater, respectively, than those of nonsmokers. Significant differences in heart rate were observed between smokers and nonsmokers at 10, 12, 16 and 24 h, and significant differences in systolic blood pressure were seen between smokers and nonsmokers at 12, 30 and 36 h in the single-dose study. With multiple doses, significant differences in systolic and diastolic blood pressures were detected between smokers and nonsmokers only at 72.5 and 82 h. Here, it is demonstrated for the first time that the pharmacokinetic and hemodynamic effects of a nicotine patch are significantly different between smokers and nonsmokers.

Pharmacokinetic Interaction of the Direct Renin Inhibitor Aliskiren with Furosemide and Extended‐Release Isosorbide‐5‐Mononitrate in Healthy Subjects

This study investigated the pharmacokinetics, safety, and tolerability of aliskiren administered alone or in combination with either the loop diuretic furosemide or an oral extended-release formulation of isosorbide-5-mononitrate (ISMN). In separate studies, 22 healthy subjects (ages 18-45 years) received either ISMN 40 mg or furosemide 20 mg once-daily for 3 days followed by a 3-day washout. Subjects then received aliskiren 300 mg once-daily for 7 days followed by combination therapy for 3 days. Pharmacokinetic assessments were taken at regular intervals over 24 h after dosing on the last day of each treatment period. At steady state, aliskiren AUC(tau) was decreased by 7% (geometric mean ratio [90% CI], 0.93 [0.84, 1.04]), and C(max) by 20% (0.80 [0.65, 0.97]) with furosemide coadministration compared with aliskiren administration alone. Aliskiren coadministration reduced furosemide AUC(tau) by 28% (0.72 [0.64, 0.81]) and C(max) by 49% (0.51 [0.39, 0.66]) compared with furosemide alone. Coadministration of aliskiren and ISMN was associated with only minor changes in the pharmacokinetic parameters of aliskiren (AUC(tau) 1.03 [0.90, 1.18]; C(max) 0.94 [0.69, 1.29]) and ISMN (AUC(tau) 0.88 [0.71, 1.10]; C(max) 0.94 [0.79, 1.13]). Headache and dizziness were the most common adverse events in both studies; dizziness and BP values below normal (SBP < 90 and/or DBP < 50 mmHg) were more frequent with aliskiren and ISMN coadministration than with either agent alone. Coadministration of aliskiren and ISMN had no clinically relevant effect on either aliskiren or ISMN pharmacokinetics. In conclusion, coadministration of aliskiren and furosemide reduced furosemide exposure and had a minor effect on aliskiren pharmacokinetics. The clinical significance of reduced systemic exposure to furosemide during coadministration of aliskiren is uncertain.

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 (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.

Pharmacokinetic Interaction Between Efavirenz and Carbamazepine After Multiple‐Dose Administration in Healthy Subjects

The effect of efavirenz on the pharmacokinetics of carbamazepine and vice versa was investigated in adult healthy subjects in a randomized, open-label, 2-period crossover, multiple-dose study. Subjects were randomized to receive either efavirenz 600 mg qd for 14 days or carbamazepine titrated to 400 mg qd for 21 days followed with both drugs for another 21 or 14 days. The pharmacokinetics was evaluated for efavirenz, carbamazepine, and the major metabolite of carbamazepine, carbamazepine-10,11-epoxide. Coadministration of carbamazepine with efavirenz significantly reduced the exposure of efavirenz (geometric mean ratios [90% confidence interval]: area of plasma concentration-time curve during the dosing interval of 24 hours [AUCtau], 0.64 [0.60-0.68]; maximum plasma concentration [C(max)], 0.79 [0.74, 0.85]) and carbamazepine (AUC(tau), 0.73 [0.67-0.80]; C(max), 0.80 [0.76, 0.85]) but had minimal impact on the exposure of carbamazepine-10,11-epoxide (AUC(tau), 0.99 [0.85-1.15]; C(max), 1.05 [0.91, 1.22]). In summary, a 2-way pharmacokinetic interaction between efavirenz and carbamazepine was demonstrated in this study.

Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co‐administered in healthy female subjects

* Voriconazole, a broad-spectrum antifungal drug, is a substrate and inhibitor of CYP2C19 and CYP3A4 isozymes. * Ethinyl oestradiol and norethindrone, components of the combination oral contraceptive drug Ortho-Novum 1/35, also are substrates of cytochrome P450 CYP2C19 and CYP3A4 isozymes. * Because co-administration of voriconazole and Ortho-Novum 1/35 could potentially result in pharmacokinetic interactions that increase systemic exposure of one or both drugs to unsafe levels, clinical studies are needed to define better the two-way pharmacokinetic interaction between these drugs. * Although co-administered voriconazole and oral contraceptive did result in increased systemic exposures of all three drugs relative to respective monotherapy, co-administered treatment was generally safe and well tolerated. * It is recommended, however, that patients receiving co-administered voriconazole and oral contraceptives be monitored for the development of adverse events commonly associated with these medications. To assess the two-way pharmacokinetic interaction between voriconazole and Ortho-Novum 1/35, an oral contraceptive containing norethindrone 1 mg and ethinyl oestradiol 35 microg. In this open-label, three-period, fixed-sequence study, 16 healthy females received voriconazole (400 mg q12 h, day 1; 200 mg q12 h, days 2-4) (period 1), oral contraceptive (q24 h, days 12-32) (period 2), and combination voriconazole (400 mg q12 h, day 57; 200 mg q12 h, days 58-60) and oral contraceptive (q24 h, days 40-60) (period 3). Voriconazole geometric mean AUC(tau) and C(max) increased 46% (12 682-18 495 ng h ml(-1); 90% confidence interval [CI] 32, 61) and 14% (2485-2840 ng ml(-1); 90% CI 3, 27), respectively, when co-administered with oral contraceptive vs. voriconazole alone. Ethinyl oestradiol geometric mean AUC(tau) and C(max) increased 61% (1031-1657 ng h ml(-1); 90% CI 50, 72) and 36% (119-161 ng ml(-1); 90% CI 28, 45), respectively, and norethindrone geometric mean AUC(tau) and C(max) increased 53% (116-177 ng h ml(-1); 90% CI 44, 64) and 15% (18-20 ng ml(-1); 90% CI 3, 28), respectively, during voriconazole co-administration vs. oral contraceptive alone. Neither ethinyl oestradiol nor norethindrone levels were reduced in subjects following voriconazole co-administration. Adverse events (AEs) were generally mild, occurring less in subjects receiving voriconazole alone (36 events) vs. oral contraceptive alone (88 events) or combination treatment (68 events); four subjects experienced a severe AE. Co-administration of voriconazole and oral contraceptive increased systemic exposures of all analytes relative to respective monotherapy. Although generally safe and well tolerated, it is recommended that patients receiving co-administered voriconazole and oral contraceptive be monitored for development of AEs commonly associated with these medications.

Significant Decrease in Nelfinavir Systemic Exposure After Omeprazole Coadministration in Healthy Subjects

To assess the effect of omeprazole on the multiple-dose (steady-state) pharmacokinetics and safety of nelfinavir, and to evaluate the safety and tolerability of nelfinavir when administered alone and with omeprazole. Open-label, two-period, single-fixed-sequence study. Clinical research unit of a large, teaching hospital. Twenty healthy volunteers (mean age 26 +/- 9 yrs, range 18-48 yrs). Intervention. Subjects received nelfinavir 1250 mg every 12 hours for 4 days (period 1). After a 7-day washout period, subjects were coadministered nelfinavir 1250 mg every 12 hours and omeprazole 40 mg every 24 hours for 4 days (period 2). The pharmacokinetics of nelfinavir and its active metabolite M8 were determined on day 4 of both periods. Plasma samples were assayed by a high-performance liquid chromatography-ultraviolet method for nelfinavir and M8 concentrations, and noncompartmental pharmacokinetic analysis was performed by using analytical software. In the presence of omeprazole, nelfinavir area under the concentration-time curve over the dosing interval (AUC(tau)), maximum observed plasma concentration (C(max)), and minimum observed plasma concentration (C(min)) were reduced by an average of 36%, 37%, and 39%, respectively, relative to administration of nelfinavir alone. The AUC(tau), C(max), and C(min) of M8 were reduced by an average of 92%, 89%, and 75%, respectively. The slopes of the terminal elimination phase of nelfinavir and M8 plasma concentration-time curves were similar between treatments. Nelfinavir was well tolerated when administered alone and when coadministered with omeprazole. The observed reduction in the systemic exposure to both nelfinavir and its active metabolite M8 after coadministration with omeprazole could result in loss of virologic control and potential emergence of drug resistance. Hence, omeprazole should not be coadministered to patients taking nelfinavir.

Effect of Coadministered Ketoconazole, a Strong Cytochrome P450 3A4 Enzyme Inhibitor, on the Pharmacokinetics of Ciclesonide and its Active Metabolite Desisobutyryl-Ciclesonide

Cytochrome P450 (CYP) 3A4 isoenzyme has been identified in vitro as the key enzyme to metabolize desisobutyryl-ciclesonide (des-CIC), the pharmacologically active metabolite of the inhaled corticosteroid ciclesonide. This pharmacokinetic drug-drug interaction study was conducted to confirm this major metabolic pathway in vivo by using the strong CYP3A4 inhibitor ketoconazole, and to assess the effect of ketoconazole on the pharmacokinetics of ciclesonide and des-CIC. Fourteen healthy adults participated in this open-label, nonrandomized, fixed sequence, two-period, repeated-dose pharmacokinetic study. During the first 7-day treatment period, the subjects orally inhaled ciclesonide 320 microg once daily. During the second 7-day treatment period, the subjects continued with the same dose of orally inhaled ciclesonide and concomitantly received oral ketoconazole 400 mg once daily. Pharmacokinetic profiles for ciclesonide and des-CIC were obtained on day 7 of each study period. For the parent compound, ciclesonide, no changes in the pharmacokinetic parameter estimates--the area under the serum concentration-time curve during the dosage interval (AUC(tau)), maximum serum concentration (C(max)) and time to reach the C(max)--were observed. In contrast, the AUC(tau) and C(max) of des-CIC increased approximately 3.5-fold and 2-fold under the influence of the CYP3A4 inhibitor ketoconazole. The CYP3A4 pathway is the major pathway for biotransformation of the active metabolite of ciclesonide in humans. While elimination of des-CIC was reduced by strong CYP3A4 inhibitor coadministration in vivo, activation of the parent compound ciclesonide to des-CIC was not affected. Dose adjustment is not necessary when ciclesonide needs to be coadministered with ketoconazole, because the potency of an inhaled corticosteroid is mediated by topical concentrations in the lung and because ciclesonide has a very low potential to produce systemic adverse effects.

Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil

The aim of this study was to systematically investigate the mutual pharmacokinetic interactions in healthy volunteers between sildenafil, a phosphodiesterase-5 inhibitor, and bosentan, a dual endothelin receptor antagonist, both approved for treating pulmonary arterial hypertension (PAH). A randomised, double-blind, placebo-controlled, parallel-group study with three treatment arms (sildenafil plus placebo, bosentan plus placebo and sildenafil plus bosentan) was conducted in 55 healthy male volunteers (51 completers). Study duration was 18 days per treatment group. Sildenafil was administered three times daily on Days 1-6 and 11-16 (20 mg initially, increased to 80 mg after 3 days), and bosentan (125 mg) was administered twice daily on Days 7-17. On Day 16, bosentan decreased the maximum plasma concentration of sildenafil (c)(max)) by 55.4% [90% confidence interval (CI) 40.3-66.6%] and the area under the plasma concentration versus time curve over a dosing interval (AUC(tau)) by 62.6% (90% CI 56.8-67.7%). Sildenafil increased bosentan C(max) by 42.0% (90% CI 15.4-74.8%) and (AUC(tau)) by 49.8% (90% CI 28.7-74.5%). Bosentan and sildenafil in combination were well tolerated, with no serious adverse events reported. All adverse events were of mild or moderate intensity. In healthy volunteers, there is a mutual pharmacokinetic interaction between bosentan and sildenafil that may influence the dosage of each drug in a combination treatment. The clinical implications of combination therapy with bosentan and sildenafil are as yet unknown, and further trials in patients with PAH are needed.

Modeling and simulation of intravenous levetiracetam pharmacokinetic profiles in children to evaluate dose adaptation rules

To develop a pharmacokinetic model for intravenous levetiracetam in children, based on adult intravenous data and pediatric oral data. Data from two adult Phase-I studies in which levetiracetam was given intravenously were utilized to develop the adult population pharmacokinetic two-compartment intravenous model. After model qualification, combination with an existing pediatric one-compartment oral population pharmacokinetic model enabled simulation of twice-daily intravenous infusions of levetiracetam in children. Median and 90% confidence intervals for C(trough), C(max) (end of infusion) and AUC(tau) were simulated for 2000 children and compared to the values observed in adults. The population pharmacokinetic two-compartment model successfully described intravenous levetiracetam pharmacokinetics in healthy adults. After combination with the oral pediatric population model, steady-state concentrations at the end of 15-, 30- and 60 min b.i.d. levetiracetam intravenous infusions in children were predicted to be 29-41, 17-24 and 6-13% higher than those observed after oral dosing of 30 mg/kg b.i.d. Concentrations returned to the range of oral exposures within 1h after the infusion peak. The combined model predicted that steady-state peak plasma concentrations and AUC(tau) in children receiving 30 mg/kg twice daily as 15 min intravenous infusions were within the range of predicted and observed C(max,ss) and AUC(tau )values of adults receiving 15 min intravenous infusions of 1500 mg levetiracetam. The simulations suggest that levetiracetam may be administered intravenously in children as 15 min infusions.

Open‐label steady‐state pharmacokinetic drug interaction study on co‐administered quetiapine fumarate and divalproex sodium in patients with schizophrenia, schizoaffective disorder, or bipolar disorder

To determine whether there is a pharmacokinetic drug interaction between quetiapine fumarate and divalproex sodium. The pharmacokinetics and short-term tolerability and safety of coadministered quetiapine and divalproex were examined in adults with schizophrenia/schizoaffective disorder (Cohort A) or bipolar disorder (Cohort B) in an open-label, parallel, 2-cohort drug-interaction study conducted at three centers in the United States. Cohort A was administered quetiapine (150 mg bid) prospectively for 13 days, with divalproex (500 mg bid) added on days 6-13. Cohort B was administered divalproex (500 mg bid) for 16 days, with quetiapine (150 mg bid) added on days 9-16. Quetiapine and valproic acid plasma concentration-time data over a 12-h steady-state dosing interval were used to determine C(max), T(max), C(min), area under the plasma concentration-time curve (AUC(tau)), and oral clearance (CL/F). In Cohort A (n = 18), addition of divalproex did increase the C(max) of quetiapine by 17% but did not change AUC(tau). In Cohort B (n = 15), addition of quetiapine decreased both total valproic acid C(max) and AUC(tau) by 11%. No differences were observed in adverse events (AEs) with either quetiapine or divalproex monotherapy or their combination. Combination therapy with quetiapine (150 mg bid) and divalproex (500 mg bid) resulted in small and statistically non-significant pharmacokinetic changes.

Multiple‐dose pharmacokinetics of peginterferon alfa‐2b in patients with renal insufficiency

To evaluate the safety, tolerability and multiple-dose pharmacokinetics of pegylated interferon (PEG-IFN) alfa-2b in patients with moderate or severe renal insufficiency and in those with normal renal function. In an open-label study, subjects with normal renal function (creatinine clearance >80 ml min(-1) per 1.73 m2) and patients with moderate (30-50 ml min(-1) per 1.73 m2) or severe (10-29 ml(-1) min(-1) per 1.73 m2) renal impairment received weekly injections of PEG-IFN alfa-2b (1.0 microg kg(-1)) for 4 weeks. Safety assessments were made before each injection and blood samples were taken up to 168 h after the final dose. Renal insufficiency increased PEG-IFN alfa-2b exposure. Area under the curve for 0-tau (dosing interval of 168 h), AUC(tau), was increased 30% and 120% in patients with moderate or severe renal insufficiency, respectively. Mean maximum serum concentration was almost doubled in patients with severe insufficiency [1305.8 pg ml(-1); 95% confidence interval (CI) 825, 1786] compared with subjects with normal renal function (731.4 pg ml(-1); 95% CI 407, 1056), whereas the apparent volume of distribution was reduced (0.80 l kg(-1)vs. 1.28 l kg(-1), respectively). Elimination half-life was extended in patients with moderate and severe renal insufficiency (65.6 h and 64.9 h, respectively) compared with subjects with normal renal function (51.5 h). Significant differences were observed in the AUC and C(max) values of patients with severe renal dysfunction, compared with those who had normal renal function (P < 0.05; Kruskal-Wallis test). PEG-IFN alfa-2b was well tolerated and adverse events were similar in both treatment groups. Exposure to PEG-IFN alfa-2b is increased in patients with renal insufficiency, suggesting that doses of the drug should be reduced by 50% in patients with severe renal insufficiency and by 25% in those with moderate insufficiency.

Steady‐State Pharmacokinetics of Emtricitabine and Tenofovir Disoproxil Fumarate Administered Alone and in Combination in Healthy Volunteers

The approved antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate, were considered good candidates for a fixed-dose combination product that could be administered as a single pill once daily (qd), thereby simplifying existing treatment regimens and promoting patient adherence. As both drugs are extensively renally eliminated, a randomized, 3-way crossover study was conducted in 19 healthy volunteers to formally evaluate the potential pharmacokinetic interaction when the drugs are administered alone and together (ie, 200 mg emtricitabine qd for 7 days, 300 mg tenofovir disoproxil fumarate qd for 7 days, and 200 mg emtricitabine plus 300 mg tenofovir disoproxil fumarate qd for 7 days) with no washout between treatments. Steady-state pharmacokinetic parameters (AUC(tau), C(max), and C(min)) of emtricitabine and tenofovir (as tenofovir disoproxil fumarate) in combination were essentially equivalent versus each drug alone, providing a pharmacokinetic rationale for combining these products in emtricitabine/tenofovir disoproxil fumarate fixed-dose tablets.

The Prokinetic Cinitapride Has No Clinically Relevant Pharmacokinetic Interaction and Effect on QT during Coadministration with Ketoconazole

The present clinical trial was designed to evaluate the possible pharmacokinetic and electrocardiographic interactions of the gastroenteric prokinetic drug cinitapride with ketoconazole. The safety and tolerability of the study treatments were also evaluated. After a placebo-controlled, double-blind, crossover design, 16 healthy male (n = 8) and female (n = 8) volunteers were randomized into four treatment groups of four subjects (two males and two females): cinitapride (CTP; 1 mg t.i.d.) + ketoconazole (KET; 200 mg b.i.d.), CTP + placebo (PL), PL+KET, and PL+PL. Treatments were given for 7 days with a washout period of 14 days between crossover treatments. Cinitapride is rapidly absorbed after oral administration and is metabolized by the cytochrome P450 CYP3A4 and CYP2C8 isozymes. At steady state, coadministration with ketoconazole, a potent CYP3A4 inhibitor, increased mean C(max,ss) and AUC(tau) by 1.63- and 1.98-fold, respectively. Measurement of mean QTc interval or baseline-corrected QTc intervals on day 7 showed small increases that were due to the effects of ketoconazole alone. Comparing CTP+KET versus PL+KET, the differences between mean increases in the QTc parameters were always less than 2 ms. Finally, no outlier increase of the QTc interval versus baseline >60 ms was identified after any treatment. The study showed that cinitapride, either given alone or after coadministration with ketoconazole 200 mg b.i.d., had no effect on cardiac repolarization as measured by changes in the heart rate-corrected QT interval on the surface electrocardiogram.

Selegiline Transdermal System: An Examination of the Potential for CYP450‐Dependent Pharmacokinetic Interactions With 3 Psychotropic Medications

Selegiline transdermal system (STS) is a recently approved monoamine oxidase inhibitor antidepressant. This article reports results from 3 studies examining the potential for cytochrome P450-dependent pharmacokinetic interactions between STS and 3 psychotropic medications that might be coadministered. Three open-label, randomized, Latin square, 3-sequence crossover design studies were conducted with healthy volunteers to determine the pharmacokinetic parameters of STS 6 mg/24 h and test drug (alprazolam, olanzapine, or risperidone) when administered alone and concomitantly. All pharmacokinetic parameters of interest were unaltered following selegiline or test drug monotherapy when compared to concomitant therapy. This was confirmed by least squares mean ratios and their 90% confidence intervals of log(e)-transformed C(max) and AUC(tau) values, using either standard bioequivalence criteria of 80% to 125% or study-defined 70% to 143% boundary criteria. These results demonstrate that STS 6 mg/24 h may provide an antidepressant option that is unlikely to result in CYP450-mediated pharmacokinetic drug-drug interactions.

Pharmacokinetics and variability of mycophenolic acid from enteric‐coated mycophenolate sodium compared with mycophenolate mofetil in de novo heart transplant recipients

Sequential pharmacokinetic assessments were performed at five centers within the context of a multicenter, single-blind, randomized clinical trial comparing the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) and mycophenolate mofetil (MMF, CellCept) in de novo heart transplant recipients. Patients were randomized to either EC-MPS 1080 mg bid or MMF 1500 mg bid, as part of a triple immunosuppressive therapy including cyclosporine microemulsion. Steady-state pharmacokinetic profiles of mycophenolic acid (MPA) and its inactive phenolic glucuronide (MPAG) were assessed at weeks 2, 12, and 52. Pharmacokinetic parameters were evaluated in 32 patients (17 on EC-MPS and 15 on MMF). Dose-normalized peak (C(max,ss)) and area under the curve (AUC(tau,ss)) of MPA and MPAG increased between week 2 and week 12 assessments for both treatments. Comparisons between EC-MPS and MMF showed no statistically significant differences in MPA and MPAG AUC(tau,ss), C(max,ss), and trough (C(min,ss)) values (p-values ranged from 0.225 to 0.990). Consistent with the delayed release characteristics of EC-MPS, C(max,ss) occurred approximately one hour later compared with MMF. Inter-subject coefficients of variation (%CV) for MPA pharmacokinetic parameters of both EC-MPS and MMF were high (37-72% for AUC(tau,ss) at weeks 2 and 12). Also within patients, the pharmacokinetics of MPA varied considerably. Specifically, intra-subject %CVs for MPA AUC(tau,ss), C(max,ss), and C(min,ss) were 28%, 63%, and 34% with EC-MPS and 54%, 139%, and 41% with MMF respectively. These results indicate that a dose of EC-MPS 1080 mg bid in combination with cyclosporine provides adequate systemic MPA exposure in de novo heart transplant patients, comparable with MMF 1500 mg bid. Overall, there is a large inter- and intra-subject variability in MPA pharmacokinetic parameters with both treatments.

Pharmacokinetics of the Oral Direct??Renin Inhibitor Aliskiren Alone and??in Combination with Irbesartan in??Renal Impairment

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. 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. 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. 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.

Pharmacokinetics and Tolerability of??Duloxetine following Oral Administration to Healthy Chinese Subjects

The objectives of the study were to characterise the pharmacokinetics and assess the tolerability of duloxetine in healthy Chinese subjects after single and multiple oral 60 mg dosing. This was a single-centre, double-blind, randomised, placebo-controlled, single-period study in healthy native Chinese subjects. A total of 32 subjects, 19 men (14 on duloxetine, 5 on placebo) and 13 women (10 on duloxetine, 3 on placebo) between the ages of 20 and 39 years, participated in the study. Duloxetine 60 mg (enteric-coated pellets in a capsule) was given orally once on day 1 and once daily on days 4 to 9. Sequential blood samples were collected over 72 hours after the dose on days 1 and 9, and a predose sample was obtained on days 7 and 8. Duloxetine concentrations in plasma were determined by a validated liquid chromatography-tandem mass spectrometry method. The tolerability evaluation included a physical examination, vital signs, adverse event monitoring and clinical laboratory evaluations. Duloxetine disposition on oral administration is characterised by a one-compartment pharmacokinetic model. Duloxetine is well absorbed, with a median time of maximum plasma concentration at 6 and 4 hours following single and multiple dosing, respectively. At steady state, the mean apparent oral clearance (CL(ss)/F), mean apparent volume of distribution (V(ss)/F) and mean terminal elimination half-life (t((1/2))) were 86.8 L/h, 1570L and 11 hours, respectively. CL/F and V(ss)/F on single dosing were not statistically significantly different (p > 0.05) compared with multiple dosing. The linearity index, calculated as the ratio of the area under the plasma concentration-time curve (AUC) during the dosing interval tau at steady state (AUC(tau)(,ss)) to the AUC from time zero to infinity after single dosing (AUC(infinity,single dose)) was 1.15 (coefficient of variation 35.7%). The accumulation in duloxetine exposure was estimated to be 50% on multiple dosing compared with single dosing, consistent with the t((1/2)) and dosing interval (24 hours). The pharmacokinetic parameters of duloxetine in Chinese subjects were not statistically significantly different from those reported previously in Caucasian and Japanese subjects. There were no clinically significant adverse events, abnormal safety laboratory data or vital sign changes reported. Duloxetine pharmacokinetics in healthy Chinese subjects given a 60 mg once-daily dosing regimen were well characterised and consistent with known duloxetine pharmacokinetics in healthy Caucasian and Japanese subjects. Both single dosing and multiple once-daily dosing of duloxetine 60 mg were well tolerated by healthy Chinese subjects in this study.

Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers

Aliskiren is a novel, orally active direct renin inhibitor that lowers blood pressure alone and in combination with existing antihypertensive agents. As aliskiren does not affect cytochrome P450 enzyme activities, is minimally metabolised, and is not extensively protein bound, the potential for drug interactions is predicted to be low. Four open-label studies investigated the pharmacokinetic interactions between aliskiren 300 mg and the antihypertensive drugs amlodipine 10 mg (n = 18), valsartan 320 mg (n = 18), hydrochlorothiazide 25 mg (HCTZ, n = 22) and ramipril 10 mg (n = 17) in healthy subjects. In each study, subjects received multiple once-daily doses of aliskiren and the test antihypertensive drug alone or in combination in two dosing periods separated by a drug-free washout period. Plasma concentrations of drugs were determined by liquid chromatography and mass spectrometry methods. At steady state, relatively small changes in exposure to aliskiren were observed when aliskiren was co-administered with amlodipine (AUC(tau) increased by 29%, p = 0.032), ramipril (C(max,ss) increased by 31%, p = 0.043), valsartan (AUC(tau) decreased by 26%, p = 0.002) and HCTZ (C(max,ss) decreased by 22%, p = 0.039). Co-administration with aliskiren resulted in small changes in exposure to ramipril (AUC(tau) increased by 22%, p = 0.002), valsartan (AUC(tau) decreased by 14%, p = 0.062) and HCTZ (AUC(tau) decreased by 10% and C(max,ss) by 26%, both p < 0.001). All other changes in pharmacokinetic parameters were also small, and not statistically significant. None of the observed pharmacokinetic changes was considered clinically relevant. Aliskiren inhibited plasma renin activity (PRA) and also prevented the reactive rise in PRA induced by valsartan. The most commonly reported adverse events were headache, dizziness and gastrointestinal symptoms (all mild in severity), which were similar in frequency during antihypertensive drug treatment alone and in combination with aliskiren except for an increase in dizziness during treatment with the combination of aliskiren and HCTZ. In conclusion, aliskiren shows no clinically relevant pharmacokinetic interactions and is generally well tolerated when administered in combination with amlodipine, valsartan, HCTZ or ramipril.

Study of the Pharmacokinetic Interaction Between Simvastatin and Prescription Omega‐3‐Acid Ethyl Esters

The coadministration of prescription omega-3-acid ethyl esters (P-OM3) with a statin may present a treatment option for patients with mixed hyperlipidemia. This open-label, randomized, 2-way crossover, drug-drug interaction study evaluated the impact of P-OM3 capsules on plasma simvastatin pharmacokinetics in 24 healthy volunteers. Under fasted conditions, 80 mg simvastatin was administered with or without 4 g P-OM3 for two 14-day periods. After 14 days of dosing to achieve steady state, no significant differences were found in either the extent (AUC(tau)) or rate (Cmax) of exposure to simvastatin or its major beta-hydroxy metabolite after coadministration of P-OM3 with simvastatin compared with administration of simvastatin alone. At steady state, the coadministration of P-OM3 capsules did not appear to affect the pharmacokinetics of simvastatin tablets. The combination of P-OM3 capsules and simvastatin appeared to be well tolerated.