Jacqueline McCrea

Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans.

The pharmacokinetics of the angiotensin II receptor antagonist losartan potassium and its active carboxylic acid metabolite EXP3174 were characterized in 18 healthy male subjects after administration of intravenous losartan, intravenous EXP3174, and oral losartan. In these subjects, the average plasma clearance of losartan was 610 ml/min, and the volume of distribution was 34 L. Renal clearance (70 ml/min) accounted for 12% of plasma clearance. Terminal half‐life was 2.1 hours. In contrast, the average plasma clearance of EXP3174 was 47 ml/min, and its volume of distribution was 10 L. Renal clearance was 26 ml/min, which accounted for 55% of plasma clearance; terminal half‐life was 6.3 hours. After oral administration of losartan, peak concentrations of losartan were reached in 1 hour. Peak concentrations of EXP3174 were reached in 312 hours. The area under the plasma concentration‐time curve of EXP3174 was about four times that of losartan. The oral bioavailability of losartan tablets was 33%. The low bioavailability was mainly attributable to first‐pass metabolism. After intravenous or oral administration of losartan the conversion of losartan to the metabolite EXP3174 was 14%.

Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone

Aprepitant is a neurokinin1 receptor antagonist that, in combination with a corticosteroid and a 5‐hydroxytryptamine3 receptor antagonist, has been shown to be very effective in the prevention of chemotherapy‐induced nausea and vomiting. At doses used for the management of chemotherapy‐induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids such as dexamethasone and methylprednisolone, which are substrates of cytochrome P4503A4. The effects of aprepitant on the these 2 corticosteroids were evaluated.

Effects of losartan on blood pressure, plasma renin activity, and angiotensin II in volunteers.

Losartan is an orally active, nonpeptide angiotensin II (Ang II) (site-1) receptor antagonist. We conducted a multiple-dose study in healthy male volunteers to investigate the tolerability, blood pressure effects, and changes in plasma renin activity (PRA) and plasma Ang II concentration associated with once-daily administration of 100 mg losartan for a week. Subjects were studied on a standardized sodium diet (24-hour urinary sodium excretion, 98 +/- 37 [SD] mEq per 24 hours on the placebo run-in day). Measurements of blood pressure, heart rate, PRA, Ang II, and aldosterone were taken during a placebo run-in day and after single and multiple (7 days) daily doses of losartan (100 mg, n = 10) or placebo (n = 4). Ang II was measured specifically by high performance liquid chromatography coupled with radioimmunoassay. In subjects given losartan, respective decreases (systolic/diastolic) from run-in in supine blood pressure 6 hours after dosing were (mean +/- SD), compared with the placebo run-in day, first dose: -8.8 +/- 9.6/-6.8 +/- 5.0, last dose: -11.6 +/- 8.9/-7.0 +/- 4.8 mm Hg (p < 0.05 for all changes). At this 6-hour time point, corresponding increases from run-in in PRA were from 1.2 +/- 0.6 to 12.0 +/- 6.3 (first dose) and 9.6 +/- 4.9 (last dose) ng angiotensin I per milliliter per hour and in Ang II were from 4.3 +/- 1.7 to 72.4 +/- 33.3 and 45.7 +/- 14.1 pg/mL. All changes in PRA and Ang II were statistically significant within the losartan-treated group, and the biochemical changes were significantly greater than those in the placebo-treated group. The increment in Ang II was less after the last dose than after the first (p < 0.05). The drug was well tolerated by all subjects. These data indicate that, under the conditions of this study, losartan administration (100 mg/day for eight doses over 9 days) results in treatment-related decreases in blood pressure and increases in PRA and Ang II octapeptide.

Effects of aprepitant on the pharmacokinetics of ondansetron and granisetron in healthy subjects

BACKGROUND The neurokinin-1-receptor antagonist aprepitant, when given in combination with a corticosteroid and a 5-hydroxytryptamine type 3 (5-HT(3))-receptor antagonist, has been shown to be effective for the prevention of acute and delated chemotherapy-induced nausea and vomiting (CINV). OBJECTIVE Two studies were conducted to determine whether concomitant administration of aprepitant altered the pharmacokinetic profiles of ondansetron and granisetron, two 5-HT(3)-receptor antagonists commonly used as antiemetic therapy for CINV. METHODS The 2 studies were randomized, open-label, crossover trials conducted in healthy subjects aged between 18 and 46 years. Study 1 involved the following 2 treatment regimens: aprepitant 375 mg PO, dexamethasone 20 mg PO, and ondansetron 32 mg IV on day 1, followed by aprepitant 250 mg PO and dexamethasone 8 mg PO on days 2 through 5; and dexamethasone 20 mg PO and ondansetron 32 mg IV on day 1, followed by dexamethasone 8 mg PO on days 2 through 5. Study 2 involved the following 2 treatment regimens: aprepitant 125 mg PO with granisetron 2 mg PO on day 1, followed by aprepitant 80 mg PO on days 2 and 3; and granisetron 2 mg PO on day 1 only. Individual plasma samples were used to estimate area under the plasma concentration-time curve from time zero to infinity (AUC(0- infinity )), peak plasma concentration, and apparent terminal elimination half-life (t(12)) of both ondansetron and granisetron. RESULTS Study 1 included 19 subjects (10 women, 9 men), and study 2 included 18 subjects (11 men, 7 women). Coadministration of aprepitant 375 mg produced a small but statistically significant increase in the AUC(0- infinity ) for intravenous ondansetron (from 1268.3 to 1456.5 ng.h/mL; P = 0.019), with no significant effect on peak concentration at the end of the infusion (360.8 ng/mL with aprepitant vs 408.4 ng/mL without) or t(12) (5.0 vs 4.5 hours, respectively). Coadministration of aprepitant 125 mg/80 mg did not alter the mean pharmacokinetic characteristics of oral granisetron (AUC(0- infinity ), 101.4 ng.h/mL with aprepitant vs 92.2 ng.h/mL without; maximum plasma concentration, 9.0 ng/mL with and without aprepitant; time to maximum plasma concentration, both 3.0 hours; t(12), 6.5 vs 6.9 hours, respectively). CONCLUSION Concomitant administration of aprepitant had no clinically significant effect on the mean pharmacokinetic characteristics of either ondansetron or granisetron in these healthy subjects.

Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe.

Aprepitant is a neurokinin1 receptor antagonist that enhances prevention of chemotherapy‐induced nausea and vomiting when added to conventional therapy with a corticosteroid and a 5‐hydroxytryptamine3 (5‐HT3) antagonist. Because aprepitant may be used with a variety of chemotherapeutic agents and ancillary support drugs, which may be substrates of cytochrome P450 (CYP) 3A4, assessment of the potential of this drug to inhibit CYP3A4 activity in vivo is important. The effect of aprepitant on in vivo CYP3A4 activity in humans with oral midazolam used as a sensitive probe of CYP3A4 activity was evaluated in this study.

Phenotypic and genotypic investigations of a healthy volunteer deficient in the conversion of losartan to its active metabolite E‐3174

Losartan is a potent angiotensin II–receptor antagonist with an active carboxylic acid metabolite, E-3174. This metabolite is a more potent angiotensin II antagonist than losartan and has a longer half-life. 1 In clinical pharmacokinetic studies, the extent of conversion of losartan to E-3174 after oral and intravenous administration was found to be 14.3% ± 3.9%. 1 However, minimal conversion of losartan to the active metabolite was observed in 4 subjects (<1% of individuals studied), suggesting a rare deficit in drug metabolism because more than 500 subjects in pharmacokinetic studies conducted (up to 1993) demonstrated adequate levels of E-3174 after the administration of losartan. 2,3

Single- and Multiple-Dose Pharmacokinetics of Etoricoxib, a Selective Inhibitor of Cyclooxygenase-2, in Man

The single‐ and multiple‐dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase‐2, were examined in two clinical studies. Single‐dose pharmacokinetics—including dose proportionality, absolute bioavailability of the highest dose‐strength (120‐mg) tablet, and the effect of a high‐fat meal on the bioavailability of that tablet—were investigated in a two‐part, open, balanced crossover study in two panels of healthy subjects (12 per panel). Steady‐state pharmacokinetics were investigated in an open‐label study in which 24 healthy subjects were administered 120‐mg single and multiple (once daily for 10 days) oral doses of etoricoxib tablets. The pharmacokinetics of etoricoxib were found to be consistent with linearity through doses at least twofold greater than the highest anticipated clinical dose of 120 mg. Etoricoxib administered as a tablet was rapidly and completely absorbed and available; the absolute bioavailability was estimated to be 100%. A high‐fat meal decreased the rate of absorption without affecting the extent of absorption of etoricoxib; therefore, etoricoxib can be dosed irrespective of food. Steady‐state pharmacokinetics of etoricoxib, achieved following 7 days of once‐daily dosing, were found to be reasonably predicted from single doses. The accumulation ratio averaged 2.1, and the corresponding accumulation t1/2 averaged 22 hours, supporting once‐daily dosing. Etoricoxib was generally well tolerated.

Concurrent Administration of the Erythromycin Breath Test (EBT) and Oral Midazolam as In Vivo Probes for CYP3A Activity

Given the prominent role of CYP3A in the metabolism of drugs, it is important to identify whether new chemical entities will affect this enzyme system and produce clinically relevant drug interactions. This study evaluated concomitant administration of intravenous [14C N‐methyl] erythromycin (3μCi) (erythromycin breath test; EBT) and 2 mg oral midazolam as probes of systemic and of systemic plus presystemic CYP3A activity, respectively Twelve males received the probes in a two‐period crossover fashion: one period included the probes on two occasions, 5 days apart; in the second period, 200 mg ketoconazole was given orally 2 hours prior to the probes. The within‐subject CV for EBT (%14CO2/h) and midazolam AUC0‐last was 4.9% and 16.9%, respectively. Ketoconazole reduced %14CO2/h by 43% and increased midazolam AUC0‐last by approximately fivefold. In a nonrandomized third period (N = 5), ketoconazole was given simultaneously with midazolam (no EBT); midazolam AUC0‐last was similar whether ketoconazole was given 2 hours prior to or simultaneously with the midazolam. The low midazolam dose was generally well tolerated; mild sedation was occasionally seen. Concurrent administration of the EBT and oral midazolam is a sensitive and reproducible tool to screen new chemical entities for potentially important CYP3A interactions.

Absence of a Pharmacokinetic Interaction between Losartan and Hydrochlorothiazide

To support the use of a combination of losartan, a highly specific and selective AT1 angiotensin II receptor antagonist, and hydrochlorothiazide for treatment of hypertension, a pharmacokinetic drug interaction study was conducted. In this open‐label, randomized, three‐period, crossover study, patients with mild to moderate hypertension received a 12.5‐mg tablet of hydrochlorothiazide, a 50‐mg losartan tablet, or a combination tablet of 12.5 mg of hydrochlorothiazide and 50 mg of losartan for 7 days. Twelve patients (age range, 35–55 years; mean age, 44 years) were allocated to treatment. Drug interactions were evaluated by comparing the 24‐hour area under the concentration‐time curve (AUC24) for losartan and its active metabolite, E‐3174, when losartan (50 mg) was given alone or in combination with 12.5 mg hydrochlorothiazide. The urinary recovery over the 24‐hour period of hydrochlorothiazide was compared for hydrochlorothiazide (12.5 mg) given alone or in combination with 50 mg losartan. A clinically significant interaction was defined as a treatment difference of more than 35%. There was no evidence of a clinically significant effect of hydrochlorothiazide on the pharmacokinetics of losartan or E‐3174, as the geometric mean AUC24 ratio (90% confidence interval [CI]) was 1.02 (0.95, 1.09) for losartan and 1.02 (0.96, 1.09) for E‐3174. Based on urinary recovery over a 24‐hour period of hydrochlorothiazide, losartan did not affect the pharmacokinetics of hydrochlorothiazide, as the geometric mean ratio of urinary hydrochlorothiazide recovery (90% CI) was 0.898 (0.79, 1.20). There was a minor (17%) decrease in the AUC24 of hydrochlorothiazide after administration of the combination tablet. Coadministration of hydrochlorothiazide and losartan was well tolerated.

Single- and Multiple-Dose Pharmacokinetics and Tolerability of Telcagepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, in Adults

Telcagepant is a novel, orally active, and selective calcitonin gene‐related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half‐life was approximately 6 hours. A greater than dose‐proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice‐daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.