Ramanuj Achari

Lack of a Clinically Significant Pharmacokinetic Interaction between Fenofibrate and Pravastatin in Healthy Volunteers

This study was conducted to evaluate the potential pharmacokinetic interaction between fenofibrate and pravastatin. A total of 23 healthy adult volunteers received single‐dose 201 mg fenofibrate alone, 201 mg fenofibrate + 40 mg pravastatin, and 40 mg pravastatin alone in a three‐period crossover experiment. Plasma samples were collected at predetermined times and were analyzed with validated methods for the quantitation of fenofibric acid, pravastatin, and 3α‐hydroxy‐iso‐pravastatin (3α‐iso‐PV). Pharmacokinetic parameters of these three compounds were calculated using noncompartmental methods and compared by analyses of variance and bioavailability assessments. Concomitant administration of fenofibrate and pravastatin did not affect the pharmacokinetics of either fenofibric acid or pravastatin. However, the AUC0‐∞ and Cmax of 3α‐iso‐PV were increased by 26% and 29%, respectively. The moderate increase in the formation of this pravastatin metabolite should not raise any clinical concerns due to its much lower pharmacological potency compared to pravastatin and lack of toxicity.

The Effects of Multiple Doses of Fenofibrate on the Pharmacokinetics of Pravastatin and Its 3α‐Hydroxy Isomeric Metabolite

Published data indicate that coadministration of multiple doses of the fibrate drug, gemfibrozil, led to a 202% increase in pravastatin systemic exposure (area under the plasma concentration‐time curve, AUC). To evaluate the effects of another fibrate drug, fenofibrate, on the pharmacokinetics of pravastatin, 24 healthy subjects took pravastatin (40 mg once daily) on study days 1 to 15 and fenofibrate (160 mg once daily) on study days 6 to 15. Blood samples were collected for 24 hours after dosing on days 5, 6, and 15. Plasma concentrations of pravastatin and its active metabolite, 3α‐hydroxy‐iso‐pravastatin, were measured, and pharmacokinetics was assessed. Safety assessments were based on adverse events, physical examinations, electrocardiogram results, vital signs, and clinical laboratory testing. Safety results were unremarkable. Coadministration of fenofibrate had modest effects on pravastatin and 3α‐hydroxy‐iso‐pravastatin systemic exposures (AUC). Increases in pravastatin systemic exposures (19%‐28%, on average) and 3α‐hydroxy‐iso‐pravastatin systemic exposures (24%‐39%, on average) were observed upon coadministration, but individual changes were variable. Pravastatin and 3α‐hydroxy‐iso‐pravastatin systemic exposures were not statistically significantly different following the 1st and 10th doses of fenofibrate.

Dual Effects of Rifampin on the Pharmacokinetics of Atrasentan

The effect of rifampin, a cytochrome P450 3A4 inducer, on the pharmacokinetics of atrasentan was assessed in 12 healthy male subjects in an open‐label study. Single doses of atrasentan 10 mg were administered orally on days 1 and 12. Rifampin 600 mg was given once daily from days 4 through 14. On day 12, atrasentan and rifampin were administered simultaneously. Blood samples were collected before and during 72 hours after each atrasentan dose. On average, rifampin increased atrasentan peak plasma concentrations by 150% and reduced its terminal half‐life by 77% (P < .05), without affecting the AUC or peak time of atrasentan. Rifampin may affect atrasentan pharmacokinetics by acting as both an inhibitor of organic anion transporting polypeptide‐mediated hepatic uptake of atrasentan and an inducer of atrasentan metabolism. The effect of rifampin on atrasentan pharmacokinetics may depend on the time of rifampin administration relative to that of atrasentan.

Pharmacokinetics of Esmolol in Hepatic Disease

Esmolol is an intravenous beta blocker with a short duration of action. The pharmacokinetics of esmolol and its acid metabolite, ASL‐8123, were studied in nine patients who had stable, biopsy‐proved Laennecs cirrhosis and in three normal volunteer controls. Kinetics were determined after a four‐hour continuous infusion of esmolol at a rate of 200 μg/kg/min. Blood samples were collected during the infusions and at frequent intervals thereafter. The parameters studied were the steady state concentration, the total body clearance, the elimination half‐life, the area under the curve, and the volume of distribution. No significant differences in any of these parameters were detected between control subjects and those with hepatic disease, for either esmolol or its acid metabolite. It is concluded from this study that Laennecs cirrhosis does not cause any change in the pharmacokinetics of esmolol or its major metabolite. Therefore, adjustments in dosage of esmolol are not required for patients with Laennecs cirrhosis.

Metabolism and Urinary Excretion of Esmolol in Humans

The urinary excretion patterns of esmolol, a short‐acting beta blocker, and its major metabolite were investigated in eight healthy men after intravenous infusion of 50, 100, 200, and 300 μg/kg/min of esmolol for six hours and 150 μg/kg/min for 24 hours. Esmolol and the metabolite concentrations in urine were determined by high‐performance liquid chromatography. The mean urinary recoveries of the unchanged drug were 0.64%, 0.67%, 0.69%, 0.77, and 0.98% after the 50, 100, 150, 200, and 300 μg/kg/min dose, respectively. Recovery of the metabolite was independent of dose, and the overall mean recovery accounted for 73% of administered dose. The results of this study indicate that esmolol is extensively metabolized, and the extent of the metabolism is not dose related in the dosage range used. The renal route plays a very minor role in the elimination of the drug but is important for the elimination of the metabolite.

Effect on bioavailability of admixing the contents of lansoprazole capsules with selected soft foods

OBJECTIVE This study was designed to compare the bioavailability of lansoprazole when administered as an intact capsule and when the contents are admixed with various soft foods. BACKGROUND Patients sometimes cannot swallow or have difficulty swallowing intact capsules such as lansoprazole. To enable them to ingest the drug, the contents of the capsule can be admixed with small amounts of soft foods. METHODS Twenty-four healthy adult volunteers participated in this single-dose, 4-period crossover study by ingesting the contents of a 30-mg lansoprazole capsule that had been emptied into either a tablespoon of yogurt (regimen A), Ensure pudding (regimen B), or cottage cheese (regimen C), or given as an intact capsule (regimen D) during the first study period. The regimen assignments were rotated at weekly intervals so that each subject received each regimen. Blood samples were obtained over the 12-hour period after administration of each regimen, and pharmacokinetic parameters were determined. RESULTS Of the 23 subjects who completed all 4 periods of the study, 18 were male and 5 were female. Their mean (+/- SD) age was 33.3+/-11.6 years, and their ages ranged from 19 to 52 years. No statistically significant differences between regimens were detected in mean maximum concentration, area under the curve (AUC) from time zero to the last measurable concentration, and AUC from time zero to infinity (AUC0-infinity) using analysis of variance. A statistically significant difference was detected in the time to maximum concentration between regimens C and D at 2.1 and 1.5 hours, respectively (P < or = 0.05). Bioavailability was assessed by the two 1-sided tests procedure using a 90% CI for the AUC0-infinity ratio of test-to-reference regimens. The 90% CIs were all within an acceptable equivalence range of 0.80 to 1.25. CONCLUSION These results indicate similar bioavailabilities between the regimen in which the lansoprazole capsule was emptied and administration of the intact capsule. However, they may have limitations in predicting the results in ill, elderly, or very young patients.

Pharmacokinetics and Safety of ABT-578, a Sirolimus (Rapamycin) Analogue, after Single Intravenous Bolus Injection in Healthy Male Volunteers

AbstractObjective: ABT-578, a tetrazole analogue of sirolimus (rapamycin), possesses anti-restenosis activity. The aim of this study was to assess the safety and pharmacokinetics of escalating single intravenous (IV) doses of ABT-578 in a phase 1, double-blind, randomised, placebo-controlled study. Methods: Sixty adult healthy males were divided into five IV-dose groups of 100, 300, 500, 700 and 900μg. Doses were administered as IV bolus over 3 minutes, with eight subjects and four subjects receiving ABT-578 and placebo, respectively, in each dose group. Higher doses were administered after evaluating safety from the preceding lower doses. Blood concentrations of ABT-578 were sampled for 168 hours and measured using LC-MS/MS with a limit of quantification of 0.20 ng/mL. Results: The pharmacokinetics of ABT-578 were essentially linear across the 100–900μg dose range as illustrated by the dose-proportional increases in concentration at 5 minutes (C5) after the end of infusion and area under the concentration-time curve (AUC). The mean half-life ranged between 26.0 and 40.2h over the studied doses and was not significantly different over the 300–900μg dose range. The mean clearance values ranged from 2.90 to 3.55 L/h. Single IV bolus doses up to 900μg of ABT-578 were well tolerated and no clinically significant changes in physical examination results, vital signs or laboratory test results were observed. Conclusion: It can be concluded that the pharmacokinetics of IV ABT-578 are dose-proportional over the 100-900μg dose range. Single IV bolus doses up to 900μg were well tolerated in healthy male subjects.

Bioavailability of lansoprazole granules administered in juice or soft food compared with the intact capsule formulation

BACKGROUND The ability to administer the contents of an encapsulated-dose formulation in liquids or soft foods without compromising drug bioavailability is highly desirable for patients who are unable to swallow or have difficulty swallowing. OBJECTIVE The purpose of this study was to compare the bioavailability of lansoprazole granules administered in 2 types of juice and a soft food with that of the intact capsule administered with water. METHODS Healthy adult volunteers were eligible for this single-center, Phase I, single-dose, randomized, open-label, 4-period crossover study. Subjects received the enteric-coated granular contents of a 30-mg lansoprazole capsule in 3 test regimens (in 180 mL of orange juice, 180 mL of tomato juice, or 1 tablespoon of strained pears, each followed by 180 mL of water) and 1 reference regimen (the 30-mg intact capsule with 180 mL of water). The regimens were rotated at > or = 6-day intervals so that each subject received all 4 regimens. Blood samples for pharmacokinetic analyses were obtained during the 12 hours after each regimen. RESULTS Twenty healthy adult volunteers (10 men, 10 women; mean age, 36 years [range, 19-53 years]) completed this study. Bioavailability of the 3 test regimens was assessed using the two 1-sided tests procedure for mean maximum plasma concentration and area under the plasma concentration-time curve (AUC) from time 0 through the last measurable concentration and AUC from time 0 to infinity. These results were compared with that of the intact capsule. This comparison indicated that the 90% CIs for all 3 test regimens were within the acceptable bioequivalence range of 0.80 to 1.25. Lansoprazole was well tolerated, with most of the adverse events being mild. Headache was the most frequently reported adverse event. CONCLUSION The results of this study indicate that the bioavailability of lansoprazole granules, when administered in orange juice, tomato juice, or a small amount of strained pears, was similar to that of the intact capsule in these healthy adult volunteers.

Terazosin : a new alpha adrenoceptor blocking drug

Terazosin (Hytrin®; Abbott Laboratories, North Chicago, IL) is a new, selective alpha‐adrenoceptor blocking agent used on once‐a‐day basis for therapy of mild‐to‐moderate hypertension. Its pharmacologic properties are similar to those of prazosin. Terazosin however, differs from prazosin in that its water solubility is 25 times greater than that of prazosin and its elimination half‐life is about three times that of prazosin. Greater water solubility facilitates intravenous formulation, and longer half‐life allows once‐daily administration of terazosin. Terazosin is effective in lowering blood pressure and has a beneficial effect on plasma lipid profile. The major advantage of terazosin compared with prazosin, however, is its long duration of action. Terazosin is safe and effective when used in combination with diuretics and other antihypertensive agents, and in the long‐term treatment of patients with mild to moderate essential hypertension.

The Relationship between Terazosin Dose and Blood Pressure Response in Hypertensive Patients

A double‐blind, randomized, placebo‐controlled, multicenter study was conducted to describe the dose‐response curve for terazosin on blood pressure. A total of 128 patients with mild to moderate essential hypertension (supine diastolic blood pressure, 100 to 114 mmHg) participated in the study. The study consisted of a 4‐week single‐blind placebo lead‐in period and a 14‐week double‐blind treatment period. Patients were randomized in equal numbers to four parallel treatment groups: terazosin 1, 2, and 5 mg; terazosin 2, 5, and 10 mg; terazosin 20, 40, and 80 mg; and placebo. The 24‐hour ambulatory blood pressure measurements were performed at the end of the placebo lead‐in period and at the end of each 4‐week fixed‐dose period. The nonlinear, mixed‐effect model computer program was used to analyze the dose‐response relationship. There was a strong dose‐response relationship between fall in blood pressure and the 1 to 10 mg terazosin dose, as well as a plateauing of response for terazosin doses above 10 mg. The maximum antihypertensive response (Emax) to terazosin was 10.7 mmHg for systolic blood pressure and 8.0 mmHg for diastolic blood pressure. The daily dose of terazosin, which produced 50% of the maximum response (ED50), was 3.0 mg for systolic blood pressure and 1.5 mg for diastolic blood pressure. The results of this study suggest that although some patients may benefit from terazosin doses of greater than 10 mg, doses up to 10 mg will maximize therapeutic benefit for most patients, with acceptable side effects.