The pharmacokinetics of irbesartan in hypertensive children and adolescents.

An open-label study was conducted to characterize the pharmacokinetics and antihypertensive response to irbesartan in children (1-12 years) and adolescents (13-16 years) with hypertension. Patients received single once-daily oral doses of irbesartan 2 mg/kg (maximum of 150 mg once daily) for 2 to 4 weeks (+/- nifedipine or hydrochlorothiazide). Plasma irbesartan concentrations were determined by a validated high-performance liquid chromatography/fluorescence method from blood samples taken predose, up to 24 hours after dosing on Day 1, and up to 48 hours after the final dose. The plasma concentration-time profiles were similar between the 6- to 12-year and the 13- to 16-year age groups and to that previously determined from a study of adult subjects receiving approximately 2 mg/kg (i.e., 150 mg) oral irbesartan once daily. Mean reductions in systolic/diastolic blood pressure were 16/10 mmHg at Day 28 with irbesartan monotherapy (n = 8). Irbesartan was well tolerated and may be a treatment option for pediatric hypertensive patients.

A double-blind, randomized, crossover assessment of blood pressure following administration of avitriptan, sumatriptan, or placebo to patients with mild to moderate hypertension.

We examined the effects of avitriptan, a 5-hydroxytryptamine 1-like (5HT1) receptor agonist for the treatment of migraine, in patients with medicated, controlled, mild to moderate hypertension relative to placebo and sumatriptan. The study was randomized, double-blinded, placebo-controlled, and 4-way crossover in design. Twenty patients (12M, 8F) participated. As required by protocol, all were stable on medications for mild to moderate hypertension, with a supine diastolic blood pressure of < 95 mmHg. Qualified subjects were randomized to receive oral administration of either 75 or 150 mg of avitriptan, 100 mg sumatriptan or placebo during the four treatment visits. Supine blood pressure and pulse rates were recorded up to 24 h after drug administration. Avitriptan 150 mg significantly increased peak diastolic and systolic blood pressure, and mean arterial pressure compared to placebo and sumatriptan 100 mg (p < 0.05). Only those hypertensive patients receiving medication for hypertension should receive anti-migraine medications, such as avitriptan, which are 5HT1-like receptor agonists.

Pharmacokinetics and pharmacodynamics of irbesartan in patients with hepatic cirrhosis.

The effect of hepatic impairment on the clinical pharmacology of the angiotensin II (AII) receptor antagonist irbesartan was assessed by comparing pharmacokinetic and pharmacodynamic parameters in 10 patients with hepatic cirrhosis with a matched group of 10 healthy volunteers. The pharmacokinetics and pharmacodynamics of irbesartan, 300 mg taken orally once daily, were evaluated after single- and multiple-dose (7 consecutive days) administration to normotensive subjects in an open-label, multiple-dose, parallel group study. Pharmacokinetic data obtained after administration of single and multiple doses of irbesartan showed no significant difference between the two groups in time to maximum observed plasma concentration of drug (tmax), half-life (t1/2), area under the plasma concentration-time curve (AUC), apparent oral clearance (Cl(t)/F), renal clearance (Cl(r)), and accumulation index (AI). Steady-state levels of irbesartan were reached within 3 days in both treatment groups. After irbesartan administration on day 1, mean increases from baseline in plasma AII levels and plasma renin activity (PRA) were greater in the group with cirrhosis than in the control group. On day 7, mean increases from baseline in PRA were greater in the control group than in the group with cirrhosis. No discontinuations or serious adverse events occurred during the study. The pharmacokinetics of irbesartan after repeated oral administration were not significantly affected in patients with mild-to-moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.

Pharmacokinetics and pharmacodynamics of irbesartan in healthy subjects.

The safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of the angiotensin II (AII) AT1 blocker irbesartan were assessed in healthy subjects. In this single-center, placebo-controlled, double-blind within dose group, sequential, dose-ascending study, 48 men were randomized to receive irbesartan at doses of 150 mg, 300 mg, 600 mg, or 900 mg daily. Subjects received a single dose of irbesartan (n = 9 per group) or placebo (n = 3 per group), followed by 3 days of placebo, and then multiple doses of irbesartan or placebo once daily for 7 days. The values for plasma area under the concentration-time curve (AUC) of irbesartan were dose proportional up to 600 mg. There were no significant differences between the dose groups in time to maximum concentration (tmax) or half-life (t1/2) after single and multiple doses. After multiple doses, urinary recovery was significantly lower in the 600-mg and 900-mg dose groups compared with the 150-mg and 300-mg dose groups. Steady-state concentrations of irbesartan were achieved within 3 days of administration with no clinically important accumulation. Irbesartan produced dose-dependent increases in plasma renin activity and AII levels. Irbesartan was well tolerated at doses from 150 mg to 900 mg daily; a maximally tolerated dose was not reached. Modest decreases in blood pressure without orthostatic symptoms were observed at irbesartan doses of 300 mg or higher. These results demonstrated the dose-proportionality of irbesartan 150 mg to 600 mg and indicated that doses up to 900 mg daily were well tolerated.

Monitoring of acute migraine attacks: placebo response and safety data.

In the course of evaluating the safety and efficacy of an investigational compound for acute migraine headaches, a large number of patients received placebo at a single site, offering the opportunity to characterize subjective and clinical physiologic responses of migraine patients to placebo in a controlled environment. In a single-site, double-blind, placebo-controlled study, 67 patients reported to the clinic while suffering a moderate to severe acute migraine headache and received oral placebo. For 6 hours after treatment, a continuous electrocardiogram (ECG) was performed, and headache severity, adverse events, and vital signs were recorded. Patients returned and repeated the procedure when free from pain. A headache was considered to be improved if its severity dropped to "mild" or "none." Twenty-five patients (37%; 95% CI: 26% to 50%) experienced headache improvement within 2 hours of receiving placebo, and 32 patients (48%: 36% to 60%) improved within 4 hours. There were no clinically important ECG changes during the migraine visit, and there were no clinically relevant differences in vital signs between the migraine and pain-free visits. Thus, a substantial placebo response occurs in migraine headache. Hemodynamic and ECG parameters are unchanged between migraine and pain-free states.

Measurement of 2,4-toluenediamine in urine and serum samples from women with Même or Replicon breast implants.

The objective of this matched case-control study was to determine whether women with Même or Replicon polyurethane-covered silicone breast implants are exposed to clinically significant levels of free 2,4-TDA from biodegradation of the polyurethane foam. Urine and serum samples were obtained from 61 patients with Même or Replicon breast implants and 61 controls on two separate occasions separated by 10 +/- 3 days. Free TDA was analyzed by gas chromatography combined with negative chemical ionization mass spectrometry with lower limit of quantitation in both urine and serum of 10 pg/ml. The results were correlated with the length of time since implantation. No patients or controls had detectable free 2,4-TDA in their sera. Thirty patients had quantifiable levels of free 2,4-TDA, and 18 had detectable levels in their urine. Controls had no quantifiable levels, but 7 subjects had detectable levels. The biodegradative half-life of the polyurethane foam was estimated to be 2 years. A risk assessment using the cancer potency estimate calculated by the FDA from rat data and the National Academy of Sciences methodology provided a theoretical lifetime risk of approximately one in one million. It was concluded that the polyurethane foam cover on the Même and Replicon breast implants biodegrades. The risk assessment of approximately one in one million derived from this study strengthens earlier conclusions by the Health Protection Branch (Canada) that there is no significant risk of cancer from exposure to the 2,4-TDA formed from this biodegradation.

The pharmacokinetics of pravastatin in patients on chronic hemodialysis.

OBJECTIVE: The single-dose and steady-state pharmacokinetics of the HMG CoA reductase inhibitor pravastatin and its two metabolites, SQ 31,906 and SQ 31,945, were evaluated in 12 hemodialysis patients. A single 20-mg i.v. dose was employed, followed by daily oral dosing of 20 mg over four hemodialysis intervals. RESULTS: No statistical differences in the pharmacokinetics of pravastatin or SQ 31,906 were evident when comparing the first and last days of oral dosing with pravastatin. The pharmacokinetic parameters of pravastatin and SQ 31,906 were similar to those of healthy volunteers. SQ 31,945, the inactive polar metabolite, did accumulate in dialysis patients, as evidenced by an accumulation index of 1.7 +/- 1.0. Although metabolic clearance is the predominant mode of elimination of pravastatin, hemodialysis clearances of pravastatin, SQ 31,906 and SQ 31,945 will contribute to total body clearance since dialytic clearance ranged from 40 to 80 ml.min-1. CONCLUSION: Pravastatin can be safely administered in the usual dosages to subjects with renal failure on hemodialysis and no change in dosing is necessary.

The pharmacokinetics of irbesartan in renal failure and maintenance hemodialysis.

PURPOSE: An open-label, multiple-dose, parallel-group study was conducted to evaluate the pharmacokinetics of the angiotensin II receptor antagonist irbesartan in subjects with varying degrees of renal function. METHODS: Forty subjects were divided into four treatment groups on the basis of 24-hour creatinine clearance (CLCR): normal renal function (> 75 ml/min/1.73 m2), mild to moderate renal impairment (30 to 74 ml/min/1.73 m2), severe renal impairment (< 30 ml/min/1.73 m2), and maintenance hemodialysis. Subjects received 100 mg irbesartan daily for 8 days (or 300 mg daily for 9 days for the hemodialysis group). Serial blood and urine samples were collected for 24 hours after the first and last of eight successive daily doses. In addition, arterial and venous blood samples were collected during two hemodialysis sessions from subjects requiring maintenance hemodialysis. RESULTS: There was no statistically significant linear relationship between CLCR and maximum plasma concentrations, dose-adjusted area under the plasma concentration time curve values on days 1 or 8, or any other pharmacokinetic parameters among the renal function groups studied. There was no indication of drug accumulation with repetitive dosing. In the subjects receiving hemodialysis, arterial-venous concentration differences for irbesartan were negligible, suggesting that this compound is not cleared through hemodialysis. In addition, irbesartan was well tolerated. CONCLUSION: Based on pharmacokinetic parameters, no starting dose adjustment is necessary in subjects with mild to severe renal impairment, inclusive of hemodialysis. Subjects with volume depletion may have an exaggerated response to an initial dose of irbesartan and, under such circumstances, volume depletion should be corrected or a lower starting dose of irbesartan should be considered.

Evaluation of cerebral pharmacokinetics of the novel antidepressant drug, BMS-181101, by positron emission tomography.

BMS-181101 is a novel antidepressant drug that is currently under clinical investigation. The goal of this study was to evaluate the pharmacokinetics and receptor binding of this agent in the brains of healthy human volunteers. BMS-181101 was radiolabeled with 11C by methylation with [11C]CH3I of the 5-hydroxypiperazine precursor and the product was purified by high-performance liquid chromatography. Cerebral pharmacokinetics of [11C]BMS-181101 were studied by dynamic positron emission tomography imaging in six healthy volunteers. Two studies were performed in each subject. For the first study the subject was injected with 10 mCl of high specific activity [11C]BMS-181101 (approximately 1700 mCi/mumol) and serial positron emission tomography images and arterial blood samples were collected over 90 min. Thirty minutes after acquiring the final image, each subject was coinjected with a second dose, 10 mCi of [11C]BMS-181101 plus 3 mg of unlabeled drug (final specific activity approximately 1.5 mCi/mumol), and imaging/blood collection was repeated. The data were analyzed by calculating regional tracer accumulation (percent injected dose/g) at 60 min after injection and compartmental modeling. Measurements of percent injected dose/g yielded similar values for all brain regions, independent of specific activity. Kinetic modeling of time activity curves for cerebellum, caudate, putamen, thalamus, pons and temporal, occipital and frontal cortex demonstrated that tissue distribution can be described by a simple two-compartment flow model. Statistical comparisons of the apparent distribution volumes for each region failed to reveal significant differences between the high and low specific activity studies. These results indicate that the central nervous system distribution of [11C]BMS-181101 is dominated by blood flow and significant receptor-specific localization does not occur in any brain region.

Invasive pharmacodynamics of fosinopril in patients with congestive heart failure.

Five patients with NYHA Class III CHF received 5 mg of fosinopril on each of 4 days. Hemodynamics were measured with a Swan-Ganz catheter after dosing on day 1. Measurements of plasma fosinoprilat, ACE activity, renin, and aldosterone were obtained. An Emax model was used to fit the effect-site concentration and mean arterial pressure change. A linear model was used to fit the effect-site concentration and the pulmonary artery wedge pressure (PAWP) change. At steady state on day 4, AUC0-24 was 1668 +/- 476 ng.hr/mL and Cmax was 143.5 +/- 33.6 ng/mL. The mean elimination half-life of fosinoprilat was 11.3 +/- 0.7 hours, and median Tmax occurred at 3 hours, corresponding to maximum plasma ACE inhibition. Plasma renin activity was unchanged, and mean plasma aldosterone level declined. Emax modeling using fosinoprilat concentrations and mean arterial pressure showed good prediction of the pharmacodynamic effects from the effect-site concentration. A linear relationship was observed between the effect-site concentrations of fosinoprilat and PAWP. When expressed in an Emax model, the pharmacodynamic actions of fosinopril in patients with CHF are a reflection of its pharmacokinetics.

Single-dose and steady-state pharmacokinetics of fosinopril and fosinoprilat in patients with hepatic impairment.

The single-dose and steady-state pharmacokinetics of the angiotensin-converting enzyme (ACE) inhibitor fosinopril and its active diacid, fosinoprilat, were evaluated in 6 healthy volunteers and 12 patients with alcoholic cirrhosis. Fosinopril was administered at a dosage of 10 mg once daily for 14 days. Results in the two groups were similar, with no evidence of accumulation of fosinoprilat in hepatically impaired patients. Mean (+/- SD) maximum observed plasma concentrations of fosinoprilat in the healthy subjects were 112.0 +/- 67.2 ng/mL after the first dose and 144.1 +/- 61.7 ng/mL at steady-state. Corresponding values for the hepatically impaired patients were 111.4 +/- 40.1 ng/mL and 140.2 +/- 50.9 ng/mL. The area under the serum concentration versus time curve for healthy volunteers was 790.7 +/- 431.0 ng.hr/mL after the first dose and 940.3 +/- 400.4 ng.hr/mL at steady-state. Similar values were noted in hepatically impaired patients: 926.0 +/- 293.9 ng.hr/mL and 1,255.4 +/- 434.0 ng.hr/mL for first dose and steady-state, respectively. No statistically significant differences were detected in fosinoprilat pharmacokinetic values between healthy and hepatically impaired subjects. Absence of accumulation can be attributed to the dual route of elimination of fosinoprilat reported in previous studies. Renal excretion of fosinoprilat in hepatically impaired patients prevents increased accumulation. The present findings suggest that the starting dose of fosinopril used in hypertensive patients with normal renal and hepatic function can also be used in patients with hepatic impairment secondary to cirrhosis.

Fosinopril monotherapy: relationship between blood pressure reduction and time of administration.

The time to peak antihypertensive effect and the trough-to-peak ratio were determined in 64 Caucasian patients (19 men, 45 women) with mild to moderate hypertension [supine diastolic blood pressure (DBP) 95 to 115 mmHg]. They received placebo or fosinopril 10, 20, or 40 mg once daily for 4 weeks. The study consisted of a 4-week placebo lead-in, 4 weeks' double-blind treatment, and a 1-week placebo washout period. Vital signs were determined biweekly before dosing, and blood pressures were measured every 1 to 2 h during two 27-h periods at the beginning and end of treatment. After the first and last doses of all three regimens, the peak effect on blood pressure occurred 5 to 7 h after all three dosages. Neither peak nor trough blood pressure changes showed a clear dose-response relationship. Trough to peak ratios for the first dose, corrected for placebo effects, were 79% for fosinopril 10 mg, 48% for fosinopril 20 mg, and 74% for fosinopril 40 mg, and the trough-to-peak ratios for the last dose were 41% for fosinopril 10 mg, 32% for fosinopril 20 mg, and 44% for fosinopril 40 mg. In the 38 responders among the 48 patients receiving fosinopril (supine DBP decrease of at least 5 mmHg at 24 h postdose), trough-to-peak ratios ranged from 50 to 81%, and the range indicates that fosinopril is efficacious when administered once daily. Adverse effects were mild to moderate, and no patient discontinued treatment. Changes in the laboratory test results, electrocardiograms, or the results of physical examinations were unremarkable.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the steady-state pharmacokinetics of fosinopril, lisinopril and enalapril in patients with chronic renal insufficiency.

The phosphinyl ester prodrug fosinopril, a new angiotensin converting enzyme (ACE) inhibitor, is fully hydrolysed after oral administration to the pharmacologically active diacid, fosinoprilat. This metabolite is cleared by both hepatic and renal routes, while most other ACE inhibitors are cleared exclusively by the kidney. In the present study, after administration of multiple fixed oral doses the accumulation of the active moieties of fosinopril, enalapril and lisinopril was compared in patients with renal insufficiency. 29 patients with creatinine clearances (CLCR) less than 30 ml/min received either fosinopril 10mg (n = 9), enalapril 2.5mg (n = 10) or lisinopril 5mg (n = 10) once daily for 10 days in a nonblind (open-label) parallel study. Pharmacokinetic parameters including area under the serum concentration-time curve (AUC), peak serum concentration (Cmax) and time to peak concentration (tmax), as well as renal function, blood pressure, and plasma renin activity (PRA) and aldosterone levels, were determined on the first and last days of the study. The percentage (+/- SEM) increases in AUC from day 1 to day 10 for fosinoprilat, enalaprilat and lisinopril were 26.8 +/- 9.9 (nonsignificant), 76.6 +/- 16.6 (p less than 0.001) and 161.7 +/- 31.8% (p less than 0.001), respectively. These results indicate that there was significantly less accumulation of fosinoprilat, based on accumulation indices, relative to either enalaprilat (p less than 0.05) or lisinopril (p less than 0.001) during the study. The Cmax of fosinopril increased significantly less than that of lisinopril (21.1 vs 123.6%; p less than 0.01). Renal function was not altered in any group, and blood pressure changed modestly.(ABSTRACT TRUNCATED AT 250 WORDS)

Imidazo[1,5-a]pyridines: a new class of thromboxane A2 synthetase inhibitors.

The synthesis and structure-activity profile of a new class of potent and highly specific thromboxane A2 synthetase inhibitors is described. The most potent member of this series in vitro is determined to be imidazo[1,5-a]-pyridine-5-hexanoic acid (9).