Neville F. Ford

Comparison of the Steady-State Pharmacokinetics of Fosinopril, Lisinopril and Enalapril in Patients with Chronic Renal Insufficiency

SummaryThe 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 < 0.001) and 161.7 ± 31.8% (p < 0.001), respectively. These results indicate that there was significantly less accumulation of fosinoprilat, based on accumulation indices, relative to either enalaprilat (p < 0.05) or lisinopril (p < 0.001) during the study. The Cmax of fosinopril increased significantly less than that of lisinopril (21.1 vs 123.6%; p < 0.01). Renal function was not altered in any group, and blood pressure changed modestly. PRA increased and plasma aldosterone decreased slightly after administration of each drug, although PRA in the fosinopril group was twice that in the other 2 groups. The results suggest that the nonrenal route of elimination of fosinoprilat helps minimise its accumulation in patients with renal insufficiency, and the minimal accumulation may reduce the risk of concentration-related adverse events.

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 Day1, 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 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 maybe a treatment option for pediatric hypertensive patients.

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.

The pharmacokinetics of irbesartan in renal failure and maintenance hemodialysis

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.

Clopidogrel resistance: pharmacokinetic or pharmacogenetic?

Clopidogrel is important for the management of acute coronary syndromes and, along with aspirin, is recommended in the American College of Cardiology/American Heart Association guideline. It is also used along with aspirin, during the placement of coronary artery stents. Clopidogrel resistance was recognized in such procedures, as several patients did not have the anticipated platelet aggregation response to an ex vivo adenosine diphosphate challenge. From the EXCELSIOR study, which investigated the phenomenon, it was appreciated that it was present prior to treatment with clopidogrel and was therefore an intrinsic property of the patients platelets. From other studies, it was appreciated that the patients who had clopidogrel resistance had a defective allele *2/ in the CYP2C19 gene. Furthermore, there was a dose response evident in that the homozygotes CYP2C19*2/*2 had platelets that responded even less well to clopidogrel than the heterozygotes CYP2C19*2 that responded less well than the wild‐type homozygote. The involvement of the phenomenon with CYP2C19 led some to believe that it was a pharmacokinetic issue. However, the major oxidative metabolic pathway for clopidogrel by which the reactive intermediate is formed is CYP3A4. It is suggested that there is a linkage between a polymorphism of the platelet receptor P2Y12 and the polymorphism of CYP2C19.

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 (Clt/F), renal clearance (Clr), 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.

Defining the Maximum Tolerated Dose: Investigator, Academic, Industry and Regulatory Perspectives

The maximum tolerated dose (MTD) is an important concept in drug development, as it determines the optimal dose range for efficacy trials.14 Determination of the MTD in Phase I helps to ensure both that the doses tested in Phase II are safe and that the potentially efficacious dose range is evaluated. At present, there is no consensus regarding what constitutes an MTD in humans. Considerable confusion arises from the use of different operational definitions of the MTD and from the failure of many investigators to state their definitions of the MTD in reporting their studies. The MTD has been variously defined as the maximum dose administered during a trial that elicits no toxicity,5 the dose that produces mild to moderate sublethal toxic effects in a significant percent of individuals,6 or some percentile of the tolerance distribution.7 We believe that a discussion of the MTD will help clarify the important issues and promote standardization. A variety of perspectives are presented in this arti-

The pharmacokinetics of pravastatin in patients on chronic hemodialysis

AbstractObjective: 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.

Effect of Hydrochlorothiazide on the Pharmacokinetics and Pharmacodynamics of the Angiotensin II Blocker Irbesartan

SummaryThe primary objective of this study was to assess the effect of hydrochlorothiazide on the pharmacokinetics of irbesartan in patients with mild-to-moderate hypertension. In addition, this study compared the pharmacodynamic and tolerability profiles of irbesartan administered both alone and in combination with hydrochlorothiazide. The study consisted of a placebo lead-in period (period A) to establish the stability of blood pressure (seated diastolic blood pressure 95 to 110mm Hg), a 7-day, single-blind treatment period (irbesartan 150mg every day) (period B), and a 7-day, double-blind treatment period [irbesartan 150mg every day plus either placebo (n = 18) or hydrochlorothiazide 25mg every day (n = 18)] (period C). Non-Black men and women 45 to 65 years of age with hypertension were included. The pharmacokinetic profile [maximum concentration of irbesartan in plasma (Cmax), time taken to reach Cmax (tmax), and the area under the plasma concentration versus time curve during a dosage interval (AUCtau)] of irbesartan was unaffected by the addition of hydrochlorothiazide. Mean changes in 24-hour AUC values for seated blood pressures from day 7 of period B to day 7 of period C were significantly lower in patients treated with irbesartan plus hydrochlorothiazide compared with those of patients treated with irbesartan plus placebo. Plasma angiotensin II levels, plasma renin activity, and urinary excretion of sodium, chloride and potassium were significantly increased, whereas urinary aldosterone and creatinine excretion remained unchanged with concomitant hydrochlorothiazide administration.Adding hydrochlorothiazide to irbesartan: (a) does not alter the pharmacokinetics of irbesartan, (b) produces further reductions in blood pressure, (c) produces further increases in plasma angiotensin II levels and plasma renin activity, and (d) is not associated with any clinically important tolerability concerns.

Effect of Nifedipine on the Steady-State Pharmacokinetics and Pharmacodynamics of Irbesartan in Healthy Subjects

Background: In clinical practice, nifedipine has the potential to alter the pharmacokinetics, and therefore possibly the pharmacodynamics and efficacy or safety, of irbesartan. The objectives of the current study were to determine the effects of concomitant administration of nifedipine on the steady-state pharmacokinetics and pharmacodynamics of irbesartan in 12 healthy subjects. Methods and Results: This was an open-label, randomized, crossover study. Each subject received irbesartan 300 mg once daily for 4 days in one period and irbesartan 300 mg once daily plus long-acting nifedipine (Procardia XL, Pratt Pharmaceuticals, New York, NY) 30 mg once daily for 4 days in the other period. The order of treatment periods was random ized, and a minimum 7-day washout phase separated the two periods. Steady state was achieved by day 3. On day 4, no significant differences were observed between the two treatments with respect to maximum concentration of irbesartan at the end of the dosing interval (Cmax) or the area under the plasma concentration versus time curve during a dos ing interval (AUCtau) of irbesartan. Steady-state Cmax and AUCtau met the criteria for bioequivalence when irbesartan was administered alone or with nifedipine. On day 4, mean plasma renin activity was somewhat higher at every point but one when irbesartan was administered with nifedipine; however, no significant difference was observed between the two treatments in mean 24-hour AUC values. On day 4, there was a modest overall decrease from baseline in mean blood pressure for both treatments. No significant differences were observed between the two treatments in mean 24-hour AUC values for seated diastolic or systolic blood pressure. No serious adverse events were reported. Conclusions: Concomitant administration of nifedipine 30 mg with irbesartan 300 mg for 4 days in healthy subjects (1) does not alter the steady-state pharmacokinetic parameters of irbesartan, (2) results in Cmax and AUCtau values for irbesartan that meet the criteria for bioequivalence, and (3) is well tolerated.