Ralph H. Raymond

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.

Modeling and Simulation of Abatacept Exposure and Interleukin‐6 Response in Support of Recommended Doses for Rheumatoid Arthritis1

Abatacept is a recombinant soluble fusion protein that inhibits the CD80/CD86:CD28 costimulatory signal required for T cell activation and has demonstrated efficacy in the treatment of rheumatoid arthritis. The objectives of this analysis were to provide support for a body weight‐tiered dosing regimen approximating 10 mg/kg by (1) quantifying the effect of body weight on exposure and (2) characterizing the relationship between exposure and serum interleukin (IL)–6 concentration. The abatacept exposure and exposure‐response models were developed with 2148 abatacept serum concentrations (from 388 subjects) and 1894 IL‐6 serum concentrations (from 799 subjects), respectively, followed by simulation with these models to address the above objectives. Abatacept exposure was characterized by a linear 2‐compartmental model, in which clearance was linearly related to body weight. The IL‐6 response was characterized by an indirect‐response model, in which the IL‐6 production rate increased with baseline C‐reactive protein levels. Model‐based simulations demonstrated that body weight‐tiered dosing was desirable to ensure consistent steady‐state abatacept trough concentrations across a range of body weights; doses approximating 10 mg/kg (500, 750, 1000 mg for subjects weighing <60, 60–100, and >100 kg, respectively) provided consistent exposure across the body weight groups. In addition, doses >10 mg/kg did not result in further increases in IL‐6 suppression. These modeling and simulation results indicate that the body weight‐tiered abatacept therapeutic doses approximating 10 mg/kg will ensure consistent abatacept exposure and optimal IL‐6 suppression.

The effect of sorivudine on dihydropyrimidine dehydrogenase activity in patients with acute herpes zoster

Bromovinyl‐uracil (BVU) is the principal metabolite of sorivudine, a potent anti‐zoster nucleoside. BVU binds to, and irreversibly inhibits, the enzyme dihydropyrimidine dehydrogenase (DPD). The objective of this study was to assess the time course of recovery of DPD activity after oral administration of sorivudine in patients with herpes zoster and to correlate restoration of DPD activity and levels of uracil with the elimination of sorivudine and its metabolite BVU from the circulation.

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.

Pharmacokinetic and Pharmacodynamic Evaluation of Warfarin and Nefazodone Coadministration in Healthy Subjects

Nefazodone, an antidepressant with serotonin and norepinephrine receptor modulating activity, is highly protein bound and eliminated by oxidative metabolism. This study evaluated the potential for clinically significant drug interactions with warfarin and nefazodone coadministration. Eighteen subjects received warfarin daily for 14 days, achieving steady‐state warfarin concentrations and a stable prothrombin ratio. Nefazodone 200 mg every 12 hours (n = 12) or placebo every 12 hours (n = 6) was then added to the daily warfarin dose for the next 7 days in a double‐blind, randomized design. No serious or unexpected adverse events or events suggestive of abnormal bleeding occurred during coadministration. The addition of nefazodone had no effect on the unbound fraction of total warfarin in plasma or on the steady‐state pharmacokinetics of R‐warfarin based on within‐subject or comparison to placebo‐treated subjects. The steady‐state AUCTAU over the dosing interval and Cmax of S‐warfarin decreased by 12%; however, this change is clinically insignificant because the prothrombin ratio and bleeding time remained unchanged. The steady‐state minimum concentrations for nefazodone and metabolites, achieved on coadministration day 3, were typical of healthy men treated with this nefazodone dosage. In conclusion, warfarin and nefazodone coadministration was safe and well‐tolerated with no clinically significant interactions.

Comparison of Pharmacokinetics of Lanoteplase and Alteplase During Acute Myocardial Infarction

ObjectiveLanoteplase is a rationally designed variant of tissue plasminogen activator. The aim of this study was to examine the pharmacokinetics and functional activity of a single intravenous bolus dose of lanoteplase with those of a bolus plus two-step infusion of alteplase.DesignSeven-centre substudy of the InTIME-I angiographic trial in patients presenting within 6 hours of onset of suspected acute myocardial infarction.Patients and ParticipantsA total of 31 patients (28 males, 3 females) enrolled in this substudy [mean age 59 (range 26 to 76) years].MethodsTwenty-three patients randomised to lanoteplase received single bolus doses of 15 kU/kg (n = 5), 30 kU/kg (n = 3), 60 kU/kg (n = 9), or 120 kU/kg (n = 6). Eight patients received alteplase ≤-100mg as a bolus followed by a two-stage 90 min infusion. Blood samples were analysed for antigen concentration and plasminogen activator (PA) activity.ResultsThe distribution plasma half-life of approximately 35 min for lanoteplase was at least five times longer than that of alteplase. Lanoteplase plasma clearance averaged 3 L/h (50 ml/min), whereas the mean plasma clearance of approximately 24 L/h (400 ml/min) for alteplase approaches hepatic blood flow following acute myocardial infarction. PA activity after lanoteplase 120 kU/kg remained for 6 hours, compared with less than 4 hours after alteplase 100mg.ConclusionsThe longer antigen and activity half-lives, slower clearance and less complicated administration of lanoteplase compared with alteplase suggest that it may offer advantages for use as a single intravenous bolus to achieve reperfusion after myocardial infarction.

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.

Pharmacodynamics and Pharmacokinetics of Irbesartan in Patients With Mild to Moderate Hypertension.

Background: The pharmacodynamics (plasma angiotensin II [AII], plasma renin activity [PRA], renal function, blood pressure [BP], urinary excretion of major metabolites of pros tacyclin [PGI 2-M], and thromboxane A2 [TXA2-M]) and pharmacokinetics of irbesartan were assessed in hypertensive patients. Methods and Results: Twenty-four white patients with seated diastolic blood pressure 95 to 110 mmHg were randomized to double-blind irbesartan 300 mg or placebo once daily for 4 weeks, following a placebo lead-in. Irbesartan-treated patients had significantly greater 24- hour area under the curve values for mean change from baseline in AII and PRA versus pla cebo-treated patients on day B15 (AII [pg.h/mL]: 261 ± 515 vs 12 ± 51; PRA [(ng/mL/h).h]: 74 ± 162 vs -2 ± 14; P values < .05). Irbesartan significantly lowered BP without clinically important changes in renal function. Irbesartan had no effect on 24-hour urinary TXA2-M excretion, but significantly increased 24-hour PGI2-M excretion versus placebo on day B29 (20.7 ± 23 pg/mg creatinine vs -2.3 ± 43 pg/mg creatinine; P < .05). Pharmacokinetics were comparable to those from previous studies. The hourly relationship between plasma irbesartan concentration and antihypertensive effect indicated a broad, clockwise hysteresis, with peak concentration occurring at 1.5 hours, whereas peak antihypertensive effect occurred at 4 hours. Conclusions: Irbesartan increases plasma AII and PRA and lowers BP consistent with AT1 receptor blockade, without clinically important effects on renal function.

Pharmacokinetic and Pharmacodynamic Evaluation During Coadministration of Nefazodone and Propranolol in Healthy Men

Potential interactions between nefazodone (200 mg every 12 hours) and propranolol (40 mg every 12 hours) were assessed in 18 healthy male volunteers in an open‐label, randomized, three‐way crossover study. The nature, frequency, and severity of adverse events during coadministration of nefazodone and propranolol were similar to those observed with either treatment alone. There were no clinically significant effects on vital signs, electrocardiographic results, or laboratory parameters. With coadministration, the maximum peak concentration (Cmax) and area under the concentration‐time curve over the dosing interval (AUCτ) of propranolol decreased 29% and 14%, respectively; Cmax and AUCτ of 4‐hydroxy‐propranolol decreased 15% and 21%, respectively. Despite decreased plasma concentrations of the β‐antagonists, the reduction in exercise‐induced tachycardia and post‐exercise double product was slightly greater with coadministration than with propranolol alone. Administration of nefazodone alone did not significantly affect either pharmacologic parameter. The pharmacokinetics of nefazodone and its metabolites were largely unaffected during coadministration. Coadministration of propranolol and nefazodone results in modest pharmacokinetic inequivalencies, but no clinically significant alterations of the pharmacodynamics of propranolol.

The effects of age and gender on the pharmacokinetics and pharmacodynamics in healthy subjects of the plasminogen activator, lanoteplase

AIMS To investigate the influence of age and gender on the intravenous pharmacokinetics and pharmacodynamics of the plasminogen activator, lanoteplase. METHODS Forty healthy subjects (10 each of young males, elderly males, young females and elderly females) received a single bolus 10 kU kg(-1) intravenous dose of lanoteplase. Plasma from blood serially collected for 24 h post-dose was analyzed for lanoteplase (antigen), fibrinogen, plasminogen and α2-antiplasmin concentrations, plasma plasminogen activation activity (PPAA) and rapid plasminogen activator inhibitor (PAI-1). RESULTS Lanoteplase mean total systemic clearance (CL(t)) values ranged from 1.9 to 2.8 l h(-1) and mean steady-state volume of distribution (V(ss)) values ranged from 12.3 to 15.6 l. Age-by-gender interactions were observed for lanoteplase CL(t) (P= 0.04), but no differences were observed for V(ss) or elimination half-life. Elderly females had a 27% lower mean CL(t) than young females (95% CI for the difference 0.17, 1.27 l h(-1)) and 32% lower CL(t) than elderly males (95% CI for the difference 0.15, 1.65 l h(-1)). PPAA AUC/dose values did not show an age-by-gender interaction. Haemostasis parameters indicated only a slight degree of systemic plasminogen activation. CONCLUSIONS Elderly females had a lower mean lanoteplase CL(t) than elderly males and young females. However, no difference was observed between young and elderly females for the AUC/dose of PPAA. In addition, there were no age-related or gender-related differences observed in the other pharmacodynamic parameters measured.