Single-dose pharmacokinetics of nefazodone in healthy young and elderly subjects and in subjects with renal or hepatic impairment

The single-dose pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were examined in 12 healthy younger subjects 55 years of age (YNG), 12 elderly subjects 65 years of age (ELD), 12 patients with biopsy proven hepatic cirrhosis (HEP) and 12 patients with moderate renal impairment (REN), Cl_CR 20–60 ml·min^–1. The study was of parallel group design, with each of the four subject groups receiving escalating single oral doses of 50, 100 and 200 mg of nefazodone at 1 week intervals. Serial blood samples for pharmacokinetic analysis were collected for 48 h following each dose and plasma samples were assayed for NEF, HO-NEF and mCPP by a validated HPLC method.Single oral doses up to 200 mg of nefazodone were well tolerated by all subjects. Maximum plasma levels of NEF and HO-NEF were generally attained within 1 h after administration of nefazodone. HO-NEF and mCPP plasma levels were about 1/3 and <1/10 those of NEF, respectively. There were no apparent gender-related pharmacokinetic differences in any group of subjects. NEF and HO-NEF pharmacokinetics were dose dependent in all four subject groups; a superproportional increase in AUC and an increase in t_1/2 with increasing dose was obtained, indicative of nonlinear pharmacokinetics. Relative to normal subjects, elderly and cirrhotic subjects exhibited increased systemic exposure to NEF and HO-NEF, as reflected by AUC, at all doses of nefazodone; subjects with moderate renal impairment did not.Elderly and cirrhotic patients may require lower doses of NEF to achieve and maintain therapeutic effectiveness.     

Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease

Repaglinide is a novel insulin secretagogue developed in response to the need for a fast-acting, oral prandial glucose regulator for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Repaglinide is metabolized mainly in the liver; its pharmacokinetics may therefore be altered by hepatic dysfunction. This open, parallel-group study compared the pharmacokinetics and tolerability of a single 4 mg dose of repaglinide in healthy subjects (n = 12) and patients with chronic liver disease (CLD) (n = 12). Values for AUC and Cmax were significantly higher in CLD patients compared with healthy subjects, and the MRT was prolonged in CLD patients. Values for tmax did not differ between the groups, but t1/2 was significantly prolonged in CLD patients compared with previously determined values in healthy subjects. AUC was inversely correlated with caffeine clearance in CLD patients but not in healthy subjects. Blood glucose profiles were similar in both groups. Adverse events (principally hypoglycemia) were similar in the two groups; none was serious. Repaglinide clearance is significantly reduced in patients with hepatic impairment; the agent should be used with caution in this group.     

The pharmacokinetics of teniloxazine in healthy subjects and patients with hepatic cirrhosis.

The single-dose and steady-state pharmacokinetics of teniloxazine, an investigational drug with antidepressant and anti-anoxic properties, were compared in 12 healthy volunteers and 12 cirrhotic patients, following oral administration of 80 mg teniloxazine maleate every 12 h for 7 days. In healthy volunteers, an increase in oral clearance, CLo (from a mean (s.d.) value of 14.6 (3.9) to 18.0 (6.6) ml min-1 kg-1; mean % ratio between the two values (95% CI), 123 (94-151)) and a significant shortening of t 1/2 (from 6.2 (2.7) to 4.8 (1.4) h; mean % ratio (95% CI), 78 (58-98)) were observed upon repeated administration, suggesting autoinduction of teniloxazine metabolism. In cirrhotic patients, the pharmacokinetic parameters of teniloxazine remained essentially invariant with time. Compared with normal subjects, CLo was about halved in cirrhotic patients, whereas t 1/2 was more than doubled. As a consequence of these modifications, the multiple-dose regimen resulted in a two-fold mean drug accumulation in cirrhotic patients, compared with virtually no accumulation in healthy volunteers. Although no adverse events were noted in either study group, it is suggested that maintenance doses for patients with liver dysfunction should initially be at the lower end of the therapeutic range.     

Single-dose and steady-state pharmacokinetics of tomoxetine in normal subjects

A pharmacokinetic profile of tomoxetine, a selective norepinephrine uptake inhibitor, was developed in human volunteers following single and multiple oral administrations. Following the administration of a single 90-mg oral dose of tomoxetine to four normal volunteers, the plasma half-life was 4.3 +/- 0.5 hours. Mean plasma clearance was 0.60 +/- 0.14 L/Kg/hr, and the mean volume of distribution was 3.7 +/- 0.9 L/kg. Multiple doses of tomoxetine (20 mg bid and 40 mg bid) for seven days were administered to an additional seven subjects. The data appeared to have a bimodal distribution. The mean plasma half-life determined following the last dose was 4.6 +/- 0.5 hours in five subjects. The other two subjects, one at each dose level, demonstrated accumulation of tomoxetine occurring from the first to last dose where tomoxetine disappeared from plasma with a mean half-life of 19 hours.     

Single-dose pharmacokinetics of levetiracetam in healthy Chinese male subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Levetiracetam has been evaluated for epilepsy since 1992. * Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. * Although this antiepileptic has been well studied in Western countries, this paper describes the first such trial of the drug in a Chinese population. WHAT THIS STUDY ADDS: * Information is given on the pharmacokinetics, dose proportionality, safety and tolerability profile of levetiracetam in healthy male Chinese volunteers, and the results are compared with published data obtained in White subjects. * The pharmacokinetics and the pattern of adverse events of levetiracetam in Chinese subjects are similar to the data reported in White subjects. AIMS: The main aims of this study were to evaluate the pharmacokinetics of levetiracetam in healthy male Chinese volunteers and to assess the dose proportionality between the 500-mg and 1500-mg single doses. METHODS: This was a randomized, single-centre, single-dose, two-way crossover study. Twenty-six healthy male Chinese subjects were enrolled. All subjects received a single dose of 500 mg or 1500 mg levetiracetam tablet(s) on the dosing day, and the wash-out period was 7 days. Blood was obtained for a 36-h pharmacokinetic evaluation. RESULTS: Following single-dose administration of 500 mg and 1500 mg of levetiracetam, the median t(max) was 0.5 and 0.5 h; t(1/2) was 7.3 +/- 0.8 and 7.3 +/- 0.7 h; C(max) was 13.6 +/- 3.2 and 47.1 +/- 12.1 microg ml(-1); AUC(0-infinity) was 109.3 +/- 14.1 and 340.4 +/- 50.6 microg h(-1) ml(-1); and AUC(0-t) was 105.7 +/- 13.3 and 329.0 +/- 47.9 microg h(-1) ml(-1), respectively. CONCLUSIONS: Both C(max) and AUCs were dose-proportional over the range of 500-1500 mg. The pharmacokinetic data obtained in these Chinese subjects were similar to the historical data from a matched group of White subjects.     

Single-dose pharmacokinetics of sodium ferric gluconate complex in iron-deficient subjects

STUDY OBJECTIVES: To determine the single-dose pharmacokinetics of intravenous sodium ferric gluconate complex in sucrose injection (SFGC) in iron-deficient human volunteers, and to assess iron transport. DESIGN: Open-label, randomized study. SETTING: Clinical research facility. SUBJECTS: Fourteen iron-deficient men and women. INTERVENTIONS: Subjects were randomized to receive a single intravenous dose of either SFGC 62.5 mg administered over 30 minutes or SFGC 125 mg over 60 minutes. Five days later, the same subjects were rerandomized to receive a second intravenous dose of SFGC, either 62.5 mg administered over 4 minutes or 125 mg over 7 minutes. MEASUREMENTS AND MAIN RESULTS: Blood samples were collected at predefined times before, during, and up to 72 hours after the infusion to determine the single-dose pharmacokinetics of SFGC. Assays were performed for both total iron and transferrin-bound iron, from which drug-bound iron could be calculated. Urine was collected over 24 hours before dosing and for 24 hours after the start of infusion to determine the renal elimination of iron. Clearance of SFGC from serum was rapid and far exceeded rates reported for iron dextran. Pharmacokinetic parameters were unaffected by dose or infusion rate. Serum iron derived from SFGC did not exceed the binding capacity of transferrin. Serum iron from SFGC became rapidly available (< 24 hrs) as transferrin-bound iron, but only after passage through another compartment, presumably the reticuloendothelial system (RES). At least 80% of the administered iron was transported to bone marrow within 24 hours after infusion. CONCLUSIONS: Iron derived from SFGC appears to be rapidly transferred to a bioavailable iron compartment as transferrin-bound iron after digestion in the RES. At the doses administered in this study, liberation of potentially toxic, free iron was not detectable.     

Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects.

As a result of the low oral bioavailability of ganciclovir, a prodrug was developed to improve the bioavailability of ganciclovir. This study was designed to investigate the fasting, single-dose pharmacokinetics as well as the absolute and relative bioavailability of a valine ester prodrug of ganciclovir, valganciclovir, as compared to oral and intravenous ganciclovir in asymptomatic HIV+ and CMV+ subjects. In this open-label, randomized, three-period crossover study, 18 subjects received, in random order, single oral doses of valganciclovir 360 mg and ganciclovir 1000 mg and an intravenous infusion of ganciclovir 5 mg/kg over 1 hour. Valganciclovir was rapidly and extensively hydrolyzed to ganciclovir, resulting in significantly greater bioavailability compared to 1000 mg oral ganciclovir (60.9% vs. 5.6%, respectively). Higher peak serum concentrations were reached earlier following valganciclovir (ganciclovir [2.98 +/- 0.77 micrograms/mL at 1.0 +/- 0.3 h]) than following oral ganciclovir (0.47 +/- 0.17 microgram/mL and 2.2 +/- 1.0 h). Mean total ganciclovir AUCs following oral ganciclovir (1000 mg) and 360 mg valganciclovir (3.8 +/- 1.2 and 10.8 +/- 1.9 micrograms-h/mL) were less than that following a standard 5 mg/kg intravenous infusion of ganciclovir (25.1 +/- 3.8 micrograms-h/mL). In summary, valganciclovir is a prodrug with a favorable safety profile with enhanced bioavailability and significantly higher serum concentrations of ganciclovir than following oral administration of ganciclovir itself.     

Single-dose and steady-state pharmacokinetics of doxazosin given in combination with chlorothiazide to hypertensive subjects

The pharmacokinetics of doxazosin were determined in hypertensive subjects after a single dose of 1 mg, and at steady-state while receiving doses of 1, 2, 4 and 8 mg of the drug daily. Chlorothiazide 500 mg once daily was administered as additional therapy throughout the study. After a single dose doxazosin was rapidly absorbed, with peak plasma drug concentrations (Cmax) occurring after 2.1 +/- 0.4 hours. The elimination half-life in plasma was 10.7 +/- 1.2 hours. These parameters remained essentially unchanged during maintenance administration of doxazosin at each of the dose levels. Calculations of Cmax and area under the concentration-time curve (AUC0----infinity) indicated that the pharmacokinetic disposition of the drug remained linear over the dose range 1 to 8 mg.     

Effect of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide in healthy subjects

AIMS: Our aim was to investigate the effects of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide, a novel short-acting antidiabetic drug. METHODS: In a randomized crossover study with two phases, 10 healthy volunteers took 600 mg rifampicin or placebo orally once daily for 5 days. On day 6 of both phases, they ingested a single 60 mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 7 h postdose. RESULTS: Rifampicin decreased the mean AUC(0,7 h) of nateglinide by 24% (range 5-53%; P = 0.0009) and shortened its half-life (t(1/2)) from 1.6 to 1.3 h (P = 0.001). However, the peak plasma nateglinide concentration (Cmax) remained unchanged. The AUC(0,7 h) of the M7 metabolite of nateglinide was decreased by 19% (P = 0.002) and its t(1/2) was shortened from 2.1 to 1.6 h by rifampicin (P = 0.008). Rifampicin had no significant effect on the blood glucose-lowering effect of nateglinide. CONCLUSIONS: Rifampicin modestly decreased the plasma concentrations of nateglinide probably by inducing its oxidative biotransformation. In some patients, rifampicin may reduce the blood glucose-lowering effect of nateglinide.     

Single-dose and steady-state pharmacokinetics and pharmacodynamics of perindopril in hypertensive subjects.

In a double-blind, placebo-controlled, parallel group study, 24 essential hypertensive subjects were randomised to receive either placebo or 2, 4, or 8 mg perindopril. Perindopril, its deesterified metabolite, perindoprilat, and perindoprilat glucuronide were separated with an ion-exchange resin and determined by a radioimmunoassay (RIA). Pharmacokinetic and pharmacodynamic parameters were estimated for 96 h after the first dose and after 4-week once-daily treatment. Perindopril peak levels were achieved in less than or equal to 2 h after dosing with an elimination t1/2 of 1-2 h. Peak levels of perindoprilat were achieved more slowly, reaching a maximum level 5-8 h after dosing, and had an elimination t1/2 of 40 h. Levels of the perindopril glucuronide peaked approximately 0.5 h later than perindopril, with an elimination t1/2 of approximately 2 h. Perindopril, perindoprilat, and its glucuronide conjugate followed linear kinetics in the dose range of 2-8 mg, and there was no evidence of accumulation with chronic dosing. Perindopril 4 and 8 mg produced significant decreases in predose blood pressure (BP) with chronic dosing, with maximal decreases occurring 5-7 h after dosing. Perindopril also produced a prolonged dose-dependent inhibition of plasma angiotensin-converting enzyme (ACE) activity that was maximum after 4 h and had not fully recovered by 48 h after a single dose.     

Single-dose pharmacokinetics of temocapril and temocapril diacid in subjects with varying degrees of renal impairment

Objective: The aim of this study was to determine the influence of renal impairment on the single-dose pharmacokinetics of temocapril and its pharmacologically active metabolite, temocapril diacid. Methods: A single oral dose of 20?mg temocapril hydrochloride was given after an overnight fast to eight healthy (control) subjects (group A, n=8) with a mean baseline creatinine clearance (CL_CR) of 115.2?ml?·?min^?1 and to three groups of patients with decreased renal function (mean CL_CR 56.9?ml in group B, n=8, 30.0?ml?·?min^?1 in group C, n=8 and 15.4?ml?·?min^?1 in group D, n=5). Results: The mean peak concentration and median time to peak concentration for both temocapril and its diacid metabolite as well as the mean area under the curve (AUC_0∞) for temocapril did not differ significantly between groups. The mean AUC_0∞ for temocapril diacid increased only two- to threefold from group A to D. The mean terminal elimination half-life (t½) for temocapril diacid was prolonged in subjects with impaired renal function. However, prolongation of mean t½ and increase in AUC_0?∞ did not parallel the decrease of mean renal clearance for temocapril diacid. Conclusion: The results suggest the existence of an alternative pathway in addition to the renal excretion of temocapril, e.g. via the bile. This pathway substantially contributes to the elimination of the active metabolite, temocapril diacid, in patients with decreased renal function. Nonetheless, to avoid any risks, the dose of temocapril hydrochloride in patients with moderate to severe renal impairment should be reduced.     

Omapatrilat in patients with hepatic cirrhosis. Pharmacodynamics and pharmacokinetics

OBJECTIVE: The pharmacodynamics and pharmacokinetics of omapatrilat, a member of a new class of cardiovascular compounds, the vasopeptidase inhibitors, were evaluated in subjects with hepatic cirrhosis (n = 10) and in healthy subjects (n = 10) matched for age, weight, gender and smoking history. METHODS: All subjects received omapatrilat 25 mg orally once daily for 14 days. Plasma renin and urinary atrial natriuretic peptide (ANP) levels were measured to assess the effect of omapatrilat on cirrhotic subjects. The effect of omapatrilat on blood pressure as well as changes in ANP and plasma renin levels were not altered by hepatic impairment. Pharmacokinetic parameters were determined from plasma omapatrilat concentrations. RESULTS: There were no significant differences between the two subject groups with regard to log-transformed area under the curve or maximum observed plasma concentration. Systemic accumulation was similar in the two groups. CONCLUSION: These results suggest, based on findings in otherwise healthy cirrhotic subjects, that no adjustment of standard dosing regimens is indicated for hypertensive patients with mild to moderate cirrhosis.     

Single-dose pharmacokinetics of metoclopramide

Summary The time courses of plasma metoclopramide concentrations were followed in six subjects after oral and intravenous single dose administration. Plasma concentration-time data following i.v. administration in each subject were found to fit a two compartment model with a mean terminal half-life of 4.55 h±0.80 h and a mean distribution half-time of 0.35 h±0.09 h. Volumes of distribution were high (3.43±1.181 · kg^–1), and clearances (0.53±0.191 · kg^–1h^–1) approached liver plasma flow. This suggests that metoclopramide occurs at higher concentrations in tissues than in plasma, and that its clearance is probably limited by liver blood flow rather than liver metabolic capacity. The post-absorption decline in metoclopramide plasma levels after oral administration was also biexponential in each subject. The terminal half-life was 5.17 h±0.98 h. Mean volume of distribution and mean clearance were similar to intravenous values (after adjustment for bioavailability). Oral absorption was rapid with peak plasma concentrations being reached at a mean time of 0.93 h. A mean bioavailability of 0.77 was calculated for the six subjects, and it was postulated that this incomplete availability is due to a first-pass effect. The inter-individual variation in the degree of first-pass was considerable (0.47–1.14).     

The pharmacokinetics and pharmacodynamics of rocuronium in patients with hepatic cirrhosis

Aims To determine the effects of hepatic cirrhosis on the pharmacodynamics and pharmacokinetics of rocuronium bromide. Methods We studied 21 healthy patients and 17 patients with mild or moderate cirrhosis (Child-Pugh Class A and B). Patients were premedicated with diazepam orally; anaesthesia was induced with fentanyl and thiopentone, and maintained with isoflurane 0.6% (end-tidal) and nitrous oxide 66% in oxygen. The compound action potential of the adductor pollicis muscle in response to supramaximal stimulation of the ulnar nerve was recorded using the train-of-four (TOF) twitch technique. A bolus dose of rocuronium 0.6 mg kg⁻¹ was then given. Venous blood samples were taken for up to 8 h, and plasma rocuronium concentrations determined by h.p.l.c. Results The time to onset of neuromuscular block and maximal block achieved did not differ between the two groups. The mean (s.d.) recovery times were prolonged in the cirrhotic compared with the healthy group: 25% recovery T₁:T₀, 53.7 (18.1) vs 42.3 (14.2) min; 50% recovery T₁:T₀, 73.9 (33.9) vs 52.6 (19.8) min; 75% recovery T₁:T₀, 84.2 (24.5) vs 66.8 (27.2) min (all P<0.05); recovery of T₄:T₁ to 70%, 114.9 (31.7) vs 76.1 (28.8) min (P<0.01). A pharmacokinetic and pharmacodynamic model was fitted to the data for each patient. Three compartments were used to model the pharmacokinetic data; an effect compartment was added to model the pharmacodynamic data. Plasma clearance was significantly reduced in the cirrhotic group (2.66 (0.60) vs 3.70 (1.03) ml kg⁻¹ min⁻¹; P<0.005). The central (V₁ ) and steady state volumes of distribution (V_ss ) did not differ significantly between the groups. The slow redistribution (t½,λ1 ) and elimination (t_½,z ) half-lives were both significantly prolonged in cirrhosis (28.3 (12.1) vs 16.8 (4.6) min, P<0.005; and 143 (80) vs 92 (40) min, P<0.05 respectively). The exit rate constant for the effect compartment k_eo was significantly increased in the cirrhotic group (0.25 (0.18) vs 0.16 (0.06) min⁻¹; P<0.05), but cirrhosis had no significant effect on the parameters of the concentration-effect relationship Cp^ss50 and γ. Conclusions Hepatic elimination is an important pathway in the clearance of rocuronium, and delayed disposition causes the effect to be prolonged.     

Population pharmacokinetics of tolvaptan in healthy subjects and patients with hyponatremia secondary to congestive heart failure or hepatic cirrhosis

Tolvaptan is a selective V₂‐receptor antagonist used to treat hypervolemic and euvolemic hyponatremia. A population pharmacokinetic (PK) analysis was performed for tolvaptan in NONMEM® based upon data obtained from three trials conducted in 93 healthy subjects and six trials conducted in 628 congestive heart failure (CHF) patients or 24 hepatic cirrhosis patients receiving oral tolvaptan (5 to 240 mg). A two‐compartment model with first‐order absorption and elimination best described tolvaptan PK. Relative oral bioavailability was modeled relative to 100% for a 30 mg dose and ranged from 79.4% to 122%. Body weight and the impact of CHF or hepatic cirrhosis relative to healthy subjects were statistically significant (p < 0.001) predictors of both the apparent oral clearance (CL/F) and apparent central volume of distribution (V_c/F). The CL/F was reduced to 58.2% for New York Heart Association (NYHA) Class 1 or 2 CHF, 45.5% for NYHA Class 3 or 4 CHF, and 58.0% for hepatic cirrhosis relative to healthy subjects. V_c/F was reduced to 59.9% for NYHA Class 1 or 2 CHF and 51.3% for NYHA Class 3 or 4 CHF, and was 64.8% larger for severe hepatic cirrhosis (Child‐Pugh score ≥ 10) relative to healthy subjects. A slight additional decrease in CL/F of 18.3% was also detected for patients with moderate hyponatremia (serum sodium of 115–130 mEq/l) after adjusting for CHF or cirrhosis (p < 0.001). This population PK model enabled assessment of tolvaptan PK with varying degrees of CHF and hepatic cirrhosis with fluid overload and may be used to explore PK‐PD relationships with respect to fluid and electrolyte balance. Copyright © 2013 John Wiley & Sons, Ltd.     

The pharmacokinetics and pharmacodynamics of perindopril in patients with hepatic cirrhosis.

1. Perindopril, a new ACE inhibitor, is a prodrug requiring conversion into its active form perindoprilat by hydrolysis in the liver. 2. The pharmacodynamics and pharmacokinetics of perindopril (8 mg oral) and perindoprilat (2 mg intravenously) were studied in a double-blind randomised crossover study in a group of patients with compensated biopsy-proven hepatic cirrhosis. 3. Blood pressure and heart rate responses were similar after the two routes of administration as were plasma renin activity and aldosterone levels following dosing. 4. The AUC of perindoprilat after oral administration of perindopril represented 46 +/- 4% of the total AUC of perindopril and its metabolite when expressed in molar terms. Comparison with the AUC of perindoprilat after its intravenous administration suggested that 30 +/- 6% of the oral dose of perindopril was converted to its active metabolite. 5. The findings are comparable with those in healthy subjects. It appears that the presence of relatively mild hepatic cirrhosis does not significantly alter the pharmacokinetics of perindopril.     

Single-dose pharmacokinetics of felbamate in patients with renal dysfunction

Aims The purpose of this study was to evaluate the effects of renal impairment on the single-dose pharmacokinetics of the antiepileptic felbamate.
Methods Twelve subjects with three levels of renal dysfunction (creatinine clearance >30–80, >10–30 or 5–10  m  min⁻¹ ) and four controls with normal renal function (creatinine clearance >80  ml min⁻¹ were studied). Plasma and urine samples were obtained for 144  h following administration of a single 1200  mg dose.
Results Compared with controls, apparent total body clearance, renal clearance and urinary excretion of felbamate were decreased, and half-life, C _max and AUC values were increased in subjects with renal dysfunction. The magnitude of these changes was associated with the degree of renal dysfunction. Nonrenal clearance and apparent volume of distribution values were also lower in renal dysfunction subjects, but there was no association between the extent of these changes and degree of renal dysfunction. Renal clearance of felbamate accounted for approximately 30% of apparent total body clearance in the control group and from 9–22% in the renal failure patients. Renal clearance of felbamate was significantly correlated with creatinine clearance ( r ²=0.75; P <0.001).
Conclusions These data suggest that initial dosage and titration of felbamate may require adjustment in patients with renal dysfunction.