Steady-state pharmacokinetics of nefazodone in subjects with normal and impaired renal function

The steady-state pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were compared in subjects with normal and impaired renal function. Patients: The Study was of parallel group design which included 7 subjects with normal (NOR) renal function, CL_CR72 ml·min^–1·1.73 m^–2, 6 with moderate (MOD) renal impairment, CL_CR 31–60 ml·min^–1·1.73 m^–2 and 9 with severe (SEV) renal impairment, CL_CR30 ml·min^–1·1.73 m^–2. Subjects in each renal function group received a 100-mg oral dose of nefazodone hydrochloride BID for 7 days and a single morning dose on day 8. Starting 48 h after the last 100-mg dose, 200-mg doses were administered on a similar schedule to 3, 4 and 3 subjects from each renal function group (NOR, MOD and SEV, respectively). Single trough blood samples just prior to each morning dose (C_min) and serial samples after the dose on day 8 were obtained at each dose level for pharmacokinetic analysis. Plasma samples were assayed by a specific HPLC method for NEF, HO-NEF and mCPP.The CMIN data indicated that steady state was attained by the third day of BID administration of both the 100- and 200-mg doses of nefazodone, regardless of degree of renal function. Both NEF and HO-NEF attained steady-state C_max within 2 h after administration of nefazodone; t_max for mCPP was less defined and more delayed. HO-NEF and mCPP plasma levels were about 1/3 and <1/10 those of NEF, respectively, regardless of the status of renal function. Steady-state systemic exposure of NEF and HO-NEF, as reflected by AUC and C_max, and elimination t_1/2 values did not differ significantly among renal function groups. Conclusion: The study results suggest that dose adjustments may not be necessary, but nefazodone should be used with caution in the presence of severe renal impairment.     

Garenoxacin pharmacokinetics in subjects with renal impairment*

ABSTRACT

Objective: This open-label, parallel-group study determined the pharmacokinetics of garenoxacin in subjects with severe renal impairment, including subjects maintained on dialysis.

Research design and methods: Subjects were assigned to one of four groups according to their underlying renal function: creatinine clearance (CL_cr) > 80?mL/min, CL_cr < 30?mL/min, hemodialysis (HD), and continuous ambulatory peritoneal dialysis (CAPD). Subjects received a single oral 600?mg dose of garenoxacin. Administration of garenoxacin to subjects receiving hemodialysis was completed in two phases separated by 14 days: 3?h before HD (phase 1) and immediately after HD (phase 2).

Main outcome measures: Plasma and urine or dialysate samples were analyzed for garenoxacin, and single-dose pharmacokinetic parameters were estimated. Safety was assessed.

Results: Twenty-five subjects received garenoxacin. Compared with healthy controls, garenoxacin area under the concentration–time curve (AUC) and maximum plasma concentration were increased by 51% and lowered by 20%, respectively, in subjects with severe renal impairment. The terminal half-life was prolonged in subjects with severe renal impairment compared with healthy controls (26.5 ± 7?h vs 14.4 ± 3?h, respectively). In subjects receiving HD or CAPD, removal of garenoxacin from systemic circulation was relatively inefficient (HD, 1.5–11.5%; CAPD, 3%), suggesting no need for a supplemental dose of garenoxacin after dialysis. Garenoxacin was well tolerated.

Conclusions: Based on the broad therapeutic index of garenoxacin, the effects of renal impairment on garenoxacin exposure are not considered clinically significant. There was a modest increase in AUC in subjects with severe renal impairment and the magnitude of the changes was not considered clinically relevant.     

Single-dose pharmacokinetics and tolerability of pegylated interferon-alpha2b in young and elderly healthy subjects

AIMS: To assess the single-dose pharmacokinetics and tolerability of pegylated interferon-alpha2b (PEG-Intron) in young and elderly healthy subjects. METHODS: In this parallel-design study, a single 1 microg x kg(-1) PEG-Intron dose was given subcutaneously to 24 subjects in the age groups 20-45, 65-69, 70-74 and 75-80 years (n = 6/group). Blood sampling and tolerability assessments were performed up to 168 h postdose. RESULTS: The pharmacokinetic parameters were similar in all age groups. The elderly to young subject ratios for Cmax were 91.1, 79.5, and 107% for the 65-69 years, 70-74 years and 75-80 years groups, respectively. The corresponding values for AUC(0- infinity ) and CL/F were 111, 102 and 108%, and 82.5, 95.8 and 86.4%, respectively. Mean differences from the 20 to 45 years group and the 65-69 years, 70-74 years and 75-80 years groups for PEG-Intron Vd/F were 108, 128 and 104%, respectively. None of these differences was statistically significant based on ANOVA. Results from a Dunnett's test (as post hoc assessment) confirmed that the pharmacokinetic parameters of Group II, Group III or Group IV were not different from those of Group I. Almost all (23/24; 96%) subjects reported typical interferon-alpha side-effects (flu-like symptoms, headache). One elderly patient had a myocardial infarction 12 h postdose, but recovered fully. CONCLUSIONS: There are no pharmacokinetic reasons for initial dose adjustment of PEG-Intron based on age.     

Single-dose pharmacokinetics of paracetamol and its conjugates in Chinese non-insulin-dependent diabetic patients with renal impairment

Objective: A single oral dose of paracetamol (20 mg · kg⁻¹) was given to 38 Chinese patients with non-insulin-dependent diabetes mellitus (NIDDM) who had either normal renal function or varying degrees of renal impairment, with creatinine clearances ranging from 4 to 123 ml · min⁻¹ · 1.73 m⁻². The plasma and urinary concentrations of paracetamol and its major metabolites were measured by high-performance liquid chromatography (HPLC). Results: The absorption and elimination of paracetamol were unaffected by renal impairment. However, the area under the plasma concentration time curve and the elimination half-life of paracetamol metabolites increased significantly with worsening renal insufficiency. Mean renal clearances of paracetamol and its conjugates were significantly reduced in these subjects. There was no evidence of altered metabolic activation with renal impairment. Conclusion: The results demonstrate that paracetamol disposition is minimally affected by diabetic nephropathy; however, extensive accumulation of conjugates may occur. Received: 2 September 1996 / Accepted in revised form: 11 December 1996     

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.     

Meloxicam pharmacokinetics in renal impairment

Aims The aim of the present study was to determine how the pharmacokinetics of meloxicam are affected by kidney dysfunction and consequently to define the appropriate dose for the use of meloxicam in patients with mild or moderate renal impairment.
Methods Meloxicam was administered to subjects with mild (creatinine clearance 41–60 ml min⁻¹) to moderate (20–40 ml min⁻¹) renal impairment compared with normal renal function (>60 ml min⁻¹). Thirty-eight subjects received meloxicam 15 mg once daily over 9 days. Meloxicam plasma concentrations were determined from blood samples taken during the study and pharmacokinetic parameters calculated according to noncompartmental methods.
Results Subjects with no or mild renal impairment showed sinular pharmacokinetic profiles (geometric mean AUC_SS (%gCV) 55 (33%) vs 55 (38%) μg ml⁻¹ h). Subjects with moderate renal impairment demonstrated lower total plasma meloxicam concentrations (AUC_SS 35 (50%) μg ml ⁻¹ h, with corresponding higher plasma clearance ( P = 0.013) compared with subjects with no renal impairment. However, this was combined with higher meloxicam free fractions in moderately impaired subjects such that free meloxicam concentrations were similar in all three groups. Meloxicam was well tolerated with few adverse events occurring and no difference in incidence observable between groups.
Conclusions On the basis of these results there is no necessity for a dosage adjustment when administering meloxicam to patients with mild to moderate renal impairment.     

The pharmacokinetics and safety of darapladib in subjects with severe renal impairment

Aim

Darapladib is a potent and reversible orally active inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂). The aim of the study was to assess the effects of severe renal impairment on the pharmacokinetics and safety/tolerability of darapladib compared with normal renal function.

Methods

This was an open label, parallel group study of darapladib following 10 day once daily 160 mg oral dosing in subjects with normal (n = 8) and severe renal impairment (estimated glomerular filtration rate <30 ml min^–1 1.73 m^–2, n = 8). Plasma concentrations of total and unbound darapladib as well as total darapladib metabolites were determined in samples obtained over 24 h on day 10.

Results

Plasma concentrations of total and unbound darapladib as well as all three metabolites were higher in subjects with severe renal impairment. Area under the plasma concentration vs. time curve between time zero and 24 h (AUC(0,24 h) and maximum plasma concentration (C_max) of total darapladib in severely renally impaired subjects were 52% and 59% higher than those in the matched healthy subjects, respectively. Similar results were found with the darapladib metabolites. Darapladib was highly plasma protein bound with 0.047% and 0.034% unbound circulating in plasma in severely renally impaired and healthy subjects, respectively. Unbound plasma darapladib exposures were more than two-fold higher in severely renally impaired subjects than in healthy controls. Adverse events (AE) were reported in 38% of healthy subjects and 75% of severely renally impaired subjects, most of which were mild or moderate in intensity.

Conclusions

The results of this study showed that darapladib exposure was increased in subjects with severe renal impairment compared with healthy controls. However, darapladib was generally well tolerated in both groups.     

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.     

Nefazodone pharmacokinetics: assessment of nonlinearity,intra-subject variability and time to attain steady-state plasma concentrations after dose escalation and de-escalation

Objective: The time required to reach steady-state plasma levels after an increase and a subsequent decrease in the dose of nefazodone, an antidepressant drug with nonlinear pharmacokinetics, was assessed in 24 healthy, male volunteers. Methods: Each subject was administered 100 mg nefazodone hydrochloride b.i.d. (q 12 h) from study day 1 to 7, 200 mg b.i.d. from study day 8 to 14 and 100 mg b.i.d. from study day 15 to 21. Trough (C_min blood samples were obtained just prior to the morning dose on days 4–7, 11–14 and 16–21 to evaluate the attainment of steady state. Serial blood samples were collected for 12 h after the morning dose on days 7, 14, 16, 18 and 21 for pharmacokinetic analysis of plasma levels of nefazodone (NEF) and its metabolites, hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and triazoledione (DIONE), which were determined by validated HPLC/UV assay methods. The C_min results indicated that when nefazodone was administered at a dose of 100 mg b.i.d., steady-state plasma levels of parent compound and its metabolites were attained by the 4th day (i.e., after six doses) and when the dose was increased from 100 mg b.i.d. to 200 mg b.i.d. and then decreased back to 100 mg b.i.d., new steady-state plasma levels were also reached by the beginning of the 3rd or 4th day of each regimen. Consistent with the attainment of steady-state data, there were no statistically significant differences in C_max or AUC values for nefazodone or its metabolites between study days 7, 18 and 21. Also consistent with the known nonlinear pharmacokinetics of nefazodone, the mean nefazodone steady-state C_max and AUC values for the 200-mg dose were three fold and four fold greater, respectively, than those at the 100-mg dose level. Intrasubject variability (% cv) for NEF and its metabolites ranged from 13% to 24% for C_max and AUC after 100 mg b.i.d.. Intersubject variability was considerably greater and ranged from 29% to 131% for C_max and AUC after the same dose. Received: 12 June 1995/Accepted in revised form: 2 October 1995     

Population pharmacokinetics of nefopam in elderly,with or without renal impairment,and its link to treatment response

Aims

Nefopam is a nonmorphinic central analgesic, for which no recommendation exists concerning adaptation of regimen in aged patients with or without renal impairment. The objective was to describe the pharmacology of nefopam in aged patients to obtain guidelines for practical use.

Methods

Elderly patients (n = 48), 65–99 years old, with severe or moderate renal impairment or with normal renal function, were recruited. Nefopam (20 mg) was administered as a 30 min infusion postoperatively. Simultaneously, a 1 min intravenous infusion of iohexol was performed, in order to calculate the glomerular filtration rate. Blood samples were drawn to determine nefopam, desmethyl-nefopam and iohexol plasma concentrations. Nefopam and desmethyl-nefopam concentrations were analysed using a nonlinear mixed-effects modelling approach with Monolix version 4.1.3. The association between pharmacokinetic parameters and treatment response was assessed using logistic regression.

Results

A two-compartment open model was selected to describe the pharmacokinetics of nefopam. The typical population estimates (between-subject variability) for clearance, volume of distribution, intercompartmental clearance and peripheral volume were, respectively, 17.3 l h⁻¹ (53.2%), 114 l (121%), 80.7 l h⁻¹ (79%) and 208 l (63.6%). Morphine requirement was related to exposure of nefopam. Tachycardia and postoperative nausea and vomiting were best associated with maximal concentration and the rate of increase in nefopam plasma concentration.

Conclusions

We identified the nefopam pharmacokinetic predictors for morphine requirement and side-effects, such as tachycardia and postoperative nausea and vomiting. In order to maintain morphine sparing and decrease side-effects following a single dose of nefopam (20 mg), simulations suggest an infusion time of >45 min in elderly patients with or without renal impairment.     

Population pharmacokinetics of rosuvastatin: implications of renal impairment,race, and dyslipidaemia

ABSTRACT

Objectives: To build the structural model of pharmacokinetics for rosuvastatin and evaluate the impact of demographic characteristics including renal function on its pharmacokinetic parameters.

Methods: A population pharmacokinetic analysis of rosuvastatin in healthy volunteers, subjects with dyslipidaemia, and renal failure patients was performed using non-linear mixed-effects modelling and a two-compartment pharmacokinetic model with simultaneous first- and zero-order absorption. Demographic covariates, dyslipidaemic state and renal function were evaluated for their impact on pharmacokinetic parameters by step-wise additions or deletions using the likelihood ratio test.

Results: Typical pharmacokinetic parameters were estimated for a healthy white male subject. For example, apparent oral clearance (CL/F?) was estimated to be 257?L/h. Age, smoking status, weight, body surface area, and lean body mass had no significant effect on rosuvastatin pharmacokinetics. The model predicted that CL/F for subjects with creatinine clearance (CLCR?) of 30?mL/min (moderate renal impairment) and of 50?mL/min (mild renal impairment) was 17% and 9.7% lower, respectively, relative to subjects with CLCR of 94?mL/min, the data set median value. CL/F was reduced by 71.1% and 43.7% in subjects with dyslipidaemia and in Asian subjects, respectively.

Conclusions: Reduction of CL/F of rosuvastatin is not considered clinically significant for patients with mild-to-moderate renal impairment. Rosuvastatin CL/F was reduced in subjects with dyslipidaemia, but it is important to realise that the safety/efficacy profile of rosuvastatin has been well established in this population. However, the potential for increased exposure in Asian subjects should be considered when initiating rosuvastatin treatment or increasing dose in this population.     

Disposition kinetics of buspirone in patients with renal or hepatic impairment after administration of single and multiple doses

The single dose and steady-state pharmacokinetics of buspirone and its metabolite 1-pyrimidinyl piperazine (1-PP) have been evaluated in normal volunteers and patients with renal or hepatic impairment, using a parallel group design, with assignment of patients to study group on the basis of the degree of renal (mild, moderate, severe) or hepatic (compensated or decompensated) impairment. Each healthy volunteer or patient received a single dose of 10 mg buspirone on Day 1 of the study, and starting 36 h after the first dose, healthy volunteers and patients received 10 mg doses of buspirone every 12 hours for 9 days. On the morning of Day 10 they received the last dose. Serial blood samples were collected on Days 1, 5 and 10 and plasma was analysed for buspirone and 1-PP. The plasma concentrations of buspirone and 1-PP were highly variable regardless of the renal or hepatic function. The peak concentrations (C_max) and area under the curves (AUC) of buspirone and 1-PP on Days D 5 and 10 were higher than on Day D 1. The trough levels (C_min) and AUCs (D 5 and 10) of buspirone and 1-PP indicated, that, regardless of renal or hepatic function, steady state was reached after 3 to 5 days of dosing. At steady-state, patients with renal or hepatic impairment had significantly higher C_max and AUC values of buspirone than in normal volunteers. However, the intensity and frequency of adverse experiences in patients with renal or hepatic impairment were not significantly different from those observed in normal volunteers. There was no correlation between the average plasma concentrations of buspirone ( ) and the degree of renal impairment judged by creatinine clearance. An excellent correlation was observed between of buspirone and serum albumin (r=0.862, and P<0.0001) as well as between and bromsulphalein clearance (r=0.678, P<0.0003).In view of high intra-and inter-subject variability in buspirone concentrations, definitive dosing recommendations for patients with compromised renal or hepatic function could not be made, but such patients should initially be dosed cautiously with buspirone.     

The pharmacokinetics of escitalopram in patients with hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of escitalopram was determined by means of nonlinear mixed effect modeling, considering both the Child-Pugh classification (and its components) and cytochrome P450 2C19 (CYP2C19) activity. Twenty-four subjects were grouped according to their Child-Pugh score as healthy, with mild hepatic impairment or with moderate hepatic impairment. The subjects were administered a single oral dose of escitalopram 20 mg, and blood was sampled up to 168 hours after dosage. The serum concentration of escitalopram was determined and the pharmacokinetics assessed by nonlinear mixed effect modeling. The CYP2C19 activity was measured from the urinary excretion ratio of S/R-mephenytoin. All subjects tolerated the treatment well, and no serious adverse events were reported. Predicted mean area under the curve from zero to infinity (AUC(inf)) values were 51% and 69% higher for patients with mild and moderate hepatic impairment (Child-Pugh classification), respectively, compared with healthy subjects. The best-fitting model showed an influence of CYP2C19 activity on clearance and body weight on the volume of distribution for escitalopram. CYP2C19 activity is a better predictor of escitalopram clearance than is Child-Pugh classification.     

The effect of renal function on the pharmacokinetics of ranitidine

This open study evaluated the influence of renal function on the pharmacokinetics of ranitidine (50 mg iv infusion given over 6 min). Five groups, each of 8 subjects, 1 with normal renal function and 4 with different degrees of renal impairment were studied.Renal function was assessed in each patient by ⁵¹Cr-EDTA (glomerular filtration rate, GFR), creatinine clearance (GFR) and N-methylnicotinamide clearance (reflecting glomerular and tubular function). Sixteen blood samples (5 ml) taken up to 48 h post dose from each subject were analysed for plasma ranitidine concentrations by reversed phase HPLC.Patient groups with renal impairment had significantly increased AUC and t_1/2 with corresponding decreases in CL_p and _z when compared with normal subjects. There was also a significant increase in t_max but not in C_max. There was a high linear correlation between the degree of renal impairment and ranitidine clearance.In patients with GFR 20 ml min^–1, the AUC mean ratio (compared with normal subjects) was up to 4.6 while for patients with GFR 20–50 ml min^–1, the average AUC ratio was 2.6. It is recommended that the dose of ranitidine is halved in patients with GFR 20 ml min^–1.     

Fluvoxamine pharmacokinetics in healthy elderly subjects and elderly patients with chronic heart failure

AIMS

To investigate the effects of age and chronic heart failure (CHF) on the oral disposition kinetics of fluvoxamine.

METHODS

A single fluvoxamine dose (50 mg) was administered orally to 10 healthy young adults, 10 healthy elderly subjects and 10 elderly patients with CHF. Fluvoxamine concentration in plasma was measured for up to 96 h.

RESULTS

With the exception of apparent distribution volume, ageing modified all main pharmacokinetic parameters of fluvoxamine. Thus, peak concentration was about doubled {31 ± 19 vs. 15 ± 9 ng ml⁻¹; difference [95% confidence interval (CI)] 16 (3, 29), P < 0.05}, and area under the concentration–time curve was almost three times higher [885 ± 560 vs. 304 ± 84 ng h ml⁻¹; difference (95% CI) 581 (205, 957), P < 0.05]; half-life was prolonged by 63% [21.1 ± 6.2 vs. 12.9 ± 6.4 h; difference (95% CI) 8.2 (2.3, 14.1), P < 0.01], and oral clearance was halved (1.12 ± 0.77 vs. 2.25 ± 0.66 l h⁻¹ kg⁻¹; difference (95% CI) −1.13 (−1.80, −0.46), P < 0.001]. A significant inverse correlation was consistently observed between age and oral clearance (r=−0.67; P < 0.001). The coexistence of CHF had no significant effect on any pharmacokinetic parameters in elderly subjects.

CONCLUSIONS

Ageing results in considerable impairment of fluvoxamine disposition, whereas CHF causes no significant modifications. Therefore, adjustment of initial dose and subsequent dose titrations may be required in elderly subjects, whereas no further dose reduction is necessary in elderly patients with CHF.