Effect of severe renal impairment on the pharmacokinetics of azimilide following single dose oral administration

AIMS: To assess the influence of severe renal impairment on azimilide pharmacokinetics. METHODS: A single oral dose of 125 mg azimilide dihydrochloride was administered to subjects with normal and severely impaired renal function. Blood and urine samples were collected for 22-28 and 10 days, respectively. RESULTS: Azimilide renal clearance decreased in subjects with renal impairment (mean 14 vs 4.8 ml h-1 kg-1, 95% confidence interval on the ratio 0.23, 0.50). However, no change in any other pharmacokinetic parameter including oral clearance (mean 109 vs 104 ml h-1 kg-1, 95% confidence interval on the ratio 0.67, 1.36) was observed. CONCLUSIONS: Since azimilide blood concentrations are essentially unaffected by renal function, an a priori dosage regimen adjustment is not required in patients with renal impairment.     

Pharmacokinetics and effects on blood pressure of a single oral dose of milrinone in healthy subjects and in patients with renal impairment

Summary Milrinone, a new, nonglycosidic inotropic agent with peripheral vasodilating properties, was given as a single oral 5 mg dose to 7 healthy subjects, 7 patients with moderate renal impairment (CRI I, creatinine clearance 30–63 ml/min) and 7 patients with severe renal impairment (CRI II, creatinine clearance 9–29 ml/min). All except one of the patients with renal impairment had hypertension. The mean urinary recovery of milrinone was 82% in healthy subjects, the renal clearance was 288 ml/min and the plasma half-life (t_1/2) was 0.94 h. In CRI the mean plasma t_1/2 was prolonged (CRI I 1.78 h, CRI II 3.24 h). There was a significant linear relationship between creatinine clearance and the elimination rate constant, and between creatinine clearance and the renal clearance of milrinone. During the study day there was a tendency to a decrease in supine BP from 1 to 6–8 h after dosing, with the maximal decrease at 2–3 h (healthy subjects 118/71107/56, CRI 159/95136/79 mmHg). The same degree of change was seen in standing BP. A slight rise in standing HR was seen from 2–6 h after dosing. Changes in BP and HR are difficult to evaluate since the study was not placebo-controlled.The plasma elimination rate of milrinone was decreased in CRI and dose adjustment may be necessary. Placebo-controlled studies of milrinone in hypertensive patients would be required to validate its possible antihypertensive effect.     

Disposition kinetics of spironolactone in hepatic failure after single doses and prolonged treatment

Summary Six male patients with histologically characterised, decompensated liver disease who had not previously received spironolactone, were given orally Aldactone^® 7 mg/kg with³H-spironolactone 100 µCi. The kinetics of the drug were studied in plasma and urine for 6 days. Then, Aldactone^® 7 mg/kg was given daily for 12 consecutive days, and the pharmacokinetics of a single dose of³H-spironolactone were re-examined. The kinetics of total radioactivity, as well as of fluorigenic metabolites in plasma, after the first single dose of spironolactone did not differ in patients and normal test subjects; similar percentages of the dose given were excreted within 6 days in urine from patients (47.47±4.88%) and from controls (53.68±2.04%). The kinetics of CH₂Cl₂/H₂O distribution coefficients of labelled material in plasma and urine, as well as TLC analysis of the CH₂Cl₂ soluble fraction, revealed no significant differences from controls. After treatment for 12 days with spironolactone, 4 out of 6 patients showed marked acceleration in the rate of elimination of radioactivity from plasma and a corresponding increase in excretion of labelled compounds in urine. Analysis of the excretion products in urine revealed proportionally increased excretion and no evidence of selective induction of a single degradation step. In contrast, delayed elimination was observed in the 2 other patients after 12 days' treatment. However, this was due to dehydration and oliguria caused by over-treatment with the diuretic.     

Pharmacokinetics of triptorelin after intravenous bolus administration in healthy males and in males with renal or hepatic insufficiency

Aims Triptorelin is a gonadotropin-releasing hormone (GnRH) analogue with enhanced affinity for GnRH receptors and a prolonged half-life due to its resistance to enzymatic degradation. The sustained-release formulation of this molecule is advantageous in conditions requiring chronic hormone suppression. Methods This was an open study to determine the pharmacokinetics of a single i.v. bolus dose of 0.5 mg triptorelin acetate in four groups of six male subjects; namely in healthy subjects (Group I), in patients with varying degrees of renal insufficiency (Groups II and III), and in patients with hepatic insufficiency (Group IV). Results The maximum concentrations of triptorelin were found to be similar for all four study groups (geometric mean C_max between 41.6 mg ml⁻¹ and 53.9 mg ml⁻¹ ). The total clearance of triptorelin decreased with increasing renal impairment, and was even lower in patients with hepatic insufficiency (geometric mean CL_tot: 210 ml min⁻¹, 113 ml min⁻¹, 86.8 ml min⁻¹ and 57.3 ml min⁻¹ for Groups I, II, III and IV, respectively). Serum triptorelin concentrations in all four groups were adequately described by a three-compartment model. The elimination half-life for patients with hepatic impairment was similar to that of patients with renal impairment (geometric mean t_{1/2, z}: 6.6 h, 7.7 h and 7.6 h for Groups II, III and IV, respectively), but significantly longer than in healthy volunteers (2.8 h for Group I). The first and second distribution half-lives were similar for the four groups studied, with geometric mean distribution half-lives of about 0.1 h (6 min) and 0.75 h (45 min), respectively. Conclusions Although both renal and hepatic function are important for the clearance of triptorelin, the liver plays the predominant role in subjects suffering from some degree of renal impairment.     

Pharmacokinetics of cefadroxil in patients with terminal renal impairment

The pharmacokinetics of cefadroxil were studied in 15 subjects divided into 3 groups: healthy volunteers, patients with terminal renal impairment in interdialysis sessions and patients with terminal renal impairment undergoing hemodialysis sessions.The serum levels of the antibiotic were determined by a microbiologic plate diffusion method using Bacillus subtilis (ATCC no. 6633) as the test organism.Renal impairment causes a decrease in the elimination rate of the antibiotic. The serum half-life has a value of 1.20 ± 0.21 h in the healthy volunteers, 26.56 ± 8.00h in patients in interdialysis periods and 2.45 ± 0.72 h in patients undergoing hemodialysis sessions.Hemodialysis partially restores absorption and elimination of cefadroxil to levels which approach those established in healthy volunteers.     

Clinical pharmacological studies with the vasodilator endralazine in patients with renal impairment

Summary The influence of renal impairment on the pharmacokinetics of endralazine was studied in 12 patients; 4 patients on regular haemodialysis therapy (creatinine clearance less than 5 ml/min) and 8 patients with varying degrees of renal impairment (creatinine clearance 11–52 ml/min). Following an oral dose of 10 mg endralazine the mean terminal elimination half-life (t_1/2) in the dialysis sub-group was prolonged at 7.1 h (range 3.3 to 14 h), compared to 3.6 h in the other renal patients (and compared to 2.3 h in hypertensive patients with normal renal function). After one week's therapy with 10 mg B.D. endralazine in the 8 patients with moderate renal impairment there was a significant increase in t_1/2 to 8.6 h but there was no significant change in the area under the drug concentration-time curve and no evidence of drug accumulation. In this study those patients with the poorest renal function had the longest t_1/2 after acute dosing. There was a significant correlation between creatinine clearance and acute t_1/2 but there was considerable variability in individual patients and, even with severe degrees of renal impairment, major dose adjustments do not appear necessary.     

Pharmacokinetics of butorphanol nasal spray in patients with renal impairment

1The pharmacokinetics of butorphanol were evaluated in 18 female volunteers with varying degrees of renal function following a single, 1 mg transnasal dose of butorphanol tartrate. The creatinine clearance (CL_CR) values for subjects in the normal (NOR), moderately impaired (MI), and severely impaired (SI) groups were ≥70 ml min⁻¹, 30–60 ml min⁻¹, and ≤30 ml min⁻¹, respectively. 2Serial blood and urine samples were collected immediately after dosing for 48 h. Plasma concentrations of butorphanol were determined using a specific radioimmunoassay. Urine concentrations of butorphanol and its metabolites (hydroxy-butorphanol, norbutorphanol and their glucuronide conjugates) were determined using h.p.l.c. with fluorescence detection. 3There was no significant difference between the three treatments for peak plasma concentration of butorphanol and time to peak. Statistically significant differences were detected among the study groups for AUC, t_1/2, MRT, and CL_R with the mean values for severely impaired subjects significantly different from those of normal renal subjects; mean values for moderately impaired subjects were not significantly different from either the normal or severely impaired groups for all respective parameters. 4The elimination half-life of butorphanol increased from 5.75 h in NOR to 10.48 h in SI. A similar trend was observed for MRT. Creatinine clearance (CL_CR) significantly correlated with CL_R (r=0.563, P=0.019), CL_T/F (r=0.505, P=0.033), t_1/2 (r=−0.554, P=0.017) and λ (r=0.606, P=0.008). 5Although the exposure of butorphanol was greater in subjects with renal impairment, there was no trend for an increase in the number of adverse experiences reported by subjects with renal dysfunction. 6Patients with less than 30 ml min⁻¹ creatinine clearance may require less frequent administration of transnasal butorphanol as compared with subjects with normal or moderately impaired renal function.     

Posology adjustments of oral antineoplastic agents for special populations: patients with renal impairment,hepatic impairment and hematologic toxicities

Background: Oral antineoplastic agents (OAA) have reached 30–50% of all antineoplastic treatments. Although they seem safer than parenteral therapy, many severe problems can occur if the dose is not adequately adjusted in special situations. Our objective is to create a comprehensive guide with dosage adjustment recommendations for OAA in cases of renal and hepatic impairment and hematologic toxicities.

Research design and methods: We analyzed all OAA approved by EMA in July 2017. We assessed data related to dose adjusted from the FDA’s and EMA’s summary of product characteristics.

Results: 53 OAA were analyzed. We identified 44 (83%) OAA requiring dosage adjustments in special situations: 20 (37.7%) in renal impairment, 37 (69.8%) in hepatic impairment, and 22 (41.5%) in patients with hematologic toxicity. The dose adjustment recommendations varied in 31 (58.5%) OAA between the FDA and EMA. Detailed recommendations for each OAA were collated into comprehensive tables.

Conclusions: Most OAA have to be adjusted in special situations. Given the number of OAA available for different indications, this review can serve as an easy tool to help health professionals dose these complex treatments.     

Pharmacokinetics of sotalol after chronic administration to patients with renal insufficiency

Summary Ten hypertensive patients with moderate to severe impairment of renal function were treated with sotalol for 5 to 10 weeks (average 6.4 weeks). Dosage was individually titrated (range 80 to 480 mg daily). The drug was given once daily in the morning. In eight patients blood pressure was satisfactorily controlled. Higher steady-state levels were observed than have been reported after similar doses in patients with normal renal function. The apparent first-order elimination rate constant and plasma clearance were significantly correlated with glomerular filtration rate. For an anuric patient, serum half-life was calculated to be 69 h. In relation to the raised plasma levels, side effects were uncommon. Since sotalol is excreted predominantly via the kidney, therapy in patients with impaired renal function should start with a low dose and any increase in dosage should be made carefully. As the anti-hypertensive effect does not appear to be correlated with the plasma level or with tolerance, adjustment of dose should be based on clinical response.     

Steady-state levels of pefloxacin and its metabolites in patients with severe renal impairment

Summary Twenty patients (aged 26–70 years) with severely impaired renal function received pefloxacin twice daily for 5 days as 12 mg·kg^–1 administered as a 1 h i.v. infusion, or 800 mg administered as tablets.On Day 5 the minimal and maximal plasma concentrations were 5.9 and 11.5 mg·l^–1 respectively, after the infusion, and 8.0 and 10.4 mg·l^–1, respectively, after oral administration. The steady-state level of the N-desmethyl metabolite ranged from 0.9 (infusion) to 1.2 mg·l^–1 (oral route), and that of the N-oxide metabolite ranged from 6.2 (infusion) to 9.0 mg·l^–1 (oral route). The minimal concentration of unchanged drug was related to the age of the patients (infusion), but the N-oxide concentration was influenced by the degree of renal impairment (both routes).The pefloxacin levels were similar to those achieved in healthy subjects, but reduced renal function leads accumulation of its biotransformation products, especially of the N-oxide metabolite which lacks antibacterial activity.     

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 effects of hepatic impairment on the pharmacokinetics of fosfluconazole and fluconazole following a single intravenous bolus injection of fosfluconazole

AIMS: Fosfluconazole is a phosphate pro-drug of fluconazole (FLCZ). This study was conducted to determine the pharmacokinetics of fosfluconazole and FLCZ following a single intravenous injection of fosfluconazole in subjects with hepatic impairment and to compare them with healthy subjects. METHODS: Twenty-four subjects (12 with normal hepatic function and 12 with chronic stable mild to moderate impaired hepatic function) received a single 1000-mg bolus intravenous injection of fosfluconazole. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 192 h and 48 h postdose, respectively. RESULTS: The total clearance of fosfluconazole was higher and the t(1/2,Z) and mean residence time were shorter in hepatically impaired subjects than in normal subjects. This may reflect more rapid conversion to FLCZ. The degree of protein binding of fosfluconazole (> 90%) and the amount of fosfluconazole excreted in the urine were similar in both groups. Slightly higher mean plasma concentrations of FLCZ were observed in the impaired group than in the normal group; however, hepatic impairment had no statistically significant effect on the FLCZ pharmacokinetic parameters apart from t(max). The t(max) values were 4.8 h and 3.1 h in the normal and impaired subjects, respectively. The shorter t(max) for FLCZ is also consistent with the more rapid conversion in the impaired subjects. The ratios (95% confidence intervals) for C(max) and AUC of FLCZ (impaired/normal) were 106.0% (92.8, 121.2) and 115.6% (86.4, 154.7), respectively. There were no serious adverse events, and no discontinuations due to adverse events or laboratory test abnormalities. The adverse events reported were mostly mild in severity and no trend could be discerned between the groups. CONCLUSIONS: Fosfluconazole was more rapidly converted to FLCZ in the hepatically impaired subjects but the FLCZ pharmacokinetic parameters (except t(max)) were not statistically significantly affected by hepatic impairment. Fosfluconazole was well tolerated by both groups. These results suggest that there is no requirement to adjust the dose of fosfluconazole when administered to subjects with mild to moderate hepatic impairment.     

Pharmacokinetics of antofloxacin hydrochloride in healthy male subjects after multiple intravenous dose administration

1. The purpose of the study was to evaluate pharmacokinetic characteristics of antofloxacin hydrochloride, a new fluoroquinolone antibiotic, during a multiple, intravenous dosing regimen.

2. Twelve healthy, Chinese male volunteer subjects were each given 300?mg of antofloxacin by intravenous infusion once daily for 7 days. Blood and urine samples were taken at designated time points for analysis of antofloxacin concentration by high-performance liquid chromatography (HPLC). Safety and tolerability were assessed by evaluation of subject complaints, vital signs, electrocardiograms, electroencephalograms, clinical chemistry parameters, haematology and urinalysis and prothrombin time.

3. The serum steady concentration of antofloxacin was obtained in 96?h after the administration of a daily intravenous dose of 300?mg of the drug. In the present study, the following pharmacokinetic parameters after 7 days of treatment with antofloxacin were determined to be: C_max 3.81?±?0.66?mg/L, C_min 0.85?±?0.19?mg/L, AUC_0–24 60.51?±?8.30?mg/L·h, C_av 2.52?±?0.35?mg/L, PTF 87.45?±?3.37%, t_1/2β 20.34?±?1.88?h. The C_max and AUC_0–24 after 7-day treatment were both higher than after the first dose (by 43% and 110%, respectively). The cumulative urinary elimination of antofloxacin within 96?h after the last dose was about 56%.

4. During the study, there were neither subject complaints nor significant adverse clinical findings.

5. Antofloxacin, administered intravenously as a single, daily 300?mg dose for 7 days, demonstrated favourable pharmacokinetic characteristics and tolerability. The results of this study indicate that antofloxacin hydrochloride is suitable for further clinical study.

     

Pharmacokinetics of canrenone and metabolites after base hydrolysis following single and multiple dose oral administration of spironolactone

Summary The pharmacokinetics of canrenone and total metabolites after base hydrolysis was studied in eight young volunteers following single and multiple dose oral administration of spironolactone. The plasma levels of canrenone and total metabolites were fitted to a two-compartment open model with a first-order absorption process. From our eight normal subjects studied, the harmonic mean of the distributive half-life (t_1/2) of canrenone was found to be 1.66 h, and the harmonic mean of the terminal elimination half-life (t_1/2) to be 22.6 h. Harmonic means of the distributive and elimination half-lives of total metabolites after base hydrolysis were 2.48 h and 28.8 h respectively. The accumulation ratio of canrenone was 2.53, whereas that of total metabolites was 1.89. Despite the fact that spironolactone has been shown to induce hepatic metabolism of other drugs, no evidence of autoinduction was noted in the present study, as plasma levels of canrenone and total metabolites were found to obey a linear two-compartment model with reproducible absorption and disposition after single and multiple doses.     

Erythromycin absorption in healthy volunteers from single and multiple doses of enteric-coated pellets and tablets

Summary The absorption of erythromycin from two different enteric-coated preparations was evaluated in three groups of healthy volunteers. After a single dose, taken after an overnight fast, absorption was significantly better from enteric-coated pellets than from tablets; both the mean peak serum concentration and the peak mean level were higher (p<0.01) in all three groups, and the mean area under the serum concentration-time curve (AUC) was at least 65% larger. Eight out of 23 subjects showed no or only a very low serum concentration after the enteric-coated tablets. In a follow-up study, 250 mg doses were given 6-hourly for 3 days, and again the mean maximum serum concentration was significantly higher (p<0.05) after the pellets. In conclusion, enteric-coated pellets led to more regular and predictable absorption of erythromycin than did coated tablets.     

Pharmacokinetics of enprofylline in patients with impaired renal function after a single intravenous dose

Summary Enprofylline, a new bronchodilating drug, was given i.v. at 1.0 mg/kg to 7 healthy subjects and to 14 patients with differing degrees of chronic renal insufficiency. Plasma and urine concentrations of unchanged drug were followed by HPLC. In the patients the plasma half-life was prolonged and the total and renal clearances were reduced in direct proportion to the degree of renal insufficiency as determined by creatinine clearance. The unbound fraction of enprofylline in plasma increased from 55% in the healthy subjects to 66% in the group of patients with the highest degree of renal impairment. The volume of distribution terms, V and V_ss, both tended to decrease with decreasing creatinine clearance. When the volume term calculations were based on the unbound drug level in plasma, this tendency was enhanced. Side-effects were noted in 4 subjects, and to some extent were related to the plasma level of the drug.     

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.     

Effect of renal function on risedronate pharmacokinetics after a single oral dose

AIMS: To determine the relationship between risedronate pharmacokinetics and renal function. METHODS: Risedronate was administered to adult men and women (n=21) with various degrees of renal function (creatinine clearance 15-126 ml min-1 ) as a single oral dose of 30 mg. Serum samples were obtained for 72 h after dosing, and urine samples were collected for 72 h after dosing and then periodically for 6 weeks. Risedronate concentrations were determined using an enzyme-linked immunosorbent assay (ELISA). Risedronate serum concentration-time and urinary excretion rate-time profiles were analysed simultaneously using nonlinear regression. RESULTS: Renal clearance and volume of distribution were linearly related to creatinine clearance (r2=0.854, P<0.001; and r2=0.317, P<0.01, respectively). Decreases in predicted renal clearance and volume of distribution of 82 and 69%, respectively, were observed when creatinine clearance decreased from 120 to 20 ml min-1. A 64% decrease in predicted oral clearance was observed when creatinine clearance decreased from 120 to 20 ml min-1 (P=0.064). Iohexol clearance, a predictor of renal function, produced similar results to those observed with creatinine clearance. Risedronate was well tolerated by the study population. CONCLUSIONS: Risedronate renal clearance was significantly related to a decrease in renal function. There was a consistent reduction in oral clearance with a decrease in creatinine clearance. However, based on the regression analysis, generally no dosage adjustment appears to be necessary for most patients with mild or moderate renal impairment (creatinine clearance >20 ml min-1 ).