Clinical pharmacokinetics of antibiotics in patients with impaired renal function.

Many antibiotics are eliminated renally and dosage adjustments are commonly made in patients with renal insufficiency. This is a critical review of antibiotic pharmacokinetics in patients with various degrees of renal function. Detailed information regarding pharmacokinetic alterations with specific antibiotics or antibiotic classes has been compiled and tabulated. From pharmacokinetic evidence, recommendations for dosage adjustments of antibiotics are supplied. The criteria used for assigning rating levels to specific pharmacokinetic articles as well as the grading system for dosage adjustments are outlined. In addition, a basic review of pharmacokinetic alterations in renal failure and factors affecting the removal of drugs by haemodialysis is included.     

Clinical pharmacokinetics of nimodipine in normal and impaired renal function

Twelve patients with different degrees of renal function were investigated. Six of them had moderately impaired renal function (glomerular filtration rate-GFR 20-60 ml/min) and six were preuraemic (GFR less than 20 ml/min). Patients received a single oral dose of 30 mg nimodipine on the first and eighth day, from the second to the seventh day they received 30 mg thrice daily. The results of this study were compared with the data of a similar study with six healthy volunteers (GFR greater than 90 ml/min) who also received for one week nimodipine 40 mg three times daily. In these subjects peak plasma levels of nimodipine ranged between 15.5 and 106.7 micrograms/1 on first treatment day and did not differ significantly from those on the 7th day of therapy ranging between 17.0 and 80 micrograms/1. Mean terminal elimination half-life of nimodipine was 2.77 +/- 0.46 h in normal renal function, but was 22.23 +/- 6.94 h in patients with impaired renal function (12 patients with GFR less than 60 ml/min). The mean area under the plasma level time curve (AUC) with 541.5 +/- 16.93 ng ml-1 h increased in patients with renal insufficiency compared to those with normal renal function (74.65 +/- 9.44 ng ml-1 h). Dosage adjustment of nimodipine appears to be necessary in renal failure.     

Clinical pharmacokinetics of bezafibrate in patients with impaired renal function

Summary The pharmacokinetics of the new lipidlowering drug bezafibrate has been investigated in patients with impaired renal function and hyperlipoproteinaemia. 12 patients received a single oral dose of bezafibrate 300 mg. Plasma and urine samples were collected and bezafibrate was analyzed by gas chromatography. Eight of the patients had moderately impaired renal function, with a creatinine clearance between 20 and 40 ml/min; the mean plasma half-life of bezafibrate in them was 7.8±3.9 h (SD) and the plasma clearance was 0.03±0.02 l/kg · h. Three of the patients had a creatinine clearance>40 ml/min; in them the plasma half-life was shorter, 4.6±1.2 h, and the plasma clearance was higher, 0.06±0.01 l/kg · h. The slowest elimination of bezafibrate was found in a patient with a creatinine clearance of only 13 ml/min. This patient had a plasma half-life of 20.1 h, which is ten times longer than has been reported in healthy volunteers. Thus, when treating hyperlipoproteinaemia in patients with impaired renal function, the dosage of bezafibrate must be individualized because of its reduced renal elimination.     

Clinical pharmacokinetics of oral buspirone in patients with impaired renal function

12 patients with mild to moderate impairment of renal function and 12 healthy subjects each received 20mg buspirone as a single dose in this acute study. Six anuric patients with chronic renal failure were given two 20mg doses of buspirone, the first 2 days before haemodialysis (between dialyses) and the second during hemodialysis (2 hours before dialysis began). The differences between the median pharmacokinetic values of buspirone for healthy subjects, patients with mild to moderate renal impairment, and anuric patients were not statistically significant. Similarly, there were no significant differences between values in mild to moderate renal failure vs healthy subjects. Some of the median pharmacokinetic values for the active buspirone metabolite 1-(2-pyrimidinyl)-piperazine (1-PP), however, differed significantly for anuric patients, compared with healthy subjects or patients with mild to moderate renal impairment. When assessed between and during haemodialysis, the anuric patients had significantly (p less than 0.05) greater pharmacokinetic median values: half-life (t 1/2) = 15.2 vs 9.8 hours; area under the concentration-time curve (AUC) = 604 vs 404 nmol/L.h; and mean residence time (MRT) = 9.28 vs 6.96 hours. No firm recommendation for specific dosage can be made based on the present data. However, it does appear that in patients with mild to moderate renal impairment, the pharmacokinetics of buspirone and its active metabolite 1-PP are similar to those in individuals with normal renal function. For anuric patients higher concentrations of the 1-PP metabolite are attained while they are not undergoing haemodialysis. A dosage reduction of 25 to 50% might be necessary when buspirone is given to anuric patients.     

On the pharmacokinetics of latamoxef in normal and impaired renal function

Pharmacokinetics of latamoxef (Moxalactam) have been investigated in 10 normal volunteers and 20 patients with impaired renal function after i.v. injection of 2 g. Elimination observed in normal volunteers can best be described by a two-compartment model. In the presence of impaired renal function elimination of latamoxef is markedly prolonged. The result is a larger area under the serum level curve (area under the curve; AUC). AUC and glomerular filtration rate (as well as AUC and plasma creatinine as approximate measure of renal function) can be brought into a mathematical relation. From these relations a dose reduction factor (DRF) can be derived. By means of this factor a dose can be calculated for each arbitrary degree of renal impairment which causes the same AUC that would be anticipated in a subject with normal renal function. Dosing proposals are given in tabular form. These allow to bring about, that in each conceivable degree of renal failure, an AUC would be reached as it would have been attained in normal subjects.     

Oral flecainide pharmacokinetics in patients with impaired renal function

The pharmacokinetics of flecainide acetate were studied in 20 patients with varying degrees of renal impairment following a single oral dose. The patients were divided into two groups, on the basis of renal creatinine clearance (CLCR), for statistical and kinetic analysis. Patients with a CLCR between 4 and 41 mL/min/m2 were designated group 1 and those below 4 mL/min/m2 or unmeasurable because of lack of urine output were designated group 2. In both groups peak plasma flecainide concentrations, time to peak concentrations, and apparent volume of distribution (Vd) were similar to those reported in healthy subjects with normal renal function. The mean flecainide plasma elimination half-lives from both groups 1 and 2 were longer than those previously reported by several investigators in normal subjects. Nine patients in group 1 and seven patients in group 2 had half-lives within the range reported in healthy subjects. Therefore, CLCR alone is not a good predictor of plasma elimination half-life following a single oral dose of flecainide. Although renal clearance of flecainide is significantly reduced in end-stage renal disease (ESRD), total plasma clearance of flecainide (CLflec) was not reduced to the same degree, although there was a significant, modest correlation with CLCR. Less than 1% of the administered oral dose of flecainide was removed during hemodialysis. The relationship between dosage and plasma elimination half-life in patients with ESRD needs further study to evaluate possible dose-dependent kinetics.     

Regadenoson pharmacokinetics and tolerability in subjects with impaired renal function

The authors have investigated the pharmacokinetics and tolerability of regadenoson, a selective A2A adenosine receptor agonist for use in drug-stressed myocardial perfusion imaging in subjects with varying degrees of renal function. Sixteen subjects with different creatinine clearance values (range: 15-132 mL/min) received a single intravenous bolus dose of 400 microg regadenoson. A population pharmacokinetic model was developed to describe the pharmacokinetics of regadenoson in these subjects. Regadenoson elimination half-life was prolonged with decreasing renal function. However, maximum plasma concentrations, number, or severity of adverse events did not differ significantly between the subjects. Heart rate increased in all subjects after regadenoson injection but returned to normal within 150 minutes. There were no blood pressure pattern differences with respect to renal function. Results from this study do not indicate that dose adjustments are necessary when subjects with decreased renal function are administered the clinically relevant dose of 400 microg regadenoson.     

Raloxifene pharmacokinetics in males with normal and impaired renal function

AIMS: To compare raloxifene pharmacokinetics between renally impaired and healthy subjects. METHODS: Raloxifene 120 mg was administered to 10 males with renal impairment (creatinine 2-4 mg dl(-1)) and to 10 healthy males. Data were analysed by two noncompartmental and one compartmental nonlinear regression methods. RESULTS: The medians (95% confidence interval) of the area under the curves (AUC) were 35.1 (25.8, 74) and 20.5 (16.8, 28.0) h ng ml(-1) per mg kg(-1), P < 0.01, and of the clearances (CL/F) were 28.5 (13.5, 38.8) and 48.8 (35.8, 59.4) l h(-1) kg(-1), P < 0.01, in renally impaired and healthy subjects, respectively. 95% Confidence intervals on the differences for AUC and CL/F were 6.5-44.1 and -35.1 to -7.9, respectively. CONCLUSION: Exposure to raloxifene was twice as high in males with renal impairment compared with healthy subjects.     

The pharmacokinetics of pioglitazone in patients with impaired renal function

AIMS: To evaluate the effect of renal impairment on the pharmacokinetics and safety of pioglitazone and its metabolites M-III and M-IV with impaired renal function and normal renal function. METHODS: In a phase-I, open-label, parallel-group study, six healthy subjects with normal renal function (creatinine clearance> 80 ml min-1), nine patients with moderate renal impairment (creatinine clearance 30-60 ml min-1) and 12 patients with severe renal impairment (creatinine clearance < 30 ml min-1) received single and multiple oral doses of pioglitazone 45 mg. The serum pharmacokinetic profiles of pioglitazone and its metabolites M-III and M-IV were assessed for the first and last dose administered (day 1 and day 12, respectively). RESULTS: Pharmacokinetic data revealed no significant accumulation of pioglitazone or its metabolites M-III and M-IV in patients with renal impairment. There was no significant difference in the pharmacokinetic profile of pioglitazone in subjects with normal and with moderately impaired renal function. After single oral doses, mean area under the concentration-time curve (AUC) values were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (13 476 vs 17 387, P = 0.371; -23%; confidence interval (CI) -57, 38), M-III metabolite (13 394 vs 15 071, P = 0.841; -11%; CI -74, 194) and M-IV metabolite (27 991 vs 49 856, P = 0.006; -44%; CI -62, -17). After repeated oral doses of pioglitazone, mean AUC values (microg.h l-1) were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (8744 vs 14,565, P = 0.004; -40%; CI -57, -16), M-III (3991 vs 7,289, P = 0.0009; -45%; CI -60, -25) and M-IV (21 080 vs 25 706, P = 0.181; -18%; CI 39, 10). The tolerability and safety profile of pioglitazone was comparable between groups. CONCLUSIONS: Pioglitazone was well tolerated in patients with varying degrees of renal impairment. Although mean serum concentrations of pioglitazone and its metabolites are increased in patients with severe renal impairment, adjustment of starting and maintenance doses in these patients is probably unwarranted.     

Effect of impaired renal function and haemodialysis on the pharmacokinetics of aprepitant

BACKGROUND: The neurokinin NK(1)-receptor antagonist aprepitant has demonstrated efficacy in preventing highly emetogenic chemotherapy-induced nausea and vomiting. OBJECTIVE: The objective of the present study was to investigate the effects of impaired renal function on the pharmacokinetics and safety of aprepitant. SUBJECTS AND METHODS: A total of 32 patients and healthy subjects were evaluated in this open-label, two-part study. Pharmacokinetic parameters after a single oral dose of aprepitant 240 mg were measured in eight patients with end-stage renal disease (ESRD) requiring haemodialysis, eight patients with severe renal insufficiency (SRI [24-hour creatinine clearance <30 mL/min/1.73 m(2)]) and 16 healthy and age-, sex- and weight-matched subjects (controls). RESULTS: In ESRD patients, the area under the plasma concentration-time curve (AUC) from 0 to 48 hours (AUC(48)) for aprepitant was on average approximately 36% lower than that observed in control subjects (ratio [ESRD patients/healthy controls] of geometric means = 0.64), but the 90% confidence interval 0.52, 0.78 for the ratio of true mean AUC(48) fell within the predefined target interval of 0.5, 2.0. Also in ESRD patients, there was no statistically or clinically significant difference in unbound aprepitant AUC (which may be more clinically relevant than total aprepitant AUC) when compared with healthy control subjects. Aprepitant pharmacokinetic parameters in ESRD patients were clinically similar when haemodialysis was initiated at 4 hours or 48 hours after aprepitant administration. In SRI patients, the ratio (SRI patients/healthy controls) of aprepitant AUC from zero to infinity (AUC(infinity)) geometric mean value was 0.79 with a 90% confidence interval of 0.56, 1.10. On average, in SRI patients the principal aprepitant pharmacokinetic parameters (AUC(infinity), initial maximum plasma concentration [C(max)], time to initial C(max), and apparent elimination half-life) were not statistically different from those obtained in healthy control subjects. Aprepitant was generally well tolerated in both ESRD and SRI patients. CONCLUSION: The results of this study demonstrate that ESRD, haemodialysis and SRI have no clinically meaningful effect on aprepitant pharmacokinetics. Therefore, no dosage adjustment of aprepitant is warranted in SRI or ESRD patients.     

Antihypertensive therapy with co-dergocrine mesilate/nifedipine in comparison with nifedipine in type II diabetes

In a randomized cross-over study the antihypertensive effects of nifedipine and the combination of co-dergocrine and nifedipine (Pontuc) respectively as well as the influence of both preparations on the glucose metabolism was tested in 22 hypertensive patients with diabetes type II over a period of 4 weeks. During treatment with the combination a significantly more pronounced blood pressure reduction was achieved compared to monotherapy with nifedipine, whereas the heart rate was significantly increased only by nifedipine. Both drugs--nifedipine and co-dergocrine/nifedipine--did not change the concentrations of glucose in the blood or urine or of HbA1.     

Clinical effects of intravenous nifedipine on renal function

Nifedipine, a calcium antagonist, was administered intravenously (13.3 micrograms/min) for 45 min, and the changes in blood pressure, glomerular filtration rate (GFR), renal blood flow (RBF), total renal resistance, urinary volume, urinary sodium and potassium excretion, plasma renin activity, and plasma aldosterone concentration were studied. GFR and RBF were measured by intravenous infusion of sodium thiosulfate and sodium para-aminohippurate, respectively. The subjects included 12 cases of essential hypertension, nine of chronic glomerular nephritis with hypertension, 14 of chronic glomerular nephritis without hypertension, and 12 normotensive controls. In patients with essential hypertension, GFR and RBF increased markedly (by 45.6% and 44.8%, respectively), but in normotensive and hypertensive patients with chronic glomerular nephritis, these indices did not change significantly. The urinary volume and urinary sodium excretion increased in all groups. The natriuresis induced by nifedipine is probably due to the increase of GFR and RBF. The results of this study suggest a difference in renal vascular pathophysiology between essential hypertension and chronic glomerular nephritis. The results also suggest a functional change of the renal vascular system in essential hypertension, i.e., the increased vascular tone and the particular sensitivity of renal arterioles to nifedipine.     

Evaluation of effect of impaired renal function on lamivudine pharmacokinetics

Aims

This study aimed to describe lamivudine pharmacokinetics in patients with impaired renal function and to evaluate the consistency of current dosing recommendations.

Methods

A total of 244 patients, ranging in age from 18 to 79 years (median 40 years) and in bodyweight from 38 to 117 kg (median 71 kg), with 344 lamivudine plasma concentrations, were analysed using a population pharmacokinetic analysis. Serum creatinine clearance (CLCR) was calculated using the Cockcroft–Gault formula; 177 patients had normal renal function (CLCR > 90 ml min⁻¹), 50 patients had mild renal impairment (CLCR = 60–90 ml min⁻¹), 20 patients had moderate renal impairment (CLCR = 30–60 ml min⁻¹), and five patients had severe renal impairment (CLCR < 30 ml min⁻¹).

Results

A two-compartment model adequately described the data. Typical population estimates (percentage interindividual variability) of the apparent clearance (CL/F), central (V_c/F) and peripheral volumes of distribution (V_p/F), intercompartmental clearance (Q/F) and absorption rate constant (K_a) were 29.7 l h⁻¹ (32%), 68.2 l, 114 l, 10.1 l h⁻¹ (85%) and 1 h⁻¹, respectively. Clearance increased significantly and gradually with CLCR. Our simulations showed that a dose of 300 mg day⁻¹ in patients with mild renal impairment could overexpose them. A dose of 200 mg day⁻¹ maintained an exposure close to that of adults with normal renal function. However, the current US Food and Drug Administration recommendations for lamivudine in other categories of patients (from severe to moderate renal impairment) provided optimal exposures.

Conclusions

Lamivudine elimination clearance is related to renal function. To provide optimal exposure, patients with mild renal impairment should receive 200 mg day⁻¹ instead of 300 mg day⁻¹.     

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.     

The pharmacokinetics of racemic verapamil in patients with impaired renal function

The pharmacokinetics of verapamil were studied in patients with renal failure who were undergoing maintenance hemodialysis and in normal subjects after an IV infusion of 10 mg and a single oral dose of 120 mg. Plasma levels of verapamil and its active metabolite, norverapamil, were analyzed by a sensitive and specific HPLC procedure. Severe renal failure requiring hemodialysis did not change the time course of verapamil and norverapamil plasma concentrations after either the IV or oral dose. The terminal elimination rate constant, clearance, volume of distribution, and bioavailability of verapamil were not significantly different between the two groups of subjects. In addition, the apparent maximal plasma concentration, terminal elimination rate constant, and area under the curve for norverapamil were similar in patients with renal failure and normal subjects. The study showed that the plasma disposition of verapamil and norverapamil was not affected in patients with impaired renal function. Furthermore, this study does not indicate that any change in dosage is necessary when single doses of verapamil are administered to patients with renal failure.     

Flecainide pharmacokinetics after multiple dosing in patients with impaired renal function

Study objective: To determine the pharmacokinetics of oral flecainide acetate after single and multiple doses in patients with impaired renal function. Design: Paired study of single followed by multiple oral doses. Setting: Patients enrolled in a Veterans Administration Hospital renal subspecialty clinic and dialysis unit. Patients: Twenty men and one woman between the ages of 33 and 74 years with impaired renal function including ten patients with end-stage renal disease receiving maintenance hemodialysis. Interventions: All patients received a single, oral, 200-mg dose of flecainide acetate followed by sequential venous blood sampling. Seven to 14 days after the single-dose study, each patient received 100 mg of flecainide acetate by mouth every 12 hours or every 24 hours for 10 days. Venous blood samples were drawn periodically during multiple dosing and sequentially after the last dose. Measurements and primary results: Peak flecainide acetate concentrations (micrograms/L) were 330 +/- 104 micrograms/L (mean +/- SD) after the single dose and 687 +/- 505 micrograms/L after multiple doses. Time to peak occurred at 3.3 +/- 2.3 hours and 2.7 +/- 1.2 hours after single and multiple doses, respectively. The apparent volume of distribution was 8.2 +/- 2.9 L/kg and 9.2 +/- 5 L/kg after single and multiple dose studies, respectively. Plasma elimination half-life after the single dose (20.4 +/- 9.0 hours) was significantly shorter (P less than .001) than after multiple doses (37.8 +/- 39.7 hours), as was total body clearance: 391 +/- 154 mL/min versus 302 +/- 194 mL/min. There were no statistically significant differences between pharmacokinetic measurements determined for patients on chronic hemodialysis when compared with nondialysis patients during the multiple-dose study.(ABSTRACT TRUNCATED AT 250 WORDS)     

The pharmacokinetics of Casodex enantiomers in subjects with impaired liver function

1. Casodex is a novel non-steroidal antiandrogen being developed for the treatment of prostatic cancer. The antiandrogenic activity is predominantly in the R(-) enantiomer with little, if any, activity in the S(+) enantiomer. 2. The pharmacokinetics of the enantiomers of Casodex have been investigated over 28 days following a single oral dose of Casodex (50 mg) to 10 male subjects with histologically verified liver cirrhosis or fatty liver with fibrosis. Ten age matched male subjects with normal hepatic function served as a control group. 3. For both groups plasma concentrations of (S)-Casodex were lower than those for (R)-Casodex; this difference was about 10-fold at early time points and increased to about 25-fold by 24 h after dosage. 4. The kinetics of (R)-Casodex were similar in subjects with and without liver disease (Cmax: 750 vs 848 ng ml(-1); tmax: 24 - 30 h; t(1/2): 7.40 vs 7.22 days; AUC: 182 vs 225 microg ml(-1) h). 5. The kinetics of (S)-Casodex could not be described in the majority of subjects; in the remainder the mean terminal phase half-life for both groups was less than 1 day.