Ofloxacin pharmacokinetics in chronic renal failure and dialysis.

Data on the pharmacokinetics of ofloxacin in chronic renal failure, in patients who were not dialysed or were receiving haemodialysis or continuous ambulatory peritoneal dialysis (CAPD), are reviewed. In addition, a large pool of data obtained in patients with a wide range of renal dysfunction is provided. The good absorption of ofloxacin after oral administration is not influenced by renal failure. Total plasma clearance (CL) is largely dependent on renal elimination of the drug, and renal clearance (CLR) and urinary recovery are reduced in parallel with reductions in renal function. Consequently, the serum half-life progressively increases when creatinine clearance decreases. Although there is wide variation in the published absolute values for the CL and CLR of ofloxacin, all studies show a similar pattern in the pharmacokinetic behaviour of the drug in chronic renal failure. A proposed protocol for ofloxacin dosage adjustment in chronic renal failure is reported which differs slightly but significantly from that recommended by the manufacturer. This new dosage regimen was derived from the pharmacokinetic results after single and multiple oral administration of the drug to patients with chronic renal failure. Since no clinically relevant losses of ofloxacin occur during haemodialysis or continuous ambulatory peritoneal dialysis (CAPD), the same protocol should be followed in these patients as in undialysed patients with terminal chronic renal failure.     

Pharmacokinetics of ornidazole in patients with renal insufficiency; influence of haemodialysis and peritoneal dialysis.

The pharmacokinetics of ornidazole (Tiberal) was studied after intravenous administration of a single 500 mg dose in eight patients with advanced chronic renal failure (ACRF) (creatinine clearance 2-16 ml/min), in seven patients treated by haemodialysis (residual renal creatinine clearance 0-5 ml/min) and in five patients treated by continuous ambulatory peritoneal dialysis (CAPD) (residual renal creatinine clearance 0-6 ml/min). In ACRF patients, the half-life of ornidazole was 10.8 +/- 1.4 h, the total plasma clearance 46.3 +/- 2.3 ml/min and the volume of distribution 0.73 +/- 0.06 l/kg. During haemodialysis, ornidazole was partly removed: the dialyser extraction ratio was 42 +/- 5% and the dialysis clearance 64 +/- 7 ml/min. During CAPD, peritoneal excretion was low: the dialysis clearance was 3.0 +/- 0.4 ml/min and in 48 h 6.0 +/- 1.1% of the administered dose was found in the peritoneal fluids. In these patients, the half-life of ornidazole was 11.8 +/- 0.8 h and total plasma clearance was 48.3 +/- 5.5 ml/min, values which were close to those determined in non dialysed patients. In patients with end-stage renal disease, the half-life of ornidazole is comparable to that of subjects with normal renal function. This is due to the predominantly extra-renal elimination of the drug. Therefore, there is no need to modify the usual dosage of ornidazole for these patients. Because of the large elimination of the drug during haemodialysis it is necessary to administer the drug after the dialysis session.     

Propranolol disposition in renal failure.

1 Previous studies of propranolol disposition in renal failure have been conflicting. 2 Using simultaneous administration of [3H]-propranolol intravenously and unlabelled propranolol orally the principal determinants of drug distribution were calculated in normals, patients with severe renal impairment (creatinine clearance 14.5 +/- 2.8 ml/min) but not on haemodialysis and patients on haemodialysis (creatinine clearance less than 5 ml/min). 3 The effect of haemodialysis on propranolol binding and free fraction was also examined. The percentage of propranolol unbound rose from 7.1% to 9.9%. (P less than 0.001) 20 min following heparinization and beginning haemodialysis. This was accompanied by a large rise in free fatty acids from 0.567 +/- 0.059 to 3.326 +/- 0.691 mumol/ml (P less than 0.005). 4 The blood to plasma concentration ratios of propranolol were significantly higher in patients with renal failure (P less than 0.02) and on haemodialysis (P less than 0.001) and were significantly negatively correlated (P less than 0.001) with the haematocrit. 5 Although the half-life propranolol was significantly shortened in the patients with renal failure (P less than 0.02), there was no change in the apparent liver blood flow, extraction ratio or the principal determinants of steady-state drug concentrations in blood namely oral and intravenous clearance from blood. 6 There is, therefore, no pharmacokinetic basis to adjust the dosage of propranolol in patients with renal failure.     

High haemodialysis clearance of ornidazole in the presence of a negligible renal clearance

Summary The pharmacokinetics of ornidazole was studied in 6 patients treated by haemodialysis and in 8 subjects with a creatinine clearance between 4 and 99 ml/min × 1.73 m². Blood and urine collections were performed for 72 h after i.v. and oral administration of 1.0 g ornidazole.Total body clearance, half-life, volume of distribution and systemic availability were independent of renal function and did not differ from previously reported values in normal volunteers. The haemodialysis clearance of ornidazole was >100% higher than the total body clearance. The renal clearance of ornidazole accounted for less than 7% of the total body clearance. The percentage of the dose of ornidazole recovered in urine as parent compound or as the biologically active metabolites [-(chloromethyl)-2 hydroxymethyl-5 nitroimidazole-1 ethanol and 3-(2 methyl-5 nitroimidazole-1-yl)1,2 propanediol] decreased linearly with decreasing renal function.Although the sum of those three compounds recovered in urine accounted for less than 10% of the total dose of ornidazole administered, they yielded therapeutic concentrations (>4 µg/ml) in urine over 24 h after dosing.Due to the peculiar pharmacokinetic behaviour of ornidazole, i.e. high haemodialysis clearance in the absence of significant renal clearance, no dosage adjustment is necessary while renal function declines, but an increased dose is mandatory while patients are on dialysis.     

Galantamine population pharmacokinetics in patients with Alzheimer's disease: modeling and simulations

Galantamine is a reversible, competitive inhibitor of acetylcholinesterase and an allosteric modulator of nicotinic acetylcholine receptors. It is cleared by renal and hepatic mechanisms, including metabolism by the CYP 450 2D6 and 3A4 isoenzymes. The authors estimated the population pharmacokinetics of galantamine using nonlinear mixed-effects modeling as implemented in NONMEM software. Data from 15 clinical studies (1089 individuals, 7480 concentration measurements in total) were used to examine the effect of body size, demographic characteristics, and concomitant disease status on galantamine pharmacokinetic parameters. Galantamine clearance was shown to decrease with age and increase with body weight and creatinine clearance of individuals. Median clearance in male and female patients with Alzheimer's disease (AD) was 14.8 and 12.4 L/h, respectively. The dissimilarity was related to the body weight difference, not to the real gender effect. Metabolic clearance was reduced by 60% in patients with moderate or severe hepatic dysfunction (Pugh score 7 or higher). Simulations were performed to assess the impact of hepatic impairment and renal insufficiency on peak plasma concentration of galantamine. Simulations confirmed the need for slower dose titration in patients with hepatic impairment: 4 mg daily during 1 week followed by 4, 8, and 12 mg bid, with each dose level during 1 week compared to the standard titration scheme 4-8-12-16 mg bid. However, no significant differences between plasma levels in AD patients with and without severe renal insufficiency were found. CYP 450 2D6 genotype also influenced galantamine clearance but not to the extent that dose adjustment is required.     

Dosage of ribavirin in patients with hepatitis C should be based on renal function: a population pharmacokinetic analysis

A combination of interferon alfa and ribavirin is standard therapy for chronic hepatitis C virus (HCV). Ribavirin dosage is currently based on body weight. The aim of this study was to critically evaluate current dosage recommendations on the basis of a population pharmacokinetic analysis. The data consisted of 383 ribavirin plasma concentration samples collected from 63 patients undergoing treatment of HCV. Forty-four patients had normal range serum creatinine with an estimated glomerular filtration rate (GFR = estimated creatinine clearance) of 57-144 mL/min. Another 19 patients had renal impairment with a GFR of 5-57 mL/min. Population factors were age, gender, body weight, serum creatinine, and GFR. A population pharmacokinetic analysis with a two-compartment model was carried out using nonlinear mixed effect modeling. Ribavirin clearance was found to be linearly dependent on renal function with a small nonrenal clearance dependent on body weight and age. Estimated GFR was a significantly better predictor of ribavirin clearance than body weight alone. There remained a significant 40% interindividual variability in ribavirin total clearance not explained by estimated GFR and body weight. The volume of distribution was large and proportional to body weight (V = 44.3 x body weight), which resulted in a long half-life (100-500 hours, depending on GFR) and a long time to steady state (3-12 weeks). Ribavirin dosage should mainly be based on renal function and not, as currently recommended, on body weight alone. A ribavirin-dosing schedule based on GFR and body weight to reach an intended target concentration is proposed. Ribavirin monitoring may be useful for optimizing HCV treatment not only in patients with renal insufficiency but also in other patients considering the time to steady state and the interindividual variability in ribavirin clearance.     

Pharmacokinetics of meropenem in subjects with renal insufficiency

Summary The pharmacokinetics of IV meropenem (500 mg over 30 min) has been studied in 6 healthy volunteers and 26 patients with various degrees of renal impairment. Blood samples were taken at different times over 24 h in healthy subjects and 36 to 48 h in uraemic patients, and four or five urine samples were collected over 24 or 48 h. Meropenem concentrations in plasma and urine were measured by a microbiological assay.The mean peak plasma concentration of meropenem ranged from 28 to 40 g·ml^–1 and was not affected by the degree of renal impairment. The terminal half-life of meropenem was approximately 1 h in subjects with normal kidney function and it was proportionately increased as renal function decreased. A significant linear relationship between total body clearance and creatinine clearance as well as between renal clearance and creatinine clearance was observed. The mean apparent volume of distribution at steady state was not significantly altered in uraemic patients. The mean cumulative urinary recovery of meropenem in healthy volunteers was 77% of the administered dose and it was significantly decreased in patients with renal impairment. Haemodialysis shortened the elimination half-life, from 9.7 h during the predialysis period to 1.4 h during the dialysis period. The dose of meropenem should be reduced in relation to the decrease in creatinine clearance.     

Single dose pharmacokinetics of lamivudine in subjects with impaired renal function and the effect of haemodialysis

Aims The purpose of this study was to investigate the pharmacokinetics of a single oral dose of lamivudine administered to subjects with renal impairment and to determine whether lamivudine was dialysable in subjects with severe renal impairment undergoing haemodialysis.
Methods Twenty-nine subjects were enrolled, nine with normal renal function (creatinine clearance (CL_CR ) 82–117  ml  min⁻¹ ), eight with moderately impaired renal function (CL_CR 25–49  ml  min⁻¹ ), six with severe impairment (CL_CR 13–19  ml  min⁻¹ ) and six with severe impairment who were also receiving haemodialysis. After an overnight fast, nondialysis subjects received a single oral dose of lamivudine. Subjects on haemodialysis were given two doses on separate occasions (intra and interdialysis). Blood was obtained before lamivudine administration and at regular intervals to 48  h post dose. Timed urine collections were performed for subjects able to produce urine. Pharmacokinetic parameters were calculated by using standard non compartmental techniques.
Results Decreasing renal function was associated with reduced lamivudine clearance in a proportional and apparently linear relationship. Lamivudine was well dialysed with an extraction ratio in the order of 50%. However, because lamivudine has a large volume of distribution (≈100  l), a haemodialysis session of 4  h did not affect overall exposure to a clinically significant degree in most subjects.
Conclusions Impaired renal function does require lamivudine dose modification according to the degree of impairment, but no further modification of dose is required for subjects undergoing regular haemodialysis.     

The pharmacokinetics of ofloxacin in healthy adult male volunteers

Conclusion In healthy subjects ofloxacin pharmacokinetics were found to be linear in the dose range studied (100–400 mg). The terminal half-time was 7.5–8 h and plasma ofloxacin concentrations were still detectable at 16 and 24 h after administration. The ratio of renal ofloxacin clerance: creatinine clearance was 1.35–1.82 and was not significantly different for the three doses. The non-renal clearance of ofloxacin was 40–60 ml·min^–1, i.e. 20–30% of the total body clearance.Food intake delayed the absorption of ofloxacin but did not significantly modify its elimination.     

Pharmacokinetics of sisomicin in patients with normal and impaired renal function; its efficacy in urinary tract infection

Summary Serum concentration, biological half-life, distribution space and serum clearance of sisomicin, a new aminoglycoside antibiotic, have been studied in twenty-three patients in comparison with the pharmacokinetics of¹²⁵I-labelled iothalamate, a compound only filtered by the kidney. 10 patients had normal or borderline abnormal serum creatinine (<1,5 mg/100 ml), 8 had various degrees of renal insufficiency (serum creatinine 1.7 – 9.6 mg/100 ml) and 6 were being treated by intermittent haemodialysis. After intravenous injection of sisomicin 1 mg/kg body weight in patients with normal or borderline renal function its half-life was 3.5 h, very similar to that of iothalamate, 3.2 h. The mean distribution space was 20.1 % per cent of body weight; iothalamate, 23.7 %. In patients with renal insufficiency there was a positive correlation between serum creatinine level and the half-life of sisomicin, and an even stronger correlation between the clearances of iothalamate and sisomicin. In patients dependent on haemodialysis, the mean serum half-life between dialysis was 40 h, compared to approximately 100 hours for iothalamate, which implies additional extrarenal clearance or tubular secretion of sisomicin. The results of pharmacokinetic studies indicated that a regime of sisomicin 1 mg/kg every 8 to 12 hours in patients with normal renal function would result in serum and urine levels sufficiently high to treat most urinary tract infections. In patients with impaired renal function the dosage interval should be increased according to the serum creatinine level, and in patients dependent on haemodialysis one standard dose at the end of each dialysis period should suffice. 9 patients with a chronic urinary tract infection severely complicated by an underlying disease were treated according to this dosage regimen with a satisfactory bacteriological and clinical result. No adverse reactions or signs of accumulation were observed.     

Oral absorption of cimetidine and its clearance in patients with renal failure

Summary The plasma concentration curve after a single oral dose of cimetidine 200 mg was followed in 27 patients with varying degrees of chronic renal failure (creatinine clearance 1–52 ml/min) and in 46 patients with normal serum creatinine. Compared to the latter patients, the plasma concentration was higher and the elimination rate was slower in all uraemic subjects, including a group with moderate renal impairment. The preliminary recommendations of dosage for patients with a creatinine clearance below 5 ml/min, and for patients on regular haemodialysis, is cimetidine 200 mg every 12 h, 5–15 ml/min 200 mg every 12 to 8 h, 15–30 ml/min 200 mg every 8 h and 30–52 ml/min 200 mg every 6 h.     

Single-dose pharmacokinetics of pravastatin and metabolites in patients with renal impairment.

The disposition of a single 20-mg oral dose of pravastatin was assessed in subjects with various degrees of renal function. Sixteen subjects (13 males, 3 females) with creatinine clearance values ranging from 15 to 112 mL/min/1.73 m2 completed the study. Area under the serum concentration-time curve, maximum serum concentration, time to maximum serum concentration, terminal serum elimination half-life, apparent clearance, and apparent volume of distribution for pravastatin were not affected by renal impairment, whereas the renal clearance of pravastatin decreased as creatinine clearance decreased (r2 = 0.697, P less than .001). The area under the serum concentration-time curve and time to maximum serum concentration of SQ 31,945 (a hepatic metabolite) increased in patients with renal impairment, whereas the terminal elimination rate constant and renal clearance of SQ 31,945 significantly decreased as a function of creatinine clearance. The renal clearance of another metabolite (SQ 31,906) also significantly declined with decreasing renal function. This single-dose study demonstrates that pravastatin pharmacokinetics were not affected in patients with renal impairment, probably because of its dual route of elimination.     

Effect of renal function on the pharmacokinetics and pharmacodynamics of trandolapril.

1. The pharmacokinetics and pharmacodynamics of a single dose of trandolapril, an angiotensin converting enzyme (ACE) inhibitor with an active metabolite, trandolaprilat, which is in part further metabolised prior to renal elimination, were evaluated in 31 subjects with a wide range of renal function (creatinine clearance 4-112 ml min-1 1.73 m-2). 2. The pharmacokinetics of trandolapril were unaffected by differences in renal function. 3. In contrast, there was a close correlation between the renal clearance (0-96 h) of trandolaprilat and creatinine clearance (r = 0.95, P = 0.0001). The maximum plasma concentration of trandolaprilat, and the area under the concentration curve (0-96 h) correlated inversely with creatinine clearance (r = -0.59, P < 0.001; and r = -0.61, P < 0.001 respectively). 4. Significant changes in plasma trandolaprilat concentrations were seen only in patients with creatinine clearances of 30 ml min-1 1.73 m-2 or less, suggesting that a dose reduction in trandolapril might be advisable in severe renal impairment. 5. However, the majority of parameters of ACE inhibition were unrelated to creatinine clearance, although area under the curve for ACE inhibition (0-336 h) showed a weak negative correlation (r = -0.49, P < 0.01). Similarly, weighted mean changes in blood pressure were not influenced by renal function. 6. Therefore, while the pharmacokinetic parameters of trandolaprilat correlated with creatinine clearance, pharmacodynamic measurements (ACE inhibition and blood pressure changes) in general showed no such relationship, indicating that dose adjustment of ACE inhibitors in renal impairment should be based on pharmacokinetic results only in conjunction with pharmacodynamic data.     

Oral pharmacokinetics and ascitic fluid penetration of ofloxacin in cirrhosis

Plasma and ascitic fluid concentrations of ofloxacin were determined in 12 cirrhotic patients after a single dose and repeated 200 mg oral doses. The single dose kinetics were compared to those obtained in 12 healthy volunteers. Mean plasma elimination half-life was 11.6 h in cirrhotics and 7.0 h in controls. Mean total clearance was 2.3 times lower in patients than in controls, due to a significant decrease of renal clearance of the drug, unrelated to creatinine clearance. Mean apparent volume of distribution was 1.2 l/kg in patients and 1.8 l/kg in controls. Estimated by the ratio of AUC in peritoneal fluid and plasma, ascitic fluid penetration was 80% after the first oral dose. Ascitic fluid concentrations equaled corresponding plasma concentrations after 10 h, without pronounced accumulation of ofloxacin in ascites. We may conclude that, in cirrhotic patients with normal serum creatinine, a significant impairment of renal tubular handling of ofloxacin could be observed and led to a delayed elimination half-life of the drug. Because of its broad spectrum of activity, low side-effect profile, and large ascitic fluid penetration after oral administration, ofloxacin appears to be a new therapeutic approach of severe infections in cirrhotic patients, in particular spontaneous bacterial peritonitis.     

Pharmacokinetics of cibenzoline in patients with renal impairment

Pharmacokinetic values of cibenzoline, a new, investigational, antiarrhythmic drug, were determined in 13 patients with varying degree of renal impairment, creatinine clearance range between 5 and 53 mL/min. Cibenzoline plasma levels were measured after direct intravenous injection of one single 1 mg/kg dose. The apparent volume of distribution of the drug (276 1) was similar to that reported in healthy subjects. Total body clearance decreased with creatinine clearance, and there was a close correlation between cibenzoline renal clearance and creatinine clearance (r = 0.956; P less than 0.001). Plasma elimination half-life was prolonged, with values ranging from 7:4 to 23.6 hours. This study showed that cibenzoline total body clearance correlated with the degree of renal impairment, and it is suggested that in patients with chronic renal failure dosage should be adjusted according to creatinine clearance values.     

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.     

Multiple dose kinetics of ofloxacin and ofloxacin metabolites in haemodialysis patients

Summary 7 patients with end-stage renal disease on regular haemodialysis were treated orally with a loading dose of 200 mg ofloxacin and multiple maintenance doses of 100 mg per 24 h for 10 days. The pharmacokinetics of ofloxacin and its metabolites were studied at the end of the treatment period. Plasma and dialysate concentrations of ofloxacin and ofloxacin metabolites were measured by HPLC.Peak (3.1 mg·1^–1) and trough levels (1.6 mg·1^–1) and the AUC of ofloxacin were comparable to the values in healthy volunteers given 300 to 400 mg ofloxacin p.o. The mean half-life, determined in the dialysis-free interval (t_1/2) and during the haemodialysis session (t_1/2HD), was 38.5 h and 9.9 h, respectively. Extrarenal clearance (32.7 ml·min^–1) was unchanged as compared to that reported in healthy volunteers after a single dose of ofloxacin. The fractional removal by haemodialysis amounted to 21.5%. Two metabolites, ofloxacin-N-oxide and demethyl-ofloxacin, were detected in plasma. Despite prolonged t_1/2 of both metabolites (66.1 and 50.9 h) and multiple doses of ofloxacin the peak concentrations of the metabolites reached only 14% and 5% of that of the parent drug, respectively.It is concluded that in patients on regular haemodialysis treatment the dosage adjustment employed resulted in safe and therapeutically favourable plasma concentrations. The observed accumulation of ofloxacin metabolites does not appear to have any toxic or therapeutic significance.     

Haemodialysis does not affect the pharmacokinetics of nifedipine.

To establish dosage recommendations in patients with end-stage renal disease undergoing chronic haemodialysis, nifedipine kinetics were studied between and during haemodialysis sessions. In eight patients, during the interdialytic period, peak plasma concentrations of nifedipine (29-332 ng/ml) were reached 0.5-1.0 h after administration of a single 10 mg oral dose. Elimination half-life and oral plasma clearance were respectively 2.6 +/- 0.5 h and 1 176 +/- 412 ml/min. Nifedipine plasma protein binding was decreased in uraemic patients (88.8 +/- 0.3% vs 94.4 +/- 0.1%) but not affected by haemodialysis. Removal by haemodialysis was low: the dialyser extraction ratio and the dialysis clearance were respectively 2.3 +/- 0.8% and 2.8 +/- 0.9 ml/min.     

Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function

AIM

To evaluate the influence of different stages of chronic renal insufficiency on the pharmacokinetics and safety/tolerability of the transdermally applied dopamine agonist rotigotine in an open label group comparison including 32 subjects (healthy, mild, moderate or severe impairment of renal function and patients with end-stage renal insufficiency requiring haemodialysis).

METHODS

All subjects received a single transdermal 10 cm² patch (24 h patch-on period) containing 4.5 mg rotigotine (nominal drug release 2 mg 24 h⁻¹). Main evaluations included relative bioavailability and renal elimination of rotigotine and its metabolites.

RESULTS

Point estimates for the ratios between the groups with moderate to severe renal impairment and healthy subjects for the pharmacokinetic parameters AUC(0,t_last) and C_max for the active substance unconjugated rotigotine were near 1:0.88 for AUC and 0.93 for C_max for moderate renal impairment, 1.14 and 1.18 for severe renal impairment and 1.05 and 1.25 for end-stage renal insufficiency requiring haemodialysis. There was no correlation of these parameters with creatinine clearance. The amount of unconjugated rotigotine excreted into urine and renal clearance decreased with increasing severity of renal insufficiency but had no observable effect on total clearance as the amounts excreted were below 1% of the administered dose. Occurrence of adverse events did not increase with the degree of renal insufficiency.

CONCLUSIONS

The pharmacokinetic profiles of unconjugated rotigotine were similar in healthy subjects and subjects with impaired renal function indicating that no dose adjustments are required for transdermal rotigotine in patients with different stages of chronic renal insufficiency including patients on haemodialysis.     

Pharmacokinetics of baclofen in spastic patients receiving multiple oral doses

The pharmacokinetics of racemic baclofen as determined from plasma and urine data in six spastic patients treated with individualized oral doses, 30–80 mg daily, are presented. Peak plasma concentrations were achieved 1.9 h (±0.7) after a dose. The fluctuation in the plasma concentration was great, ranging from 188 to 439%. The total body clearance averaged 175 ml·min^–1 (±44), plasma protein binding 35% (±6). Baclofen was for the greater part excreted unchanged by the kidney, 65% (±16). Its apparent renal clearance equalled the creatinine clearance. The contribution of the renal clearance to the total body clearance can explain the previously described toxicity when renal impairment is present. The results agree with earlier reports on single doses in healthy subjects.