Pharmacokinetics of temocapril and temocaprilat after 14 once daily oral doses of temocapril in hypertensive patients with varying degrees of renal impairment

Aims The aim of this study was to determine the potential influence of renal impairment on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat. Methods Non-compartmental pharmacokinetics were assessed in four groups of hypertensive patients (n=8 per group, four investigational centres) with normal (creatinine clearance determined via 24 h urine sampling, CL_CR, ≥60 ml min⁻¹ ) and impaired renal function (CL_CR 40–59, 20–39, <20 ml min⁻¹ ) after 14 once daily oral doses of 10 mg temocapril hydrochloride. Results For temocapril, there were no statistically significant differences in median t_max or mean C_max, AUC_SS, t_½,Z, CL/F between the four groups. Renal clearance, CL_R, for temocapril showed a linear decreasing trend with decreasing CL_CR [ mean (s.d.): 32.2 (10.7) to 3.7 (3.0) ml min⁻¹]. Steady-state for temocaprilat was reached on day 5. For temocaprilat, no statistically significant differences in mean C_max or median t_max were detected. With decreasing mean CL_CR, mean AUC_SS for temocaprilat increased statistically significantly although only 2.4-fold [mean (s.d.): 2115 (565) to 4989 (2338) ng ml⁻¹ h] and t_½,Z was prolonged [mean (s.d.): 15.2 (1.2) to 20.0 (7.5) h]. CL_R for temocaprilat showed a linear decreasing trend with decreasing CL_CR [mean (s.d.): 20.2 (4.3) to 3.0 (1.8) ml min⁻¹]. Conclusions These results indicate that impaired renal function has only a limited effect on the pharmacokinetics of temocapril and its active metabolite, temocaprilat. This may be attributed to the dual, i.e. renal and biliary, elimination pathway of the drug.     

Pharmacokinetics of gentamicin in malnourrished infants

Summary The pharmacokinetics of gentamicin was investigated in normal and malnourished infants aged 4–10 months. Neither mean elimination nor distribution half life show any difference, but the volume of distribution was higher in malnourished babies, probably due to their larger total body water.     

Population pharmacokinetic modelling of gentamicin and vancomycin in patients with unstable renal function following cardiothoracic surgery

AIMS: To describe the population pharmacokinetics of gentamicin and vancomycin in cardiothoracic surgery patients with unstable renal function. METHODS: Data collected during routine care were analyzed using NONMEM. Linear relationships between creatinine clearance (CL(Cr)) and drug clearance (CL) were identified, and two approaches to modelling changing CL(Cr) were examined. The first included baseline (BCOV) and difference from baseline (DCOV) effects and the second allowed the influence of CL(Cr) to vary between individuals. Final model predictive performance was evaluated using independent data. The data sets were then combined and parameters re-estimated. RESULTS: Model building was performed using data from 96 (gentamicin) and 102 (vancomycin) patients, aged 17-87 years. CL(Cr) ranged from 9 to 172 ml min(-1) and changes varied from -76 to 58 ml min(-1) (gentamicin) and -86 to 93 ml min(-1) (vancomycin). Inclusion of BCOV and DCOV improved the fit of the gentamicin data but had little effect on that for vancomycin. Inclusion of interindividual variability (IIV) in the influence of CL(cr) resulted in a poorly characterized model for gentamicin and had no effect on vancomycin modelling. No bias was seen in population compared with individual CL estimates in independent data from 39 (gentamicin) and 37 (vancomycin) patients. Mean (95% CI) differences were 4% (-3, 11%) and 2% (-2, 6%), respectively. Final estimates were: CL(Gent) (l h(-1)) = 2.81 x (1 + 0.015 x (BCOV(CLCr)-BCOV(CLCr Median)) + 0.0174 x DCOV(CLCr)); CL(Vanc) (l h(-1)) = 2.97 x (1 + 0.0205 x (CL(Cr)-CL(Cr Median))). IIV in CL was 27% for both drugs. CONCLUSIONS: A parameter describing individual changes in CL(cr) with time improves population pharmacokinetic modelling of gentamicin but not vancomycin in clinically unstable patients.     

Pharmacokinetics of carteolol in patients with impaired renal function

Summary In order to determine the appropriate dosage of carteolol in renal dysfunction, the pharmacokinetics of carteolol has been examined in appropriate patients. The plasma concentrations and urinary excretion of carteolol were investigated in 15 patients with varying degrees of renal impairment during the administration of 5–20 mg carteolol hydrochloride (5 mg/tablet) for 2–45 months.Plasma carteolol levels were linearly correlated with the serum creatinine concentration (r = 0.87) and reciprocally with the creatinine clearance (r = 0.82). The urinary carteolol concentration was correlated with the urinary creatinine concentration (r = 0.69) and the urinary carteolol excretion was also correlated with the creatinine clearance (r = 0.79). These relationships become even closer when the plasma carteolol concentrations and urinary excretion rate of carteolol were factored by the administered tablets. The fractional renal excretion of carteolol was virtually constant at various degress of renal function, and it always exceeded 100%, which indicates that carteolol was actively secreted, even in patients with renal failure. The estimated tubular secretion rate of carteolol was logarithmically correlated with the fractional renal excretion of carteolol (r = 0.93).The results indicate that the dose of carteolol should be determined according to the degree of renal impairment.     

Pharmacokinetics of cephacetrile in patients with normal or impaired renal function

Summary The pharmacokinetics of cephacetrile, administered as a single i. v. injection of 15 mg/kg, have been determined in 8 patients with normal renal function and in 12 patients with a varying degree of renal impairment. A two-compartment model was used to describe the biphasic decline in serum concentrations and to calculate the amount of antibiotic in the central and peripheral compartments. In patients with normal renal function the following values were obtained for various pharmacokinetic parameters: =3.971 h^–1; =0.343 h^–1; K₁₂=1.745 h^–1; K₂₁=0.763 h^–1; K_el=1.793 h_–1; V_c=8.181; V_p=18.401 and V_dss=26.581. Cephacetrile had some of the highest apparent distribution volumes of all the cephalosporins. Impaired renal function significantly affected , , K₁₂, and K_el. A linear relationship between K_el of cephacetrile and creatinine clearance was demonstrated. The elimination of cephacetrile in anuric patients was about ten times slower than in patients with normal renal function.     

Influence of age on amikacin pharmacokinetics in patients without renal disease. Comparison with gentamicin and tobramycin

Summary The influence of age on amikacin pharmacokinetics was examined in 87 patients with normal renal function. All patients had a gram negative infection, were febrile, weighed within 20% of their ideal body weight, did not receive penicillin antibiotics concurrently, had normal hematocrits and had a measured 24 h creatinine clearance greater than 80 ml/min/1.73 m². 31 patients were 20–39 years old, 27 patients were between the ages of 40–59 years, and 29 patients were 60–79 years old. These patients were compared to patients in similar previous studies who received gentamicin or tobramycin. No significant differences in clearance, volume of distribution or half-life were found due to age within a single drug group (amikacin, gentamicin, or tobramycin) or among the 3 drug groups. However, a substantial amount of intersubject variability existed in the calculated pharmacokinetic parameters. Patients over 40 years old tended to be underdosed with amikacin and the other 2 aminoglycosides. The average amikacin dose needed to achieve the desired steady-state concentrations was 18.9 mg/kg/day. 52% of the amikacin patients required doses greater than the recommended maximum (15 mg/kg/day). Since aminoglycoside pharmacokinetics do not change as age increases, doses do not need to be arbitrarily changed in older patients with normal renal function.     

Pharmacokinetics of lansoprazole in patients with renal or liver disease of varying severity

Summary The pharmacokinetics of lansoprazole (L) after a single oral dose of 30 mg was determined in 18 healthy volunteers, 17 renal failure patients and 24 hepatic failure patients; 8 hepatitis and 16 with compensated (CC) or uncompensated (UCC) cirrhosis.In renal failure, the absorption of L was unchanged, its half-life being similar to that in healthy subjects; a small change seen in mild renal failure patients (creatinine clearance between 40 and 60 ml/min) was attributed to the age of the patients. Urinary elimination, essentially as metabolites of lansoprazole, was decreased, in relation to the degree of renal impairment.In hepatitis patients, the AUC and t_1/2 of L were doubled, without any change in C_max. In cirrhotics t_max was prolonged, the AUC was increased (P<0.001) and there was prolongation of t_1/2 (6.1 h in CC and 7.2 h in UCC compared to 1.4 h in healthy subjects). These changes resulted from a decrease in the clearance of L. There was also an increase in its sulphone metabolite (C_max, R_m) and a decrease in the hydroxylated metabolite (C_max, R_m) in relation to the degree of liver disease, and reflecting a decrease in hydroxylation and biliary elimination.Thus, renal failure had no effect on the pharmacokinetics of L, but severe hepatic failure caused marked changes. A repeated dosing study would be necessary to evaluate the repercussions of the possible accumulation in cirrhotic patients.     

The safety of cefuroxime and gentamicin in patients with reduced renal function

Summary

The glomerular and tubular function of 7 patients with a spectrum of renal impairment was measured before, during and after 4-days' treatment with cefuroxime and gentamicin. Neither the mean plasma urea nor creatinine concentrations of the group increased after combined treatment, nor was the excretion of cefuroxime slowed. The ability to acidify and to concentrate the urine did not change. In only 1 patient did plasma creatinine increase and GFR fall. This patient had an unexpectedly high plasma gentamicin concentration and was taking frusemide. However, an eighth patient with acute renal failure caused by bacteraemic shock rapidly recovered renal function while being treated with cefuroxime and gentamicin for 15 days after large doses of frusemide intravenously. This limited study suggests that the useful combination of cefuroxime and gentamicin need not be denied to patients with reduced renal function, but emphasizes that the plasma gentamicin concentration must always be monitored.     

Pharmacokinetics of tenoxicam in patients with impaired renal function

Summary The pharmacokinetics of tenoxicam after a single oral dose of 20 mg has been studied in 12 patients with various degrees of decreased renal function. Unchanged tenoxicam and its 5OH-metabolite in plasma and urine were determined by HPLC. The mean areas under the plasma concentration-time curve (138±53 µg/ml·h) and terminal half-lives in patients with impaired renal function did not differ from values previously reported in normal volunteers, nor did the peak concentration of tenoxicam. The half-life of 5OH-tenoxicam and unchanged tenoxicam where the same. The urinary excretion of 5OH-tenoxicam fell with decreasing renal function. Thus no dosage adjustment should be necessary and the usual daily dose of tenoxicam may be administered once daily also to patients with renal failure.     

Pharmacokinetics of gentamicin in protein-energy malnutrition

Summary The pharmacokinetics of i.m. gentamicin was the same in malnourished (n=6) and normal (n=4) children.     

Pharmacokinetics of flutamide in patients with renal insufficiency

AIMS: The aim of this study was to determine the pharmacokinetic parameters of flutamide, a nonsteroidal antiandrogenic compound, and its pharmacologically active metabolite, hydroxyflutamide, in renal insufficiency. Haemodialysis (HD) clearance of flutamide and hydroxyflutamide was also determined. METHODS: Pharmacokinetic parameters were assessed for flutamide and hydroxyflutamide in 26 male subjects with normal renal function (creatinine clearance by 24 h urine collection, CLcr, greater than 80 ml min(-1) 1.73 m(-2); n=6) or reduced renal function; CLcr=50-80 (n=7), 30-49 (n=3), 5-29 (n=4), and <5 ml min(-1) 1.73 m(-2)-HD (n=6), following a single, oral 250 mg flutamide dose. Subjects undergoing HD received a second 250 mg dose of flutamide 4 h prior to HD; blood and dialysate were collected during HD to determine dialysability of flutamide and hydroxyflutamide. RESULTS: Cmax, tmax, AUC, t1/2, and renal clearance of flutamide and hydroxyflutamide did not differ between groups. Less than 1% of the dose appeared in dialysate as hydroxyflutamide. No serious adverse events were observed. CONCLUSIONS: Renal function did not affect flutamide nor hydroxyflutamide disposition. HD did not alter hydroxyflutamide pharmacokinetics. Dosing adjustments for renal impairment or HD are not indicated for flutamide.     

Pharmacokinetics of flecainide in patients with mild and moderate renal failure compared with patients with normal renal function

Summary We have studied the pharmacokinetics of flecainide after the oral administration of 100 mg to 8 patients without renal impairment and 8 patients with mild to moderate renal failure. Both groups gave comparable results with respect to the peak plasma concentrations and the time to peak. There was a significant correlation between renal flecainide clearance and endogenous creatinine clearance. The elimination half-time in the patients with impaired renal function was significantly longer (19.9, SD 9.9 h) than that in the patients with normal renal function (11.5, SD 4.2 h), but the variability in the elimination half-time in renal failure could not be explained on the basis of the available results.dedicated to Professor Dr. U. Geßler on the occasion of his 65th birthday     

Pharmacokinetics of lisinopril in hypertensive patients with normal and impaired renal function

Summary The pharmacokinetics of lisinopril was studied after administration of single and multiple doses of 5 mg to hypertensive patients with normal and impaired renal function.In patients with severe renal failure the peak concentrations were higher, the decline in serum concentration was slower and the time to peak concentration was extended. Accumulation of lisinopril was highly correlated with the creatinine clearance. The effective half-life was doubled and tripled in patients with mild and severe renal impairment, respectively, as compared to patients with a normal renal function. Lisinopril lowered blood pressure in all three groups over 24 h.It is suggested that smaller doses of lisinopril should be administered to patients with severe renal failure.     

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.     

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.     

Pharmacokinetics of atenolol in relation to renal function

Summary The pharmacokinetics of atenolol were determined following acute intravenous and chronic oral administration to 20 subjects with a glomerular filtration rate (GFR) between 5 and 113 ml/min. Plasma levels in a further 5 patients on haemodialysis were measured after intravenous treatment. The mean half life of elimination increased from 5.9 h in patients with normal renal function to 42.1 h in preuraemic patients (GFR <10 ml/min) following a single i. v. dose. The half life of elimination following chronic oral administration was not significantly different. Mean peak plasma concentrations increased from 540 ng/ml in patients with normal renal function to 1493 ng/ml in preuraemic patients following chronic oral treatment with 100 mg/day. The mean half life of elimination during a single haemodialysis treatment was 4.3 h. In patients with a GFR >30 ml/min the normal daily dose of atenolol should be employed, in patients with a GFR between 10 and 30 ml/min the dose should be reduced by half, and in patients with a GFR <10 ml/min a reduction by three quarters of the normal dose is recommended.     

Pharmacokinetics of quinine in patients with chronic renal failure

Methods: We investigated the pharmacokinetics of quinine (Qn) following administration of a single oral dose of 600 mg Qn sulphate in six male Thai patients with a moderate degree of chronic renal failure (CRF), and six male Thai subjects with normal renal function. Results: The drug was well tolerated in both groups of subjects; no major adverse reactions were observed. A marked alteration in the pharmacokinetics of Qn was found in patients with CRF compared to healthy subjects; there were six signifiicant changes in the pharmacokinetic parameters. Absorption was delayed, but increased in CRF (t_max 4.5 vs 1.6 h, C_max 6.17 vs 3.45 g·ml^–1). Total clearance was significantly reduced 0.94 vs 2.84 ml·min^–1·kg^–1, whereas V_z/f remained unchanged (1.82 vs 2.78 1·kg^–1). This resulted in the increased values of AUC and prolongation of the t_1/2z and MRT in the patients (AUC 181.5 vs 61.8 g·min^–1·ml^–1, t_1/2z 26 vs 9.7 h, MRT 36.4 vs 11.3 h). Median concentrations of plasma unbound fraction of Qn collected at 4 h after drug administration in patients and healthy subjects were 7.3 vs 9.8%, respectively.     

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.     

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.     

Pharmacokinetics of ramipril in hypertensive patients with renal insufficiency

In an open trial, the pharmacokinetics of ramipril and its active metabolite ramiprilat were studied in 25 hypertensive patients with various degrees of renal insufficiency given 5 mg ramipril p.o. for 14 days. Ramipril was rapidly absorbed and reached a peak concentration after 1-2 h. Cmax was greater in patients with severe renal insufficiency, which might indicate a reduced renal elimination rate, although, the rapid decline of the concentration-time curve for ramipril was almost independent of renal function. The mean initial apparent half-lives on Days 1 and 12, respectively, were 2.8 and 3.4 h (Group I: creatinine clearance 5-15 ml/min), 1.8 and 2.3 h (Group II: creatinine clearance 15-40 ml/min), and 1.9 and 1.9 h (Group III: creatinine clearance 40-80 ml/min). No accumulation was observed after multiple dosing. In contrast, the kinetics of its active acid metabolite ramiprilat was significantly influenced by renal function. The mean times to the peak plasma concentration were 5.7 h in Group I, 4.4 h in Group II and 3.8 h in Group III. The initial decline in plasma ramiprilat was dependent upon renal function; the mean initial apparent half-lives (Days 1 and 12, respectively) were 16.0 and 14.8 h (Group I), 10.1 and 9.5 h (Group II) and 10.6 and 8.0 h (Group III). Mean trough concentrations and absolute accumulation also increased with worsening renal function, and the renal clearance of ramiprilat was significantly correlated with the creatinine clearance. The subsequent long terminal phase at low plasma ramiprilat concentrations represented slow dissociation of the ACE-inhibitor complex.(ABSTRACT TRUNCATED AT 250 WORDS)