Determination of phenobarbitone population clearance values for South African children

Non-linear Mixed Effects Modelling (NONMEM) was used to estimate phenobarbitone population clearance values for South African children, using 52 serum levels gathered from 32 patients during their routine care. NONMEM was also used to evaluate the influence of fixed effects such as weight, age and concomitant medication. The final model describing phenobarbitone clearance was CL=[Exp(0.0288 Wt–2.53)] M, where CL=clearance (l·h^–1), Exp=the base of the natural logarithm, Wt=patient weight (kg) and M=a scaling factor for concomitant medication with a value of 1 for patients on phenobarbitone monotherapy, 0.62 for those receiving concomitant valproate and 0.87 for those patients receiving concomitant carbamazepine or phenytoin. Mean (95% confidence interval) phenobarbitone clearance values were 7.6 ml·h^–1·kg^–1 (6.2, 9.0 ml·h^–1·kg^–1) for the monotherapy group, 5.0 ml·h^–1·kg^–1 (4.0, 6.0 ml·h^–1·kg^–1) in the presence of concomitant valproate and 6.8 ml·h^–1·kg^–1 (5.6, 8.0 ml·h^–1·kg^–1) in the presence of concomitant carbamazepine or phenytoin. These values are similar to those previously reported from both traditional and NONMEM pharmacokinetic studies.     

Pharmacokinetics of ciprofloxacin tablets in renal failure; influence of haemodialysis

Summary The pharmacokinetics of ciprofloxacin has been studied after a single oral dose of 500 mg given to 5 normal subjects (N) and to 15 patients grouped according to their residual renal creatinine clearance: Group I, 8–30 ml·min^–1, Group II, <8 ml·min^–1, and Group III, haemodialysed patients studied twice — during an interdialysis period (IIIa) and in a 4 h haemodialysis session (IIIb). Ciprofloxacin was assayed by reverse phase HPLC using a spectrofluorimetric detection. The peak plasma concentration (2–5 mg·l^–1) was reached within 2 h after drug administration. Apparent volume of distribution, 6.6 (N), 5.0 (I), 2.7 (II) and 4.2 (IIIa) l·kg^–1 and total plasma clearance, 770 (N), 440 (I), 378 (II) and 314 (IIIa) ml·min^–1 were decreased in relation to the degree of renal impairment. Mean plasma half-lives for patients in the 4 groups were 7.3 (N), 10.4 (I), 7.2 (II) and 9.3 (IIIa) h. In groups N, I and II, 40, 16 and 8% of the administered dose was eliminated through the kidney, with mean renal clearances of 305±63,61±21 and 21±3 ml·min^–1. A linear relationship was found between the renal clearance of ciprofloxacin and the glomerular filtration rate (r=0.75,n=15). Ciprofloxacin was partly removed by haemodialysis (IIIb): the dialyser extraction ratio was 23% and the dialysis clearance was 40 ml·min^–1.     

Pharmacokinetics of ranitidine in patients undergoing haemofiltration

Summary The pharmacokinetics of ranitidine was investigated in 11 patients with acute or end stage renal failure during haemofiltration. Each patient received 50 mg ranitidine i.v.The mean distribution and elimination half lives were 0.13 and 2.57 h, respectively. The total body clearance (CL) and volume of distribution (V_z) were 298 ml·min^–1 (5.19 ml·min^–1·kg^–1) and 1.081·kg^–1, respectively. About 17.1% of the administered dose was removed by haemofiltration (in approximately 201 filtrate). Five of the patients still had some urine output and they excreted 0.1 to 11.8% of the dose in urine in 24 h. The haemofiltration clearance was 66.9 ml·min^–1 at a filtrate flow rate of 86 ml·min^–1, corresponding to a mean sieving coefficient of 0.78 (n=6). As plasma concentrations were still in an effective range after haemofiltration, dose supplementation is not recommended.     

The disposition and protein binding of batanopride and its metabolites in subjects with renal impairment

Summary We have studied the disposition of batanopride and its three major metabolites (the erythro-alcohol, threo-alcohol, and N-desethyl metabolites) in 27 subjects with various degrees of renal function after intravenous infusion of a single dose of 3.6·mg·kg^–1 of batanopride over 15 min.The subjects were assigned to one of three treatment groups: group 1, normal renal function (creatinine clearance 75 ml·min^–1·1.73 m^–2; n=13); group 2, moderate renal impairment (creatinine clearance 30–60 ml·min^–1·1.73 m^–2; n=8); group 3, severe renal impairment (creatinine clearance 30 ml·min^–1·1.73 m^–2; n=6).The terminal half-life of batanopride was significantly prolonged from 2.7 h in group 1 to 9.9 h in group 3. The renal clearance of batanopride was significantly lower in group 3 (25 ml·min^–1) compared with group 1 (132 ml·min^–1).There were no differences in plasma protein binding or steady-state volume of distribution of batanopride among the groups.There were significantly lower renal clearances for all three metabolites in groups 2 and 3 compared with group 1. The half-lives of all three metabolites were significantly prolonged in group 3 compared with group 1.The dose of batanopride may need to be reduced in patients with creatinine clearances less than 30 ml·min^–1·1.73 m^–2 to prevent drug accumulation and avoid possible dose-related adverse effects.     

The pharmacokinetics of cotinine in plasma and saliva from non-smoking healthy volunteers

Summary Cotinine is a major metabolite of nicotine in man. Its disposition kinetics has been followed in plasma and saliva from nine nonsmokers, 23 to 56 years of age. Cotinine 5, 10 and 20 mg was given intravenously and orally to each subject, and plasma, saliva and urine samples were collected for 96 h.The kinetics of cotinine was best described by a multi-compartment model with three distinct phases both in plasma and saliva. Regardless of the mode of administration, there was no indication of dose-dependent kinetics. Mean total plasma clearance was 63.8 ml·h^–1·kg^–1 and mean renal clearance was 4.7 ml·h^–1·kg^–1, i.e. only 10% of the dose was excreted unchanged in the urine. The volume of distribution, as calculated from the plasma curves, was slightly greater than the body weight, 1.1 l·kg^–1. The concentration of cotinine was 20 to 40% higher in unstimulated mixed saliva than in plasma during the absorption, distribution and elimination phases. As the clearance and distribution values in saliva were directly proportional to the corresponding values in plasma, similar terminal half-life values were obtained in the two body fluids, 15.5 and 16.8 h for plasma and saliva, respectively.Thus the kinetics of cotinine is linear after intravenous and after oral dosing, and salivary concentrations give the same information about cotinine disposition in the body as do plasma concentrations.     

Pharmacokinetics of teicoplanin in patients on continuous ambulatory peritoneal dialysis

Summary We have studied the pharmacokinetics of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, in five patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD). Although teicoplanin was eliminated in the peritoneal fluid, relatively little was recovered (6.8±1.2% of the given dose). The following values were obtained: elimination half-time 102–347 h; total body clearance 4.16–7.38 ml·h^–1·kg^–1, peritoneal clearance 0.31–0.37 ml·h^–1·kg^–1. Because the elimination of teicoplanin is about four times less in patients undergoing CAPD compared with subjects with normal renal function, the dose of teicoplanin should be reduced appropriately in such cases.     

Influence of usual intake of dietary caffeine on single-dose kinetics of theophylline in healthy human subjects

Summary The influence of usual multiple ingestions of dietary caffeine on oral single-dose pharmacokinetics of theophylline has been investigated in 6 healthy male subjects. The subjects consumed 2 to 7 cups of regular instant coffee during the 24 h study period.Their mean serum concentrations of caffeine varied from 1.2 to 3.1 mg/l. After their usual intake of dietary caffeine, the serum concentrations of theophylline from 3 to 24 h after administration were significantly higher than after deprivation of dietary caffeine. The apparent elimination of theophylline half-life was prolonged from 6.3 (0.61) h (mean with (SEM)) to 8.3 (0.47) h (32% increase, P<0.01) and the total body clearance was reduced from 55.0 (1.31) ml·h^–1·kg^–1 to 42.5 (2.63) ml·h^–1·kg^–1 (23% decrase, P<0.001). Saturation of theophylline metabolism and/or competition between theophylline and caffeine metabolism in addition to theophylline derived from caffeine may be the cause of the delayed elimination of theophylline.The present study has indicated that a significant reduction in theophylline metabolism may be caused by a conventional intake of dietary caffeine. In bronchodilator therapy with theophylline, therefore, the daily consumption of caffeine should be taken into consideration.     

Biliary elimination of indomethacin in man

Summary The biliary elimination of indomethacin 100 mg p.o. has been investigated in patients with a T-tube drain after cholecystectomy, who had normal or abnormal liver function (Group In=5, and Group IIn=4, respectively). In plasma, the concentration maximum (Group I 9.5±1.4 µmol·1^–1; Group II 19.4±3.8 µmol·1^–1) and the total clearance (Group I 1.56±0.28 ml·min^–1·kg^–1, Group II 0.5±0.06 ml·min^–1·kg^–1) were significant different in the two groups. The bile:plasma ratio (bpr) in Group I was 1.3±0.33 and 10.1±3.2, respectively, for indomethacin (In) and conjugated In. The conjugated fraction of In was 87.5±1.9% of the total concentration. In Group II the bpr was lower (0.65±0.1). In is eliminated in bile by diffusion and conjugated In by active secretion. In Group I 0.99±0.1 mg In and 6.1±0.7 mg conjugated In and in Group II 2.1±0.3 mg In (p<0.05) were eliminated in bile. No influence of In on the biliary lipids was observed or on the bile acid-independent fraction of bile flow. It is concluded that the total plasma clearance of In was dependent of liver function. Conjugated In undergoes enterohepatic circulation.     

Pharmacokinetics of dexamethasone in premature neonates

Objective: Dexamethasone is frequently used in premature neonates with bronchopulmonary dysplasia, however little is known about its disposition in this population. Methods: We evaluated the pharmacokinetics of dexamethasone in 9 premature neonates with a mean gestational age of 27.3 weeks and a postnatal age of 21.8 days. Results: There was a strong relationship between clearance (4.96 ml·min^–1·kg^–1) and gestational age (r=0.884). Pharmacokinetic parameters were grouped based on a gestational age of less than 27 weeks (Group I) and greater than 27 weeks (Group II). Mean clearance in group I and group II was 1.69 and 7.57 ml·min^–1·kg^–1, respectively. Mean distribution volume in group I and II was 1.26 and 2.19 l·kg^–1, respectively. No significant relationships were noted between the disposition of dexamethasone and ventilator requirements or adverse effects. Conclusion: The pharmacokinetics of dexamethasone in premature neonates was related to gestational age.     

The pharmacokinetics ofα-human atrial natriuretic polypeptide in healthy subjects

Summary We have analysed the pharmacokinetics of-human atrial natriuretic polypeptide (-hANP) in healthy subjects, using a two-compartment open model following bolus intravenous injection. The plasma half-times for the fast and slow components were 1.7±0.07 min and 13.3±1.69 min respectively. V₁ (the volume of the central compartment), V_z (volume of distribution) and V_ss (volume of distribution at steady-state) were 5370±855 ml (89.5±14.3 ml·kg^–1), 32000±4620 ml (533±77.0 ml·kg^–1), and 11900±1530 ml (198±25.5 ml·kg^–1) respectively. The mean plasma clearance was 1520±121 ml·min^–1 (25.4±2.0 ml·min^–1·kg^–1.     

Effect of antipyrine coadministration on the kinetics of acetaminophen and lidocaine

Summary Pharmacokinetic interactions between antipyrine and acetaminophen were evaluated in 7 healthy volunteers. On 3 occasions subjects received:1, antipyrine 1.0 g intravenously (i.v.);2, acetaminophen 650 mg i.v.;3, antipyrine 1.0 g and acetaminophen 650 mg i.v. simultaneously.Between Trials 1 and 3, antipyrine elimination t_1/2 (17.2 vs 17.4 h), clearance (0.44 vs 0.43 ml·min^–1·kg^–1) and 24-h recovery of antipyrine and metabolites (313 vs 293 mg) did not differ significantly. Between Trials 2 and 3, acetaminophen V_z was reduced (1.14 vs 1.00 l·kg^–1), t_1/2 prolonged (2.7 vs 3.3 h), clearance reduced (4.8 vs 3.6 ml·min^–1·kg^–1), and fractional urinary recovery of acetaminophen glucuronide reduced.Eight additional subjects received 50 mg of lidocaine hydrochloride i.v. in the control state, and on a second occasion immediately after antipyrine 1.0 g given i.v.The two trials did not differ significantly in lidocaine V_z (2.6 vs 2.7 l·kg^–1), t_1/2 (2.0 vs 2.4 h) or clearance (15.0 vs 13.5 ml·min^–1·kg^–1).Although acetaminophen does not alter antipyrine kinetics, acute administration of antipyrine appears to impair acetaminophen clearance, possibly via inhibition of glucuronide formation. However, antipyrine has no significant effect on the kinetics of a single i.v. dose of lidocaine.     

Pharmacokinetic characteristics and tolerability of a novel intravenous immunoglobulin preparation

In two independent trials 10 and 12 healthy volunteers received the novel intravenous immunoglobulin (IVIG) preparations BT 511 and BT 507, respectively. BT 511 contains 5 g human plasma proteins per 100 ml, more than 95% of which are immunoglobulins of the G class (IgG). BT 507 contains in addition 61 IU antibody against hepatitis B surface antigen (anti-HBs)·ml^–1. In trial I volunteers received 4.0 ml/kg (n+4) and 8.0 ml·kg^–1 (n+6) BT 511 to study the tolerability and the magnitude of the increase in immunoglobulins in plasma as well as their decline over 1 month. After administration of the lower dose, plasma IgG increased from 10.7 to 14.7 g·l^–1 directly after the infusion. Following the 8.0 ml·kg^–1 dose a more pronounced increase from 12.4 to 21.2 g·l^–1 was observed. No adverse events occurred. After 1 month IgG concentrations had almost reached baseline values at 12.2 g·l^–1 in the 4.0 ml·kg^–1 group, but were still significantly increased at 15.2 g·l^–1 after the high dose. There was a linear correlation between the maximal IgG plasma concentration and the subsequent decline of IgG during the 29-day observation period. After administration of BT 507 maximal anti-HBs concentrations of 1778 mU·ml^–1 occurred 1.4 h after termination of the infusion. The terminal elimination half-life was 22.4 days, and total clearance and volume of distribution were determined to be 0.122 ml·min^–1 and 5.41, respectively. The pharmacokinetic parameters calculated for anti-HBs as an indicator of IgG were in accordance with the pharmacokinetic behaviour of native IgG.     

Lack of relationship between tolbutamide metabolism and debrisoquine oxidation phenotype

Summary The oxidative metabolism of tolbutamide was studied in 13 healthy subjects of known debrisoquine phenotype. Three were poor (PM) and ten were extensive (EM) metabolisers of debrisoquine.The mean values for total plasma clearance, elimination half-life, and metabolic clearance were 0.26 ml·min^–1·kg^–1, 3.4 h, and 0.17 ml·min^–1. kg^–1 in PM subjects and 0.22 ml·min^–1·kg^–1, 4.3 h and 0.15 ml·min^–1·kg^–1 in EM subjects. Total urinary recovery (% of dose) and ratio of hydroxy- to carboxytolbutamide were 69.4% and 0.219 respectively in PM subjects and 70.9% and 0.226 in EM subjects. There were no statistically significant differences between EM and PM metabolisers for any of these parameters. In addition there was no correlation between the debrisoquine metabolic ratio and tolbutamide urinary metabolite recovery or plasma clearance.These data indicate that hydroxylation of debrisoquine and tolbutamide are not catalyzed by the same enzyme.The ratio of hydroxy- to carboxytolbutamide in our subjects, and in other recent studies, suggests that some previous publications were inaccurate and their conclusions about the genetic control of tolbutamide metabolism were incorrect.     

Pharmacokinetics of cefonicid in children

Summary The pharmacokinetics of cefonicid was studied in 17 children requiring antibiotic treatment for respiratory or urinary tract infections. After informed consent had been obtained from the parents, a single dose of cefonicid 50 mg/kg/body weight was given by intramuscular injection.The mean peak serum concentration of 212.63 µg/ml was reached at 1.00 h, as absorption occurred at a very fast rate with a mean constant of 3.24 h^–1. Mean values for half-life, apparent volume of distribution (V_z), total body clearance (CL), and renal clearance (CL_R) were 3.24 h, 0.21 l·kg^–1, 16.67 ml·min^–1 and 13.60 ml·min^–1 respectively. There was an inverse relationship between age and V_z, whereas CL and CL_R were positively correlated with age. Cefonicid concentrations in urine were many times higher than the MICs of susceptible strains of bacteria.The study demonstrated that i.m. cefonicid 50 mg·kg^–1 gave serum concentrations well within the therapeutic range for susceptible bacteria, and that its pharmacokinetic properties allow single daily doses to be used to treat infections in children.     

Bioavailability and pharmacokinetics of oxazepam

Summary Six healthy volunteers received oxazepam 15 mg i.v. and orally at an interval of at least one week. The kinetic variables of i.v. oxazepam were: elimination half-life (t_1/2) 6.7 h, total clearance (CL) 1.07 ml·min^–1·kg^–1, volume of distribution (V_c) 0.27 l·kg^–1 (0.21–0.49) and volume of distribution at steady-state (V_ss) 0.59 l·kg^–1. The intravenous disposition of unbound oxazepam was characterized by a clearance of 22.5ml·min^–1·kg^–1 and a distribution volume of 12.3 l·kg^–1. After oral oxazepam the peak plasma level was reached in 1.7 to 2.8 h. The plasma t_1/2 at 5.8 h was not significantly different from the i.v. value. Absorption was almost complete, with a bioavailability of 92.8%. Urinary recovery was 80.0 and 71.4% of the dose after intravenous and oral administration, respectively. Renal clearance (CL_R) of the glucuronide metabolite was 1.10 ml·min^–1·kg^–1 (0.98–1.52). Oxazepam was extensively bound to plasma protein with a free fraction of 4.5%.     

Diurnal variation of methotrexate disposition in children with acute leukaemia

Summary There is recent evidence that survival is improved when maintenance therapy for acute lymphocytic leukaemia in children is given at night. We have examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement.In 6 children with leukaemia there was a significant fall in methotrexate plasma clearance at night (from 5.6 to 4.7 ml·kg^–1·min^–1). Renal clearance of methotrexate tended to fall at night and unbound renal clearance fell significantly (from 17.5 to 8.5 ml·min^–1·kg^–1 P<0.05). Creatinine clearance did not exhibit diurnal variation, whereas there was a significant fall in the non-glomerular clearance of methotrexate (from 14.8 to 6 ml·min^–1·kg^–1).Since methotrexate is a weak organic acid, its tubular secretion depends on urinary pH. At night urinary pH is more acidic, and this may result in more reabsorption and hence reduced renal clearance.     

The influence of steady-state ciprofloxacin on the pharmacokinetics and pharmacodynamics of a single dose of diazepam in healthy volunteers

Summary The effects of pretreatment with a seven day course of ciprofloxacin on pharmacokinetics and pharmacodynamics of an intravenous (5 mg) dose of diazepam were investigated in a group of 12 healthy volunteers in a double-blind placebo-controlled crossover study.Ciprofloxacin pretreatment significantly reduced diazepam CL (without ciprofloxacin: 19.5 ml·h^–1kg^–1; with ciprofloxacin: 12.3 ml·h^–1kg^–1). Diazepam t_1/2 was also prolonged (without ciprofloxacin: 36.7 h; with ciprofloxacin: 71.1 h), but volume of distribution was unaltered (without ciprofloxacin: 1.1 l·kg^–1; with ciprofloxacin: 1.1 l·kg^–1).However, no significant changes were detected in psychometric tests of digit symbol substitution, tapping rate and short memory, as well as levels of concentration, vigilance and tension measured by visual analogue scales.     

The pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis and in patients with chronic renal disease

Summary We have studied the pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis, patients with chronic renal failure, and healthy subjects, and have assessed the predictive value of routine tests of liver function and renal function (creatinine clearance) for theophylline and enprofylline total body clearances.Theophylline clearance was significantly decreased in the patients with liver cirrhosis compared with both the patients with renal failure and the healthy subjects (the mean values in the three groups were 24, 47, and 46 ml·h^–1·kg^–1 respectively.Enprofylline clearance was significantly decreased in the patients with chronic renal failure, compared with both the patients with liver cirrhosis and the healthy subjects (the values in the three groups were 64, 250, and 289 ml·h^–1·kg^–1 respectively.There was a strong correlation between creatinine clearance and enprofylline clearance, while there was only a poor correlation between the liver function tests and theophylline clearance.It appears that in various clinical situations enprofylline elimination can be predicted more precisely than theophylline elimination, which may make the drug safer in clinical practice.     

Pharmacokinetics of enprofylline in healthy elderly subjects

Summary The pharmacokinetics of enprofylline, a new potent antiasthmatic, has been studied in 20 healthy, elderly subjects, aged 65 to 81 years, and in 7 young adult controls, aged 23 to 37 years. The dose of 1 mg/kg body weight was given as an i.v. infusion. Plasma levels of enprofylline were followed for about 7 h and urine levels for 24 h. Both groups eliminated the major portion of the dose (about 83%) by renal excretion.As expected the mean creatinine clearance (92.5 ml·min^–1· 1.73 m^–2) was moderately decreased in the elderly subjects. The total clearance of enprofylline was 0.16 1·h^–1·kg^–1 and the renal clearance was 0.13 l·h^–1·kg^–1, which was significantly lower than that in the young controls (0.28 and 0.22 l·h^–1·kg^–1) respectively. Thus, the enprofylline clearance had fallen relatively more (about 40%) than the decrease in creatinine clearance (about 20%) with age. The half-life of enprofylline in old age was 2.5 h, which was significantly longer than in the younger adults (1.8 h).It is concluded that the pharmacokinetics of enprofylline was significantly influenced by advanced age, mainly due to reduced renal excretion. This reduction was more pronounced than anticipated from the age-dependent decline in creatinine clearance.     

Calcitonin gene-related peptide (CGRP) causes redistribution of blood flow in humans

Summary In normal human subjects (n=6), blood flow in the common carotid artery, assessed with an ultrasonic duplex-scanning unit, was increased up to 152% of basal levels by 60-min infusions of human calcintonin gene-related peptide I (CGRP) 80 pmol·kg^–1·h^–1, but it was not affected by 20 pmol·kg^–1·h^–1 CGRP or 88 pmol·kg¹·h^–1 human calcitonin.In the superior mesenteric artery, on the other hand, blood flow was reduced by 80 pmol·kg^–1·h^–1 CGRP to 58% of the basal level, but not by 20 pmol·kg^–1·h^–1 CGRP or with 88 pmol·kg^–1·h^–1 calcitonin.Blood flow in the abdominal aorta remained largely unchanged under the same conditions.Skin blood flow, assessed by a laser Doppler unit, was increased up to 682% of the basal level by 80 pmol·kg^–1·h^–1 CGRP, but not by 20 pmol·kg^–1·h^–1 CGRP or calcitonin.Thus CGRP increased regional blood flow to the brain and the skin at the expense of the gastrointestinal tract.