The pharmacokinetics of orally absorbed cefuroxime compared with amoxycillin/clavulanic acid

The pharmacokinetics of a new orally absorbed pro-drug of cefuroxime were compared with those of co-administered amoxycillin and clavulanic acid in six healthy male volunteers. Doses of 600 mg of acetoxyethyl cefuroxime and 500 mg amoxycillin plus 250 mg clavulanic acid were each administered for ten doses 8 hourly. Tissue penetration after the first dose of the antibiotic was estimated by a cantharides blister method. The faecal flora of the volunteers was studied throughout the study. The pharmacokinetics of cefuroxime and amoxycillin were very similar, peak levels of about 6.4 mg/l being found between 2 and 2.5 h after administration. The peak serum level of clavulanic acid was 4.3 mg/l at 1.25 h after administration. The serum half-lives were about 1.1 h for all three agents. No drug accumulation occurred over the four days of the study. The 0-8 h urinary recovery of cefuroxime was 30%. All three agents penetrated the blister fluid rapidly, the main peak levels being 64% of the peak serum level for cefuroxime, 72% for amoxycillin and 55% for clavulanic acid. The incidence of side effects was similar for each regimen. Three volunteers having diarrhoea after cefuroxime showed significant alterations in their bowel flora.     

Clinical pharmacokinetics during plasma exchange

Drug removal during plasma exchange (PE) is a complex phenomenon that is defined by the molecule pharmacokinetic characteristics. Plasma-protein binding and the volume of distribution (Vd) are two kinetic parameters that strongly affect the efficiency of drug removal by PE. The effect of PE on drug kinetics has been specifically studied with antivirals, cardiotonic agents, antibiotics, corticosteroids, antalgics, anti-epileptic agents and non-steroidal anti-inflammatory drugs. This effect can be evaluated using different parameters: extracorporeal clearance, half-life, amount eliminated, and fraction of the drug removed. The estimated fraction eliminated (Fe) from the body by PE is the best parameter to evaluate the effectiveness of the exchange procedure; it can account for 0.5-30 per cent. Results reported in the literature showed that PE most influences drugs with a low Vd, regardless of the extent of protein binding. We established that, during PE, there is a linear relationship between Fe and the fraction of the drug in extracellular fluids. The fraction eliminated during PE is approximately one-seventh of the fraction of the drug in extracellular fluids. We propose to use this extracellular fraction as a predictive index: when < 20, extraction is low; the amount eliminated becomes consequential only when the index > 20. Dosage supplementation may be needed to maintain an adequate drug concentration in the body. Practically, for drugs with a low Vd (< 0.3 l/kg), it seems necessary to adjust the dosage.     

Effect of montelukast on single-dose theophylline pharmacokinetics

The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist in development for treatment of asthma, on single-dose theophylline plasma concentrations was studied in three separate clinical trials. Montelukast was evaluated at 10 mg once daily (the clinical dosage), 200 mg once daily, and 600 mg (200 mg three times daily). At the clinical dosage, montelukast did not change single-dose theophylline plasma concentration in a clinically important manner. The geometric mean ratios for theophylline area under the plasma concentration versus time curve (AUC0-->infinity ) (0.92) and maximal plasma concentration (Cmax ) (1.04) were well within the predefined and generally accepted bioequivalence range of 0.80 and 1.25. Montelukast decreased theophylline Cmax by 12% and 10%, AUC0-->infinity by 43% and 44%, and elimination half-time by 44% and 39% at 200 mg/d (oral and intravenous, respectively), and at 600 mg/d, montelukast decreased theophylline Cmax by 25%, AUC0-->infinity by 66%, and elimination half-time by 63%. These results show that montelukast at the clinical dosage did not change theophylline pharmacokinetics in a clinically important manner, but at 20- to 60-fold higher dosages, montelukast significantly reduced the theophylline pharmacokinetics parameters; an apparent dosage dependence is suggested.     

Effect of lomefloxacin on theophylline pharmacokinetics.

A study involving 25 health male volunteers was conducted to evaluate the effect of lomefloxacin on the pharmacokinetics of theophylline. The mean age was 22.4 +/- 3.0 years, and the mean weight was 77.3 +/- 7.7 kg. A single 6-mg/kg aminophylline dose was given intravenously on study days 1 and 15. The subjects received a 400-mg lomefloxacin dose (four 100-mg capsules) on study days 9 through 15. No treatment was given on study days 2 through 8. Thirteen blood samples were collected within 24 h after each aminophylline dose. Theophylline concentrations in serum were measured by enzyme immunoassay (EMIT). The mean aminophylline dose was 437 +/- 36 mg, equivalent to 344 mg of theophylline. Multiple doses of lomefloxacin had no effect on the area under the concentration-time curve from 0 h to infinity, maximal concentration, or clearance of theophylline from serum. There was a slight increase in the theophylline half-life from 6.72 +/- 1.63 to 7.02 +/- 1.37 h after lomefloxacin dosing (P = 0.04); however, the change was clinically insignificant. No change in theophylline dose is required when lomefloxacin therapy is instituted in a patient receiving theophylline.     

Population pharmacokinetics of theophylline in very premature Japanese infants with apnoea

OBJECTIVE: To estimate the population pharmacokinetics of theophylline in very premature infants using the non-linear mixed effects modelling. METHOD: A total of 167 serum concentration measurements obtained from routine theophylline monitoring of 107 very premature Japanese infants were collected. RESULTS: The final pharmacokinetic parameters were CL (mL/h) = [6.98 . body weight (BW) (kg)(2.17) + 0.244 . post-conceptional age (weeks)] . 1.24(oxygen support), Vd (L) = 0.492 . BW (kg) and F = 0.660, respectively. Clearance was increased by 24% for patients receiving oxygen support. The inter-individual variabilities in clearance and apparent volume of distribution were 15.6% and 80.4%, respectively, and the residual variability was 34.2% as a coefficient of variation. CONCLUSION: Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target theophylline concentrations, thus enabling the clinician to achieve the desired therapeutic effect in very premature Japanese infants.     

Maturational changes of theophylline pharmacokinetics in preterm infants

The pharmacokinetics of theophylline were studied at steady state by stable isotope methodology in nine individual preterm infants. Maturational variables such as postnatal age, postconceptional age, gestational age, duration of treatment, and body weight at the time of the study were analyzed for their influence on theophylline kinetics during the first 6 months of life. The strongest statistical correlations were found between the logarithm of theophylline half-life (t1/2) and the postnatal age (r = 0.98; p less than 0.001) and the postconceptional age (r = 0.96; p less than 0.001). Step-wise multiple regression analysis revealed postnatal age as the most powerful predictor for theophylline t1/2 in the neonatal period (partial correlation coefficients were 0.78 for postnatal age, 0.19 for postconceptional age, and 0.10 for gestational age). Gestational age, duration of treatment, and weight did not correlate significantly with any pharmacokinetic parameters. We propose that theophylline metabolizing function of the liver increases in a logarithmic fashion during the first 6 months of life.     

Influence of lomefloxacin on the pharmacokinetics of theophylline.

The effect of multiple doses of lomefloxacin (400 mg twice a day) on the clearance of theophylline and the urinary excretion of its metabolites was investigated in 15 healthy male subjects. Concentrations of theophylline in plasma were measured by TDx (Abbott Diagnostics, Mississauga, Ontario, Canada). Urinary excretion of theophylline and its three major metabolites and lomefloxacin in plasma were assayed by high-performance liquid chromatography. Total theophylline clearance remained unchanged before lomefloxacin treatment and after lomefloxacin single- and multiple-dose treatments (58.02, 56.57, 54.07 ml/min, respectively). The urinary recovery of unchanged theophylline and its major metabolites stayed stable during the study. We conclude that lomefloxacin can be added to the list of fluoroquinolones that can be administered safely with theophylline.     

The influence of caffeine on the steady-state pharmacokinetics of theophylline

During this open, two-period crossover study in eight healthy volunteers, 1200 mg anhydrous theophylline was administered as a two-stage infusion during 24 hours on day 6. During one of the 8-day periods, 300 mg caffeine, t.i.d., was administered orally. After the start of the theophylline infusion, plasma concentrations of theophylline and caffeine and urinary excretion of theophylline and four metabolites were determined frequently during 60 hours. With caffeine administration theophylline steady-state concentration and area under the curve increased by 23% and 40%, respectively, whereas the volume of distribution at steady state seemed unchanged. The cumulative urinary excretion of 1-methyluric acid and 1-methylxanthine did not reach a plateau, suggesting a capacity-limiting factor in their formation. Notwithstanding the mutual interference of theophylline and caffeine metabolism, the reduction in apparent total body clearance and elimination rate constant of theophylline by 29% and 31%, respectively, indicated a pronounced influence of concomitant administration of realistic amounts of caffeine.     

Lack of effect of ofloxacin on theophylline pharmacokinetics in rats

Effect of ofloxacin, a new quinolone antibacterial agent, on the pharmacokinetics of theophylline was studied in rats in comparison with that of enoxacin and cimetidine. Ofloxacin by pretreatment with five oral doses of 50 mg/kg did not increase serum concentrations of theophylline (5 mg/kg, i.v. single) and showed no significant effect on total body clearance, serum half-life (T1/2) and AUC of theophylline, while enoxacin by the same pretreatment increased significantly serum theophylline concentrations and resulted in significant effect on all the pharmacokinetic parameters. Coadministration of ofloxacin (80 mg/kg, p.o. twice) did not induce a significant effect on the pharmacokinetic parameters of theophylline at repeated doses (50 mg/kg, i.v., twice daily for 3 days). On the contrary, coadministration of enoxacin and cimetidine at the same dose as ofloxacin remarkably increased serum concentrations of theophylline at the same repeated doses, and caused a significant decrease in clearance and an increase in T1/2 and AUC. The three drugs had no influence on rat serum protein binding of theophylline. Ofloxacin exhibited a weak inhibitory effect on rat hepatic microsomal cytochrome P-450-dependent monooxygenases, whereas enoxacin and cimetidine induced a significant inhibition of the enzymes. Thus, it is concluded that ofloxacin has no significant effect on the pharmacokinetics of theophylline in rats, and that enoxacin raises serum theophylline concentrations and results in a significant effect on the theophylline pharmacokinetics by inhibition of the hepatic microsomal monooxygenases in rats.     

Effect of combination therapy with ciprofloxacin and clarithromycin on theophylline pharmacokinetics in healthy volunteers.

Five adults completed this four-way randomized crossover study to compare the effects of oral treatment with ciprofloxacin, clarithromycin, and a combination of the two drugs on theophylline pharmacokinetics. The area under the concentration-time curve for theophylline during combination therapy was not different from that for ciprofloxacin alone. Beta error may explain this finding, but any real effect from combination treatment appears to be clinically unimportant.     

Application of population pharmacokinetics to the optimization of theophylline therapy

The aim of this study was to determine theophylline clearance (Cl) values in adult patients using serum concentrations gathered from routine clinical care. This information was used to estimate an a priori dosing regimen that would permit steady-state concentrations of 5–15 mg/litre, now recommended for the treatment of chronic asthma, and to evaluate the need to establish monitoring strategies when theophylline is given at these lower doses and when it can be expected that almost no adverse effects are likely. Retrospective data from 204 astlumatic and COPD patients, with a total of 517 serum concentrations, were studied. Population pharmacokinetic analysis was performed with the MULTI(ELS) computer program according to a one-compartment model. The influence of the following factors on theophylline Cl were investigated: body weight (TBW, IBW and LBM) and age as continuous variables, and gender, smoking habit and the presence of congestive heart failure (CHF) as indicator variables. To validate the results of the population pharmacokinetic analysis, a second independent group of 63 patients was studied prospectively. Hypothesis testing to evaluate potentially significant factors produced a final model in which Cl was based on IBW (kg) and age (years), and was reduced by 25% in patients with moderate CHF and increased by 28% in patients who smoked (Cl (litres/h) = (0.037 IBW-0.006 age) × 1.284 smoke × 0.751 CHF). The variability in Cl, expressed as the coefficient of variation, was 36%. In adult non-smoker and non-CHF patients, application of a maintenance dosing regimen calculated from IBW and age using the final model for Cl would theoretically afford only 1.5% of patients with potentially toxic concentrations. Thus, measurement of serum theophylline concentrations (STC) would only be required when other conditions known to alter theophylline metabolism exist, such as smoking or disease factors. These appreciations could have important clinical implications at a time when the potential immunomodulatory activity of theophylline is being emphasized and health resources should be allocated properly.     

Effect of norfloxacin on theophylline pharmacokinetics at steady state.

Norfloxacin is a currently marketed fluoroquinolone antibiotic. Other quinolones which are structurally similar to norfloxacin, particularly enoxacin, inhibit theophylline clearance. Since norfloxacin may be administered to patients also receiving theophylline, we studied the effect of norfloxacin on the pharmacokinetics of theophylline in 10 healthy male volunteers. A randomized, crossover study design with a 2-week washout period between treatments was used. Subjects received oral theophylline (200 mg of aminophylline [theophylline ethylenediamine]) three times daily for 4 days either alone or with 400 mg of norfloxacin (orally) twice daily for the same period. Theophylline concentrations in serum were significantly higher (P less than 0.05) at 0, 3, 4, 10, and 12 h following the final dose in the norfloxacin treatment group than in the group receiving only theophylline. However, mean theophylline oral clearance was not significantly different between the two treatments (2.85 +/- 0.68 liters/h without norfloxacin versus 2.56 +/- 0.53 liters/h with norfloxacin [P = 0.08]). Similarly, no significant differences were observed in theophylline half-life (P = 0.11). We conclude that norfloxacin is unlikely to have a clinically significant effect on theophylline disposition in most patients.     

Influence of hypothermia on the pharmacokinetics of gentamicin and theophylline in piglets

The influence of hypothermia on gentamicin and theophylline pharmacokinetics was studied in anesthetized pigs given an iv bolus of gentamicin and theophylline during normothermia (37 degrees C) and again 1 wk later after the induction of controlled hypothermia (29 degrees C). During hypothermia, the elimination half-time for gentamicin was significantly prolonged (135 +/- 19 min at 37 degrees C vs. 187 +/- 7 min at 29 degrees C), and there were significant decreases in the volume of the central compartment (Vc) of gentamicin, the gentamicin volume of distribution (Vd), and the gentamicin total body clearance (TBC). Hypothermia was associated with a small but significant decrease in theophylline Vd and Vc, but no change in TBC. In separate experiments, cardiac output decreased during the induction of hypothermia in a temperature-dependent fashion. The changes in gentamicin Vd and TBC may be explained by the decrease in cardiac output and the associated decrease in glomerular filtration rate. This study suggests that the elimination of theophylline, which has a relatively low hepatic extraction ratio, is not influenced by the hypothermia-induced decrease in liver blood flow.     

The pharmacokinetics and sputum penetration of ampicillin and amoxycillin following simultaneous i.v. administration

Five patients with exacerbation of chronic bronchitis received as a single iv injection 500 mg of ampicillin and 500 mg of amoxycillin. Blood and sputum samples were collected at timed intervals following dosing and the concentrations of the two antibiotics present in the samples were determined by HPLC analysis. No statistically significant differences were observed between the serum concentrations of ampicillin and amoxycillin, and the pharmacokinetics of the two drugs were almost identical, with half lives of 93 min (amoxycillin) and 103 min (ampicillin). Sputum amoxycillin concentrations were significantly higher (Student's paired t-test; P less than 0.001) than those of ampicillin, with mean levels two hours after dosing of 2.9 mg/l (range 1.9-4.0) for amoxycillin and 1.4 mg/l (range 0.8-2.4) for ampicillin.     

Effects of dietary protein on theophylline pharmacokinetics and caffeine and aminopyrine breath tests

The effects of low- and high-protein diets on theophylline kinetics and the time course of changes in 13C-labeled caffeine and aminopyrine CO2 breath tests were examined in six young men. With a low-protein diet, mean theophylline clearance fell 21% (P less than 0.04) and the t1/2 rose from 8.0 to 10.6 hours (P less than 0.02). With a high-protein diet, mean theophylline clearance rose 26% (P less than 0.004) and the t1/2 shortened to 7.4 hours (P less than 0.03). Theophylline volume of distribution and protein binding did not change. Renal clearance of theophylline was lowered during the low-protein diet. Theophylline clearance correlated with caffeine breath test values during the low- (r = 0.73) and high- (r = 0.70) protein diets. Theophylline clearance correlated less well with the aminopyrine breath test values during the low- (r = 0.47) and high- (r = 0.55) protein diets. Thus dietary protein significantly influenced theophylline clearance, but the caffeine and aminopyrine breath tests showed a differential response to this important environmental factor.     

Steady-state population pharmacokinetics of sustained release theophylline in adult asthmatic patients

The steady-state population pharmacokinetics of theophylline were studied in 52 asthmatic adult patients who received sustained-release theophylline as armophylline or euphylline. A total of 92 steady-state plasma theophylline concentration-dosage pairs were analyzed using a nonlinear mixed effects model. The pharmacokinetic model used was a one-compartment open model with single path Michaelis-Menten elimination. Dosage was adjusted to body weight. The effects of age, gender, alcohol consumption, cigarette smoking, dosage form, concurrent treatment with beta-agonists or steroids, outpatient dosing, and plasma caffeine concentration on maximum elimination rate (Vm) and Michaelis constant for theophylline metabolism (Km) were investigated. Hypothesis testing produced a final model in which Km = 0.42 (mg/l), and Vm (mg/kg per day) was based on cigarette smoking and dosage form, with Vm = 7.54 + 2.01 (smoking) + 1.08 (euphylline). Estimated coefficients of variation for interindividual variability in Km and Vm were 162.6% and 48.1%, respectively. Residual variability in dosage rates was estimated as 0.90 mg/kg per day. The identification of factors influencing theophylline disposition should prove useful for the a priori design of theophylline dosage regimens and monitoring of drug levels during therapy.     

Clinical efficacy and tolerance of bacampicillin and amoxycillin suspensions in children with acute otitis media

A total of 97 children with acute otitis media were entered into a single-blind, parallel-group study to compare the efficacy and tolerance of suspensions of bacampicillin, given twice daily, with amoxycillin, given three times daily. The daily dosage was about 40 mg/kg body weight in each case and the duration of treatment was 10 days. Patients were examined before the start of treatment, at an early follow-up visit within 2-3 weeks after the start of treatment and at a late follow-up visit 4-6 weeks after the start of treatment. The initial bacteriology revealed a relatively high proportion of Branhamella catarrhalis and a low incidence of pneumococci. In total, 92 patients were evaluated for efficacy at early follow-up, where both bacampicillin and amoxycillin showed equal and good treatment results in approximately 90% of cases. Evaluation at the last valid visit showed that 80-90% of the patients were either cured or improved. The failure frequency tended to be somewhat higher with amoxycillin.     

Are theophylline determinations useful to the clinician during treatment with a sustained-release form of theophylline?

The aims of the study were the correlation between dosage and plasmatic levels of slow release theophylline and the reason for dosage adjustment. 64 pharmacokinetic studies were performed in 58 asthmatic children between 17 months and 16 years. Plasmatic levels of theophylline were performed by fluoroimmunology technique at H0 (before the dose) 2 (H2), 4 (H4), 6 (H6) and 8 (H8) hours after the dose of slow release theophylline. The best correlation between dose and plasmatic levels were observed at H4 and H6 for Armophylline and Euphylline respectively. Dosage adjustment were based both upon clinical state and plasmatic levels in 55 cases. In 9 cases the modification of dose were decided only because of plasmatic levels out the therapeutic range. The authors proposed a schema of dosage modifications based upon clinical state; plasmatic levels must be used as a guide for dose adjustment in patients clinically uncontrolled.     

Effect of levofloxacin on theophylline clearance during theophylline and clarithromycin combination therapy.

OBJECTIVE: To report a case of decreased theophylline clearance by the addition of levofloxacin in a patient receiving theophylline and clarithromycin. CASE SUMMARY: A 59-year-old Japanese man who was receiving theophylline for emphysema experienced stimulation, insomnia, and tachycardia due to theophylline toxicity after clarithromycin and levofloxacin were added to the regimen. The combination of these agents resulted in a decrease in theophylline clearance to approximately 60% of the initial value obtained while the patient was receiving theophylline alone. The adverse effects disappeared after the dosage was reduced and the theophylline serum concentration decreased; however, there was no change in theophylline clearance. After discontinuation of levofloxacin, the theophylline serum concentration decreased, and theophylline clearance returned to the initial level even though clarithromycin was continued. DISCUSSION: Levofloxacin is believed not to influence the clearance of theophylline, although some new fluoroquinolones have been reported to do so. This case indicates that levofloxacin and clarithromycin inhibited theophylline metabolic pathways catalyzed by both CYP1A2 and CYP3A4 and resulted in the decrease in theophylline clearance. The clearance of theophylline, therefore, is not influenced by clarithromycin alone. CONCLUSIONS: Careful monitoring is required when levofloxacin is prescribed for patients who are taking clarithromycin with theophylline.