Population pharmacokinetics of steady-state carbamazepine in Egyptian epilepsy patients.

WHAT IS KNOWN AND OBJECTIVE: Individualization of carbamazepine (CBZ) dosage regimen in patients with epilepsy based on based on therapeutic drug monitoring (TDM) followed by estimation of pharmacokinetic (PK) parameters can help in better control of epilepsy. Our objective was to establish a population (POP) PK model of CBZ for Egyptian adult and pediatric patients with epilepsy. METHOD: Single steady-state (SS) trough plasma concentrations of CBZ were available for 302 patients with epilepsy (55·6% men and 44·4% women) who were categorized as children (n = 118) and adults (n = 184) with mean age (years) ± SD of 10·6 ± 4·8 and 29·4 ± 9·9, respectively. Carbamazepine was given as an oral suspension (n = 19) or controlled release tablet (n = 283) with average dose of 15·0 ± 7·8 mg/kg per day. A one-compartment model with first-order absorption and elimination for SS conditions (ADVAN2, SS2, TRANS2) was applied using NONMEM 6.2. Separate absorption rate constants were modelled for the two formulations. The mean POP CL, its intersubject variability (ISV), as well as residual error of CBZ concentration were estimated. RESULTS AND DISCUSSION: The POP estimate for CL was 3·5 L/h with coefficient of variation value of 2·6%, which was consistent with literature data. The ISV on CL was 44·5%. The POP PK model was validated by bootstrap re-sampling, and the individual estimates were within the 95% CI of the bootstrap results. Different covariates that might affect CBZ CL have been evaluated but the limited number of samples per individual prevented precise covariate analysis. WHAT IS NEW AND CONCLUSION: The POP PK model we have developed for CBZ shows good predictive performance in Egyptian adult and pediatric patients with epilepsy. Another PK study to better define the effect of different covariates would improve on the model for dosage individualization.

Aminoglycoside and vancomycin serum concentration monitoring and mortality due to neonatal sepsis in Saudi Arabia.

OBJECTIVE: To assess the effectiveness of monitoring of serum concentration of aminoglycosides in neonates. METHOD: A retrospective evaluation of serum concentration monitoring of aminoglycosides (gentamicin and amikacin) and vancomycin in neonates treated for sepsis in a maternity and children hospital in Jeddah, Saudi Arabia, over the period 1998-2000. RESULTS: The total number of requests for monitoring increased sixfold in 1999 and 12-fold in 2000 relative to 1998. For aminoglycosides, the incidence of both subtherapeutic peak and toxic trough serum levels decreased significantly (P < 0.05) in 1999 and 2000 compared with 1998. Furthermore, the rate of neonatal mortality caused by sepsis showed reduction in both 1999 (34%) and 2000 (35%) in comparison with 1998 (45%). Vancomycin trough (effective) concentration monitoring revealed no change in the incidence (30%) of levels at subtherapeutic values (<5.0 microg/mL) between the compared years. Furthermore, the rate of toxic levels (>10 microg/mL) increased in both 1999 (31%) and 2000 (39%) relative to 1998 (25%). CONCLUSION: Therapeutic drug monitoring of vancomycin needs re-evaluation in the hospital to explain why existing methods are ineffective.

Some international approaches to aminoglycoside monitoring in the extended dosing interval era.

Aminoglycosides have rightly remained a cost-effective anti-microbial strategy for the treatment of gram-positive infections for some 25 years. However, in recent years there has been a review of the traditional thrice-daily administration regimen in favor of an extended dosing interval strategy that takes into account the individual patient's renal function. The general recommendations that have been provided to date have been adopted in various ways internationally. These approaches were a matter of discussion for the Clinical Pharmacokinetics Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology at its congress (Vancouver, Canada; November 1997), and will again be a workshop issue at the Cairns (Australia) congress of the Association (September 1999). The present report provides examples of how these practices have been applied at a group of centers from Canada (2 centers), The Netherlands, Egypt, and Australia. These reports demonstrate a variety of approaches and highlight the need for further research for assessing clinical outcomes from different dosing strategies.

Assessment of liver function by the MEGX test in patients with schistosomiasis and cirrhosis.

OBJECTIVES: The aim of this study was to determine the effect of schistosomiasis infection on hepatic function in Egyptian patients with posthepatitic cirrhosis. DESIGN AND METHODS: Hepatic function, was assessed in 66 Egyptian patients, with (n = 30) and without (n = 36) schistosomal liver fibrosis due to Schistosoma mansoni and in 20 healthy controls, using the monoethylglycinexylidide (MEGX) test. Serum MEGX concentrations were measured before and 5, 15, 30, 60, 120, and 180 min after a lidocaine bolus. The sero-prevalence of antibodies to hepatitis C was also determined in the patients. RESULTS: MEGX test results were significantly lower in patients than in controls at all time points. MEGX test results declined with advancing Child Class. Receiver operating characteristic (ROC) curve analysis revealed the following areas under the ROC curves for discrimination of Child Class C from Child Classes A/B: 30 min, 0.762; 60 min, 0.743; 120 min, 0.731; 15 min, 0.728; 180 min, 0.728; 5 min, 0.602. Schistosomiasis infection had no influence on MEGX test results when cirrhotic patients with (Schisto+) and without (Schisto-) schistosomiasis were compared. While the prevalence of the hepatitis B surface antigen was only 16.7% (Schisto-) and 26.7% (Schisto+), there was an extremely high sero-prevalence of antibodies to hepatitis C (HCV) in both groups: 88.9% (Schisto-) and 73.3% (Schisto+). CONCLUSIONS: The association of schistosomal liver fibrosis with cirrhosis does not additionally influence MEGX formation. In addition, HCV rather than schistosomiasis infection must be considered as a major cause for the progressive liver disease in these patients.

Spotlight on the continual applicability of routine plasma monitoring antiepileptic drugs in the treatment of epilepsy.

The continual applicability of routine plasma measurement of antiepileptic drugs (AEDS) was assessed in 301 epileptic patients with mean age and body weight+/-SD of 30+/-10.6 years and 55+/-19 kg, respectively. The AEDS used included carbamazepine (CBZ), phenytoin (PHT) or valproic acid (VPA) which were given either alone (monotherapy) or in combination (polytherapy). The incidence of uncontrolled epilepsy was significantly higher (P<0.001) in polytherapy vs monotherapy of AEDS and when plasma levels of the drugs were in the subtherapeutic range (P<0.01 for PHT, and P<0.001 for CBZ). Subtherapeutic levels of CBZ were seen with fixed and reasonable doses of 600 mg of the drug given daily. Also, the concentration dose ratios of AEDS were significantly lower in polytherapy vs monotherapy. In conclusion, routine plasma monitoring of AEDS especially in uncontrolled cases of epilepsy could be considered as a fast tool for proper therapeutic approach and dose optimisation in these psychologically and socially devastating episodes.

Disposition of intravenous theophylline in asthmatic children: Bayesian approach vs direct pharmacokinetic calculations.

Fifteen children (mean age +/- SD: 6.4 +/- 3.4, range: 2-12 years) with an acute asthma attack were treated by an intravenous dosage regimen of theophylline (30 min loading infusion of 6 mg/kg body weight followed by a constant infusion of 1 mg/kg, twice for 6 hr each). Three blood samples were drawn (each 15 min after the bolus infusion and after the two infusion periods of 6 hr). Plasma clearance (CL), apparent volume of distribution (Vd) and elimination half-life (t1/2) were estimated by the Bayesian approach using either only the first peak level (Bay 1) or all three monitored concentrations (Bay 3). These values were compared to the parameters calculated by a standard pharmacokinetic procedure (SC). Therapeutic steady state plasma levels around 12 micrograms/ml were rapidly achieved, and the pharmacokinetic parameters (CL = 1.1-1.5 ml/min/kg, Vd = 0.44-0.50 l/kg, t1/2 = 3.5-5.4 hr) differed slightly between the 3 methods applied. There was a significant linear correlation between the Bayesian-derived and SC-derived pharmacokinetic parameters. However the method Bay 1 seems to overestimate the elimination rate of theophylline more than Bay 3 does. In conclusion, Bayesian-based therapeutic plasma level monitoring (Bay 3 are better than Bay 1) can be utilized for individualized pharmacokinetic calculations and proper dosage predictions of theophylline in pediatric patients.

Site-dependent small intestinal absorption of ranitidine.

The site-dependent, small intestinal absorption characteristics of ranitidine were estimated by the intestinal steady state perfusion technique (triple lumen tubing system) combined with simultaneous measurement of serum concentrations of ranitidine. Ranitidine 150 mg.l-1 was perfused at 10 ml.min-1 for 180 min in different sites of the small intestine between 65-250 cm beyond the teeth. Each of 9 healthy, male volunteers was examined twice, using perfusion sites in different regions of the small intestine to permit intraindividual comparisons. The absorption rates (micrograms.30 cm-1.min-1) calculated from intestinal samples showed distinct site-dependence; the highest rates (medians 160-923 micrograms.30 cm-1.min-1) were found in the most proximal region (duodenojejunal junction), and the most distal perfusion sites (distal jejunum/ileum) showed median rates from 193 to 265 micrograms.30 cm-1.min-1. In both of these regions there was a significant positive correlation between the net intestinal water flux and the movement of ranitidine. Within the mid-jejunum, every subject showed marked secretion of ranitidine into the gut lumen (medians -338 to -124 micrograms.30 cm-1.min-1), and in this region there was no influence of water flux on ranitidine movement. The intraluminal results were confirmed by the corresponding site-dependent areas under the serum concentration-time curves (AUC), which decreased with the distance of the perfusion site from the teeth. After the more distal perfusions individual AUCs amounted to 64-16% of the AUCs obtained after more proximal applications. The results demonstrate the small intestine as the site of a gradient of absorption of ranitidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Generation of pharmacokinetic data during routine therapeutic drug monitoring: Bayesian approach vs. pharmacokinetic studies.

In three groups (each n = 12) of unselected hospitalized patients treated either with digoxin, theophylline, or gentamicin routinely performed TDM measurement of trough steady-state plasma levels (+ peak levels in case of gentamicin) was combined with a pharmacokinetic study at steady state (multiple blood sampling during one dosing interval). Pharmacokinetic parameters (apparent volume of distribution Vd, total plasma clearance CL) needed for individualization of dosage were evaluated by the Bayesian approach and a model-(in)dependent pharmacokinetic program (TOPFIT). Comparison of both methods revealed some small differences in the pharmacokinetic parameters for all three drugs. Mean deviations of the Bayesian estimates from the pharmacokinetic calculations of the three drugs ranged between 20 and 38% for Vd and between 13 and 22% for CL, indicating that the Bayesian approach provided reliable pharmacokinetic estimates for individualizing drug dosage under routine conditions. Therefore, it is suggested that routine TDM combined with Bayesian-based analyses can be regarded as an alternative to pharmacokinetic studies in clinically relevant populations.

Pharmacokinetics and pharmacodynamics of famotidine in patients with reflux oesophagitis.

The pharmacokinetics, pharmacodynamic effect and clinical efficacy of famotidine were studied in 10 patients with reflux oesophagitis Grades I and II. For the pharmacokinetic studies the patients received 20 mg famotidine i.v. The half-life of famotidine was 3.8 h, the total plasma clearance was 297 ml.min-1, and a steady state volume of distribution of 1.2 l.kg-1 was found. For pharmacodynamic assessment, intraoesophageal pH-metry was performed without and after acute treatment with famotidine 20 mg i.v. and following 3 weeks of oral famotidine 80 mg b.d. The resultant percentage total acid exposure time (pH < 4 within 24 h) were 23.9%, 19.0% and 19.2% (median), respectively (NS). At the end of 6 weeks of oral therapy, symptomatic and endoscopic improvement had occurred in 9 and 5 patients, respectively. Our study shows that the pharmacokinetics of famotidine in patients with reflux oesophagitis is comparable to that in healthy volunteers and peptic ulcer patients. The clinical response to the treatment appeared comparable to that found after other H2-receptor antagonists.