摘要:

Drug metabolic interactions present potential risks in patient care, but their frequency and relative importance as a clinical problem remains unclear. To assess the frequency and clinical outcome of potentially harmful drug metabolic interactions in hospitalized patients, the authors performed a survey of the medication data of patients treated on internal and pulmonary medicine wards in a university hospital. The database was searched for concomitantly administered drug pairs that would, according to Hansten and Horn's drug interaction database, carry a high risk for a clinically harmful metabolic drug interaction. Coadministrations involving warfarin or cisapride were subjected to further analysis regarding clinical outcome. A total of 142 patients were exposed to 150 interactions with potentially harmful clinical outcome, resulting in a frequency of 0.9% (95% CI 0.7% to 1.0%). Inhibition of warfarin metabolism by metronidazole produced significant overanticoagulation as evidenced by elevated international normalized ratio values, whereas inducers (rifampicin and phenobarbital) of warfarin metabolism significantly reduced the efficacy of warfarin. One case of minor bleeding and one case of clavicular vein thrombosis were detected as possible consequences of disturbed anticoagulation. The coadministration of cisapride and erythromycin significantly prolonged the corrected QT (QTc) interval and was associated with clinical symptoms of cardiac arrhythmias. Coadministration of cisapride with fluconazole or miconazole was not associated with prolongation of the QTc interval or cardiac sequelae. Evaluations of patient materials are needed to assess the clinical relevance of metabolic drug interactions.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Genetic polymorphism of the cytochrome P450 isoenzymes CYP2D6 and CYP2C19 was determined by phenotyping four ethnic groups of the Israeli population. The groups consisted of Ethiopian subjects, Yemenite subjects, and Russian subjects representing first-generation new immigrants and an Israeli Arab group. Dextromethorphan was used as the probe for CYP2D6 activity and mephenytoin was used for CYP2C19 activity. The two drugs were administered simultaneously and urine samples were collected over a period of 8 hours. The CYP2D6 phenotype was determined from the ratio of dextromethorphan conversion to dextrorphan and the CYP2C19 phenotype from the ratio ofS-mephenytoin andR-mephenytoin. The used liquid chromatographic method was able to completely separate dextrorphan and dextromethorphan. Fluorescence detection allowed dextromethorphan quantification at 1 ng/mL. Mephenytoin enantiomers were completely separated in high-performance liquid chromatography and the respective fractions were collected and analyzed using a gas chromatography/mass spectrometry system with selective ion monitoring. The prevalence of poor metabolizer phenotype of dextromethorphan (CYP2D6) in the Yemenite (0%) and Ethiopian groups (0%) was significantly different from the prevalence in the Russian (17%) and Israeli Arab (9%) groups. A significant difference was also found in the distribution of the metabolic ratio of the extensive metabolizer phenotype between the Ethiopian group and the Russian and Yemenite groups. No significant difference was found in the prevalence of poor mephenytoin metabolizer phenotype (CYP2C19) between the Yemenite (8%), Ethiopian (6%), Russian (9%), and Israeli Arab (8%) groups. No difference was observed in the distribution of metabolic ratio within the extensive metabolizer phenotype subgroups of the four ethnic groups.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The authors examined the interindividual correlation between saliva and serum concentrations of lamotrigine (LTG) and the relationship between LTG concentration in saliva and the free LTG concentration in serum in 40 patients with epilepsy, aged 16 to 73 years, receiving stable doses of LTG and comedication. Saliva was collected before and after stimulation of salivary flow. The free LTG fraction was determined by equilibrium dialysis and ultrafiltration. Drug analysis was performed by high-performance liquid chromatography . The correlation between LTG daily dose and serum concentration was weak but significant (r= 0.47). There was high correlation between LTG concentration in serum and unstimulated (r= 0.85) or stimulated (r= 0.94) saliva, and between total LTG concentration in serum and the free LTG fraction as determined by ultrafiltration (r= 0.95) and equilibrium dialysis (r= 0.93). Lamotrigine concentration in stimulated saliva was significantly correlated to the free LTG fraction. Protein binding of LTG calculated from concentration in stimulated saliva, as determined by ultrafiltration and equilibrium dialysis, was 51.8% ± 13.03%, 68.05% ± 7.59%, and 58.72% ± 7.68% (mean ± standard deviation) respectively. The differences between the three methods were significant. The authors conclude that saliva sampling may be a useful alternative to blood tests for monitoring LTG treatment.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The vancomycin pharmacokinetic profile was characterized in six pediatric patients and the potential of nonlinear mixed effects modeling and Bayesian forecasting for vancomycin monitoring was explored using NONMEM V (1.1). Based on steady state serial vancomycin concentrations, the estimates of mean t½, Vd, and Cl derived by the Sawchuk and Zaske method(1)were 3.52 hours, 0.57 L/kg, and 0.12 L/h per kg, respectively. NONMEM analysis demonstrated that a weight-adjusted two-compartment model described individual patients' data better than a comparable one-compartment model. The two-compartment estimates of mean t½&agr;, t½&bgr;, Vss, and Cl were 0.80 hour, 5.63 hours, 0.63 L/kg, and 0.11 L/h per kg, respectively. The relatively long mean t½&agr; suggests that peak vancomycin concentrations measured earlier than 4 hours postdose do not reflect postdistributional serum concentrations. NONMEM population modeling revealed that a weight-adjusted two-compartment model provided a better fit than a comparable one-compartment model. The resulting population parameters and variances were fixed in NONMEM to obtain Bayesian predictions of individual vancomycin serum concentrations. Bayesian estimation with either a single midinterval or trough sample has the potential to provide accurate and precise predictions of vancomycin concentrations. This should be evaluated using a vancomycin population pharmacokinetic model based on a larger sample of pediatric patients.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

A limited sampling model (LSM) is proposed for the first-time assessment of pharmacokinetic parameters (area under the concentration–time curve (AUC), Cmax, and T½) in children after a single oral dose of drug. Three drugs were evaluated in this study. The LSM was developed for each drug from the data of 10 healthy adult volunteers. The relationship at selected time points between plasma concentration and the AUC or Cmaxwas evaluated by multiple linear regression. The multiple linear regression that gave the best correlation coefficient (r) for 3 sampling times versus AUC or Cmaxwas chosen as the LSM. Pharmacokinetic parameters generated using sparse sampling (3 blood samples) were compared with pharmacokinetic parameters generated using extensive sampling (>7 blood samples). The results indicated that a limited sampling model can be developed from adult data to estimate pharmacokinetic parameters in children with fair degree of accuracy.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

A phase I study was conducted to determine the pharmacokinetics, safety, and tolerability of sirolimus, a new immunosuppressive drug, in 45 healthy men between 19 and 36 years of age. Nine subjects in each group were randomly assigned to receive single oral doses of either sirolimus (n = 6) or placebo (n = 3) in group I (0.3 mg/m2), group II (1 mg/m2), group III (3 mg/m2), group IV (5 mg/m2) and group V (8 mg/m2). No serious adverse events occurred during the study. Twenty-eight of the 45 volunteers (62%) reported an adverse event; 19 of 30 (63%) were in the sirolimus group and 9 of 15 (60%) were in the placebo group (ns). Asthenia was the most common adverse event, occurring in 7 of 30 (23%) in the sirolimus group compared with 6 of 15 (40%) in the placebo group (ns). Absorption occurred within 1 hour in all volunteers. Whole blood peak concentration and area under the concentration–time curve increased proportionally with dose. Mean (± SD) whole blood terminal disposition half-life (t½), apparent oral dose clearance (Cl/F), and volume of distribution (Vss/F) were 82 ± 12 hours, 278 ± 117 mL/h·kg and 23 ± 10 L/kg, respectively. Distribution of sirolimus into formed blood elements was extensive, with a mean whole blood-to-plasma ratio of 36. Single oral doses of sirolimus (0.3 to 8 mg/m2) solution were well tolerated in healthy male volunteers.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Therapeutic drug monitoring (TDM) has assumed an important place in patient management in the last few decades. In this study, serum drug levels determined in 7759 specimens sent to the Department of Pharmacology and Clinical Pharmacology in 1994 and 1998 for TDM were retrospectively evaluated. Monitored drugs were carbamazepine, valproate, phenytoin, phenobarbital, digoxin, theophylline, and salicylate. The comparison of the results obtained for the relevant 2 years showed that there was a remarkable increase in the number of requests for TDM per year and in the rate of serum drug levels that were within therapeutic range. Serum antiepileptic drug level monitoring accounted for a major part of the data. Overall data suggest that the use of TDM in antiepileptic drugs is improving; conversely, digoxin and theophylline are still not being properly monitored. In this study, the results are discussed in the light of rational TDM criteria.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Mycophenolate mofetil, the oral prodrug of mycophenolic acid, is indicated as immunosuppressive therapy after renal transplantation. To aid in the investigation of pharmacokinetic–pharmacodynamic relationships of mycophenolic acid in the clinical setting, limited blood sampling strategies have been proposed, and models from these developed, for the estimation of mycophenolic acid area under the concentration–time curve (AUC). In the current study, the authors investigated the predictive performance of six published models to estimate AUC. A total of 49 profiles from 25 renal transplant patients were used to test each model's performance against a full 14 time-point AUC. A wide range of agreement was found when predicted AUCs were compared with full AUCs using linear regression analysis (range:r2= 0.499 to 0.836). Model 1, which uses 4 time-points over 6 hours, was found to be superior to all other models. The range of time-points used in this model takes into account patients with variable absorption. This model should be further tested on data sets from other centers. The relatively poor performance of the other models may be caused by their inability to describe the peak concentration in these patients. Caution is warranted when using limited sampling strategies on patients whose absorption of mycophenolic acid is altered, compared with those of the pharmacokinetic profiles from which the model was developed.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The population pharmacokinetics of ribavirin were assessed in patients with chronic hepatitis C virus (HCV) infection treated with interferon &agr;-2b and ribavirin in four clinical efficacy studies. The authors collected 3450 ribavirin serum concentrations from 1105 patients at different treatment weeks for inclusion in the analysis. Population factors included gender, age, body weight, serum creatinine, creatinine clearance, and previous interferon treatment history. Ribavirin apparent clearance (CL/F) was calculated from individual patients' daily doses divided by concentration values, and the influence of these factors was assessed by multiple regression. Body weight, gender, age, and serum creatinine affected CL/F. Population mean CL/F estimates were 17.9 L/h (female) and 21.5 L/h (male) assuming an age of 40 years and body weight of 70 kg. Ribavirin apparent clearance increased as a function of body weight and decreased at ages greater than 40 years. Serum creatinine had little influence on CL/F, which may reflect the relatively normal renal function of these patients. Total CL/F variability was approximately 28%. The four covariates in the model explained 27% of this variability, and were thus of limited clinical significance because of the substantial residual variability not accounted for by the model. In assessing the relationship between pharmacokinetics and pharmacodynamics, the week 4 hemoglobin nadir value was negatively associated with week 4 ribavirin concentrations. The percentage of reduction from baseline was positively associated with ribavirin concentrations, although these data were highly variable. Loss of HCV-RNA at 24 weeks after completion of treatment was considered a response to interferon and ribavirin treatment in a logistic regression analysis of clinical and pharmacokinetic variables and treatment response in the interferon-naïve patients. Hepatitis C virus genotype, pretreatment HCV-RNA titer, duration of treatment period, week 4 ribavirin concentration, and patient age affected the likelihood of response. Higher ribavirin concentrations at treatment week 4 were associated with a higher response rate. Variables that have predictive value for treatment outcome in patients treated with interferon and ribavirin are similar to those previously reported for interferon monotherapy.

ISSN:0163-4356    

出版商:OVID    

年代:2000

数据来源: OVID