摘要:

A variety of medications are used in treating patients infected with the human immunodeficiency virus (HIV). These medications are used to control viremia and to prevent and treat opportunistic infections. An individual is often required to take numerous drugs at the same time and thus clinicians are confronted with potential drug interactions, some of which are significant. Three different groups of anti-HIV drugs are used to treat patients. These groups include nucleoside reverse transcription inhibitors, non-nucleoside reverse transcription inhibitors, and protease inhibitors. This article reviews the most relevant drug interactions that occur during the treatment of HIV-infected patients with traditional and also alternative drugs. The role of therapeutic drug monitoring in the routine management of HIV-infected patients is discussed.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The objective of this study was to develop and validate a limited sampling strategy (LSS) that allows accurate and precise estimation of the area under the plasma concentration versus time curve (AUC) of nevirapine, when used in the licensed dosage of 200 mg twice daily. Because nevirapine has a long plasma elimination half-life and the plasma concentration shows little variation within the 12-hour dosing interval, the authors also wanted to explore whether a time frame exists for which a single-sample LSS can be applied. Twenty HIV-1-infected individuals receiving steady-state treatment with nevirapine (200 mg twice daily) were enrolled. For the development of the LSS, 10 patients were randomly selected from the study population (index set). The pharmacokinetic results from the other 10 patients (validation set) were used for prospective validation of the proposed LSS. Blood samples were obtained before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after ingestion. The relationship between the nevirapine concentration at each of the designated time points and the AUC12hwas evaluated by univariate and multivariate linear regression analysis. At each of the sampling times, a strong correlation was observed between the nevirapine concentration and the corresponding AUC12h(r> 0.97). This allows for a single-sample LSS, using any time point during the dosing interval. When a single equation is preferred, the concentration of nevirapine in a random sample drawn 2 to 4 hours after ingestion of nevirapine (C2–4h; in &mgr;g/mL) can be used for accurate estimation of the AUC12h(in h · &mgr;g/mL) by using the equation AUC12h(h · &mgr;g/mL) = 11.699 (h) × C2–4h(&mgr;g/mL) - 4.381 (h · &mgr;g/mL). Validation of this equation resulted in a predicted AUC12hthat was nonbiased and very precise. These data show that the nevirapine concentration at each time point during the dosing interval can be used for accurate estimation of the AUC12h. Even more practical, a sample obtained at any time between 2 and 4 hours after ingestion of nevirapine can be used. The authors therefore conclude that less intensive sampling (i.e., a single sample) can readily be used to assess the AUC12hof nevirapine when used in a dosage of 200 mg twice daily.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Quinine sulfate has been the drug of choice for the treatment of the ever-increasing number of cases of falciparum malaria in tropical countries. Because of the spectrum of adverse effects produced by the drug in the so-called cinchona syndrome, the variation in its pharmacokinetics during the episodes of falciparum malaria, and the different therapeutic regimens proposed in different countries, the authors monitored quinine plasma concentrations in daily samples of 20 men of the Amazon region in Brazil with nonsevere falciparum malaria who were administered 1 g quinine sulfate every 12 hours for 7 days. Three blood samples were collected from each patient each day: two immediately before administration of the drug (7 am and 7 pm ) and one at 11 am . A total of 440 samples were analyzed by a validated method developed in the authors' laboratories using the high-performance liquid chromatographic technique. The overall quinine plasma levels obtained varied from 1.52 to 16.89 &mgr;g/mL. From the second day of treatment, overall levels varied from 2.33 to 14.29 &mgr;g/mL; the peak concentrations showed values from 4.22 to 16.89 &mgr;g/mL, showing the efficacy of the therapeutic regimen used. Adverse effects (signs and symptoms of cinchonism) were observed in all patients. However, no cases of hypoglycemia were detected. Intrapatient comparisons of the obtained quinine plasma concentrations were statistically significant. The quinine dose may be reduced on day 4 of treatment when asexual parasitemia is absent. This way, no resistance to the drug is observed, cinchonism can be minimized, and good adherence to the regimen is obtained.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Sixteen hospitalized white European Spanish psychiatric patients treated with thioridazine alone were studied with respect toCYP2D6genotype, debrisoquine metabolic ratio (MR), and the plasma levels of thioridazine and its metabolites mesoridazine and sulforidazine. After decreasing the dose of thioridazine the debrisoquine MR and thioridazine plasma levels were redetermined.At the initial determination (regular clinical doses, 20–300 mg/day), 14 of 16 patients (88%) were classified as poor metabolizers of debrisoquine (PMs). However, after complete withdrawal of thioridazine in 10 patients, all 10 became extensive metabolizers except two who were genotypically PMs (*4/*4). The inhibition of debrisoquine metabolism was genotype dependent. All patients with wt/wt genotype treated with a dose 150 mg/d were phenotypically PMs, all patients with wt/*4 genotype treated with a dose of 50 mg/d or greater were PMs. The debrisoquine MR from all dose changes correlated with the dose (p < 0.001) and plasma level (p < 0.001) of thioridazine.The CYP2D6 hydroxylation capacity was inhibited by thioridazine as determined by the debrisoquine MR. This inhibition was reversible by thioridazine withdrawal, and thus seems to be dose dependent and related toCYP2D6genotype. One must consider the effects of thioridazine dosage on CYP2D6, because it may influence the metabolism of concomitant drugs or produce clinically important adverse effects such as cardiotoxicity. An awareness of this problem and cautious dosage adjustment of other drugs metabolized by the same enzyme are recommended during treatment with thioridazine.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The authors assessed differences in both therapeutic and dyskinesia-matched concentrations of levodopa by kinetic–dynamic modeling in a large cohort of patients with Parkinson disease grouped by severity of symptoms. The goal was to provide a kinetic–dynamic approach to levodopa therapy monitoring to assist treating physicians in rationalizing patients' drug schedules in line with disease progression. Eighty-six patients, grouped according to Hoehn & Yahr (H&Y) clinical stage (H&Y I, n = 23; II, n = 25; III; n = 25; IV, n = 13) enrolled in the study. After a 12-hour levodopa washout each patient was examined using a standard oral levodopa test, based on simultaneous serial measurements of plasma levodopa concentrations, finger-tapping motor effects, and dyskinesia ratings. The kinetic–dynamic modeling for both effects was carried out according to the “link” effect compartment model and sigmoidal pharmacodynamic model. Levodopa plasma kinetics did not differ among patient groups. Duration of motor response was significantly (p < 0.001) curtailed in patients in advanced clinical stages whereas dyskinesia duration showed minor changes among the three affected groups (H&Y II, III, and IV). Median effective concentrations (EC50) were increased at the more advanced clinical stage (p < 0.001), from a median 0.2 &mgr;g/mL in patients at H&Y stage I to 0.9 &mgr;g/mL in patients at H&Y stage IV, whereas the maximum effect showed less consistent changes among the four groups. Intrasubject levodopa therapeutic concentrations were lower than values for dyskinesias in patients at the moderate stage of the disease, equaling dyskinesia-matched drug concentrations in the more affected patients. These findings are in line with previous observations of major changes in levodopa concentration–effects relationship with disease progression and support a stratification of patients with Parkinson disease according to kinetic–dynamic modeling. From a practical point of view, knowledge of individual patients' kinetic–dynamic variables can help the physician assess patients' clinical needs objectively and optimize levodopa dosing according to disease progression.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The present study estimated the population pharmacokinetics of lamotrigine in patients receiving oral lamotrigine therapy with drug concentration monitoring, and determined intersubject and intrasubject variability. A total of 129 patients were analyzed from two clinical sites. Of these, 124 patients provided sparse data (198 concentration–time points); nine patients (four from a previous group plus five from the current group) provided rich data (431 points). The population analysis was conducted using P-PHARM™ (SIMED Scientific Software, Cedex, France), a nonlinear mixed-effect modeling program. A single exponential elimination model (first-order absorption) with heteroscedastic weighting was used. Apparent clearance (CL/F) and volume of distribution (V/F) were the pharmacokinetic parameters estimated. Covariate analysis was performed to determine which factors explained any of the variability associated with lamotrigine clearance. Population estimates of CL/F and V/F for lamotrigine generated in the final model were 2.14 ± 0.81 L/h and 78.1 ± 5.1 L/kg. Intersubject and intrasubject variability for clearance was 38% and 38%, respectively. The covariates of concomitant valproate and phenytoin therapy accounted for 42% of the intersubject variability of clearance. Age, gender, clinic site, and other concomitant antiepileptic drugs did not influence clearance. This study of the population pharmacokinetics of lamotrigine in patients using the drug clinically provides useful data and should lead to better dosage individualization for lamotrigine.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Using NONMEM, the population pharmacokinetics of perhexiline were studied in 88 patients (34 F, 54 M) who were being treated for refractory angina. Their mean ± SD (range) age was 75 ± 9.9 years (46–92), and the length of perhexiline treatment was 56 ± 77 weeks (0.3–416). The sampling time after a dose was 14.1 ± 21.4 hours (0.5–200), and the perhexiline plasma concentrations were 0.39 ± 0.32 mg/L (0.03–1.56). A one-compartment model with first-order absorption was fitted to the data using the first-order (FO) approximation. The best model contained 2 subpopulations (obtained via the $MIXTURE subroutine) of 77 subjects (subgroup A) and 11 subjects (subgroup B) that had typical values for clearance (CL/F) of 21.8 L/h and 2.06 L/h, respectively. The volumes of distribution (V/F) were 1470 L and 260 L, respectively, which suggested a reduction in presystemic metabolism in subgroup B. The interindividual variability (CV%) was modeled logarithmically and for CL/F ranged from 69.1% (subgroup A) to 86.3% (subgroup B). The interindividual variability in V/F was 111%. The residual variability unexplained by the population model was 28.2%. These results confirm and extend the existing pharmacokinetic data on perhexiline, especially the bimodal distribution of CL/F manifested via an inherited deficiency in hepatic and extrahepatic CYP2D6 activity.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

To examine the effects of ascites on tacrolimus disposition, the authors measured tacrolimus concentration in blood and ascitic fluid from a patient with a living related liver transplant recipient who required removal of 500 to 2400 mL ascitic fluid daily. Tacrolimus levels in ascitic fluid ranged from 0.07 to 0.29 ng/mL and in whole blood from 7.5 to 20.3 ng/mL. The tacrolimus concentration in ascitic fluid positively correlated with that in whole blood (r= 0.878,P<0.0001). Because the amounts of tacrolimus excreted into the ascitic fluid corresponded to only 0.01% to 0.09% of the dose administered, the authors concluded that the effects of ascites on tacrolimus disposition were negligible even though large amounts of ascitic fluid were drained regularly.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The authors report the case of an 8-year-old girl who underwent a liver transplant at the age of 18 months because of biliary atresia. She was treated with cyclosporin for more than 5 years. Increased hirsutism prompted a change to tacrolimus therapy. During 11 months the mean tacrolimus level was 8.2 ng/mL. The patient was hospitalized because of an episode ofShigellainfection and a threefold increase in tacrolimus level was measured. Despite a reduction of tacrolimus dose, the trough tacrolimus levels were in the range of 16.5 to 22.0 ng/mL during the subsequent 2 weeks. On resolution of the diarrhea, tacrolimus levels returned to those observed before theShigellainfection. It is suggested that the marked increase in tacrolimus levels observed in this patient is a direct result of the damage produced to the gastrointestinal mucosa by theShigellainfection.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Thiotepa is an alkylating agent widely used in high-dose chemotherapy. The pharmacokinetics of thiotepa and its main metabolite tepa show a wide interpatient variability, which may be responsible for the interpatient variability in toxicity. The aim of this study was to develop and validate a pharmacokinetically guided dosing strategy with the sum of the thiotepa and tepa area under the concentration-time curve (AUC) as the target parameter. A total of 46 patients received 77 courses of chemotherapy with thiotepa (80–120 mg/m2per day) divided into two daily 30-minute infusions in combination with cyclophosphamide and carboplatin. Patients received up to three courses of chemotherapy. The interpatient, course-to-course, day-to-day, and residual variability in the pharmacokinetics of thiotepa and tepa were estimated with a population analysis with the software program NONMEM. The planned strategy consisted of the collection of blood samples on day 1 and either day 3 or day 4 of each 4-day course. The thiotepa dose was planned to be adjusted on day 3 of each course and before the start of a new course on the basis of Bayesian predictions of the pharmacokinetics with data of day 1 and/or the possible previous course. The prediction procedure was validated by dividing the dataset into an index and validation set. The Bayesian predictions of the validation set were compared with true AUC values generated with individual fits of each course. The performance of the complete strategy was tested with a simulation procedure in 1,000 patients. Interpatient variability and course-to-course variability were in the same order (±20%); day-to-day variability was less (±15%). The sampling strategy resulted in predictions of the AUC without bias with acceptable precision (±20%). The simulation showed that variability in exposure was effectively decreased by the dosing strategy. This strategy resulted in a reduction in the variability of the exposure to thiotepa and tepa and can be implemented in a clinical study.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID