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Biomedical subjects

G J Yuen

Publications and source records attributed to G J Yuen.

11 recordsLinked to original sources
PubMed1992

Relationship between dideoxyinosine exposure, CD4 counts, and p24 antigen levels in human immunodeficiency virus infection. A phase I trial.

OBJECTIVE: To determine the relation between exposure to dideoxyinosine (ddl) and increased CD4 cell counts and suppression of serum p24 antigen in patients infected with the human immunodeficiency virus (HIV). DESIGN: Open-label, phase I study. SETTING: Two university hospitals. Patients were studied in both inpatient and outpatient settings. PATIENTS: Of 36 HIV-infected patients enrolled, 18 had adequate pharmacokinetic information for analysis. INTERVENTION: Dideoxyinosine was administered intravenously every 12 hours for 2 weeks. Patients were switched to oral administration at twice the intravenous dose. Pharmacokinetic profiles were obtained twice during each period. A 40-fold range of dose was examined. MEASUREMENTS: CD4-positive T-lymphocyte counts and serum p24 antigen levels were determined. Plasma area under the ddl concentration-time curve was determined for a single dose and at steady state. RESULTS: Increases in CD4-positive T-lymphocyte counts were independent of ddl exposure and were proportional to the starting CD4 count. Suppression of circulating p24 antigen was influenced by cumulative exposure to ddl and was statistically significant. CONCLUSIONS: The CD4-positive T-lymphocyte count increased at low ddl concentrations or exposures; the extent of this increase was directly proportional to the patient's CD4 count at the start of therapy. Suppression of p24 antigen was related to cumulative exposure to ddl. Therapeutic responses can probably be obtained with ddl, while minimizing long-term toxicity, using daily doses of 10 mg/kg body weight, or less.

Administration, Oral↗
PubMed1992

Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials.

The objective of this study was to determine the population pharmacokinetic parameters and the extent of absorption of 2',3'-dideoxyinosine, a nucleoside analog with activity against human immunodeficiency virus in vitro and in vivo, after oral and intravenous administration through the use of NON-linear Mixed Effects Modeling. The data were drawn from the pharmacokinetics section of an open-label, multicenter phase I study. One center administered ddI on a once-daily schedule. The other centers administered the drug once every 12 h. Drug was administered intravenously, and the plasma concentration-time profile was determined. Patients were then given the drug orally at twice the dose used in the intravenous portion of the study, and the pharmacokinetic profile was again determined. A 40-fold range of doses was examined. Forty-six human immunodeficiency virus-infected patients were studied. Concentrations in plasma were determined by high-pressure liquid chromatography. Clearance of the drug from plasma was 47.7 liters/h/70 kg of body weight. The terminal half-life was 1.4 h. The volume of distribution in the central compartment was 18.8 liters/70 kg. Absorption was rapid, with an absorption half-life of 0.52 h. Bioavailability with once-daily administration was 27%. For twice-daily administration, bioavailability rose to 36%. This difference was significant (P much less than 0.01). For doses of less than or equal to 5.1 mg/kg given every 12 h (10.2 mg/kg/day), bioavailability was 41%. We conclude that once-daily administration results in lower mean bioavailability, probably because of a saturation of the absorption process similar to that seen with acyclovir. This difference in bioavailability on the basis of the administration schedule explains the different short-term maximal tolerated doses identified in phase I trials of this agent.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Use of nonlinear, mixed-effects modeling for population analysis of ofloxacin: effects of age on oral drug pharmacokinetics.

To compare the effect of age on pharmacokinetics of orally administered ofloxacin, two separate studies were reanalyzed using mixed-effect modeling with the program NONMEM. Subjects were male volunteers, 36 age 65 years or greater and 24 age 18-40 years. The younger group received three 100-mg tablets and the older group received two 200-mg tablets of ofloxacin. Serial blood samples obtained throughout dosing were assayed for drug concentrations using high-performance liquid chromatography. A pharmacostatistical model was developed for the data using mixed-effect modeling with NONMEM. A one-compartment open model with first-order absorption, which included the covariables weight and age, best fit the data. Mean (SE) population values were clearance/F 0.219 (0.009) L/hr/kg, volume of distribution/F 1.50 (0.071) L/kg, and absorption rate constant 2.26 (0.048) hr-1. Older subjects had a 29% lower clearance and 13% lower volume of distribution then the younger subjects.

Administration, Oral↗
PubMed1990

Altered pharmacokinetics in the elderly.

Physiologic changes that occur in the aging process may directly affect drug pharmacokinetics. Alteration of the pharmacokinetics of these drugs in the elderly may necessitate adjustment of drug dosages to prevent toxicity or inadequate therapy. Whereas clinical tests to measure renal function may be used quantitatively to prospectively individualize a drug dosage to an elderly patient, tests for hepatic function do not correlate as well with changes in hepatic drug metabolism. Despite these limitations, recognition of the relationship between physiologic changes and drug pharmacokinetics is important to better prescribe the correct dose in the elderly population.

Aged↗
PubMed1989

Ciprofloxacin pharmacokinetics in critically ill trauma patients.

The steady-state pharmacokinetics of ciprofloxacin 200 mg intravenously every 12 hours was examined in 10 critically ill trauma patients. The mean parameter estimates for total clearance, renal clearance, non-renal clearance, and volume of distribution were 30.08 liters/hour/1.73 m2, 16.62 liters/hour/1.73 m2, 13.46 liters/hour/1.73 m2, and 2.10 liters/kg. Although the mean values were similar to those previously reported, significant individual differences were observed, with the coefficient of variation ranging from 41 to 61 percent. Non-renal clearance appeared to have a bimodal distribution. The dosage studied appeared to provide adequate serum concentration profiles to treat most pathogens found in infected trauma patients. However, the use of higher doses and more frequent dosing may be required to treat patients with Staphylococcus aureus and Pseudomonas aeruginosa infections.

Adult↗
PubMed1989

Prospective use of optimal sampling theory: steady-state ciprofloxacin pharmacokinetics in critically ill trauma patients.

We examined the use of optimal sampling theory to determine a sparse sampling design to estimate pharmacokinetic parameters of ciprofloxacin in patients who had sustained trauma. Two serum sampling strategies, consisting of six sampling times each, were derived on the basis of the patient's renal function (patients with creatinine clearance greater than or equal to 6 L/hr/1.73 m2 and patients with creatinine clearances less than 6 L/hr/1.73 m2). Two additional serum samples were obtained for other aspects to the study. A timed urine collection was also obtained. Pharmacokinetic parameter estimates were determined by comodeling the serum and urine data with a three-compartment open model (parameterized as microconstants) with a bayesian algorithm and by noncompartmental analysis. Bayesian-derived parameter estimates were total body clearance of drug from plasma, 29.8 L/hr/1.73 m2; renal clearance, 17.0 L/hr/1.73 m2; and nonrenal clearance, 12.7 L/hr/1.73 m2 and were not significantly different from noncompartmentally derived parameters (p = 0.80, p = 0.65 and p = 0.333, respectively). The study demonstrates the use of optimal sampling theory to determine an informative yet relatively sparse sampling strategy for a drug with a complex pharmacokinetic model.

Adult↗
PubMed1989

Phenytoin dosage predictions in paediatric patients.

Phenytoin dosing in paediatric patients is complicated both by alterations in patient requirements due to growth and maturation changes and by the capacity-limited characteristics of phenytoin metabolism. This study examines 2 pharmacokinetic methods to adjust phenytoin dosage based on a single dosing-rate/steady-state serum phenytoin concentration pair. A Bayesian forecaster and a fixed parameter [rate of metabolism (Vmax)] method were examined with previously published sets of a priori parameter estimates. The fixed Vmax method was utilised with the parameter derived from native Japanese (method 1), US Caucasian (method 2) and European (method 3) patients. The Bayesian forecaster used a priori parameter estimates obtained from native Japanese (method 4) and European (method 5) patients. Each method was examined retrospectively in 34 paediatric patients with a total of 48 predictions possible. Measures of absolute predictability, bias (mean error, % dose) and precision (root mean squared error, % dose), were -3.58/12.2, -1.51/12.2, 4.06/9.96, -4.38/13.2, and -3.10/11.5, for methods 1, 2, 3, 4 and 5, respectively. There was no significant difference among the 5 methods. However, the Bayesian algorithm tended to be more robust over a broad range of situations, providing predictions in all cases. The fixed Vmax methods could not provide predictions in every case. Finally, all methods had a significant number of overpredictions of dosage. Poorer results were observed when prediction of steady-state serum concentrations were performed, partly due to the retrospective nature of the study. We conclude that close monitoring of patients, regardless of the method chosen to adjust dosage, is recommended.

Adolescent↗
PubMed1983

Predicting phenytoin dosages using Bayesian feedback: a comparison with other methods.

A Bayesian feedback technique for predicting phenytoin dosage was compared to other dosing methods. Sixty-nine cases were selected on the basis of apparent reliability from 103 medical charts of epileptic patients with multiple phenytoin levels on different dosage regimens. Two published nomograms and a graphical, or computational, technique were compared to the Bayesian technique. Each method was assessed for absolute predictability using measures of bias and precision, i.e., mean percent error and root mean squared percent error, respectively. For a single previous data pair, the Bayesian method was similar to a published nomogram with regard to bias and precision. For multiple data pairs, the graphical or simultaneous equation technique tended to be less biased, but the Bayesian method had better precision. However, none of these differences was statistically significant (p greater than 0.05). The Bayesian method yielded the lowest percentage of predicted doses that exceeded 110% of the actual dose. The Bayesian method conveniently provides a single method applicable to the use of either single or multiple concentration-dosage data pairs and results in fewer extreme dosing errors.

Adult↗
PubMed1983

Phenytoin cumulation profiles.

his study was performed to determine the potential utility of the cumulation profile of phenytoin during multiple oral dosing and to examine, under ideal conditions, the variability in apparent steady state concentrations. Six male subjects were administered oral phenytoin sodium 5-6 mg/kg/d in divided doses every 12h for six days. Predose serum phenytoin concentrations were measured every 12 hours by gas liquid chromatography. The resulting data were analyzed in order to estimate maintenance doses. Subjects were then placed on the estimated daily dose and pre-dose concentrations measured daily for at least two weeks. At the end of the study, all data were fit using non-linear regression analysis to obtain the best estimates of individual kinetic parameters. Parameter values, particularly the Km value, were dependent upon the input function used, either first- or zero-order. In two subjects there was evidence of modest auto-induction. At steady-state the average coefficient of variation of predose concentrations was 10.6% (Range: 5.2-16.2%).

Administration, Oral↗