Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects.

The aim of this study was to determine whether oral ganciclovir interacted pharmacokinetically with zidovudine (AZT), didanosine (ddI), or probenecid. A multicenter, open-label, randomized, crossover pharmacokinetic study with four phases was undertaken at an outpatient private research center and at university research clinics. Twenty-six HIV-infected adults (23 men, 3 women) with cytomegalovirus (CMV) seropositivity and CD4+ T-lymphocyte count > or =100 cells/microl were studied. Patients had to be stable on antiretroviral therapy for at least 4 weeks. Patients with a history of opportunistic infection or gastrointestinal symptoms were excluded. Measurements included serial blood and urine samples during the dosing intervals at steady state. The steady-state pharmacokinetics of ganciclovir were determined after the participants had stabilized and were tolerating AZT or ddI therapy. When a 1000-mg dose of oral ganciclovir was taken every 8 hours, there was a significant mean increase in Cmax and dosing interval area under the serum concentration time curve over a dosing interval (AUC) for the two antiretroviral drugs: for AZT, 61.6% and 19.5%, respectively; for ddI when administered sequentially (2 hours before ganciclovir), 116.0% and 114.6%; and for ddI administered simultaneously with ganciclovir, 107.9% and 107.1%, respectively. There was no significant change in renal clearance for either antiretroviral drug, suggesting that the interaction did not occur through a renal mechanism. There was no significant change in mean ganciclovir Cmax and AUC(0-8) when coadministered with AZT. Mean increases in Cmax and AUC(0-8) of oral ganciclovir averaged 40.1% and 52.5%, respectively, when coadministered with probenecid, but decreased by 22.1% and 22.7%, respectively, when oral ganciclovir was administered 2 hours after ddI. There was no change in the mean ganciclovir Cmax or AUC(0-8) when administered simultaneously with ddI. The mean renal clearance of oral ganciclovir was not affected by AZT or ddI coadministration intake, but there was a mean decrease of 19% when coadministered with probenecid. We conclude the increased serum concentration and reduced renal clearance of ganciclovir suggests competition with probenecid for secretion at the renal tubule. The mechanism of the interaction of oral ganciclovir with either AZT or ddI remains to be determined. The magnitude of the effect of oral ganciclovir on ddI pharmacokinetics may result in an increase in ddI concentration-related toxicities. Similarly, the small but significant decrease in ganciclovir concentration with sequential combination ddl therapy may impair the efficacy of oral ganciclovir. For HIV-infected patients receiving ganciclovir and ddI, clinicians should recommend administering the two drugs simultaneously, and patients should be monitored closely for ddI-associated toxicities.

Revised Winter-Tozer equation for normalized phenytoin concentrations in trauma and elderly patients with hypoalbuminemia.

OBJECTIVE: To develop a revised equation reflecting the current practice of measuring unbound phenytoin at room temperature, and to evaluate the revised Winter-Tozer method of predicting normalized total phenytoin concentrations in two groups of patients with hypoalbuminemia-elderly nursing home patients and critically ill head trauma patients. DESIGN: Albumin, unbound phenytoin, and total phenytoin concentrations were obtained from two sources: prospectively from a group of elderly nursing home patients and by a retrospective chart review of trauma patients enrolled in a previous double-blind, placebo-controlled study. SETTING: Community nursing homes; a university-affiliated urban teaching hospital. PARTICIPANTS: Elderly nursing home patients (n = 46) taking chronic phenytoin therapy and patients enrolled in a double-blind, placebo-controlled study (n = 58) evaluating the use of phenytoin to prevent posttraumatic seizures. MAIN OUTCOME MEASURES: Prediction error analysis was performed by using the methods proposed by Sheiner and Beal. Bias and precision were evaluated by calculating the mean prediction error (MPE) and root mean squared error (RMSE), respectively. RESULTS: The Winter-Tozer equation consistently overpredicted the normalized phenytoin concentration in the elderly nursing home population (MPE = 3.2, RMSE = 5.9) and the trauma patients (MPE = 3.3, RMSE = 4.8). The equation was revised to reflect the increased protein binding of phenytoin with decreased temperature and resulted in significantly decreased bias in both groups of patients. CONCLUSIONS: The revised equation is useful in predicting normalized phenytoin concentrations in both elderly nursing home patients and critically ill trauma patients.

Pharmacokinetics of oral ganciclovir capsules in HIV-infected persons.

OBJECTIVES: To delineate the pharmacokinetic profile of the oral capsule formulation of ganciclovir, and determine whether oral ganciclovir has any pharmacokinetics interactions with zidovudine, didanosine or probenecid. MEASUREMENTS: Serum and urine concentrations of ganciclovir, zidovudine and didanosine were measured. From these concentrations, standard pharmacokinetic parameters such as peak concentration, area under the curve (AUC), elimination half-life and renal clearance were determined. RESULTS: The bioavailability of oral ganciclovir averages 6-9%. Inter- and intrasubject variability of AUC is low (coefficient of variation 21.8 and 12.6%, respectively). The steady-state AUCs achieved with oral ganciclovir (1000 mg three times daily or 500 mg six times daily) are approximately 70% of the AUC achieved with the daily maintenance dose of intravenous ganciclovir (5 mg/kg). Serum concentrations of ganciclovir are 20% higher when the oral formulation is administered with a high fat meal than when taken following an overnight fast. Serum concentrations of didanosine (200 mg every 12 h) are approximately doubled when taken in combination with oral ganciclovir (1000 mg every 8 h). CONCLUSIONS: Although bioavailability of the oral formulation of ganciclovir is low, the serum concentrations are predictable, with low inter- and intrasubject variability in peak concentrations and AUC. The two oral regimens studied (500 mg six times daily or 1000 mg three times daily) have comparable bioavailability. Food has a beneficial effect of increasing serum concentrations. There is a potentially important pharmacokinetic interaction between oral ganciclovir and didanosine.

Effect of food on the relative bioavailability of oral ganciclovir.

The steady-state pharmacokinetics of oral ganciclovir in the fasting versus fed state were studied in 20 patients infected with human immunodeficiency virus and with a seropositive test result for cytomegalovirus in a two-way crossover study. Patients received oral ganciclovir at a dose of 1000 mg every 8 hours for 8 days. On days 4 and 8, subjects were randomly assigned to receive the morning dose either after an overnight fast or after a standardized 602-calorie, high-fat (46.5%) breakfast. Serial blood samples were obtained over the 8-hour morning dose interval. The mean time to maximum concentration (tmax) was increased from 1.8 hours in the fasting state to 3.0 hours in the fed state. Mean maximum serum concentration (Cmax) and area under the concentration-time curve from time 0 to 8 hours (AUC0-8) of ganciclovir were significantly higher in the fed state than after an overnight fast. Because food could potentially increase the bioavailability of oral ganciclovir, patients should be instructed to take each dose of oral ganciclovir with food.

Ganciclovir absolute bioavailability and steady-state pharmacokinetics after oral administration of two 3000-mg/d dosing regimens in human immunodeficiency virus- and cytomegalovirus-seropositive patients.

Oral ganciclovir has recently been approved for use in long-term maintenance therapy in the treatment of cytomegalovirus (CMV) retinitis in immunocompromised patients. Although oral ganciclovir at a dose of 3,000 mg/d is moderately less effective than intravenous (i.v.) ganciclovir maintenance therapy (5 mg/kg as a 1-hour i.v. infusion every 24 hours), convenience and practicality make oral maintenance therapy desirable. Two dosing regimens--1,000 mg three times daily (TID) and 500 mg every 3 hours (six times daily)--have been shown to be efficacious. Eighteen human immunodeficiency virus- and CMV-seropositive patients participated in a three-way, open-label, crossover study to evaluate the steady-state pharmacokinetics and absolute bioavailability of the two oral regimens compared with the i.v. regimen. Sixteen patients completed the study and received ganciclovir as a single 5-mg/kg i.v. infusion over 1 hour, 500 mg orally every 3 hours while awake (six times daily) for 3 days, and 1,000 mg TID orally for 3 days. Blood samples were obtained over a 24-hour period after the single i.v. dose and on day 3 of the oral dosing regimens. Mean peak serum concentrations were 8.27, 1.02, and 1.18 micrograms/mL for the i.v. and oral regimens, respectively. Twenty-four-hour area under the curve (AUC) for the oral regimens--500 mg every 3 hours and 1,000 mg TID--were 15.9 and 15.4 micrograms.h/mL, respectively, as compared with a total AUC of 22.1 micrograms.h/mL for the single i.v. dose. The absolute bioavailabilities for the two oral regimens were 8.84% and 8.53%, respectively. The extent of ganciclovir absorption, peak concentrations, and average concentration at steady state were not statistically different between the two oral regimens. The peak-to-trough concentration ratio (Cmax:Cmin) was greater for the 1,000-mg TID regimen than for the regimen of 500 mg every 3 hours (5.35 vs 3.81 [P < 0.01]). Both oral regimens resulted in concentrations in the range of the concentration that inhibits 50% of most human CMV isolates. Because both oral regimens provide equivalent absorption, the 1,000-mg TID regimen may be preferred for the convenience and potentially greater compliance associated with fewer daily doses.