Carol Braun Trapnell

The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive

Rifampin (INN, rifampicin), a CYP34A inducer, results in significant interactions when coadministered with combination oral contraceptives that contain norethindrone (INN, norethisterone) and ethinyl estradiol (INN, ethinylestradiol). Little is known about the effects of rifabutin, a related rifamycin.

Increased Plasma Rifabutin Levels with Concomitant Fluconazole Therapy in HIV-Infected Patients

Chemoprophylaxis for opportunistic infections associated with the human immunodeficiency virus (HIV) is increasingly common; clinical studies support the administration of drugs to prevent Pneumocystis carinii pneumonia [1-3], disseminated Mycobacterium avium complex infection [4], cytomegalovirus infection [5], and fungal infections [6]. Because these agents are often administered concurrently in patients infected with HIV, many questions have been raised about the pharmacokinetic or pharmacodynamic consequences of the drugdrug interactions that may occur. Such interactions may also confound our understanding of the outcomes seen in large clinical trials. Two drugs that are often used concurrently in patients infected with HIV are rifabutin, for the prevention of M. avium complex bacteremia [4], and fluconazole, for the prevention of fungal infections [6]. Rifabutin is an antimicrobial agent similar in structure to rifampin. Fluconazole, which is used to treat cryptococcal meningitis and oropharyngeal and esophageal candidiasis [7], has been reported to be effective for the primary prevention of deep and superficial fungal infections in HIV-infected patients whose CD4 lymphocyte counts are less than 50 cells/mm3 [6]. Fluconazole and a related azole, ketoconazole, are potent inhibitors of hepatic microsomal enzymes, especially the cytochrome p450 3A group [8]. Inhibition of these enzymes has, in turn, been shown to cause clinically significant increases in circulating levels of concomitant drugs that are metabolized by these enzymes [9-15]. Our study was designed to assess a possible mechanism for the changes observed in the toxicity and efficacy of rifabutin with concomitant fluconazole therapy. We report the results of a steady-state pharmacokinetic and safety study of rifabutin and fluconazole during concurrent zidovudine therapy in HIV-infected persons. Methods Study Design This was a phase 1, open-label pharmacokinetic and safety study of 13 persons infected with HIV who were receiving maintenance therapy with zidovudine, 100 mg five times per day. The study enrolled HIV-infected adults who had CD4 lymphocyte counts between 200 and 500 cells/mm3, had no active disease by chest radiograph, had no clinically significant hepatic or renal impairment, and were receiving no other antiretroviral therapy or concomitant medications known to substantially modulate hepatic or renal function. Persons were excluded from participation if they had a history of known hypersensitivity to the study medications, had previously received treatment with cytolytic agents or radiation therapy, had had blood transfusion within 1 week of study entry, had received treatment with rifabutin or rifampin within 3 months of study entry, or had received treatment with fluconazole or other azole drugs within 4 weeks of study entry. Pregnant or lactating women were also excluded. Whenever possible, other concomitant medications were maintained at constant doses throughout the study. The study was approved by the Georgetown University Medical Center Institutional Review Board; each participant gave written informed consent before study entry. A medical evaluation was done within 1 week of study entry. Fluconazole, 200 mg, was administered orally every 24 hours beginning on day 3. On day 16, when fluconazole had reached steady state, participants returned to the outpatient clinic, where blood was drawn just before the morning doses of fluconazole and zidovudine were given. Blood and urine samples were collected during the 24 hours after drug administration. Beginning on day 17, oral rifabutin, 300 mg/d, was added to the fluconazole-zidovudine regimen. All study medications were administered concurrently. On day 30, when rifabutin had reached steady state, study participants returned to the clinic for serial blood and urine collections. Finally, fluconazole therapy was discontinued on day 31; rifabutin and zidovudine were continued for the remaining 2 weeks of the study. On day 44, participants returned to the clinic and again had serial blood and urine collections. Study participants received medical evaluations with routine laboratory testing to evaluate the safety of these therapies on days 16, 30, and 44. Each participant also returned to the outpatient clinic on the mornings of days 1, 15, 29, and 43 to provide an additional blood sample before receiving medication to estimate within-person variation in the trough concentrations of the appropriate study drugs. Drug Supply and Analysis Rifabutin was supplied as 150-mg capsules by Pharmacia, Inc. (Columbus, Ohio); fluconazole was supplied as 200-mg tablets by Pfizer, Inc. (Groton, Connecticut); and zidovudine was supplied as 100-mg capsules by Burroughs-Wellcome Company (Research Triangle Park, North Carolina). We collected all blood samples in heparinized tubes and promptly centrifuged them to separate the plasma. Plasma specimens were frozen at 20 C until they were assayed. Urine collection bottles were kept on ice or were refrigerated during the collection periods. A 10-mL aliquot of urine was placed in cryotubes and kept frozen at 20 C until it was assayed. Plasma and urine concentrations of fluconazole, rifabutin, and the 25-desacetyl metabolite of rifabutin, LM565, were determined by Harris Laboratories (Lincoln, Nebraska) using a validated high-performance liquid chromatography method as previously described [16, 17]. The respective interday precision (expressed as a percentage of relative standard deviation) and inaccuracy estimates for the quantity of fluconazole were 8% or less and 5%, respectively; those for rifabutin and LM565 were 10% or less and 5%, respectively. Pharmacokinetic Analysis Pharmacokinetic variables were estimated by noncompartmental analyses [18]. Steady-state estimates of the area under the concentration-time curve for rifabutin and fluconazole were obtained by using linear trapezoidal integration over a dosing interval. Renal clearance was estimated by dividing the amount excreted in the urine by the area under the plasma drug concentration-time curve. Statistical Analysis Statistical analyses were done using Statistical Analysis Systems software, version 6.06 (SAS Institute, Cary, North Carolina). Estimates of pharmacokinetic variables from the 12 evaluable participants in the presence or absence of the study drugs were compared using a paired, two-tailed t-test. Values are given as mean SD. Results Thirteen persons were enrolled in the study. Data from 12 participants were considered evaluable for data analysis; studies were discontinued in 1 participant before completion because of the development of a diffuse maculopapular rash 12 days after rifabutin therapy began. Data were not stratified for sex (9 men, 4 women) or race (9 white participants, 4 black participants) because of the small sample sizes within each group. Other demographic information included age (35.8 7.2 years), body weight (89 20 kg), CD4 lymphocyte count (369.3 63.1 cells/mm3), aspartate aminotransferase level (0.56 0.16 kat/L), and serum creatinine level (106 8 mol/L). No clinically significant changes in the results of physical examinations or laboratory evaluations were seen during the study in any of the evaluable study participants. Figure 1 shows the plasma concentrations of rifabutin and LM565 as a function of time from study days 30 (rifabutin and fluconazole) and 44 (rifabutin alone). Rifabutin levels were significantly higher during concurrent fluconazole treatment; the steady-state estimate of the area under the concentration-time curve increased 82% (5442 2404 ng h/mL compared with 3025 1117 ng h/mL; P 0.05). The area under the LM565 concentration-time curve over the 24-hour dosing interval increased 216% (959 529 ng h/mL compared with 244 141 ng h/mL; P 0.05). This finding was consistent among all study participants (Figure 2). Urinary excretion of rifabutin and LM565 also increased during concurrent fluconazole treatment. The amounts of rifabutin and LM565 excreted on day 30 compared with day 44expressed as a percentage of the rifabutin dosewere 2.5% 1.5% compared with 6.2% 2.0% (P < 0.01) and 0.8% 0.4% compared with 2.3% 0.9% (P < 0.01), respectively. The renal clearance of rifabutin, however, was unchanged (0.0502 0.0199 L/h kg1 and 0.0446 0.0248 L/h kg1). Figure 1. Steady-state concentration compared with time curves of the plasma concentrations (mean SD) of rifabutin and its 25-desacetyl metabolite, LM565, over one dosing interval. Figure 2. Area under the plasma concentration-time curve for rifabutin and its 25-desacetyl metabolite, LM565, when rifabutin is administered alone and in combination with fluconazole. The steady-state fluconazole plasma concentration did not change (area under the concentration-time curve over a dosing interval without rifabutin, 201.0 36.2 g h/mL; with rifabutin, 196.8 44.7 g h/mL), and rifabutin did not affect urinary excretion of fluconazole (percentage of fluconazole dose excreted without rifabutin, 73.7% 18.6%; with rifabutin, 68.8% 15.3%). Discussion Our data indicate that concurrent fluconazole administration markedly increases the steady-state plasma concentrations of both rifabutin and its equiactive 25-desacetyl metabolite, LM565, in HIV-infected persons receiving maintenance therapy with zidovudine. This is consistent with fluconazoles inhibition of cytochrome p450 3A [7]. Renal clearance of rifabutin was unchanged with fluconazole. This further supports our hypothesis that the increased rifabutin concentrations are due to the inhibition of metabolism. Interestingly, LM565 concentrations increased 2.5-fold higher than rifabutin with concurrent fluconazole, which may represent the inhibition of further metabolism of this metabolite [19]. Although study participants were receiving other concurrent medications, these were minimized, and persons who were receiving medications known to alter drug disposition were excluded from parti

Duration of vaginal retention and potential duration of antiviral activity for five nonoxynol-9 containing intravaginal contraceptives

Objective: The purpose of this study was to determine the vaginal retention of five nonoxynol‐9 intravaginal contraceptives. Method: An open‐label crossover study in 10 premenopausal volunteers was performed at an outpatient clinical research center. The outcomes are described utilizing the median and range. Result: At 8 h post‐instillation, the median amounts of nonoxynol‐9 present in the vagina were: Delfon® 7.68 mg, Conceptrol® 5.18 mg, Advantage 24® 1.95 mg, VCF® 1.74 mg, and Semicid® 1.51 mg respectively. Our calculated theoretical minimal amount needed to protect against HIV infection is 2.00 mg. Conclusion: The best vehicle for retaining nonoxynol‐9 in the vagina appears to be foam. Further research in the effectiveness of nonoxynol‐9 in prevention of the spread of HIV infection should be directed toward the use of foam vehicles to deliver nonoxynol‐9 to the vagina.

The Effect of Isotretinoin on the Pharmacokinetics and Pharmacodynamics of Ethinyl Estradiol and Norethindrone

Isotretinoin is a known teratogen, and when it is prescribed to women of childbearing potential, 2 forms of contraception must be used, commonly including hormonal contraception. Although isotretinoin and estradiol are metabolized largely by cytochrome P450 (CYP) 3A4 and glucuronidation, the potential for clinical drug interaction, with subsequent pharmacodynamic impact, has not been evaluated.

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.

Thalidomide does not alter the pharmacokinetics of ethinyl estradiol and norethindrone

To evaluate the effect of thalidomide on the plasma pharmacokinetics of ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone).

Pharmacokinetics of F105, a human monoclonal antibody, in persons infected with human immunodeficiency virus type 1

F105 is a human monoclonal antibody that binds to the CD4 binding site of human immunodeficiency virus type 1 gp120 and neutralizes clinical and laboratory isolates of the human immunodeficiency virus. This phase I study investigated the disposition of the antibody in humans. F105 was administered over a 60‐minute period at two dose levels, 100 and 500 mg/m2. Blood samples were obtained for up to 56 days. The clearance of the antibody was 0.33 ml/min with a corresponding half‐life of approximately 13 days. Peak concentrations achieved at the higher dose level were 216.19 ± 9.62 μg/ml. The disposition of the drug was linear for the doses studied. Simulations were performed to design future studies aimed at investigating the efficacy of the antibody. This study concluded that F105 can be administered as a bolus dose every 21 days.

The effect of clarithromycin, fluconazole, and rifabutin on dapsone hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283)

Sulfamethoxazole hydroxylamine formation, in combination with long‐term oxidative stress, is thought to be the cause of high rates of adverse drug reactions to sulfamethoxazole in human immunodeficiency virus (HIV)–infected subjects. Therefore the goal of this study was to determine the effect of fluconazole, clarithromycin, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with HIV‐1 infection.

Future meeting dates and sites of the American Society for Clinical Pharmacology and Therapeutics

Clinical Pharmacology & Therapeutics (1998) 63, 703–703; doi:

A Message From The Scientific Program Committee Chairperson: Submission of Abstracts For The 1999 Annual Meeting

Clinical Pharmacology & Therapeutics (1998) 63, 703–703; doi: