Journal of Antimicrobial Chemotherapy (1996) 38, 877-880

Lack of effect of fluconazole on the pharmacokinetics of rifampicin in

AIDS patients

Sutep Jaruratanasirikul* and Anun Kleepkaew

Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine,

Prince of Songkla University, Hat Yai, Songkla 90112, Thai/and

To evaluate the effect of fluconazole on rifampicin pharmacokinetics, eleven AIDS

patients received rifampicin (300 mg/day; days 1-28) and fluconazole (400 mg/day;
days 15-28). Rifampicin pharmacokinetics were studied on days 14 and 28. There
was no significant effect of fluconazole on rifampicin pharmacokinetics. These results
suggest that rifampicin dosage adjustment may not be necessary when this drug is
coadministered with fluconazole.

Introduction
Drugs are often administered concomitantly to patients with AIDS and are often
continued for the duration of their lives. These patients may receive a variety of
agents, either prophylactically or therapeutically for cerebral toxoplasmosis,
disseminated Mycobacterium avium complex infection, Pneumocystis carinii pneumonia,
tuberculosis and cryptococcal meningitis. Therefore it is important to investigate drug
interactions between agents given to patients with AIDS because they may influence
efficacy.
Fluconazole has been found to be very effective against several fungal species
and is widely used for the treatment of systemic fungal infections in AIDS patients
(Grant & Clissold, 1990). The agent has been shown to be a potent inhibitor of
fungal cytochrome P450, and may interfere with hepatic metabolism of several other
coadministered medications (Grant & Clissold, 1990). Rifampicin is still one of the
most valuable drugs for the treatment of tuberculosis (Mandell & Sande, 1991).
Occasionally, tuberculosis occurs simultaneously with fungal infections in AIDS
patients and concomitant administration of rifampicin and fluconazole may be
required (Coker et al., 1990). However, until now we have had no data to
demonstrate the effect of fluconazole on the pharmacokinetics of rifampicin.
Therefore, the aim of this study was to provide such data.

•Tel: +66 (074) 212070-9; Fax: + 66 (074) 212900, 212903, 212912.

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Materials and methods

Subjects and drugs

Eleven AIDS patients with cryptococcal meningitis participated in this study. Eight
were male and three were female. Their mean age was 34.36 ±9.10 years (range 22-54)
and their mean weight was 49.81 ± 7.82 kg (range 38-67). The protocol for the study
was approved by the Ethics Committee of Songklanagarind Hospital and written
informed consent was obtained from each patient. Patients were excluded from the
study if they were pregnant or considered unlikely to survive for more than 4 weeks.
They were also excluded if they had evidence of liver dysfunction, creatinine clearance
rate of less than 50 mL/min, vomiting or diarrhoea, or a history of rifampicin and
fluconazole intolerance.
Fluconazole was purchased from Pfizer (Thailand) and rifampicin was purchased
from Lederle (Thailand).

Drug administration and samples collection

The study was conducted in two phases. In phase I (from day 1 to day 14), all patients
received intravenous amphotericin B 0.5 mg/kg/day and oral rifampicin 300 mg/day. In
phase II (from day 15 to day 28), all the same patients received oral fluconazole 200 mg
twice daily and oral rifampicin 300 mg/day 2 h after fluconazole dose. Rifampicin
pharmacokinetics studies were carried out on days 14 and 28, and before each of these
patients underwent an overnight fast of at least 8 h, which was continued for four more
hours after rifampicin administration. Blood samples (approximately 5 mL each) were
obtained by direct venepuncture at the following times: before (time 0) and every 15 min
for 4 h, every 30 min for 1 h, then 6, 7, 8, 10, 12, 15, 18 and 24 h after rifampicin dose.
The serum obtained was stored at — 80°C until analysis.

Rifampicin assay
The concentration of rifampicin was determined by reversed phase HPLC. Papaverine
HC1 (50 mg/L) was used as the internal standard and the samples were extracted by the
method of Darouiche et al. (1990). An aliquot of the extracted sample (50 fiL) was
injected, using an automated injection system (Waters 717 plus Autosampler, Waters
Associates, Milford, MA, USA), onto a BONDAPAK Cl8 column (Waters Associates).
The mobile phase was 50 mmol/L potassium dihydrogen phosphate, acetonitrile (62:38,
v/v) pH 4.7, at a flow rate of 1 mL/min. The column effluent was monitored by UV
detection (Waters 486, Waters Associates) at 340 nm. The peaks were recorded and
integrated on a Waters 746 Data Module (Waters Associates). The limit of detection
of rifampicin was 2.5 ng per injection.

Pharmacokinetic parameters
The maximum plasma concentration ( C ^ ) and time to reach C^, ( T ^ ) were
determined by visual inspection of the individual plasma concentration-time profiles.
AUCo-24 were the areas under the concentration versus time between 0 and 24 h
calculated using the trapezoidal rule. Results were expressed as mean ± s.D. and
statistical comparisons were made using the Student's /-test for paired data.

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 Effect of fluconazole on rifampicin 879

Results and discussion

Results from our study are given in the Table. There was no statistically significant
difference in pharmacokinetic parameters for rifampicin between phase I and phase II.
Studies to define pharmacokinetic drug interaction between agents used as part of
a multidrug regimen are important because the interaction may have influence on drug
efficacy. Multidrug regimens are often administered to patients with AIDS for the
duration of their lives. The inhibitory effect of fluconazole on fungal cytochrome P450
is not selective, and it also inhibits human cytochrome P450 enzyme systems, and this
effect has been postulated to be one of the mechanisms for drug interaction with other
coadministered drugs (Grant & Clissold, 1990). A previous study in mice has shown
that fluconazole has the effect of reducing the clearance of antipyrine which is
metabolized almost entirely by oxidative metabolism by hepatic cytochrome P450
enzymes (Ladelfa et al., 1989). In addition, fluconazole also has a strong inhibitory
effect on rifabutin metabolism. Concomitant administration of fluconazole and
rifabutin in HIV positive patients has resulted in increase in both the maximal
concentration and the area under the curve of rifabutin by at least 80% (Trapnell et al.,
1993). Another previous study has shown that the prophylactic effect of rifabutin for
M. avium complex bacteraemia in AIDS patients is enhanced by concomitant treatment
with fluconazole, possibly as a result of higher rifabutin concentration due to inhibitory
effect of fluconazole (Narang et al., 1994).
Rifampicin is one of the potent inducers of hepatic cytochrome P450 oxidative
enzymes in humans, and a number of drugs have been reported to be affected by
rifampicin (Mandell & Sande, 1991). Previous study in humans has shown that
concomitant administration of fluconazole and rifampicin results in a 22% and 23%
decrease in the half-life and the AUC of fluconazole, respectively (Lazar & Wilner,
1990). Moreover, Coker et al. (1990) reported three patients with cryptococcal
meningitis in whom clinical relapse seemed to be associated with concurrent
administration of fluconazole and rifampicin. One study in AIDS patients with
oropharyngeal candidiasis suggested that fluconazole appeared less effective in reducing
Candida colony count in four patients taking antituberculous agents including
rifampicin (Dupont & Drouhet, 1988). Thus, fluconazole can be coadministered with
rifampicin, but the dosage of fluconazole may have to be increased. Conversely,
rifampicin can itself be affected by other agents including ketoconazole but not
amphotericin B (Engelhard, Stutman & Marks, 1984). However, our present study
demonstrated that there was no significant effect of fluconazole on the pharmacokinetics
of rifampicin. This may be due to a low inhibitory affinity of fluconazole for mammalian
cytochrome P450 enzyme systems and/or to the metabolic pathways of rifampicin not
being primary dependent on the activity of cytochrome P450 enzymes. Therefore, these

Table. Pharmacokinetic parameters of oral rifampicin

300 mg when it was given alone (phase I) and after
treatment with fluconazole for 14 days (phase II)
Phase I Phase II
AUCo-24 (mg.h/L) 25.12 ± 15.03 27.53 ± 19.9
C » (mg/L) 7.26 ± 2.93 7.81 ± 4.61
T^ (h) 1.91 ±0.91 2.01 ±0.92

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 880 S. Jaruratanasirikul and A. Kleepkaew

results suggest that rifampicin dosage adjustment may not be necessary when this drug
is coadministered with fluconazole.

Acknowledgements
This work was supported by a Faculty grant from Faculty of Medicine, Prince of
Songkla University. We thank Mr Desmond Burton for checking the English of the
manuscript.

References
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(Received 6 December 1995; returned 22 January 1996; revised 29 February 1996;

accepted 28 May 1996)

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