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Antimicrobial Agents and Chemotherapy, September 2000, p. 2593-2593, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
LETTERS TO THE EDITOR
Efavirenz-Induced Decrease in Plasma Amprenavir Levels in
Human Immunodeficiency Virus-Infected Patients and Correction
by Ritonavir
 |
LETTER |
Drug interactions responsible for suboptimal drug exposure
can lead to anti-human immunodeficiency virus (anti-HIV)
treatment failure. Amprenavir (APV) is an HIV protease inhibitor with
90% inhibitory concentrations of 40 and 250 ng/ml without and with 50% human serum, respectively; its mean trough plasma level (daily dose of 1,200 mg twice a day [b.i.d.]) is 250 ± 200 ng/ml (1, 3-5; S. Piscitelli, S. Vogel, B. Sadler, W. Fiske, L. Metcalf, H. Masur, and J. Falloon, Program Abstr. V Conf. Retroviruses and Opportunistic Infect., abstr. 346, p. 144, 1998). Efavirenz (EFV),
a nonnucleoside reverse transcriptase inhibitor induces cytochromes
P450-3A (CYP3A) and decreases dramatically plasma APV trough levels in
half of the patients (2; Piscitelli et al., Program Abstr. V
Conf. Retroviruses Opportunistic Infect; B. Sadler, C. Gillotin, G. E. Chittick, and W. T. Symonds, Program Abstr. XII
World AIDS Conf., abstr. 12389, p. 91, 1998).
We analyzed sequentially the APV-EFV interaction in seven HIV-infected
patients. Plasma drug trough levels were determined by
high-performance liquid chromatography (HPLC) at days 7 and 14, and subsequently as needed, after the initiation of APV (1,200 mg
b.i.d.)-EFV (600 mg once a day) therapy. One patient had the expected
and stable (365 ± 104 ng/ml) trough levels of APV (days 7, 14, 18, and
90). In three patients, APV levels were low as early as day 7 (53, 67, and 33 ng/ml) and below 20% of the expected mean APV value. Two
patients had the expected APV levels at day 7 (510 and 170 ng/ml),
which decreased to 65 and 62 ng/ml at day 14. The last patient had APV
level determinations only at days 45 and 60, and the levels were
low (62 and 48 ng/ml). At day 14, the median plasma APV trough level
was 64 (range, 33 to 260) ng/ml.
To improve the pharmacokinetic profile of APV and avoid suboptimal
exposure, ritonavir (RTV) (100 mg b.i.d.), a known strong inhibitor of
cytochromes P450-3A (CYP3A) was administered concomitantly with
reduction of APV dosages (900 mg b.i.d. to 450 mg b.i.d.) to the six
patients with low APV trough levels. However, in one patient, EFV was
stopped because of a rash, with APV levels going up from 67 to 175 ng/ml, and another patient did not accept RTV. The other four patients
received RTV, which led to the increase of APV trough levels of 15, 40, 40-, and 90-fold. One of those patient had sequential determinations of
APV levels at days 7, 14, 21, 28, 60, 90, 120, and 180 showing high and
stable levels (1,400 and 2,300 ng/ml). In all patients, the successive
determinations of EFV levels were within the therapeutic range.
Our data confirm the low plasma APV levels at day 7 in patients
receiving concomitant EFV therapy, as previously reported by Piscitelli
et al. (Program Abstr. V Conf. Retroviruses Opportunistic Infect.). Sadler et al. (Program Abstr. XII World AIDS Conf.) reported
that the magnitude of the decrease was bimodal (15% ± 3% and 67% ± 8%), with equal distributions of patients in these two subgroups.
However, the timing of the APV level determination was not mentioned.
In our study, the low level of APV was in fact observed in half of the
patients at day 7 (3 of 6) but in almost all patients at day 14 (5 of
6), reflecting the time required to approach the steady state of
induction of cytochromes P450-3A (CYP3A).
The addition of low-dose RTV therapy reversed the effect of the
induction of APV metabolism by EFV. Prior to the addition of RTV
therapy at day 15, APV levels were suboptimal and could have induced
the emergence of resistance to antiretrovirals. To avoid this,
RTV should be added as soon as EFV-APV therapy is initiated. However,
the safety of this little-documented antiretroviral combination
has to be studied.
| |
ACKNOWLEDGMENTS |
We thank Glaxo-Wellcome and Dupont Pharma for generously providing
APV and EFV and for HPLC determinations.
| |
FOOTNOTES |
*
Phone: 33 1 40 25 78 03
Fax: 33 1 40 25 88 60
E-mail: LPI{at}bichat.inserm.fr
| |
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|
| | | | |
Xavier Duval*
Vincent Le
Moing
Pascale Longuet
Catherine Leport
Jean-Louis Vildé
Service des Maladies Infectieuses et
Tropicales
Hôpital Bichat Claude Bernard
46 rue Henri Huchard
75877 Paris,
France
|
| | | | |
Claire Lamotte
Gilles Peytavin
Robert Farinotti
Service de Pharmacocinétique clinique
Hôpital Bichat Claude Bernard
|
Antimicrobial Agents and Chemotherapy, September 2000, p. 2593-2593, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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