Virus-Infected Patients )-Methadone in Human Immunodeficiency R

Transcription

Nevirapine Significantly Reduces the
Levels of Racemic Methadone and ( R
)-Methadone in Human Immunodeficiency
Virus-Infected Patients
Hartmut Stocker, Guido Kruse, Peter Kreckel, Christian
Herzmann, Keikawus Arastéh, Jörg Claus, Heiko Jessen,
Christiane Cordes, Bettina Hintsche, Frank Schlote, Lothar
Schneider and Michael Kurowski
Antimicrob. Agents Chemother. 2004, 48(11):4148. DOI:
10.1128/AAC.48.11.4148-4153.2004.
These include:
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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 2004, p. 4148–4153
0066-4804/04/$08.00⫹0 DOI: 10.1128/AAC.48.11.4148–4153.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Vol. 48, No. 11
Nevirapine Significantly Reduces the Levels of Racemic Methadone
and (R)-Methadone in Human Immunodeficiency
Virus-Infected Patients
Hartmut Stocker,1,2* Guido Kruse,3 Peter Kreckel,4 Christian Herzmann,4 Keikawus Arastéh,1,2
Jörg Claus,4 Heiko Jessen,4 Christiane Cordes,4 Bettina Hintsche,4 Frank Schlote,4
Lothar Schneider,4 and Michael Kurowski2,3
Vivantes Auguste-Viktoria-Klinikum1 and EPIMED GmbH, c/o Vivantes Auguste-Viktoria Klinikum,4 HIV-Lab,
c/o Vivantes Auguste-Viktoria Klinikum,3 and Kompetenznetz HIV/AIDS,2 Berlin, Germany
Received 21 April 2004/Returned for modification 23 June 2004/Accepted 13 July 2004
scriptase, is an inducer of a number of isoforms of the P450
enzyme family (5). Despite its potential for interactions with
the metabolism of methadone and an increased risk of severe
liver toxicity in patients with an HIV-hepatitis C virus coinfection (27), NVP is an important candidate for antiretroviral
treatment of intravenous drug users. As its pharmacokinetics
permit once-daily dosing, it is an ideal component of directly
observed therapy in methadone substitution programs.
This trial was designed to quantify the effect of coadministration of NVP on the pharmacokinetics of methadone and its
main metabolite, EDDP.
Human immunodeficiency virus (HIV)-infected patients
who take methadone for the management of intravenous drug
use frequently complain about symptoms of narcotic withdrawal after having started antiretroviral treatment containing
nevirapine (NVP) (1, 2, 18, 28, 29). Symptoms rarely appear
within the first few days, which suggests that the effect is caused
by the induction of methadone metabolism by NVP (3, 11).
One controlled trial involving eight patients has shown that
concomitant NVP treatment substantially decreases the trough
level and the area under the concentration-time curve (AUC)
of methadone (11).
Methadone is a racemic mixture of the pharmacodynamically inactive (S)-methadone and the active enantiomer (R)methadone. It contains equal parts of both enantiomers. In
some countries, methadone is frequently used in a formulation
which contains only the active enantiomer, (R)-methadone.
Both enantiomers are metabolized by members of the cytochrome P450 family. N-demethylation results in the formation
of the inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) (4, 30).
NVP, a nonnucleoside inhibitor of the HIV reverse tran-
MATERIALS AND METHODS
Subjects. Twenty-five HIV type 1-infected patients who were stably taking
once-daily doses of methadone and who required antiviral therapy were enrolled
in the study. The study design was approved by the ethics committee of the
Berliner Ärztekammer. All participants gave their written informed consent. In
order to be eligible, patients had to be taking either a treatment regimen consisting of nucleoside analogues (nucleoside reverse transcriptase inhibitors
[NRTIs]) only or no antiretroviral therapy at all.
A complete medical history was taken at the screening visit, which was scheduled 3 weeks before the start of NVP treatment. A physical examination that
included evaluation of vital signs and a routine safety laboratory examination
with blood count, coagulation tests, blood chemistry, and urinalysis were performed. Three days before the start of the treatment period, an alcohol breath
test and a screening of urine for the presence of illicit drugs were performed.
Subjects were ineligible for this study if they had a history of pancreatitis or
neuropathy within 6 months before screening, treatment for a malignancy within
* Corresponding author. Mailing address: HIV-Lab, Haus 30, c/o
Vivantes Auguste-Viktoria Klinikum, Rubensstrasse 125, 12157 Berlin, Germany. Phone: 49-3079033921. Fax: 49-3079033922. E-mail:
hartmut_s@gmx.at.
4148
Methadone is metabolized by various isoforms of the cytochrome P450 family, which can be induced by many
drugs, including nevirapine. The objective of the present study was to determine the effects of coadministration
of nevirapine and methadone on the dose-adjusted areas under the concentration-time curves (AUCs) of
racemic and (R)-methadone. Twenty-five human immunodeficiency virus-infected subjects taking stable single
daily doses of racemic methadone or (R)-methadone were included in this prospective, single-crossover trial.
At the baseline, nevirapine was either started as part of a new regimen containing two nucleoside reverse
transcriptase inhibitors (NRTIs) or added to an ongoing NRTI regimen. Patients could increase their methadone doses if withdrawal symptoms developed. Twelve-hour pharmacokinetic profiles were obtained before
and 28 days after the start of nevirapine treatment. The total concentrations of methadone and its inactive
metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), in serum were determined by liquid
chromatography-tandem mass spectrometry. Among the 20 evaluable patients, coadministration of nevirapine
significantly decreased the mean dose-adjusted AUC of methadone by 41%. AUC reductions were similar for
patients taking racemic methadone (37%; n ⴝ 11) and (R)-methadone (44%; n ⴝ 9). AUC changes ranged from
mild increases in three patients to decreases of up to 70%. Fourteen of 20 patients required additional
methadone due to withdrawal symptoms. However, the median dose increase was only 15%, which was less than
that which would have been expected from the pharmacokinetic data. The AUC of EDDP increased significantly, by 35%. Methadone dose adjustments are justified when methadone is coadministered with nevirapine.
Due to extensive variability, the adjustments must be tailored to the individual patient’s needs.
VOL. 48, 2004
NEVAPIRINE-METHADONE INTERACTION TRIAL
4149
TABLE 1. Patient characteristics
Value for:
Characteristic
No. of females/no. of males
Median age (yr [range])
Median wt (kg [range])
Median BMIa (range)
% Smokers
% Hepatitis C virus positive
Median total methadone dose (mg [range])
a
b
All patients
Patients receiving racemic
methadone
Patients receiving (R)methadone
3/17
41 (35–59)
75 (50–122)
21.8 (19.3–31.8)
100
80
NAb
2/9
40 (35–45)
66 (50–84)
21 (19.3–24.6)
100
82
140 (35–220)
1/8
43 (37–59)
78 (59–122)
27 (20.1–31.8)
100
78
75 (45–115)
BMI, body mass index.
NA, not applicable.
phase B was ACN containing 0.1% formic acid. The high-pressure liquid chromatography (HPLC) system consisted of the following components: a PerkinElmer Series 200 mobile phase delivery pump and a Gilson Abimed 233 XL
autosampler. HPLC separation was achieved by mobile phase gradient elution
(flow rate, 1.5 ml/min) with the following sequence: at 0 min, 100% mobile phase
A; at 0.3 min, 100% mobile phase A; at 0.4 min, 25% mobile phase A; at 3.3 min,
25% mobile phase A; and at 3.5 min, 100% mobile phase A. The injection
volume was 50 ␮l. During the first 90 s of each run the effluent was directed to
the waste. The flow to the mass spectrometer was maintained with a second
pump (Hitachi L-7100; Merck), which delivered methanol-water (50/50) at a rate
of 1.0 ml/min. The majority (80%) of the effluent was split off before it entered
the interface. An API 365 mass spectrometer (Applied Biosystems, Toronto,
Ontario, Canada) equipped with an electrospray ionization ion source and run
with Analyst (version 1.2) software was used for detection. Analytes were monitored in the positive multiple-reaction monitoring mode with the following
transitions of precursor to product ions: m/z 310.15 to 265.30 (methadone),
278.00 to 234.30 (EDDP), and 319.15 to 268.20 (deuterium-labeled methadone).
Standards and quality control samples were prepared in blank serum. For each
batch, two eight-point standard calibration curves for samples containing methadone and EDDP at concentrations ranging from 20 to 2,500 ng/ml and NVP at
concentrations ranging from 41 to 5,300 ng/ml were prepared in duplicate.
Quality control samples containing all analytes at concentrations of 250 and
1,000 ng/ml were prepared. Inter- and intraday coefficients of variation for
methadone, EDDP, and NVP were ⬍2, ⬍7, and ⬍5%, respectively, at concentrations of 1,000 ng/ml and ⬍6, ⬍8, and ⬍8%, respectively, at concentrations of
250 ng/ml. Mean deviations from nominal concentrations were below 8% for all
analytes and concentrations throughout the entire analysis.
Statistics. AUCs were calculated by the trapezoidal rule. Intraindividual AUC
changes were analyzed with and without adjustment for methadone doses. Median interquartile ranges (IQRs), means, and 95% confidence intervals (CIs)
were calculated for each parameter. Means and CIs for the pharmacokinetic
profile and for intraindividual AUC changes were backcalculated from logtransformed data. This procedure was chosen because log-transformed AUC
data were assumed to be normally distributed. The paired t test was used to test
for nonzero differences for the values obtained before the initiation of NVP
treatment and those obtained after 28 days of NVP treatment for the complete
study population, patients taking racemic methadone, and patients taking (R)methadone. The reported P values are two sided.
RESULTS
Twenty-five patients were included in the study, which was
conducted between March 2001 and September 2002. Five
subjects were excluded during and after the treatment phase
because of protocol violations [one subject because of intravenous use of methadone, two subjects because they had started
NVP treatment before day 0, and two subjects because they
had changed from racemic methadone to (R)-methadone during the study period]. None of the subjects withdrew due to
adverse events.
Table 1 summarizes the characteristics of the 20 remaining
subjects. Eleven subjects were taking racemic methadone, and
30 days before screening, or any major clinically significant abnormality. Patients
were also excluded if they were consuming alcohol or using illicit drugs before or
during the study period. Patients requiring treatment with medications and
herbal substances known to interfere with hepatic drug metabolism were also
ineligible. Additionally, patients were told to abstain from drinking alcohol and
grapefruit juice before and during the study period.
Study design. The primary endpoint of this trial was the intraindividual comparison of the dose-corrected AUCs from 0 to 12 h (AUC0-12) of methadone
without and with NVP. The 12-h interval covers the largest fraction of the total
AUC that includes the maximum concentration. Therefore, AUC0-12 is a sensitive parameter for the detection of pharmacokinetic interactions in this particular once-daily dosing regimen.
This was a prospective, open-label, multiple-dose, single-crossover, two-period
study conducted at the EPIMED clinical trials unit of the Vivantes AugusteViktoria Klinikum and associated physicians in Berlin, Germany. The study
consisted of a 21-day screening period, a 28-day treatment period, and a follow-up period. Treatment consisted of nevirapine at 200 mg once a day for 14
days and 200 mg twice a day (BID) for the following 14 days and thereafter. NVP
was either started in combination with two NRTIs or added to an ongoing NRTI
regimen. On day 0, eligible patients were admitted to the clinical trials unit.
Patients were asked to attend in a fasted state. Standardized meals and beverages
were provided during the following 12 h. Patients reported the time of their last
methadone intake on the previous day. Serial blood samples were taken from
each subject for the generation of the plasma methadone and EDDP concentration-time profiles. Samples were collected just before the observed methadone
intake, as well as at 1, 2, 4, 8, and 12 h postdosing. Samples were drawn into
Sarstedt (Nümbrecht, Germany) serum collection tubes. After centrifugation,
the samples were stored at ⫺20°C until analysis. On day 1, all patients received
their first dose of NVP in combination with two NRTIs. The NVP dose was
increased to 200 mg BID on day 14. Urinalysis for the detection of illicit drugs
and an alcohol breath test were performed once per week during the whole
treatment period. Methadone dose adjustments were allowed, and changes of
dose were recorded. On the morning of day 28 subjects were admitted to the
study center and blood samples were obtained before dosing as well as at 1, 2, 4,
8, and 12 h postdosing for reevaluation of the plasma total methadone and
EDDP concentration-time profiles. NVP levels were measured to document that
the concentrations were within the expected range and that study participants
adhered to their antiretroviral medication regimens. Samples were processed as
described above for sample processing on day 0.
Analytical methods. Drug levels were quantified at the HIV-Lab, Berlin,
Germany. Methadone, EDDP, and deuterium-labeled methadone [6-di(trideuteromethyl)amino-4,4-diphenyl-1-trideuteromenthyl-3-heptanone] were obtained from Promochem, Wesel, Germany. Boehringer Ingelheim, Ingelheim,
Germany, provided NVP. All solvents were purchased from VWR International,
Berlin, Germany. Ammonium acetate and formic acid were obtained from Sigma
Aldrich, Munich, Germany. Plasma total methadone, EDDP, and NVP concentrations were determined simultaneously by liquid chromatography-tandem mass
spectrometry. The assay did not discriminate between methadone enantiomers.
For sample preparation, 100-␮l aliquots of serum were spiked into polypropylene
vials. After protein precipitation and extraction with 500 ␮l of acetonitrile containing the internal standard (deuterium-labeled methadone), the samples were
spun at 13,000 ⫻ g for 6 min. The supernatants were transferred into clean tubes,
the tubes were centrifuged, and their contents were injected onto a Eurospher
C18 column (5 ␮m; 4.6 by 30 mm; Knauer, Berlin, Germany). Mobile phase A
was H2O-acetonitrile (ACN), 95/5%, and 0.0025 M ammonium acetate. Mobile
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STOCKER ET AL.
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 2. Methadone doses, dose-adjusted AUCs, and AUC changes
Dose (mg)
without/with NVP
Racemic methadone
004
006
012d
014d
017
019
021d
023
024
026
027
Median (IQR)
(R)-Methadone
001d
002
005
007
009
013
018
022d
025d
Median (IQR)
AUC/dose [(ng 䡠 h/ml)/mg]
% AUC/dose changea
% Actual dose changeb
% Theoretical dose
changec
19.3
17.2
27.8
40.9
22.0
48.7
42.9
31.3
38.4
21.6
40.6
31 (22 to 41)
⫺70
⫺54
⫺51
⫺32
⫺48
6
⫺1
⫺36
⫺15
⫺67
24
⫺35 (⫺53 to ⫺8)
29
14
0
0
35
12
0
11
80
40
33
14 (6 to 34)
229
118
104
47
92
⫺5
1
56
17
203
⫺20
56 (9 to 111)
10.1
20.9
23.6
19.9
34.9
28.2
60.9
207.7
38.7
28 (21 to 39)
⫺56
⫺58
⫺43
⫺8
⫺56
⫺41
⫺45
⫺30
⫺46
⫺45 (⫺56 to ⫺41)
0
20
17
17
67
4
56
0
0
17 (0 to 20)
Without NVP
With NVP
35/45
140/160
180/180
80/80
170/230
170/190
220/220
180/200
50/90
100/140
60/80
63.3
37.4
56.8
59.9
42.2
46.1
43.1
48.8
45.1
65.5
32.7
46 (43 to 58)
75/75
50/60
115/135
90/105
30/50
115/120
45/70
60/60
60/60
23.0
49.5
41.5
21.6
78.9
47.6
111.5
298.3
72.4
50 (42 to 79)
128
137
76
8
126
69
83
44
87
83 (69 to 126)
Calculated as 100 ⫻ {[(AUC/dosewith NVP ⫺ AUC/dosewithout NVP)]/(AUC/dosewithout NVP)}.
Calculated as 100 ⫻ [(dosewith NVP ⫺ dosewithout NVP)/dosewithout NVP].
c
Calculated as 100 ⫻ {[(AUC/dosewithout NVP) ⫺ (AUC/dosewith NVP)]/(AUC/dosewith NVP)}.
d
Individuals who required no dose increases.
a
b
nine were taking (R)-methadone. The median methadone
doses for the subgroups taking racemic methadone and (R)methadone were 140 mg (range, 35 to 220 mg) and 75 mg
(range, 45 to 115 mg), respectively. The median dose of the
active enantiomer in the total study population was 72.5 mg
(range, 17.5 to 115 mg).
No clinically relevant alterations were detected in any of the
individuals during the physical examination and routine safety
laboratory tests. Urine pHs were comparable on the two pharmacokinetic sampling days (day 0, pH 5.6; day 28, pH 5.6).
Unadjusted data. For the entire study population the mean
methadone AUC was reduced by 29% (mean intrasubject
AUC decrease, 1,319 ng 䡠 h/ml; 95% CI, 689 to 1,846 ng 䡠 h/ml;
P ⬍ 0.05). In the subgroup of patients taking (R)-methadone,
the mean AUC dropped by 34% (mean intrasubject AUC
decrease, 1,328 ng 䡠 h/ml; 95% CI, 825 to 1,748 ng 䡠 h/ml; P ⬍
0.05). The decrease in the subgroup of patients receiving racemic methadone was 24%, but this did not reach statistical
significance (P ⫽ 0.09).
Dose-adjusted data. The primary endpoint of this trial was
the intraindividual comparison of the dose-corrected AUCs
without and with NVP. All but 6 of the 20 patients required
higher methadone doses after the start of NVP therapy due to
withdrawal symptoms. The median dose increase was 15%
(IQR, 0 to 34%). Table 2 shows the methadone doses and
dose-corrected AUCs before and after NVP treatment. The
dose-adjusted pharmacokinetic profiles of methadone for all
patients are presented in Fig. 1.
For the complete study population, the mean methadone
AUC/dose ratio during NVP therapy was 41% lower than that
without NVP therapy [mean intrasubject AUC decrease, 21
(ng 䡠 h/ml)/mg; 95% CI, 16 to 26 (ng 䡠 h/ml)/mg; P ⬍ 0.001].
For the group of patients taking racemic methadone, the mean
AUC decreased by 37% [mean intrasubject AUC decrease, 18
(ng 䡠 h/ml)/mg; 95% CI, 9 to 25 (ng 䡠 h/ml)/mg; P ⬍ 0.05]. In
the group of patients taking (R)-methadone, the mean doseadjusted AUC during NVP administration was 44% lower than
that without NVP administration [mean intrasubject AUC decrease, 26 (ng 䡠 h/ml)/mg; 95% CI, 21 to 31 (ng 䡠 h/ml)/mg; P ⬍
0.001]. Figure 2 summarizes the results and shows the mean
FIG. 1. Dose-adjusted pharmacokinetic profiles of the total study
population without and with NVP treatment. Geometric means and
95% CIs are shown.
Treatment and patient
no.
VOL. 48, 2004
4151
intraindividual AUC decreases and 95% CIs. Table 2 provides
the corresponding medians and IQRs for each of the parameters. AUC changes were highly variable, ranging from slight
increases in two patients to reductions of 70% (Table 2).
The dose-adjusted mean AUC of EDDP increased from 3.7
(ng 䡠 h/ml)/mg to 5.0 (ng 䡠 h/ml)/mg (P ⬍ 0.05). AUC changes
were similar in both groups. After 28 days of antiretroviral
treatment, the median trough NVP level was 3,640 ng/ml
(IQR, 3,410 to 4,630 ng/ml). The NVP treatment was well
tolerated by all study participants. Clinically relevant events
associated with the medication, in particular, rash and clinical
symptoms of hepatotoxicity, were not reported. Alanine aminotransferase and aspartate aminotransferase values did not
change significantly throughout the whole study period, but
there was a significant and continuous increase in gamma glutamyltransferase levels, from a median of 49 U/liter on day 0 to
a median of 58 U/liter on day 28.
DISCUSSION
Methadone is subject to hepatic metabolism. Previous data
from in vitro experiments with human liver microsomes suggested that methadone is demethylated by the 3A4 isoform of
the cytochrome P450 family (21, 26). These data suggest that
the coadministration of drugs which inhibit 3A4 would lead to
a rise in methadone exposure and to opiate intoxication. However, clinical trials which investigated the pharmacokinetics of
methadone when it was coadministered with the CYP3A4 inhibitors indinavir, nelfinavir (NFV), and ritonavir (RTV) failed
to confirm this assumption. Coadministration of indinavir did
not lead to any change in methadone levels (8). Coadministration of NFV led to a decrease in methadone concentrations
(20), and the AIDS Clinical Trials Group ACTG 401 trial
found that there was a reduction in methadone levels when it
was coadministered with saquinavir (SQV)-RTV (400/400
BID), the latter being a very strong inhibitor of CYP3A4 (17).
When given alone, RTV (100 mg BID) had no influence on
methadone levels at all (25). Inducers of CYP3A4 also failed to
show the expected effects on methadone concentrations: in a
study with patients receiving rifabutin, methadone levels remained unchanged (6). These surprising results, together with
recent in vitro data, suggest that the principal cytochrome of
methadone metabolism may not be CYP3A4 but CYP2B6,
followed by CYP2C19 (16). In addition, in vitro and in vivo
evidence suggests that methadone metabolism is stereoselective (13–16, 22, 24, 31, 35). CYP2B6 has been shown to
preferentially metabolize the inactive L isomer, CYP2C19
has been shown to preferentially metabolize the active R
isomer, and CYP3A4 has been shown to preferentially metabolize both isomers (16, 31, 35). Stereoselective metabolism may partly account for the fact that amprenavir reduces
total methadone concentrations without provoking signs
and symptoms of opioid withdrawal. A trial which investigated the effect of amprenavir on methadone levels in 16
healthy subjects showed that the AUC of the active isomer
decreased by only 12%, whereas the AUC of the inactive
(S)-methadone was reduced by 40%. The opioid pharmacodynamic measures recorded in this trial were unchanged,
and none of the participants complained of withdrawal
symptoms (19). Patients who took NFV or SQV-RTV with
methadone also had greater decreases in the levels of the
inactive isomer. Again, these patients did not experience
opioid withdrawal (17, 20). However, SQV-RTV elevated
the fraction of unbound methadone by displacing it from
protein binding. This effect, which may also occur with
NFV-methadone coadministration, could be an alternative
explanation for the absence of withdrawal symptoms (17).
Two studies with patients taking methadone and lopinavirRTV reported significant reductions in methadone AUCs
(36% [10] and 26% [25]). Even though the data are conflicting, lopinavir-RTV administration does not seem to
FIG. 2. (A) Mean dose-adjusted AUCs before NVP treatment (black bars) and during NVP treatment (white bars); (B) mean intrasubject
AUC changes. Error bars show the 95% CIs for nonzero differences.
4152
STOCKER ET AL.
additional methadone should be allowed with increments in
small steps of 5 or 10 mg.
ACKNOWLEDGMENTS
This trial was sponsored by Boehringer Ingelheim. The development
of the assay and sample analysis were supported by the German
Bundesministerium für Bildung und Forschung, BMBF (Kompetenznetz HIV/AIDS grant 01 KI 0211).
We thank Steffi Lehmann, Renate Rogall, the EPIMED team, and
the patients. Special thanks go to Thomas Fischer.
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cause withdrawal symptoms in the majority of patients taking methadone. Neither study measured the levels of the
methadone enantiomers.
NVP is metabolized by CYP3A4, CYP2B6, and CYP2C19
but has no inhibitory effect on any of these enzymes when it is
present at therapeutic concentrations (34). In vivo, NVP seems
to induce the levels of expression of some of these cytochromes, but confirmatory data are scarce (23, 32; unpublished
data from Boehringer Ingelheim).
The assay that we developed for this study was not stereoselective. However, 9 of our 20 patients were taking the methadone formulation, which contains only (R)-methadone. Reductions in methadone AUCs were similar in both patients
receiving racemic methadone and those receiving (R)-methadone. Among the patients in both groups, all but three patients
suffered from withdrawal symptoms. There was a slightly
greater decrease in the AUC in the group of patients taking
(R)-methadone than in the group of patients taking racemic
methadone, but this difference was not significant. Under the
assumption that CYP3A4 may play a less important role in
methadone metabolism, our results would indicate that
CYP2B6 and possibly CYP2C19 are induced by NVP. This is
consistent with the finding that the CYP2B6 inducer efavirenz
also reduces methadone concentrations (12).
The NVP trough levels measured in this study are similar to
historical data (33), which indicates that patients were adherent to their medication regimens and that the interaction was
unidirectional.
It has previously been observed (11) that patients need to
increase their methadone doses during NVP therapy much less
than would have been expected from pharmacological data. In
our total study population, a theoretical median dose increase
of 79% would have been required to compensate for the reduction in AUCs. This is in contrast to the median dose increase of 15%. Six subjects did not require any change in their
methadone doses, despite significant reductions in methadone
exposure. It has been suggested that a gradual detoxification
from methadone occurs during NVP treatment (11). Our data
strengthen this hypothesis because, after having increased their
methadone doses, almost all of the patients still had lower
methadone AUCs without any withdrawal symptoms. Alternatively, some of the patients may have had methadone levels
well above the threshold concentration at which point withdrawal symptoms occur. A reduction in the level of methadone
exposure may have been tolerated by these individuals because
the levels still remained above this threshold.
The policy concerning methadone dosing during this study
permitted physicians to increase the dose according to the
patients’ needs. Therefore, it is likely that these data reflect the
real need for additional methadone during NVP administration. However, no general recommendation can be given as to
how much and when the dose of methadone should be increased. Therapeutic drug monitoring of methadone does not
seem to be helpful because there is no clear correlation between the pharmacokinetics of methadone and its opioid effects. Decisions must be based on clinical grounds, and dose
increases need to be individualized and should not be undertaken unless the patient complains about withdrawal symptoms, since severe intoxications leading to death have occurred
during methadone treatment (7, 9). When symptoms occur,
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Virus-Infected Patients )-Methadone in Human Immunodeficiency R

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