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Pharmacokinetic and Pharmacodynamic Study of the Concomitant Administration of Methadone and TMC125 in HIV-Negative Volunteers

From Tibotec BVBA, Mechelen, Belgium (Dr Schöller-Gyüre, Dr Woodfall, Dr De Smedt, Dr Vanaken, Ms Stevens, Ms Peeters, Ms Vandermeulen, Dr Hoetelmans); Department of Psychiatry, Academic Medical Center, University of Amsterdam, The Netherlands (Dr van den Brink); and Tibotec, Inc, Yardley, Pennsylvania (Dr Kakuda).

Address for correspondence: Monika Schöller-Gyüre, MD, Tibotec BVBA, Generaal De Wittelaan L11B 3, B-2800 Mechelen, Belgium; e-mail: mscholle{at}tibbe.jnj.com.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
TMC125 is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant HIV-1. TMC125 is an inducer of CYP3A and an inhibitor of CYP2C. This trial evaluated the effect of TMC125 on the pharmacokinetics and pharmacodynamics of methadone. In an open-label, add-on, 1-way interaction trial, 16 male HIV-negative volunteers on stable methadone maintenance therapy received 100 mg TMC125 bid for 14 days. Plasma concentrations and pharmacokinetic parameters of R- and S-methadone isomers were determined on days -1, 7, and 14 and of TMC125 on days 7 and 14. Safety and tolerability were assessed. The LSmeans ratios (90% confidence interval) for AUC_24h, C_max, and C_min of the pharmacologically active R-methadone were 1.08 (1.02-1.13), 1.03 (0.97-1.09), and 1.12 (1.05-1.19), respectively, on day 7 and 1.06 (0.99-1.13), 1.02 (0.96-1.09), and 1.10 (1.02-1.19), respectively, on day 14 compared with methadone alone. No withdrawal symptoms were observed; dose adjustment of methadone was not required. The concomitant administration of TMC125 and methadone was generally safe and well tolerated. TMC125 has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of methadone. No dose adjustment for methadone is anticipated when coadministered with TMC125.

Key Words: TMC125 • etravirine • methadone • nonnucleoside reverse transcriptase inhibitor • drug-drug interaction

A new pharmaceutical formulation of TMC125 has been developed with substantially improved bioavailability, providing clinically relevant exposures at a dose of 200 mg twice daily (bid). This new formulation was used for this study and is the formulation used in ongoing clinical trials with TMC125.

TMC125 is mainly metabolized by cytochrome P450 (CYP) 3A4 and CYP2C with subsequent glucuronidation of the metabolites.⁷ The potential of TMC125 to induce CYP450 enzymes, determined in primary hepatocyte cultures, was demonstrated by increased mRNA expression of CYP2B6, CYP2C subfamily, and CYP3A4. In vitro, TMC125 is an inhibitor of CYP2C9 and P-glycoprotein. In vivo, TMC125 is an inducer of CYP3A4 and an inhibitor of the CYP2C subfamily.⁸ TMC125 has an elimination half-life in plasma of approximately 30 to 40 hours. The drug should be taken immediately after food to enhance oral bioavailability.⁹

Methadone undergoes oxidative metabolism by various CYP450 isozymes.¹⁰ The most important enzymes in methadone metabolism are CYP3A4 and CYP2B6. CYP2D6 is mainly involved in the metabolism of the active R-isomer.¹¹ The role of CYP1A2 is probably minor, and its clinical relevance is currently under investigation.¹² The involvement of the CYP2C subfamily has not been confirmed.¹³ Recently, CYP2B6 has been discovered as playing a prominent role in methadone metabolism, especially but not exclusively in the metabolism of the inactive S-enantiomer.^13-16 P-glycoprotein (P-gp) affects the intestinal disposition of oral methadone, although its role in brain methadone access has not been confirmed.¹⁷

Antiretroviral drugs are known to have numerous interactions with methadone, mainly due to their CYP450 enzyme induction or inhibition potential.^18,19

The primary objective of this trial was to determine the effect of steady-state concentrations of TMC125 100 mg bid on the steady-state pharmacokinetics of methadone in HIV-negative subjects on stable, individualized methadone treatment. Furthermore, the pharmacokinetics of TMC125, the occurrence of opiate withdrawal symptoms, and the short-term safety and tolerability of the concomitant use of TMC125 and methadone were also evaluated.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The final protocol was reviewed and approved by an independent ethics committee (STEG, Medical Ethics Committee, Duivendrecht, The Netherlands) according to specifications outlined in the applicable regulations (eg, ICH-GCP, US Code of Federal Regulations). The trial was performed in accordance with the principles of good clinical practice. All subjects gave their written consent prior to any trial-related procedure, and their drug addiction physician provided necessary care after completion of the confinement period.

Trial Population
Sixteen HIV-1-negative volunteers on stable methadone maintenance therapy (60-150 mg methadone once daily) were enrolled in the trial. All subjects had to be able to comply with the protocol requirements, were aged 18 to 55 years, and had to have a body mass index between 18.0 and 30.0 kg/m². Females of non-child-bearing potential could be included. Male and female volunteers were required to use adequate birth control measures. All volunteers needed to be in good health, as determined by medical history, physical examination, and clinical laboratory assessments. They needed to test HIV-1 antibody negative and not have participated in previous trials of investigational drugs within the past 90 days. Volunteers with evidence of current alcohol and/or drug abuse, a lack of venous access, or a suspected allergy to TMC125 were excluded. Smoking habits had to remain stable during the trial. Volunteers were not allowed to use medication with a known effect on drug metabolism or when a relevant interaction of TMC125 with the coadministered drug could be expected.

Trial Design
Screening of subjects took place between day -40 and -20. The trial consisted of a run-in period of 14 days before the first administration of TMC125 and a treatment period of 14 days with TMC125 100 mg bid. Volunteers were admitted to the research unit 2 days before coadministration of TMC125 and remained confined until day 15. Daily safety visits took place up to 6 days after discharge. The last follow-up visit was performed on day 31 after the last administration of TMC125.

Volunteers continued their stable methadone therapy (Symoron® tablets) from day -14 (start of the run-in period) until the end of the trial. Dedicated trial personnel witnessed methadone intake from day -14 until 11 days after the last intake of TMC125 either in the research unit or in the drug addiction center. Dose adjustments of methadone were not allowed from day -14 up to and including day 7. In case methadone withdrawal symptoms were observed, the dose of methadone could be adjusted at the investigator's discretion from day 8.

Safety Assessments
Adverse events (AEs) were evaluated throughout the trial. Severity and drug relationship of AEs to methadone or TMC125 were assessed. Laboratory assessments, electrocardiograms (ECGs), vital signs assessments, and physical examinations were performed at specific time points.

Pharmacodynamic Assessments
Symptoms of methadone withdrawal were continuously monitored based on AEs. Furthermore, the Short Opiate Withdrawal Scale (SOWS) and Desires for Drugs Questionnaire (DDQ) were assessed daily from day -1 to day 14 at 2 hours after methadone intake.^20,21 At the same time points, pupillary diameter measurements were performed under standardized conditions using the Compact Integrated Pupillograph (CIP by AMTech, Weinheim, Germany) as an objective measure of methadone nervous system effects.

Pharmacokinetic and Statistical Analyses
Plasma samples for the bioanalysis of R- and S-methadone were collected on days -1, 7, and 14 before dosing, at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after dose administration. Full 12-hour pharmacokinetic profiles of TMC125 were assessed on days 7 and 14 based on plasma concentrations obtained before dosing and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours postdose.

Plasma samples were stored at -18°C until assayed. Plasma concentrations of TMC125 and R- and S-methadone were determined using validated liquid chromatography mass spectrometry/mass spectrometry (LC/MS/MS) methods. The internal standard (IS) used was stable isotope-labeled TMC125-d4. Plasma was extracted once using tertiary butyl methyl ether under alkaline conditions. Isocratic chromatographic separation was achieved at 40°C on a 3-µm Phenomenex C18 BDS (4.6 ID x 100 mm). The elution mixture consisted of a formic acid solution and acetonitril (30/70 v/v ratio). Detection was done by tandem MS (API4000 instrument, Applied Biosystems, Foster City, California) in the electrospray-positive (ESI+) multiple-reaction monitoring (MRM) mode. MRM transitions were m/z 437.00 to 165.10 and m/z 442.10 to 166.10 for TMC125 and the IS, respectively. The effective linear range was 2.00 to 5000 ng/mL with a lower limit of quantification of 2.00 ng/mL. Interbatch precision varied between 1.6% and 5.7% (percent coefficient of variation [CV%]), whereas interbatch accuracy varied between 96.1% and 100.0%.

For determination of R- and S-methadone, the applied analytical methodology was based on the work of Liang et al.²² After addition of the internal standard solution (R/S-methadone-d3) and alkaline buffering, plasma aliquots were extracted using liquid extraction with a heptane/pentane mixture (50/50 v/v). Chromatographic separation was achieved using ambient Chiral AGP chromatographic column (ChromTech, Congleton, UK, 5-µm particle size, 2.1 mm ID x 100 mm). Isocratic elution was done using a mixture of ammonium acetate buffer and methanol. Quantification was done using tandem MS detection on an API4000 instrument (Applied Biosystems) in the ESI+ mode. The following MRM transitions were monitored: m/z 310.00 to 265.00 and m/z 313.00 to 268.00 for R- and S-methadone and for the IS, respectively.

The validated linear range was 5 to 1000 ng/mL for R- and S-methadone. The lower limits of quantification were 5 ng/mL for both isomers of methadone. Interbatch precision varied between 0.4% and 4.6% and between 2.5 and 6.6% (CV%) for the R- and S-methadone assay, respectively. Interbatch accuracy varied between 97.1% and 100.6% and between 99.5 and 101.6% for the R- and S-methadone assay, respectively.

Pharmacokinetic and statistical analyses of plasma concentrations of TMC125 and R- and S-methadone and the statistical analysis of the pharmacokinetic parameters were performed using WinNonlin Professional (Version 4.1; Pharsight Corporation, Mountain View, California). Noncompartmental analysis model 200 (extravascular input, plasma data) was applied for the pharmacokinetic analysis. The predose and the maximum plasma concentration (C_0h and C_max, respectively) and time to reach C_max (t_max) were obtained by inspection of the plasma concentration-time profiles. The minimum plasma concentration (C_min) was the lowest plasma concentration observed within a dosing interval. The value of the area under the plasma concentrationtime curve from 0 to 12 or to 24 hours (AUC_12h or AUC_24h, respectively) was determined using the linear trapezoidal rule. Predose plasma concentrations on minimally 3 consecutive days before day -1, day 7, and day 14 were compared graphically to verify the achievement of steady state for both drugs.

Descriptive statistics were calculated for the pharmacokinetics of TMC125 and both isomers of methadone. Statistical analyses were performed for R- and S-methadone using treatment with TMC125 as test (day 7 or day 14) and treatment without TMC125 (day -1) as reference. The primary pharmacokinetic parameters used in the statistical analysis were C_min, C_0h, C_max, and AUC_12h or AUC_24h on the logarithmic scale. All available observations were included in the statistical analysis. The least squares means (LSmeans) of the primary parameters for each isomer were estimated with a linear mixed-effects model, controlling for treatment as fixed effect and subject as a random effect. A 90% confidence interval (CI) was constructed around the difference between the LSmeans of test and reference. Both the difference between the LSmeans and the 90% confidence limits was retransformed to the original scale. Absence of a drug-drug interaction was concluded if the confidence interval for a specific pharmacokinetic parameter was within the predefined no-effect boundaries of 80% to 125%. The pharmacokinetic parameter C_max of S-methadone is described in the literature as the parameter with the highest within-subject variability in methadone maintenance subjects.^23,24 The 90% confidence interval for the LSmeans ratio for C_max of S-methadone was estimated to be (-19.3%; +23.9%) in a cohort of 16 subjects.

Safety and pharmacodynamic parameters were evaluated by means of descriptive statistics and frequency tabulations.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The trial was conducted in 1 center. Sixteen male volunteers with a median age of 42 years (range, 36-55) were enrolled in the trial. The median body mass index was 22.8 kg/m² (range, 18-30); 14 (87.5%) subjects were Caucasian. All volunteers but 1 were smokers. At screening, all volunteers tested negative for amphetamines and benzodiazepines. Eleven volunteers (68.8%) had a positive urine drug test for cocaine, opioids other than methadone, or cannabinoids. Nine (56.3%) tested positive for hepatitis C antibodies; 4 of them had a diagnosis of hepatitis C in their medical history. No other clinically relevant findings in the medical history or currently active disorders were reported.

The mean individualized methadone dose was 82 mg per day (range, 60-130 mg per day). All volunteers completed the trial. Due to difficulties with blood sampling in 1 participant, pharmacokinetic profiles of 15 volunteers were available on day 14.

Pharmacokinetics of R-Methadone
The mean plasma concentrations of R-methadone at steady state were slightly higher when combined with TMC125 with almost overlapping mean pharmacokinetic profiles on days 7 and 14 (Figure 1). Mean values for C_0h, C_min, C_max, and AUC_24h of R-methadone were slightly increased after 7 and 14 days of coadministration of TMC125 compared to day -1 (methadone alone). The 90% CIs of the LSmeans ratios of all parameters were within the 80% to 125% range (Table I).

View larger version (10K): [in this window] [in a new window]   Figure 1. Mean plasma concentration-time curves of R-methadone (top) and S-methadone (bottom) without (day -1) and with (days 7 and 14) coadministration of TMC125 100 mg bid in volunteers on a stable methadone therapy.

Pharmacokinetics of S-Methadone
After 7 and 14 days of treatment with TMC125, plasma concentrations of S-methadone were slightly lower than those observed when only methadone was given (Figure 1). This was reflected in lower mean values for C_0h, C_min, C_max, and AUC_24h of S-methadone on days 7 and 14 (with coadministration of TMC125) compared to day -1 (methadone alone). The 90% CIs of the LSmeans ratios of all parameters were within the 80% to 125% range, except for C_0h of day 14 versus day -1 (Table I).

The pharmacokinetics of methadone were in general comparable to those described in the literature.^23-25

TMC125 Pharmacokinetics
The pharmacokinetic parameters of TMC125 in subjects on a stable, individualized methadone maintenance therapy on day 14 were in the range of those previously observed after the administration of TMC125 100 mg bid alone for 7 days in healthy subjects.²⁶

A summary list of key pharmacokinetic parameters of TMC125 for both days is presented in Table II.

Pharmacodynamic Assessments and Methadone Dose Adjustments
No clinically significant symptoms of methadone withdrawal were reported. No clinically relevant changes were observed in the SOWS or DDQ scores or median pupil diameters during the combined administration of TMC125 and methadone. Methadone dose adjustments were not required in any of the volunteers during the period of coadministration with TMC125 or in the follow-up period.

Safety
The 2 most frequently reported AEs during treatment with methadone alone were headache and constipation (each 13%) and, during the combined treatment of methadone and TMC125, headache and nausea (each 19%). No other central nervous system (CNS) or neuropsychiatric events were observed. One subject reported a grade 1 papular rash, possibly related to TMC125, which resolved spontaneously within 2 weeks. No grade 3 or 4 AEs were reported. No volunteers discontinued the trial due to an AE. There were no consistent or clinically relevant changes in physical examinations, laboratory assessments, vital signs, or ECG parameters. No clinically relevant treatment-emergent changes of the QTc interval or other conduction disorders were observed.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The coadministration of TMC125 in volunteers on stable individualized methadone treatment resulted in no clinically relevant changes in the pharmacokinetics of R- and S-methadone. The 90% confidence intervals for all LSmeans ratios were within the 80% to 125% range, except for C_0h of the S-isomer on day 14 (LSmeans ratio 0.87, 90% CI 0.79-0.96). As this isomer is pharmacologically inactive, no clinical relevance is attributed to this finding.

The design of this trial did not allow for the assessment of the effect of methadone on the pharmacokinetics of TMC125. Instead, pharmacokinetic parameters of TMC125 were compared with historical controls. After 14 days of dosing, TMC125 exposure was in the range of the exposures observed in HIV-negative volunteers after the administration of the same dose and formulation for 7 days, not using any concomitant medication.²⁶

Based on interactions of TMC125 with other CYP3A4 substrates, a decrease of methadone plasma concentrations was expected. The results of the trial, however, did not confirm this. In the case of methadone, induction of CYP3A4 may be counter-balanced by inhibition of P-gp. Although the involvement of CYP2C enzymes in the metabolism of methadone seems to be less important than has been suggested earlier,^13,14 the role of the inhibition of this metabolic pathway by TMC125 also cannot be ruled out. CYP2B6 has been shown to be involved in methadone clearance.¹⁵ Induction of the CYP2B6 pathway demonstrated in vitro may have a role in the slight decrease of the inactive S-isomer.

To allow sufficient time for the development of maximal enzyme induction, we dosed TMC125 in this trial up to 2 weeks. Methadone dose adjustment was allowed per protocol from day 8 of coadministration in case this was clinically indicated. Opiate withdrawal symptoms caused by a potential decrease of methadone concentrations were assessed using the SOWS, DDQ, and pupillometry, all performed 2 hours after methadone administration. The development of withdrawal symptoms is frequently observed in subjects using the minimal effective dose of methadone at the end of the dosing interval. Given the t_max of methadone, the choice of the time point of these assessments at 2 hours after dosing allows only a rough indication of the development of methadone withdrawal; therefore, these data should be taken with some caution. On the other hand, no increase in frequency or in severity of withdrawal symptoms was observed during the entire dosing period, and no adjustment of the methadone dose in the second week of the concomitant administration was needed. Conversely, no signs and symptoms of methadone intoxication were observed during the entire follow-up period, and no adjustment of the methadone dose was necessary during the coadministration or in the follow-up period. Supported further by the pharmacokinetic analyses, we are confident in the conclusion that the concomitant administration of TMC125 and methadone does not cause opiate withdrawal symptoms.

In this study, a lower dose of TMC125 than the dose used in ongoing clinical studies (100 vs 200 mg bid, respectively) was administered to prevent the development of severe opiate withdrawal symptoms caused by the anticipated induction of CYP3A4. The pharmacologically active R-isomer, however, showed an increase instead of a decrease of plasma concentrations. This effect was statistically significant for AUC_24h but not for C_max. Furthermore, all CIs were within the predefined no-effect boundaries of 80% to 125%. Clinically, neither symptoms of methadone intoxication, nor those of methadone withdrawal upon cessation of TMC125 coadministration, were observed. Considering the effect size and the narrow confidence intervals for the pharmacokinetic parameters of the pharmacologically active R-isomer, we believe that this interaction will not be different for the clinically effective dose of 200 mg bid, currently studied in phase III trials in HIV-1-infected subjects.

Besides the pharmacokinetic interactions with an effect on the plasma concentrations of methadone, pharmacodynamic interactions are also described when coadministering methadone with drugs affecting CNS function and/or cardiac conduction, leading to additive CNS depression and proarrhytmogenic effects.²⁷ Currently, there is no evidence of TMC125 affecting CNS function, assessed in healthy volunteers and HIV-1-infected subjects in clinical trials.²⁸ Pharmacodynamic interactions of TMC125 with drugs affecting CNS functions are not expected. The absence of AEs signaling changes of CNS function in this trial further supports the favorable safety profile of TMC125 concerning CNS effects.

A relatively small risk of QTc interval increase during methadone treatment has been recently described in the literature.^29-32 Drugs known to prolong QT interval or to cause elevation of plasma methadone concentrations might contribute to the development of dysrythmias. TMC125 does not block the human ether-a-go-go related gene (hERG) potassium channel in vitro, and a thorough QTc study demonstrated no significant effect on the QTc interval or other electrocardiogram parameters.³³ In line with these data, this trial did not reveal any clinically relevant changes in QTc interval during coadministration of TMC125 and methadone.

In conclusion, no clinically relevant changes in the pharmacokinetics of methadone were observed in this trial after the coadministration of TMC125 100 bid for 14 days in HIV-negative volunteers using stable individualized methadone treatment. No clinically relevant symptoms of opiate withdrawal or intoxication were observed. There is no need for an a priori dose adjustment of methadone doses when coadministered with TMC125.

	ACKNOWLEDGEMENTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Financial disclosure: Dr Schöller-Gyüre, Dr Woodfall, Dr De Smedt, Dr Vanaken, Ms Stevens, Ms Peeters, Ms Vandermeulen, Dr Hoetelmans, and Dr Kakuda are salaried employees of Tibotec. Funding for this study was provided by Tibotec.

The results of this study have been partly presented at the XVIth International AIDS Conference, Toronto, Canada, August 13-18, 2006, poster TUPE0084.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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