Pharmacokinetics Of Methadone Research Articles

Modeling Methadone Pharmacokinetics in Rats in Presence of P-glycoprotein Inhibitor Valspodar

To quantify the in vivo role of P-glycoprotein (P-gp) in the pharmacokinetics of methadone after intravenous and oral administration, using valspodar as a P-gp inhibitor. Methadone plasma concentrations after intravenous (0.35 mg/kg) and oral (6 mg/kg) administration were analyzed, in absence and presence of valspodar, using nonlinear mixed effects modeling (NONMEM V). Non-parametric bootstrap analysis and posterior predictive check were employed as model evaluation techniques. The pharmacokinetics of methadone in the rat was successfully modeled using a two-compartmental model with a linear elimination from the central compartment and a first-order absorption process with lag time. Valspodar increased methadone F by 122% (95%CI: 34-269%) and decreased the V ( c ) and V ( p ) by 35% (95%CI: 16-49%) and 81% (95%CI: 63-93%), respectively. No effect of valspodar on other pharmacokinetic parameters was discernible. The non-parametric bootstrap analysis confirmed the absence of bias on the parameter estimates, and visual predictive check evidence the adequacy of the model to reproduce the observed time course of methadone plasma concentrations. Valspodar increased methadone's bioavailability as consequence of P-gp inhibition, which resulted in an increased analgesic effect of methadone.

Méthadone : de la pharmacocinétique à la pharmacologie clinique

In January 2002, the official French methadone legislation prescription was modified. Thus, the number of clinicians authorized to introduce methadone substitution was increased. Knowledge of the pharmacokinetic and pharmacological properties of this compound remains particularly important for its appropriate prescription. Bearing this in mind, we linked methadone pharmacokinetics to its pharmacological use in this article. METHADONE PHARMACOLOGY: Methadone is a synthetic opiate. Its mean bioavailability is around 75%. Cytochrome P450 3A4 and 2D6 are involved in its hepatic metabolism. Its volume of distribution is of around 4 L/kg. The value of half-life elimination is of around 22 hours. These pharmacokinetic properties (long half-life, steady state concentration) are in favour of substitution use of this opiate. In practice, clinicians progressively introduce this substitution therapy to reach 80 mg +/- 20 mg per day, once daily. Therapeutic clinical goals are mainly to reduce craving, withdrawal symptoms, and to manage psychosocial problems and psychiatric co-morbidity. Practitioners should bear the latter in mind once substitution therapy has been appropriately initiated and stabilized. However, wide, interpatient, interindividual variability impacts on pharmacokinetic parameters. Subjects may be either high or poor metabolizers. Thus, bioavibility ranges from 36 to 100%. Induction or inhibition of CYP450 significantly modifies methadone pharmacodynamic properties. Genetic variability and medication can induce non response to substitution, craving, or withdrawal symptoms. PHARMACOLOGICAL INTERACTIONS: We describe here a large number of medications involved in pharmacokinetic or pharmacological interactions. Classical enzymatic inductors, such as antiepileptic molecules (phenobarbital, carbamazepin), antituberculosis compounds (rifampicin), or antiretroviral therapy (efavirenz, nevirapin, ritonavir), could possibly lead to respiratory depression for example. Metabolism inhibitors such as selective serotonin reuptake inhibitors (fluvoxamine, fluoxetine, paroxetine, sertraline) or antifungals of the azol groups could enhance plasma concentration and may sometimes lead to respiratory depression or death. Nevertheless, clinicians should know methadone pharmacokinetic properties and pharmacological interactions for the optimal opiate-dependant patients' management. Clinicians can use plasma concentrations as a useful indicator to reach substitution goals. The methadone plasmatic target value of 400 microg/ml can be recommended for therapeutic drug monitoring. This dosage not only facilitates interaction detection, but also hand encourages communication with the patient.

Relapse to Opioid Use After Treatment of Chronic Hepatitis C With Pegylated Interferon and Ribavirin

Relapse to Opioid Use After Treatment of Chronic Hepatitis C With Pegylated Interferon and Ribavirin

CLINICAL STUDY: Fluctuations in (R,S)‐methadone pharmacokinetics and response among long‐term methadone maintenance patients

Knowledge of how methadone disposition may fluctuate during the course of maintenance treatment is presently limited. This study investigated long-term fluctuations in methadone pharmacokinetics in five methadone maintenance patients who participated in two 24-hour testing sessions separated by at least one year. Results indicated substantial fluctuations between sessions in dose-corrected average steady-state plasma (R)-methadone concentrations (Cav), ranging from a 51% decrease to a 466% increase. These fluctuations were not consistently associated with changes in methadone dose or self-reported withdrawal status. The plasma (S)-:(R)-methadone Cav ratio increased significantly (12%, P = 0.04) between the sessions, suggesting a different pattern of long-term change in the pharmacokinetics of each enantiomer over time. The pronounced and variable fluctuations in methadone disposition evident in these patients highlight the need for an individualized approach to patient dosing and monitoring.

Pharmacokinetic interaction of nelfinavir and methadone in intravenous drug users

The effect of nelfinavir 1250 mg twice daily (b.i.d.) on the pharmacokinetics of methadone was determined in 14 HIV-negative methadone users. The methadone dose (20-140 mg/day) was stabilized and fixed for at least 1 month before nelfinavir (1250 mg b.i.d. for 8 days) was added to the regimen. The concentrations of methadone enantiomers were measured before and during nelfinavir treatment, and the concentrations of nelfinavir and its active metabolite, AG1402, were measured during nelfinavir treatment. Adverse events and withdrawal/intoxication symptoms were monitored throughout the study. Nelfinavir reduced the area under the concentration-time curve of R-methadone, and S-methadone by 43% and 51%, respectively. Nelfinavir and AG1402 concentrations were within the normal range of historical data, and no subject experienced withdrawal symptoms during the study or required dose adjustment during or after the study. Although nelfinavir reduced the plasma concentrations of both R- and S-methadone, it seems to have no impact on the maintenance dose of methadone. A routine reduction of methadone dose is not recommended when coadministered with nelfinavir.

Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment

Recent in vitro studies have suggested an important role of cytochrome P450 (CYP) 2B6 and CYP2C19 in methadone metabolism. We aimed to determine the influence of CYP2B6, CYP2C9, and CYP2C19 genetic polymorphism on methadone pharmacokinetics and on the response to treatment. We included 209 patients in methadone maintenance treatment on the basis of their response to treatment and their daily methadone dose. Patients were genotyped for CYP2B6, CYP2C9, and CYP2C19. Steady-state trough and peak (R)-, (S)-, and (R,S)-plasma levels and peak-to-trough plasma level ratios were measured. CYP2B6 genotype influences (S)-methadone and, to a lesser extent, (R)-methadone plasma levels, with the median trough (S)-methadone plasma levels being 105, 122, and 209 ng . kg/mL . mg for the noncarriers of allele *6, heterozygous carriers, and homozygous carriers (*6/*6), respectively (P = .0004). CYP2C9 and CYP2C19 genotypes do not influence methadone plasma levels. Lower peak and trough plasma levels of methadone and higher peak-to-trough ratios were measured in patients considered as nonresponders [median (R,S)-methadone trough plasma levels of 183 and 249 ng . kg/mL . mg (P = .0004) and median peak-to-trough ratios of 1.82 and 1.58 for high-dose nonresponders and high-dose responders, respectively (P = .0003)]. Although CYP2B6 influences (S)-methadone plasma levels, given that only (R)-methadone contributes to the opioid effect of this drug, a major influence of CYP2B6 genotype on response to treatment is unlikely and has not been shown in this study. Lower plasma levels of methadone in nonresponders, suggesting a higher clearance, and higher peak-to-trough ratios, suggesting a shorter elimination half-life, are in agreement with the usual clinical measures taken for such patients, which are to increase methadone dosages and to split the daily dose into several intakes.

Lack of an effect of atazanavir on steady-state pharmacokinetics of methadone in patients chronically treated for opiate addiction

Effective antiretroviral treatment of opiate-addicted drug users with HIV infection often requires concomitant substance abuse treatment, commonly with methadone. Pharmacological interactions between antiretroviral drugs and methadone may result in opiate withdrawal or increased side effects. To determine if atazanavir, a once-daily protease inhibitor and moderate inhibitor of P450 CYP3A4, exhibited pharmacokinetic interactions with (R)-methadone. Methadone pharmacokinetic parameters were measured in 16 patients on chronic methadone therapy prior to and after 14 days of daily administration of atazanavir. Steady-state pharmacokinetic values for total, (R)- (active) and (S)- (inactive) isomers of methadone were derived from plasma concentrations versus time data. Symptoms of opiate withdrawal and excess were monitored. For the active isomer (R)-methadone, the ratio of geometric means for coadministration with atazanavir relative to methadone alone were 1.03 [90% confidence interval (CI), 0.95-1.10] for the area under the concentration-time curve (AUC), 0.91 (90% CI, 0.84-1.00) for plasma maximal concentration and 1.11 (90% CI, 1.02-1.20) for plasma trough concentration. Confidence intervals for all three were within the no-effect or bioequivalence range of 0.80-1.25 for (R)-methadone. Inactive (S)-methadone was modestly reduced during atazanavir coadministration. Clinically relevant symptoms of opiate withdrawal or excess were not detected. Exposures to atazanavir were within range of previously reported values. No clinically relevant pharmacokinetic interactions were found between atazanavir and methadone. Dosage adjustment need not be recommended for either methadone or atazanavir when co-administered to patients treated for opiate abuse and HIV disease.

Within‐ and between‐ subject variability in methadone pharmacokinetics and pharmacodynamics in methadone maintenance subjects

To investigate within- and between-subject variability of the pharmacodynamics and pharmacokinetics of (R)- and (S)-methadone in methadone maintenance subjects at steady-state. Six non-holder subjects were studied on three occasions at 7-16 day intervals; doses (20-170 mg/day) remained unchanged. Blood samples and pharmacodynamic data were collected 10-12 times over a 24-h inter-dosing interval. All pharmacodynamic data were expressed as the area under the end-point versus time curve. Using analyses of variance with mixed effects, best estimates were made of the ratio of between- to within-subject variation, with corresponding 95% confidence intervals (CI) for within-subject variation at the average value. Subjects were relatively consistent between occasions, whereas there was much greater between-subject variability (P < 0.02) for all measures. Estimates of the ratio of between- to within-subject variation ranged from 2.2-12.8 for pharmacodynamic measures, and 1.3-7.9 for pharmacokinetic parameters. For pain, total mood disturbance, withdrawal, pupil size and respiration rate, 95% CI for within-subject measures ranged < or = 2-fold, while this was greater for subjective direct opioid effects (4.2-fold). For CL/F of the active (R)-methadone, the variance ratio was 4.9 (P < 0.0003), with 95% CI for within-subject measures ranging < or = 2-fold. (S)-methadone CL/F demonstrated greater within-subject variability (3.4-fold), possibly contributing to a smaller (2.7; P < 0.0003) ratio of between- to within-subject variance. Non-holder methadone maintenance treatment participants appear to respond consistently with respect to pharmacokinetics and pharmacodynamics over a 1-2 month period. Such knowledge may help prescribers to determine whether alternative dosing regimens or treatments might be more appropriate in this population.

Fatal methadone intoxication in an infant

Presented are the case history and toxicological findings of an infant fatality involving methadone. A mother found her 10-month-old infant unresponsive in a crib. The infant was taken to a hospital; however, she was cold and stiff on arrival and was pronounced dead. Few details regarding the case history were known at the time, and the autopsy findings were unremarkable. Specimens were submitted for a full toxicological analysis, including an alcohol analysis by headspace gas chromatography with flame ionization detection; a screen for drugs of abuse and several prescription drug classes using an enzyme-linked immunosorbent assay technique (ELISA); and a screen for basic compounds using gas chromatography–mass spectrometry (GC–MS). Positive findings were confirmed and quantitated using GC–MS. Methadone was detected in subclavian blood at a concentration of 0.67 mg/L. The cause of death was determined to be “methadone intoxication”, and the manner of death was “homicide”. A discussion of the case circumstances, the toxicology findings and methadone pharmacokinetics are presented.

The pharmacokinetics of methadone are not affected by concurrent administration with peginterferon-??-2a in hepatitis C virus (HCV) infection,

The pharmacokinetics of methadone are not affected by concurrent administration with peginterferon-??-2a in hepatitis C virus (HCV) infection,

Peginterferon Alfa-2a Does Not Alter the Pharmacokinetics of Methadone in Patients with Chronic Hepatitis C Undergoing Methadone Maintenance Therapy*

Our objective was to quantify the pharmacokinetics of methadone and the pharmacokinetics and pharmacodynamics of peginterferon alfa-2a (40 kd) in patients with chronic hepatitis C undergoing methadone maintenance therapy. Adults with chronic hepatitis C who had been receiving a consistent methadone maintenance regimen for at least 3 months were eligible for this open-label, multicenter, nonrandomized drug interaction study. All patients received 180 microg subcutaneous peginterferon alfa-2a once weekly for 4 weeks and continued their methadone regimen. Serial blood samples were collected at baseline and immediately before and for up to 168 hours after study drug administration for the purposes of quantifying methadone and peginterferon alfa-2a serum concentrations, measuring serum 2',5'-oligoadenylate synthetase activity, and determining hepatitis C virus ribonucleic acid levels. Twenty-four patients were enrolled. Methadone exposure, as measured by maximum serum concentration (C(max)) and area under the concentration-time curve (AUC) normalized to a 100-mg/d dose, after 4 doses of peginterferon alfa-2a increased by 10% to 15% when compared with baseline. The week 4/baseline ratio of the mean C(max) was 1.11 (90% confidence interval [CI], 1.02-1.22), and for AUC from time 0 to 24 hours, the week 4/baseline ratio was 1.15 (90% CI, 1.08-1.23). The mean accumulation ratios (week 4/first dose) for C(max) and AUC from time 0 to 168 hours of peginterferon alfa-2a were 2.1 and 2.3, respectively. Peginterferon alfa-2a does not appreciably alter the pharmacokinetics of methadone.

Pharmacokinetics of Methadone

Methadone is a synthetic opioid that is effective for the relief of moderate-to-severe pain and for the treatment of opioid dependence. The pharmacokinetics of methadone differ from those of morphine in that methadone has a higher bioavailability, a much longer half-life, and is hepatically metabolized by cytochrome P450 enzymes. The pharmacokinetics of methadone are variable and an understanding of the factors that impact the onset, magnitude, and duration of analgesia is required to optimize therapy. Drug interactions are common and patients receiving methadone should be monitored closely for toxicity or therapeutic failure. Special populations in whom a change from the usual dosage regimen may be necessary include pediatric patients, patients with renal failure, the elderly, and pregnant women. To achieve an optimal dosage regimen, the clinician must have an understanding of the pharmacokinetics and pharmacodynamics of methadone in addition to the relationship between these variables and their patient' demographic and pathophysiologic characteristics. A MEDLINE search was performed to identify literature published between 1966 and May 2005 relevant to the pharmacokinetics of methadone. These publications were reviewed and the literature summarized regarding unique and clinically important elements of methadone disposition including its absorption profile, distribution, and metabolism/excretion. General dosing guidelines, dosage conversions from other opioids and pharmacokinetic issues in Special populations are discussed.

Bidirectional transfer of methadone across human placenta

Methadone maintenance programs are considered the standard of care for the pregnant opiate addict. However, data on changes in methadone pharmacokinetics (PK) during pregnancy are limited and do not include its disposition by the placenta due to obvious ethical and safety considerations. Accordingly, investigations in our laboratory are focusing on human placental disposition of opiates including methadone. Recently, we reported on methadone metabolism by placental aromatase and provide here data on its bidirectional transfer across the tissue utilizing the technique of dual perfusion of placental lobule. The concentrations of the opiate transfused into the term placental tissue were those reported for its in vivo levels in the maternal serum of women under treatment with the drug. Data obtained indicated that the opiate has no adverse effects on placental viability and functional parameters and that it is retained by the tissue. Also, methadone transfer and its clearance index in the fetal to maternal direction (0.97 ± 0.05) was significantly higher ( P < 0.05) than in the maternal to fetal (0.83 ± 0.09). The observed asymmetry in methadone transfer could be explained by the unidirectional activity of the efflux transporter P glycoprotein (P-gp) that is highly expressed in variable amounts in trophoblast tissue. Therefore, placental disposition of methadone might be an important contributor to the regulation of its concentration in the fetal circulation and consequently may affect the incidence and intensity of neonatal abstinence syndrome for women treated with the drug during pregnancy.

Methadone for cancer pain.

Methadone is an opioid used in the management of cancer pain both in opioid naïve patients and in rotation from other opioids. A particular role in neuropathic pain has been suggested. The quest for evidence based palliative care prompted a formal appraisal of methadone in comparison with other analgesics. To determine the effectiveness and safety of methadone analgesia in cancer pain patients. MEDLINE (1966 to August 2002), EMBASE (1980 to August 2002), CancerLit (1993 to August 2002), CINAHL (1982 to August 2002) and Cochrane databases were searched using a strategy developed with the Cochrane Pain, Palliative and Supportive Care Group. Assiduous efforts were made to identify unpublished or current trial work. Randomised controlled trials of methadone against active or placebo comparator in patients with cancer pain were included. Outcome measures sought were reduction in pain intensity measured by an appropriate scale, adverse effects, attrition, patient satisfaction and quality of life. There were no language restrictions. Absence of patient reported data was an exclusion criterion. Eligible studies were selected with independent collaboration from a colleague in Bristol (AND). Full text was retrieved if any uncertainty about eligibility remained. Non-English texts were screened by Cochrane contacts aware of the eligibility criteria. Quality assessment and data extraction were conducted using standardised data forms. Drug and placebo dose, titration, route and formulation were compared and detail of all outcome measures (if available) recorded. Eight randomised controlled trials (five double blinded, two crossover) with 356 recruits and 326 completing patients were included. All involved active placebo (five morphine, one dextromoramide or pethidine, one diamorphine with cocaine mixture). All employed different starting doses, titration regimens and pain scoring scales. Few presented complete pain data sets and no meta-analysis has been possible. No differentiation by cancer pain syndrome was made. Complete adverse events data were recorded in every study, and were similar in incidence and severity to those experienced with morphine. There is evidence to suggest that methadone is an analgesic with similar efficacy to morphine and a comparable side effect profile. However, the majority of studies involved single dose comparisons or short term use. This methodology fails to reproduce clinical practice. Therefore there is a very significant danger that the effects of methadone accumulation leading to delayed onset of adverse effects which occurs with chronic administration has not been represented. Fixed interval dosing schedules conducted over several days are associated with a high risk of serious morbidity and mortality. There is no trial evidence to support the proposal that methadone has a particular role in neuropathic pain of malignant origin. Conclusions have been limited by the variations in trial design, dosing regimens and limited presentation of primary outcome data. The complex and highly individual pharmacokinetics of methadone require that experienced clinicians take responsibility for initiating, titrating and monitoring this drug.

Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19.

Methadone is a clinically used opioid agonist that is oxidatively metabolized by cytochrome P450 (CYP) isoforms to a stable metabolite, EDDP. Methadone is a chiral drug administered as the racemic mixture of (R)-(-)- and (S)-(+)-methadone, but (R)-methadone is the active isomer. The cytochrome P450 (CYP) isoform involved in methadone's metabolism is thought to be CYP3A4, but human drug-drug interaction studies are not consistent with this. The ability of the common human drug-metabolizing CYPs (obtained from baculovirus-infected insect cell supersomes) to generate 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrilidine (EDDP) from racemic methadone was examined and then determined if the CYP isoforms metabolized methadone stereoselectively. Only CYP2B6, 2C19, and 3A4 generated measurable EDDP from 1 microg/ml of racemic methadone. The hierarchy of EDDP generation was CYP2B6 > CYP2C19 >/= CYP3A4. At 10 microg/ml of methadone, CYP2C9 and CYP2D6 also generated EDDP, but in at least 10-fold lower quantities than CYP2B6. Michaelis-Menten kinetic data demonstrated that CYP2B6 had the highest V(max) (44 ng/min/10pmol) and the lowest K(m) (12.6 microg/ml) for EDDP formation of all the CYP isoforms. In human liver microsomes with high and low CYP2B6 expression but equivalent CYP3A4 expression, high CYP2B6 expression microsomes generated twice the amount of EDDP from 10 microg/ml of methadone than low CYP2B6 expression microsomes. When stereoselective metabolism of racemic methadone by CYP2B6, 2C19, and 3A4 was examined using an enantiospecific methadone assay, CYP2B6 preferentially metabolized (S)-methadone, CYP2C19 preferentially metabolized (R)-methadone, and CYP3A4 showed no preference. These data suggest that multiple CYPs metabolized methadone but CYP2B6 had the highest V(max)/K(m). In addition, only CYP2B6 and 2C19 showed stereoselective metabolism. Our data could explain why the plasma concentration ratio of R/S methadone is variable and why drugs that induce CYP2B6 such as nevirapine and efavirenz also induce methadone metabolism, while the CYP3A4 inducer rifabutin has no effect on methadone pharmacokinetics.

Comparative pharmacodynamics and pharmacokinetics of methadone and slow-release oral morphine for maintenance treatment of opioid dependence

Background: Slow-release oral morphine (SROM) has been proposed as an alternative maintenance pharmacotherapy to methadone for treatment of opioid dependence. However, the pharmacodynamics and pharmacokinetics of SROM have not been previously assessed in a methadone maintenance population. Methods: In 14 methadone maintenance patients reporting adequate (holders, n=7) or inadequate (non-holders, n=7) withdrawal suppression between doses, plasma drug concentrations and indices of opioid effect (withdrawal severity, pupil diameter, and respiratory rate) were determined across a 24 h inter-dosing interval on one occasion at steady-state for methadone and SROM (once-daily Kapanol™) using an open-label, crossover design. Results: Opioid effects were of a similar overall magnitude following dosing for each drug and showed an inverse association with plasma drug concentrations, which peaked later for morphine compared to ( R)-methadone (6.5±2.3 h vs. 2.5±1.4 h, P<0.001). For methadone non-holders, the number of self-reported opioid withdrawal symptoms prior to dosing was less for SROM compared to methadone (3.4±2.6 vs. 9.0±3.2, P<0.01); for holders it was approximately equal (4.4±3.0 vs. 4.0±3.7, P<0.76). Maintenance doses were more strongly related to plasma drug concentrations for SROM compared to methadone and may thus be more predictive of therapeutic response for the former medication. Twelve of the 14 subjects preferred SROM to methadone ( P=0.01). Conclusions: The pharmacodynamics and pharmacokinetics of SROM support its use as an alternative once-daily agonist option in the treatment of opioid dependence, particularly for patients responding poorly to methadone maintenance treatment.

An ad libitum schedule for conversion of morphine to methadone in advanced cancer patients: an open uncontrolled prospective study in a Chinese population.

Methadone has been used as an alternative strong opioid to morphine in the management of cancer pain. The conversion of morphine to methadone is not straightforward because of the high individual variability and unpredictability in the pharmacokinetics of methadone. An ad libitum schedule for conversion of morphine to methadone was used in 37 cancer patients who had intolerable morphine-related side effects or had pain not satisfactorily controlled by morphine. Oral morphine was discontinued on the day of conversion. Methadone was given at a dose calculated as one-twelfth of the total daily dose of morphine, up to a maximum of 30 mg/dose. Methadone was administered at patient-controlled intervals not more frequent than three hours, the need of which was indicated by the presence of pain of moderate intensity or above as rated by a verbal rating scale. When the demand for methadone was stabilized, the total daily dose was given regularly in divided doses. Pain control on day 7 was taken as the primary endpoint. Twenty-seven patients completed the study. Twenty-four patients (88.9%) were in good pain control on day 7, and all reached good pain control by day 11. The median time required to achieve good pain control was three days (range 1-11 days). A majority (88.6%) of morphine-related adverse effects improved or resolved after conversion to methadone. This ad libitum schedule is effective in conversion of morphine to methadone in these patients.

The pharmacokinetics of methadone following co-administration with a lamivudine/zidovudine combination tablet in opiate-dependent subjects.

Methadone pharmacokinetics were determined in an open-label, within subject study in 16 methadone-maintained, non-HIV-infected subjects prior to and following administration of one lamivudine 150-mg/zidovudine 300-mg combination tablet to determine whether this antiretroviral therapy alters methadone serum concentrations. No significant differences in the mean area under the serum concentration-time curve (AUC(0-24h); 8,753 +/- 4,280 vs. 8,641 +/- 4,431 microg-h/L),oralclearance(CL/F;9.9 +/- 4.9vs. 10.3 +/- 5.5 L/h),oral volume of distribution (Vd/F; 647 +/- 465 vs. 481 +/- 305 L), maximum serum concentration (Cmax; 514 +/- 223 vs. 5,510 +/- 237 microg/L), or terminal elimination half-life (t 1/2; 55.3 +/- 61.0 vs. 35.0 +/- 17.5 h) were detected. These results suggest that methadone dose change is not likely to be necessary for patients treated with lamivudine/zidovudine combination pharmacotherapy.

Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence.

Methadone is widely used for the treatment of opioid dependence. Although in most countries the drug is administered as a racemic mixture of (R)- and (S)- methadone, (R)-methadone accounts for most, if not all, of the opioid effects. Methadone can be detected in the blood 15-45 minutes after oral administration, with peak plasma concentration at 2.5-4 hours. Methadone has a mean bioavailability of around 75% (range 36-100%). Methadone is highly bound to plasma proteins, in particular to alpha(1)-acid glycoprotein. Its mean free fraction is around 13%, with a 4-fold interindividual variation. Its volume of distribution is about 4 L/kg (range 2-13 L/kg). The elimination of methadone is mediated by biotransformation, followed by renal and faecal excretion. Total body clearance is about 0.095 L/min, with wide interindividual variation (range 0.02-2 L/min). Plasma concentrations of methadone decrease in a biexponential manner, with a mean value of around 22 hours (range 5-130 hours) for elimination half-life. For the active (R)-enantiomer, mean values of around 40 hours have been determined. Cytochrome P450 (CYP) 3A4 and to a lesser extent 2D6 are probably the main isoforms involved in methadone metabolism. Rifampicin (rifampin), phenobarbital, phenytoin, carbamazepine, nevirapine, and efavirenz decrease methadone blood concentrations, probably by induction of CYP3A4 activity, which can result in severe withdrawal symptoms. Inhibitors of CYP3A4, such as fluconazole, and of CYP2D6, such as paroxetine, increase methadone blood concentrations. There is an up to 17-fold interindividual variation of methadone blood concentration for a given dosage, and interindividual variability of CYP enzymes accounts for a large part of this variation. Since methadone probably also displays large interindividual variability in its pharmacodynamics, methadone treatment must be individually adapted to each patient. Because of the high morbidity and mortality associated with opioid dependence, it is of major importance that methadone is used at an effective dosage in maintenance treatment: at least 60 mg/day, but typically 80-100 mg/day. Recent studies also show that a subset of patients might benefit from methadone dosages larger than 100 mg/day, many of them because of high clearance. In clinical management, medical evaluation of objective signs and subjective symptoms is sufficient for dosage titration in most patients. However, therapeutic drug monitoring can be useful in particular situations. In the case of non-response trough plasma concentrations of 400 microg/L for (R,S)-methadone or 250 microg/L for (R)-methadone might be used as target values.

Brief Reports

The effect of ritonavir 400 mg/saquinavir 400 mg twice daily on the stereoselective pharmacokinetics of methadone was examined in 12 HIV-infected, methadone-using study subjects. Design: A 24-hour methadone pharmacokinetic study was performed before antiretroviral therapy was begun and after 15 days of therapy. Methadone concentration was measured by a chiral plasma assay because the drug is administered as a racemic mixture of R- and S-methadone, but only the R-isomer is active. Both changes in plasma protein binding and changes in objective and subjective opioid effect were monitored. Results: Ritonavir/saquinavir administration was associated with 40% decrease in total S-methadone AUC0-24hr and 32% decrease in R-methadone area under the curve (AUC)0-24hr, and both changes were statistically significant (p = .001 for both). When AUC was corrected for the changes in protein binding induced by ritonavir/saquinavir, R-methadone free AUC0-24hr decreased 19.6% whereas the S-methadone decreased 24.6%, neither of these changes was statistically significant (p = .129 and p = .0537, respectively). This change in methadone exposure was not associated with any evidence of withdrawal from narcotics and no modification of methadone dose was required. Conclusions: Our data indicate that ritonavir/saquinavir administration is associated with induction of metabolism of methadone but this is greater for the inactive S-methadone. However, approximately 37% of the decrease in the total R-methadone exposure can be explained by protein binding displacement. Ritonavir/saquinavir can be used in HIV-infected people taking methadone without routine dose adjustments.