Authors

Paolo B. DePetrillo, MD Department of Medicine Brown University School of Medicine Roger Williams Medical Center 825 Chalkstone Avenue Providence, RI 02908-2856 USA

Paul D. Camara, MS Department of Pathology Brown University School of Medicine Roger Williams Medical Center 825 Chalkstone Avenue Providence, RI 02908-2856 USA

Renius Owen Department of Pharmacology Georgetown University Medical Center 3900 Reservoir Road NW Washington DC 20007 USA

David A. Flockhart, MD, PhD Division of Clinical Pharmacology Georgetown University Medical Center Departments of Pharmacology and Medicine 3900 Reservoir Road NW Washington DC, 20007 USA

Case Report of a Ketoconazole-Methadone Drug Interaction

We report on the case of a 39 year-old white male admitted to the Substance Abuse Treatment Center located in a university-affiliated community hospital who was found to have a rapid rate of methadone metabolism. Treatment with ketoconazole significantly decreased methadone clearance.

The patient had a history of alcohol dependence, and was referred from a methadone maintenance treatment program, where he had been involved in methadone treatment for 1 year. He was receiving 85 mg methadone daily, but had not been able to stop heroin use, usually using towards the evening or early morning hours. Two weeks prior to admission, he dropped out of the program and began to drink 1 quart of vodka daily, while using 15-20 bags of heroin per day intravenously.

Past medical history was significant for Hepatitis C. Habits included 1 pack per day of cigarettes. He denied any cocaine or benzodiazepine abuse.

On physical examination, weight was 95 kg., and he showed evidence of recent IV use in both left and right antecubital areas. He had no stigmata of chronic liver disease. Urine toxicology for cocaine, benzodiazepines, tetrahydrocannabinol, methadone was negative. The patient was detoxified from alcohol with chlordiazepoxide according to a standard protocol, and was titrated back to 85 mg/day methadone within three days after admission. At that time, the patient was found to have significant opiate withdrawal symptoms occurring within 4-6 hours after dosing, consisting of of mydriasis, diaphoresis, piloerection, and abdominal cramps.

Over the next two weeks, symptoms were treated with additional methadone doses, so that by the day 14 after admission, the patient was receiving 400 mg methadone at 7:00 AM every morning, while still experiencing significant objective symptoms of opiate withdrawal symptoms 10 - 12 hours after dosing. A clinical pharmacology consult was requested to investigate possible causes of this patient's unresponsiveness to high doses of methadone.

The patient was detoxified from methadone over the next two weeks, as it was not possible to provide him with two doses of methadone per day at the dosage he required. This is due to laws regulating methadone use where the patient resides.

One week after detoxification, the patient exhibited escalating amounts of drug seeking behavior, and complained of severe craving for heroin, though no objective symptoms of withdrawal were present on exam. We tried to obtain L-acetyl-methadone, a long acting methadone congener for this patient, but again we were unable to do so because though it has been approved for use in maintenance programs by the United States Food and Drug Administration, many states, including the state where the patient resides have not yet written the appropriate regulations for use of the drug. The patient was restarted on methadone by the attending physician at a dose of 60 mg / day, which was quickly increased to 100 mg / day. The patient began to complain of severe withdrawal symptoms 8-10 hours after the dose, which were corroborated by objective signs of mydriasis, piloerection, and diaphoresis.

Ketoconazole is a potent inhibitor of cytochrome P450 series 3A3,4,5,6,7.(1) Drugs which increase the clearance of methadone such as rifampin, phenytoin, carbamazepine and phenobarbital are known to increase the activity of this same series. We reasoned that ketoconazole might thus inhibit metabolism of methadone. In consultation with the patient, we decided examine the effect of ketoconazole on methadone clearance. If a strong effect was found, then the patient might benefit from concurrent use of methadone and ketoconazole. A second kinetic study was performed after the patient had been receiving ketoconazole 200 mg orally every morning.

The dose history for the patient is shown in Table 1.

Table Dose History and Methadone Levels

Methods

A vein in the left arm was cannulated and a heparin lock placed to facilitate multiple blood draws. Methadone hydrochloride 600 mg for the first study and 100 mg for the second study was dissolved in 250 ml of 5% dextrose and 0.9% saline and infused into a vein in the right arm at a rate of 125 cc / hour by automatic pump. The pump was terminated after exactly 120 minutes, and any residual liquid extracted and measured to accurately quantitate the actual amount of methadone infused. Blood (10 ml) was sampled at the times outlined in Table 1, which also shows the oral doses of methadone that the patient received prior to the infusion. The patient had been receiving methadone since Day 3 of hospitalization. However, only doses received on or after Day 14 were used in the analysis.

Methadone levels were determined by gas chromatography. (2) Kinetic parameters were derived using a simple one-compartment pharmacokinetic model as follows: C(t) = (D/Vd)e-kt where k=Cl/Vd, C(t) is methadone level at time t in a particular subject, D (mg) is the dose of methadone, Vd (L) is the volume of distribution of methadone for the patient, t (hours) is the interval between the last methadone dose and the sample time, and Cl is the oral clearance of methadone in L/hr. We used NONMEM 77 Version IV Level 2.0 to analyze our data. (3, 4) NONMEM, "Nonlinear Mixed Effects Model" is used to analyze individual and population data with regression-type statistical models containing both fixed (e.g., drug concentration data) and random effects (unexplainable inter- and intra-subject variation). Given the sparse data available from this individual, this approach allowed us to estimate kinetic parameter for methadone in this patient. The program was compiled on an IBM 9121-440 mainframe in double-precision format with the IBM VS Fortran VS 2 compiler with optimization.

We assumed that all of the oral drug was absorbed, and that the absorption constant Ka << K so that oral doses were modeled to be absorbed instantaneously. Genotyping for CYP2C19 and CYP2D6 was performed using PCR amplification with specific primers in Dr. Flockhart's laboratory.

Results

The patient's clearance (Cl, L/hr ± SEM) was estimated at 17.6 ± 0.7 and 10.8 ± 0.5 before and after ketoconazole dosing. The volume of distribution (Vd, L ± SEM) was estimated to be 427 ± 39 (L ± SEM). Ketoconazole did not appear to change volume of distribution. The elimination rate constant and terminal half-life were calculated to be 0.41 hr-1 and 16.8 hours before ketoconazole, and 0.25 hr-1 and 27.4 hours after ketoconazole. The patient was homozygous for the M1 allele of CYP2C19 and wild-type for CYP2D6.

Discussion

This patient had a rapid clearance of methadone which was significantly decreased by acute ketoconazole dosing at a dose rate of 200 mg every 24 hours. The observed clearance before ketoconazole, 17.6 L/hr, is much higher than reported in the literature while Vd is at the higher range of values previously reported.

The finding that the patient was homozygous for the M1 allele of CYP2C19 suggests that this system is not accounting for rapid metabolism, unless rapid metabolism for methadone segregates out with this genotype. The wild-type CYP2D6 suggests that at least in this patient CYP2D6 alleles A,B and D are not involved in rapid metabolism of methadone.

Figure 1 The open circles denote measured concentration-time values. The filled circles denote concentration-time values derived from the kinetic parameters. The time values on the two X-axes, shown as I and II, indicate time points measured from the first dose of methadone, as outlined in Table 1. The time intervals are the same for the upper and lower axes.

Although there is a possibility that clearance of methadone may increase with much higher doses of the drug, previous work suggests that AUC is proportional to dose, at least in the dose range of 0-200 mg/ day.

We hypothesize that as a result of giving this patient a single daily dose, the patient may have become tolerant to the effects produced by high peak levels of the drug, which are expected to occur 2 - 4 hours after dosing. The patient did not exhibit any sedation after the intravenous infusion of 600 mg methadone, and pupils remained > 6 mm and reactive, consistent with an opiate tolerant state. Subsequently, a rapid decline in drug level due to accelerated metabolism, and subsequent emergence of opiate withdrawal symptoms might be expected. Supporting this contention is the finding that at a blood level of 1.297 mg/L, which was obtained on Day 17 at 21:41, 14 hours after dosing with 600 mg methadone, the patient exhibited mild symptoms of withdrawal consisting of mydriasis, piloerection, diaphoresis, anxiety, and insomnia. Further support comes from the observation that this patient, who was subsequently discharged on a daily dose of 150 mg methadone / day along with 200 mg ketoconazole / day felt well throughout the dosing period on a much lower dose in the presence of a cytochrome P450 inhibitor. Knowing the kinetic parameters for methadone in this patient, we can predict peak and trough levels of the drug at steady state (5) : peak = 772 mcg/L and trough = 420 mcg / ml. Since the patient reported being comfortable in this concentration range, yet experienced withdrawal with a level of 1.297 mcg / L, before being detoxified from methadone initially, this suggests that tolerance to the effects of opiates may not require consistently elevated blood levels of the drug, but may result from high peak levels. Objective symptoms of withdrawal may thus occur at the end of a dosing period in a rapid metabolizer, especially at higher dose levels.

This patient might have benefited from twice daily dosing of methadone, to avoid a wide fluctuation in peak and trough levels, with the attendant risks of sedation and development of tolerance resulting from high peak levels, followed by sub-therapeutic levels, withdrawal symptoms, and craving for heroin. However, current drug-control laws in the United States discourage take-home doses of methadone, especially at the dose levels this patient may have required. On the basis of these results, the patient was discharged to a methadone maintenance program on methadone 150 mg / day along with ketoconazole 200 mg/day with twice monthly liver function tests to monitor possible hepatotoxicity of ketoconazole When L-acetyl-methadone becomes available, the patient will be offered this alternate treatment for opiate addiction.

We conclude that in this patient, ketoconazole significantly decreased the metabolic clearance of methadone. A further study of this drug-drug interaction is required in this population, since ketoconazole is in widespread use as a systemic anti-fungal agent in HIV positive patients. The prevalence of patients with HIV disease in the methadone maintenance population suggests the potential for a drug-drug interaction, if a patient who was initially stabilized on a particular dose of methadone receives ketoconazole. Such patients should probably be educated to report any increased sedation. Based on this report, the use of ketoconazole in methadone maintained patients who are unstable on higher doses of methadone cannot be generally recommended, due to the potential hepatotoxicity of the drug.

This patient would have been classified as a methadone treatment failure, since heroin use continued in spite of a daily dose of methadone of 85 mg / day. The identification of a patient who is a fast metabolizer of methadone is strongly suggestive, in light of the previous population data, that a certain sub-set of patients currently being treated with methadone may not be dosed appropriately, and might benefit from larger doses and/or increased frequency of dosing.

References

  1. Flockhart David A. Personal Communication.
  2. Greizerstein HB, McLaughlin IG. Sensitive method for the determination of methadone in small blood samples. Journal of Chromatography. 264(2)312-315. 1983.
  3. Beal S, Sheiner L. The NONMEM system. American Statistician. 34:118. 1980.
  4. Beal SL, Sheiner LB. Estimating Population Kinetics. CRC Critical Reviews in Biomedical Engineering. 8:195-222. 1982.
  5. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. Marcel Dekker, Inc. New York. 1982.

Author's note

This manuscript was included in a grant submitted to NIDA on February 1, 1995. Principal Investigator: Paolo B. DePetrillo, MD, Brown University School of Medicine, Providence, RI 02912, USA.

Consultant: David A. Flockhart, MD, PhD; Assistant Professor, Department of Medicine and Pharmacology, Georgetown University, Division of Clinical Pharmacology, 3900 Reservoir Road NW, Washington DC, 20007, USA.