Effects of HCV seropositive status on buprenorphine pharmacokinetics in opioid-dependent individuals.

BACKGROUND AND OBJECTIVES: The purpose of this study was to examine the effect of hepatitis C virus (HCV) infection on buprenorphine pharmacokinetics in opioid-dependent, buprenorphine/naloxone-maintained adults. METHODS: A retrospective analysis of buprenorphine pharmacokinetics in HCV seropositive and seronegative buprenorphine/naloxone-maintained individuals (N = 49) was undertaken. RESULTS: Relative to HCV seronegative subjects, HCV seropositive subjects had higher buprenorphine exposure, as demonstrated by elevated buprenorphine AUC and Cmax values (p = .03 and .02, respectively) and corresponding elevations in the metabolites, buprenorphine-3-glucuronide AUC values (p = .03) and norbuprenorphine-3-glucuronide AUC and C24 values (p = .05 and .03, respectively). DISCUSSION AND CONCLUSIONS: HCV infection was associated with higher plasma concentrations of buprenorphine and buprenorphine metabolites. SCIENTIFIC SIGNIFICANCE AND FUTURE DIRECTIONS: Findings suggest the potential for opioid toxicity among HCV-infected patients treated with buprenorphine/naloxone, and possible hepatotoxic effects related to increased buprenorphine exposure. HCV-infected patients receiving buprenorphine may need lower doses to maintain therapeutic plasma concentrations.

Interactions between buprenorphine and the protease inhibitors darunavir-ritonavir and fosamprenavir-ritonavir.

BACKGROUND: This study examined drug interactions between buprenorphine, a partial opioid agonist used for opioid dependence treatment and pain management, and the protease inhibitors (PIs) darunavir-ritonavir and fosamprenavir-ritonavir. METHODS: The pharmacokinetics of buprenorphine and its metabolites and symptoms of opioid withdrawal or excess were compared in opioid-dependent, buprenorphine-naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (11 for darunavir-ritonavir and 10 for fosamprenavir-ritonavir) before and after 15 days of PI administration. PI pharmacokinetics and adverse effects were compared between the buprenorphine-maintained participants and an equal number of sex-, age-, race-, and weight-matched, healthy, non-opioid-dependent volunteers who received darunavir-ritonavir or fosamprenavir-ritonavir but not buprenorphine. RESULTS: There were no significant changes in buprenorphine or PI plasma levels and no significant changes in medication adverse effects or opioid withdrawal. Increased concentrations of the inactive metabolite buprenorphine-3-glucuronide suggested that darunavir-ritonavir and fosamprenavir-ritonavir induced glucuronidation of buprenorphine. CONCLUSIONS: Dose adjustments are not likely to be necessary when buprenorphine and darunavir-ritonavir or fosamprenavir-ritonavir are coadministered for the treatment of opioid dependence and HIV disease.

Effect of cocaine use on methadone pharmacokinetics in humans.

Chronic cocaine use has been shown to significantly decrease buprenorphine concentrations in the blood with potential for adverse events and poor treatment response. In this study, we investigated whether a similar drug interaction occurred between cocaine and methadone. In a retrospective analysis, methadone pharmacokinetics were compared for those who were either regular cocaine users (N = 16) or with intermittent or no cocaine use (N = 23). Participants who used cocaine regularly showed a significant decrease in C(min) (p = .04) and a trend for decreased AUC (p = .09) and more rapid methadone clearance (p = .08). Regular cocaine use may adversely impact treatment outcomes for opioid dependence in those receiving methadone maintenance by decreasing methadone exposure.

Effect of cocaine use on buprenorphine pharmacokinetics in humans.

The effect of chronic cocaine use on buprenorphine pharmacokinetics was investigated to identify drug interactions and potential toxicities. In a retrospective analysis, pharmacokinetics were compared for 16 studies completed on subjects who were regular cocaine users and 74 studies on subjects who used cocaine only occasionally or not at all. All participants were stably maintained on buprenorphine/naloxone 16/4 mg daily. Participants who used cocaine regularly had lower buprenorphine exposure (AUC 34% lower; C(max) 27% lower and C(24) 37% lower; p

Interactions between buprenorphine and antiretrovirals: nucleos(t)ide reverse transcriptase inhibitors (NRTI) didanosine, lamivudine, and tenofovir.

To improve outcomes among injection drug users with HIV and/or chronic hepatitis B, it is important to identify drug interactions between antiretroviral and opiate therapies. We report the results of a study designed to examine the interaction between buprenorphine and the nucleos(t)ide reverse transcriptase inhibitors (NRTI) didanosine (ddI), lamivudine (3TC), and tenofovir (TDF). Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n = 27) participated in two 24-hour sessions to determine (1) pharmacokinetics of buprenorphine alone and (2) pharmacokinetics of both buprenorphine and either ddI, 3TC, or TDF. Among buprenorphine/naloxone-maintained study participants, no significant changes in buprenorphine pharmacokinetics were observed following ddI, 3TC, or TDF administration. Buprenorphine had no significant effect on NRTI concentrations. Concomitant use of buprenorphine with ddI, 3TC, or TDF results in neither a significant pharmacokinetic nor pharmacodynamic interaction.

Lack of clinically significant drug interactions between nevirapine and buprenorphine.

This study was conducted to determine whether drug interactions of clinical importance occur between buprenorphine, an opioid partial agonist medication used in treatment of opioid dependence, and the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n = 7) participated in 24-hour sessions to determine the pharmacokinetics of buprenorphine alone and of buprenorphine and nevirapine following administration of 200 mg nevirapine daily for 15 days. Opiate withdrawal symptoms, cognitive effects, and adverse events were determined prior to and following nevirapine administration. Modest decreases were observed for AUC for buprenorphine and its metabolites. There was a trend for more rapid clearance of both buprenorphine (p = .08) and buprenorphine-3-glucuronide (p = .08). While no single effect reached statistical significance, the joint probability that the consistent declines in all measures of exposure were due to chance was extremely low, indicating that nevirapine significantly reduces overall exposure to buprenorphine and buprenorphine metabolites. Clinically significant consequences of the interaction were not observed. Buprenorphine did not alter nevirapine pharmacokinetics. Dose adjustments of either buprenorphine or nevirapine are not likely to be necessary when these drugs are coadministered for the treatment of opiate dependence and HIV disease.

Reducing routine ionized calcium measurement.

BACKGROUND: Ionized calcium (iCa) is measured frequently in hospitalized patients, and hypocalcemia is frequently found, seemingly supporting the practice. METHODS: We retrieved the results of 58 040 iCa tests and records of intravenous (IV) and oral calcium supplementation from laboratory and hospital information systems and evaluated them for frequency of testing, frequency of hypocalcemia, and effects of calcium supplementation. RESULTS: Serial and daily iCa testing was common and responsible for a substantial fraction of all iCa tests ordered. Half of all patients tested had iCa values below the reference interval. IV, but not oral, calcium therapy increased mean iCa concentrations, but the effect of calcium administration was small compared with the spontaneous increase in iCa that occurred in similar patients who received no calcium treatment. A retrospective analysis suggested that a low total calcium (tCa) concentration (<2.00 mmol/L, <8 mg/dL) could identify most patients with low iCa (<1.0 mmol/L). Introduction of a reflexive strategy reduced iCa testing by 72%-76% and reduced IV calcium gluconate therapy by 45%-81%. CONCLUSIONS: Testing for iCa and IV calcium supplementation were significantly reduced with a reflexive calcium testing strategy that provided iCa testing only to patients with low tCa. Adverse clinical outcomes possibly associated with hypocalcemia did not increase.

Isopropanol protein precipitation for the analysis of plasma free metanephrines by liquid chromatography-tandem mass spectrometry.

BACKGROUND: High-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS)1 analysis of plasma free metanephrines is the most diagnostically sensitive and specific screening test for the diagnosis of pheochromocytoma. We sought to develop an in-house method for this expensive test METHODS: We used off-line isopropanol protein precipitation of plasma to remove interfering substances before LC-MS/MS analysis. We compared the extraction efficiency and limits of quantification of protein precipitation to those of previously reported solid-phase techniques. RESULTS: The new method had limits of quantification of 0.09 nmol/L and 0.17 nmol/L for metanephrine and normetanephrine, respectively. Method comparison with a previously described solid-phase extraction method revealed Deming regression slopes of 0.904 and 0.994, intercepts of 0.007 and 0.023, and SEs of the residuals (S(y/x)) of 0.071 and 0.284 for metanephrine and normetanephrine, respectively. Extraction efficiency of isopropanol protein precipitation was 66% for metanephrine and 35% for normetanephrine, results that were superior to the efficiencies of 4% and 1% for our adapted solid-phase extraction method. No ion suppression was observed at the retention times for metanephrine and normetanephrine. CONCLUSIONS: Isopropanol protein precipitation is a novel and effective off-line sample preparation method for metanephrines that offers a less expensive alternative to on-line solid-phase extraction for low-volume testing and requires a sample volume of only 200 microL. The mass spectrometric analysis time is equivalent to that of solid-phase techniques.

Interaction between buprenorphine and atazanavir or atazanavir/ritonavir.

Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n=10 per protease inhibitor) participated in two 24-h sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400mg daily) or atazanavir/ritonavir (300/100mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and mini-mental state examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p<0.001, p<0.001), norbuprenorphine (p=0.026, p=0.006), buprenorphine glucuronide (p=0.002, p<0.001), and norbuprenorphine glucuronide (NS, p=0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.

Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine.

This study examined drug interactions between buprenorphine, an opioid partial agonist medication used in the treatment of opioid dependence, and the nonnucleoside reverse-transcriptase inhibitors (NNRTIs) efavirenz (EFV) and delavirdine (DLV). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per NNRTI) participated in 24-h sessions to determine pharmacokinetics of buprenorphine and of buprenorphine with either EFV or DLV after administration of standard doses of either antiretroviral for 15 or 7 days, respectively. Opiate withdrawal symptoms, cognitive effects, and adverse events were determined before and after antiretroviral administration in opioid-dependent participants. The pharmacokinetics of NNRTIs in healthy control participants were used to determine the effect of buprenorphine on NNRTIs. EFV decreased the buprenorphine area under the concentration-time curve (P<.001). DLV increased buprenorphine concentrations (P<.001). Clinically significant consequences of these interactions were not observed. Buprenorphine did not alter antiretroviral pharmacokinetics. Adjustments of doses of either buprenorphine or EFV or DLV are not likely to be necessary when these drugs are administered for the treatment of opiate dependence and HIV disease.

Interactions between buprenorphine and antiretrovirals. II. The protease inhibitors nelfinavir, lopinavir/ritonavir, and ritonavir.

We examined drug interactions between buprenorphine, an opioid partial agonist available by prescription for treatment of opioid dependence, and the protease inhibitors (PIs) nelfinavir (NFV), ritonavir (RTV), and lopinavir/ritonavir (LPV/R). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per PI) participated in 24-h pharmacokinetic studies, before and after administration of each PI. Symptoms of opiate withdrawal and excess were determined before and after PI administration. PI pharmacokinetics were determined and compared between opiate-dependent participants and healthy control participants (n=15 per PI). Administration of RTV, but not of NFV or LPV/R, resulted in a significant increase in the buprenorphine area under the concentration-time curve (AUC). Symptoms of opiate excess, however, were not observed. Buprenorphine had no significant effects on PI AUC. Adjustments of doses of either buprenorphine or NFV, LPV/R, or RTV are not likely to be necessary when these drugs are administered for the treatment of opioid dependence and HIV disease.

Specific detection of anabasine, nicotine, and nicotine metabolites in urine by liquid chromatography-tandem mass spectrometry.

The sensitive and specific detection of nicotine, its metabolites, and the tobacco alkaloid, anabasine, is useful in evaluating the success of smoking cessation treatments and detecting tobacco use, passive exposure, and nontobacco nicotine exposure in potential transplant recipients, insurance clients, and elective surgical patients. Rapid sample preparation and extended high-performance liquid chromatographic separation of tobacco alkaloids and metabolites was interfaced with tandem mass spectrometry. By using deuterated internal standards and appropriate confirmatory ion mass transitions, direct injection of centrifugally clarified urine was possible. The method had excellent precision, limit of quantitation, and linearity. The rigorous separation method revealed an interferent of nicotine that had coeluted with anabasine in more rapid chromatography and that may result in tobacco use misclassification. The method provides more specific detection of tobacco exposure and illustrates the potential of centrifugal clarification for sample preparation in the detection of multiple analytes in urine.

The clinical pharmacokinetics of rifampin and ethambutol in HIV-infected persons with tuberculosis.

BACKGROUND: The pharmacokinetics of rifampin and ethambutol in HIV-infected patients with tuberculosis (TB) are incompletely characterized. We examined the pharmacokinetics of rifampin and ethambutol in a cohort of patients with HIV-related TB who were treated in the United States. METHODS: Serum drug concentrations were determined 2, 6, and 10 h after dosing in 36 HIV-infected patients with TB who were taking rifampin and in 49 who were taking ethambutol. Observed serum concentrations were compared with published normal ranges and published data. RESULTS: With daily dosing of rifampin (600 mg), 26 (77%) of 34 patients (95% confidence interval [CI], 59%-89%]) had a low maximum concentration of rifampin (<8 microg/mL), and 12 (35%; 95% CI, 20%-54%) had a very low maximum concentration (<4 microg/mL). With intermittent rifampin dosing (600 mg), 13 (68%) of 19 patients (95% CI, 44%-85%) had a low maximum concentration of rifampin, and 5 (26%; 95% CI, 11%-50%) had a very low maximum concentration. With daily ethambutol dosing (20 mg/kg), 33 (69%) of 48 patients (95% CI, 55%-81%) had a low maximum concentration of ethambutol (<2 microg/mL), and 18 (38%; 95% CI, 24%-53%) had a very low maximum concentration (<1 microg/mL). With intermittent ethambutol dosing (50 mg/kg twice weekly or 30 mg/kg thrice weekly), 13 (72%) of 18 patients (95% CI, 47%-88%) had a low maximum concentration of ethambutol (<4 microg/mL), and 5 (28%; 95% CI, 12%-54%]) had a very low maximum concentration (<2 microg/mL). CONCLUSIONS: In HIV-infected patients with TB who are receiving rifampin and ethambutol, low maximum concentrations of rifampin and ethambutol were common. For patients with HIV-related TB, therapeutic monitoring of rifampin and ethambutol levels may help clinicians achieve target serum concentrations.

The protease inhibitor lopinavir-ritonavir may produce opiate withdrawal in methadone-maintained patients.

This study examines the pharmacokinetic/pharmacodynamic interactions between (1) lopinavir-ritonavir (L/R), a fixed combination of protease inhibitors used for the treatment of HIV disease, and (2) ritonavir alone at the same dosage as that in the L/R formulation, with methadone, an opiate frequently used in substance abuse pharmacotherapy for opioid (heroin)-dependent injection drug users, many of whom are infected with HIV. L/R was associated with significant reductions in the methadone area under the concentration-time curve (P<.001), maximum concentration (P<.001), and minimum concentration (P<.001), as well as increased methadone oral clearance (P<.001) and increased opiate withdrawal symptoms (P=.013), whereas ritonavir use alone modestly and nonsignificantly increased methadone concentrations. Lopinavir is a potent inducer of methadone metabolism, and treatment with L/R requires clinical monitoring and increased methadone doses in some patients, whereas ritonavir has no significant effect on methadone metabolism.

The clinical pharmacokinetics of pyrazinamide in HIV-infected persons with tuberculosis.

The pharmacokinetics of pyrazinamide (PZA) in patients with human immunodeficiency virus (HIV)-related tuberculosis are incompletely characterized. Serum PZA concentrations were determined at 2, 6, and 10 h after dosing in 48 subjects with HIV-related tuberculosis. Estimates of drug exposure using 2-h concentrations and 2- and 3-time point estimates of area under time-concentration curves (AUCs) were compared. For daily dosing, 2-h concentrations less than low and very low literature-defined cut points (i.e., 20 and 10 mg/L) were noted for 2 subjects (4%) and 1 subject (2%), respectively. For intermittent PZA dosing, 1 subject (4%) had a 2-h concentration that was less than the low cut point (25 mg/L). Correlations between 2-h concentration and AUC estimates based on 2- or 3-time point concentration determinations were strong. In HIV-infected persons receiving antituberculosis regimens containing PZA, lower-than-expected 2-h concentrations are uncommon. For therapeutic monitoring of PZA drug exposure, determination of a 2-h postdose concentration appears as reliable as 2- or 3-time point estimates of the AUC for PZA.