RÉSUMÉ
BACKGROUND: This study aimed to assess the pharmacokinetic profile of 150 mg rifabutin (RBT) taken every other day (every 48 h) versus 300 mg RBT taken every other day (E.O.D), both in combination with lopinavir/ritonavir (LPV/r), in adult patients with human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection. METHODS: This is a two-arm, open-label, pharmacokinetic, randomised study conducted in Burkina Faso between May 2013 and December 2015. Enrolled patients were randomised to receive either 150 mg RBT EOD (arm A, 9 subjects) or 300 mg RBT EOD (arm B, 7 subjects), both associated with LPV/r taken twice daily. RBT plasma concentrations were evaluated after 2 weeks of combined HIV and TB treatment. Samples were collected just before drug ingestion and at 1, 2, 3, 4, 6, 8, and 12 h after drug ingestion to measure plasma drug concentration using an HPLC-MS/MS assay. RESULTS: The Cmax and AUC0-12h medians in arm A (Cmax = 296 ng/mL, IQR: 205-45; AUC0-12h = 2528 ng.h/mL, IQR: 1684-2735) were lower than those in arm B (Cmax = 600 ng/mL, IQR: 403-717; AUC0-12h = 4042.5 ng.h/mL, IQR: 3469-5761), with a statistically significant difference in AUC0-12h (p = 0.044) but not in Cmax (p = 0.313). No significant differences were observed in Tmax (3 h versus 4 h). Five patients had a Cmax below the plasma therapeutic limit (< 300 ng/mL) in the 150 mg RBT arm, while the Cmax was above this threshold for all patients in the 300 mg RBT arm. Additionally, at 48 h after drug ingestion, all patients had a mycobacterial minimum inhibitory concentration (MIC) above the limit (> 64 ng/mL) in the 300 mg RBT arm, while 4/9 patients had such values in the 150 mg RBT arm. CONCLUSION: This study confirmed that the 150 mg dose of rifabutin ingested EOD in combination with LPV/r is inadequate and could lead to selection of rifamycin-resistant mycobacteria. TRIAL REGISTRATION: PACTR201310000629390, 28th October 2013.
Sujet(s)
Infections opportunistes liées au SIDA/traitement médicamenteux , Antibiotiques antituberculeux/administration et posologie , Antibiotiques antituberculeux/usage thérapeutique , Co-infection/traitement médicamenteux , Inhibiteurs de protéase du VIH/usage thérapeutique , Lopinavir/usage thérapeutique , Rifabutine/administration et posologie , Rifabutine/usage thérapeutique , Ritonavir/usage thérapeutique , Tuberculose/traitement médicamenteux , Adulte , Antibiotiques antituberculeux/effets indésirables , Antibiotiques antituberculeux/sang , Burkina , Chromatographie en phase liquide à haute performance , Association de médicaments , Femelle , Études de suivi , Humains , Mâle , Tests de sensibilité microbienne , Projets pilotes , Répartition aléatoire , Rifabutine/effets indésirables , Rifabutine/sang , Spectrométrie de masse en tandemRÉSUMÉ
With the increased cases of multidrug- or rifampicin-resistant tuberculosis and co-infection with HIV globally, it is difficult to achieve ideal clinical responses because of poor drug absorption and drug-drug interactions. Herein, a bioanalytical UPLC-MS/MS method was developed and validated to quantify five anti-TB agents in human plasma samples for detecting blood drug concentrations to improve therapeutic effects. To overcome the matrix effects, stable isotope labeled analogue of each analyte was used for internal standardization. A simple single-step protein precipitation by acetonitrile was employed for the sample preparation, then the analytes including rifampicin, rifabutin, pyrazinamid, ethambutol, isoniazid and their isotope labeled internal standards (ILISs) were implemented on an HILIC silica column with a gradient mode. The linear range for each analyte was covering the peak drug concentration (Cmax) in the 20 times diluted plasma samples. The coefficient of variation of intra- and inter-day precision was less than 17.0 %, and the accuracy ranged between 91.5 and 110.0 %. The extraction recoveries of all agents were ≥90.2 %, and the matrix effects with internal standard-normalization for all agents were 97.1-110.0 %. The optimal blood sampling time was designed basing on the results of stability validation. This UPLC-MS/MS method with a run time of 3.5â¯min was successfully applied to routine therapeutic monitoring of the five anti-TB agents in patient plasma.
Sujet(s)
Antituberculeux/sang , Surveillance des médicaments/méthodes , Éthambutol/sang , Isoniazide/sang , Pyrazinamide/sang , Rifabutine/sang , Rifampicine/sang , Infections opportunistes liées au SIDA/sang , Calibrage , Chromatographie en phase liquide à haute performance/méthodes , Surveillance des médicaments/instrumentation , Humains , Normes de référence , Reproductibilité des résultats , Sensibilité et spécificité , Spectrométrie de masse en tandem/méthodes , Tuberculose/sangRÉSUMÉ
This article describes the simultaneous determination of bedaquiline fumarate (TMC-207) and rifabutin in human plasma by stable isotope dilution tandem mass spectrometry. The methodology was developed for an investigation of potential drug-drug interactions of the two anti-tuberculosis drugs when given together to healthy human volunteers. Use of the two drugs in combination to treat disease caused by Mycobacterium tuberculosis is contemplated as the bacterium becomes resistant to many currently available drugs.
Sujet(s)
Antituberculeux/sang , Diarylquinoléines/sang , Surveillance des médicaments/méthodes , Rifabutine/sang , Antituberculeux/administration et posologie , Antituberculeux/pharmacocinétique , Chromatographie en phase liquide à haute performance/méthodes , Diarylquinoléines/administration et posologie , Diarylquinoléines/pharmacocinétique , Interactions médicamenteuses , Association de médicaments , Humains , Rifabutine/administration et posologie , Rifabutine/pharmacocinétique , Spectrométrie de masse en tandem/méthodes , Tuberculose/traitement médicamenteuxRÉSUMÉ
BACKGROUND: Rifabutin (RFN) is bactericidal antibiotic with a very broad spectrum of activity against gram positive & gram negative organisms including Pseudomonas aeruginosa and specifically Mycobacterium tuberculosis. RFN inhibits DNA dependent RNA polymerase activity in susceptible cells. In the instant work, the therapeutic characteristics of RFN were intended for diagnostic rationale by labeling it with 99mTc (Technetium-99m). OBJECTIVE: The 99mTc labeled RFN (99mTc-RFN) was investigated for labeling capacity, steadiness in saline & serum, in vitro Mycobacterium tuberculosis (MBT) uptake & distribution in MBT stained animal model rats. METHOD: It was found that 99mTc-RFN prepared by mixing 2 mg of RFN, 2.5 mCi sodium pertechnetate, 150 µg stannous chloride at pH 5.4 gave highest yield after 30 minutes and was intact above 90 % after 240 min at room temperature in saline. RESULT: The 99mTc-RFN showed a stable profile in serum at 37 °C and impurities appeared up 16 h was 15.20 %. The maximum in vitro MBT uptake observed in live strain was 71.75 ± 0.75 %. The premier uptake observed in the MBT infected site (target site) was 14.15 ± 0.00 %, in animal model rat. CONCLUSION: Higher labeling capacity, steadiness in saline & serum, higher MBT uptake, maximum uptake in the MBT infected sites and precise imaging posed 99mTc- RFN as an alternate radio-drug for tuberculosis scintigraphy.
Sujet(s)
Radiopharmaceutiques , Rifabutine , Technétium , Tuberculose/imagerie diagnostique , Animaux , Humains , Mâle , Mycobacterium tuberculosis/effets des médicaments et des substances chimiques , Mycobacterium tuberculosis/métabolisme , Scintigraphie , Rats , Rifabutine/sang , Rifabutine/composition chimique , Rifabutine/pharmacocinétique , Technétium/sang , Technétium/composition chimique , Technétium/pharmacocinétique , Distribution tissulaireRÉSUMÉ
Tuberculosis (TB) with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome represents the most common infectious diseases worldwide. Anti-TB drugs are used concurrently with antiretroviral drug for treatment of TB-HIV co-morbidities. Due to lower risk of interaction with protease inhibitors, rifabutin is preferred over rifampicin in treatment of HIV and TB co-morbidity. A simple and specific liquid chromatography tandem mass spectrometry method was developed for quantification of rifabutin (RBT) and lopinavir (LPV) simultaneously in human plasma. Following extraction using 60% n-hexane in ethyl acetate, the processed samples were chromatographed on a Discovery HS C18 column (5 µm, 50 × 4.6 mm, id) using mobile phase [85% acetonitrile in ammonium acetate buffer (10 mM, pH 4.5)] at a flow rate of 0.7 mL/min. Mass spectrometric detection was performed in positive electrospray ionization mode using multiple reaction monitoring (RBT, m/z 847.7 â 815.4; LPV, m/z 629.6 â 447.4). Raloxifene and phenacetin were used as internal standards for RBT and LPV, respectively. Linearity was established in the range of 1-1,000 ng/mL and 0.5-10 µg/mL (R2 ≥ 0.99) for RBT and LPV, respectively. The recovery of LPV and RBT were always >90 and >50%, respectively. The precisions and accuracies were well within the acceptable limits of variation.
Sujet(s)
Chromatographie en phase liquide/méthodes , Lopinavir/sang , Rifabutine/sang , Spectrométrie de masse en tandem/méthodes , Stabilité de médicament , Humains , Modèles linéaires , Lopinavir/composition chimique , Lopinavir/pharmacocinétique , Reproductibilité des résultats , Rifabutine/composition chimique , Rifabutine/pharmacocinétique , Sensibilité et spécificitéRÉSUMÉ
Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.).
Sujet(s)
Antituberculeux/pharmacocinétique , Transporteurs d'anions organiques/génétique , Polymorphisme de nucléotide simple , Rifabutine/pharmacocinétique , Tuberculose pulmonaire/traitement médicamenteux , Adulte , Antituberculeux/administration et posologie , Antituberculeux/sang , Aire sous la courbe , Numération des lymphocytes CD4 , Co-infection , Éthambutol/administration et posologie , Femelle , Expression des gènes , Infections à VIH/anatomopathologie , Infections à VIH/virologie , Humains , Isoniazide/administration et posologie , Polypeptide C de transport d'anions organiques , Mâle , Méthode de Monte Carlo , Transporteurs d'anions organiques/métabolisme , Pyrazinamide/administration et posologie , Rifabutine/administration et posologie , Rifabutine/sang , Rifampicine/administration et posologie , Facteurs sexuels , Tuberculose pulmonaire/sang , Tuberculose pulmonaire/microbiologie , Tuberculose pulmonaire/anatomopathologieRÉSUMÉ
A novel assay using high pressure liquid chromatography (HPLC) coupled to mass spectrometer (MS) detection was developed and validated for the rifamycin anti-tuberculosis antibiotics rifampicin (RIF), rifabutin (RBT), rifapentine (RPT) and their active desacetyl metabolites (dRIF, dRBT and dRPT, respectively) in human plasma. The assay uses 50 µL of human plasma with a quick and simple protein-precipitation extraction to achieve a dynamic range of 75-30,000 ng/mL for RIF, RBT and RPT and 37.5-15,000 ng/mL for dRIF, dRBT and dRPT, respectively. The average %CV and %deviation were less than 20% at the lower limit of quantitation and less than 15% over the range of the curve. The method was fully validated according to FDA criteria for bioanalytical assays and has successfully been used to support three large international tuberculosis trials.
Sujet(s)
Antibiotiques antituberculeux/sang , Rifabutine/sang , Rifampicine/analogues et dérivés , Rifampicine/sang , Rifamycine/sang , Antibiotiques antituberculeux/pharmacocinétique , Précipitation chimique , Chromatographie en phase liquide/méthodes , Humains , Reproductibilité des résultats , Rifabutine/pharmacocinétique , Rifampicine/pharmacocinétique , Rifamycine/pharmacocinétique , Spectrométrie de masse en tandem/méthodesRÉSUMÉ
BACKGROUND: Pharmacokinetic interactions between rifampicin and protease inhibitors (PIs) complicate the management of HIV-associated tuberculosis. Rifabutin is an alternative rifamycin, for patients requiring PIs. Recently some international guidelines have recommended a higher dose of rifabutin (150 mg daily) in combination with boosted lopinavir (LPV/r), than the previous dose of rifabutin (150 mg three times weekly {tiw}). But there are limited pharmacokinetic data evaluating the higher dose of rifabutin in combination with LPV/r. Sub-optimal dosing can lead to acquired rifamycin resistance (ARR). The plasma concentration of 25-O-desacetylrifabutin (d-RBT), the metabolite of rifabutin, increases in the presence of PIs and may lead to toxicity. METHODS AND RESULTS: Sixteen patients with TB-HIV co-infection received rifabutin 300 mg QD in combination with tuberculosis chemotherapy (initially pyrazinamide, isoniazid and ethambutol then only isoniazid), and were then randomized to receive isoniazid and LPV/r based ART with rifabutin 150 mg tiw or rifabutin 150 mg daily. The rifabutin dose with ART was switched after 1 month. Serial rifabutin and d-RBT concentrations were measured after 4 weeks of each treatment. The median AUC0-48 and Cmax of rifabutin in patients taking 150 mg rifabutin tiw was significantly reduced compared to the other treatment arms. Geometric mean ratio (90% CI) for AUC0-48 and Cmax was 0.6 (0.5-0.7) and 0.5 (0.4-0.6) for RBT 150 mg tiw compared with RBT 300 mg and 0.4 (0.4-0.4) and 0.5 (0.5-0.6) for RBT 150 mg tiw compared with 150 mg daily. 86% of patients on the tiw rifabutin arm had an AUC0-24 < 4.5 µg.h/mL, which has previously been associated with acquired rifamycin resistance (ARR). Plasma d-RBT concentrations increased 5-fold with tiw rifabutin dosing and 15-fold with daily doses of rifabutin. Rifabutin was well tolerated at all doses and there were no grade 4 laboratory toxicities. One case of uveitis (grade 4), occurred in a patient taking rifabutin 300 mg daily prior to starting ART, and grade 3 neutropenia (asymptomatic) was reported in 4 patients. These events were not associated with increases in rifabutin or metabolite concentrations. CONCLUSIONS: A daily 150 mg dose of rifabutin in combination with LPV/r safely maintained rifabutin plasma concentrations in line with those shown to prevent ARR. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00640887.
Sujet(s)
Agents antiVIH/usage thérapeutique , Antibiotiques antituberculeux/pharmacocinétique , Lopinavir/usage thérapeutique , Rifabutine/pharmacocinétique , Adulte , Antibiotiques antituberculeux/effets indésirables , Antibiotiques antituberculeux/sang , Antibiotiques antituberculeux/usage thérapeutique , , Co-infection/traitement médicamenteux , Co-infection/métabolisme , Études croisées , Association de médicaments , Femelle , Infections à VIH/traitement médicamenteux , Infections à VIH/métabolisme , Humains , Isoniazide/usage thérapeutique , Lamivudine/usage thérapeutique , Lopinavir/sang , Lopinavir/pharmacocinétique , Mâle , Neutropénie/induit chimiquement , Rifabutine/effets indésirables , Rifabutine/sang , Rifabutine/usage thérapeutique , République d'Afrique du Sud , Stavudine/usage thérapeutique , Tuberculose/traitement médicamenteux , Tuberculose/métabolisme , Uvéite/induit chimiquementRÉSUMÉ
SETTING: Rifabutin (RBT) is reported to be as effective as and to have less inducing effect on cytochrome P450 enzymes than rifampicin against tuberculosis (TB). The optimal dose of RBT during ritonavir (RTV) co-administration remains a matter of debate. OBJECTIVE: To study the pharmacokinetics of 150 mg RBT thrice weekly during concomitant atazanavir/RTV administration in human immunodeficiency virus (HIV) infected TB patients. METHODS: This observational study was conducted in 16 adult HIV-infected TB patients being treated for TB with an RBT-containing regimen and an antiretroviral therapy regimen with RTV; the dose of RBT was 150 mg thrice weekly. Serial blood draws were performed at pre-dosing and at 1, 2, 4, 6, 8, 12 and 24 h after the drug was administered. Plasma RBT was estimated using high-performance liquid chromatography. RESULTS AND CONCLUSIONS: Peak RBT concentration was below the lower therapeutic limit (<0.3 µg/ml) in seven patients, while 10 patients had trough concentrations below the minimal inhibitory concentration against Mycobacterium tuberculosis (0.06 µg/ml), suggesting that the RBT dosage may be inadequate. Prospective studies in different settings are required to arrive at the proper therapeutic dose for RBT to be used during co-administration with RTV.
Sujet(s)
Antibiotiques antituberculeux/pharmacocinétique , Infections à VIH/traitement médicamenteux , Inhibiteurs de protéase du VIH/usage thérapeutique , Oligopeptides/usage thérapeutique , Pyridines/usage thérapeutique , Rifabutine/pharmacocinétique , Ritonavir/usage thérapeutique , Tuberculose/traitement médicamenteux , Adulte , Antibiotiques antituberculeux/administration et posologie , Antibiotiques antituberculeux/sang , Sulfate d'atazanavir , Chromatographie en phase liquide à haute performance , Calendrier d'administration des médicaments , Interactions médicamenteuses , Surveillance des médicaments/méthodes , Association de médicaments , Femelle , Infections à VIH/sang , Infections à VIH/diagnostic , Humains , Inde , Mâle , Tests de sensibilité microbienne , Polypharmacie , Rifabutine/administration et posologie , Rifabutine/sang , Tuberculose/sang , Tuberculose/diagnosticRÉSUMÉ
We describe correlates of reduced antituberculous serum drug concentrations (SDCs) in HIV-infected patients receiving treatment for active tuberculosis (TB). Cross-sectional analysis of individuals diagnosed with HIV and active TB in Northern Alberta, Canada, was performed. Of the 30 HIV-TB cases, 27 underwent measurement of SDCs. Rates of low SDCs were 9 of 26 (34%) for isoniazid (INH) and 16 of 25 (64%) for rifamycins. Increased weight and elevated body mass index (BMI) correlated with low SDCs for rifampin (P < .05) and increased weight also correlated with reduced SDCs for INH (P < .05). This suggests that conventional antituberculous dosing may be too low and consideration should be given to increase the maximum initial weight-based doses in HIV-infected patients.
Sujet(s)
Antituberculeux/sang , Co-infection/sang , Isoniazide/sang , Rifabutine/sang , Rifampicine/sang , Tuberculose/traitement médicamenteux , Adulte , Antituberculeux/pharmacocinétique , Antituberculeux/usage thérapeutique , Indice de masse corporelle , Poids , Co-infection/traitement médicamenteux , Études transversales , Surveillance des médicaments , Femelle , Infections à VIH/complications , Infections à VIH/traitement médicamenteux , Humains , Isoniazide/pharmacocinétique , Isoniazide/usage thérapeutique , Mâle , Adulte d'âge moyen , Études rétrospectives , Rifabutine/pharmacocinétique , Rifabutine/usage thérapeutique , Rifampicine/pharmacocinétique , Rifampicine/usage thérapeutique , Tuberculose/complicationsRÉSUMÉ
BACKGROUND: The protease inhibitors lopinavir and atazanavir are both recommended for treatment of HIV-infected patients. Considerable inter-individual variability in plasma concentration has been observed for both drugs. The aim of this study was to evaluate which demographic factors and concomitant drugs are associated with lopinavir and atazanavir plasma concentration. METHODS: Data from the Liverpool TDM (therapeutic drug monitoring) Registry were linked with the UK Collaborative HIV Cohort (CHIC) study. For each patient, the first measurement of lopinavir (twice daily) or atazanavir [once daily, ritonavir boosted (/r) or unboosted] plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifabutin with log-transformed drug concentration, adjusted for time since last intake. RESULTS: Data from 439 patients on lopinavir (69% 400 mg/r, 31% 533 mg/r; 3% concomitant rifabutin) and 313 on atazanavir (60% 300 mg/r, 32% 400 mg/r, 8% 400 mg) were included. Multivariable models revealed the following predictors for lopinavir concentration: weight (11% decrease per additional 10 kg; P = 0.001); dose (25% increase for 533 mg/r; P = 0.024); and rifabutin (116% increase; P < 0.001). For atazanavir the predictors were dose (compared with 300 mg/r: 40% increase for 400 mg/r, 67% decrease for 400 mg; overall P < 0.001) and efavirenz (32% decrease; P = 0.016) but not tenofovir (P = 0.54). CONCLUSIONS: This analysis confirms that efavirenz decreases atazanavir concentrations, and there was a negative association of weight and lopinavir concentrations. The strong impact of rifabutin on lopinavir concentration should be studied further.
Sujet(s)
Agents antiVIH/sang , Agents antiVIH/pharmacocinétique , Oligopeptides/sang , Oligopeptides/pharmacocinétique , Plasma sanguin/composition chimique , Pyridines/sang , Pyridines/pharmacocinétique , Pyrimidinones/sang , Pyrimidinones/pharmacocinétique , Adulte , Alcynes , Sulfate d'atazanavir , Benzoxazines/sang , Benzoxazines/pharmacocinétique , Poids , Cyclopropanes , Femelle , Infections à VIH/traitement médicamenteux , Humains , Lopinavir , Mâle , Adulte d'âge moyen , Rifabutine/sang , Rifabutine/pharmacocinétique , Royaume-UniRÉSUMÉ
BACKGROUND: Human immunodeficiency virus (HIV)-associated tuberculosis is difficult to treat, given the propensity for drug interactions between the rifamycins and the antiretroviral drugs. We examined the pharmacokinetics of rifabutin before and after the addition of lopinavir-ritonavir. METHODS: We analyzed 10 patients with HIV infection and active tuberculosis in a state tuberculosis hospital. Plasma was collected for measurement of rifabutin, the microbiologically active 25-desacetyl-rifabutin, and lopinavir by validated high-performance liquid chromatography assays. Samples were collected 2-4 weeks after starting rifabutin at 300 mg thrice weekly without lopinavir-ritonavir, 2 weeks after the addition of lopinavir-ritonavir at 400 and 100 mg, respectively, twice daily to rifabutin at 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the normal range) 2 weeks after an increase in rifabutin to 300 mg thrice weekly with lopinavir-ritonavir. Noncompartmental and population pharmacokinetic analyses (2-compartment open model) were performed. RESULTS: Rifabutin at 300 mg without lopinavir-ritonavir produced a low maximum plasma concentration (C(max)) in 5 of 10 patients. After the addition of lopinavir-ritonavir to rifabutin at 150 mg, 9 of 10 had low C(max) values. Eight patients had dose increases to 300 mg of rifabutin with lopinavir-ritonavir. Most free rifabutin (unbound to plasma protein) C(max) values were below the tuberculosis minimal inhibitory concentration. For most patients, values for the area under the plasma concentration-time curve were as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance in Tuberculosis Trials Consortium/US Public Health Service Study 23. One of the 10 patients experienced relapse with acquired rifamycin resistance. CONCLUSION: The recommended rifabutin doses for use with lopinavir-ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.
Sujet(s)
Antibiotiques antituberculeux/pharmacocinétique , Antiviraux/pharmacocinétique , Infections à VIH/complications , Infections à VIH/traitement médicamenteux , Pyrimidinones/pharmacocinétique , Rifabutine/pharmacocinétique , Ritonavir/pharmacocinétique , Tuberculose/complications , Tuberculose/traitement médicamenteux , Adulte , Antibiotiques antituberculeux/sang , Antibiotiques antituberculeux/usage thérapeutique , Antiviraux/sang , Antiviraux/usage thérapeutique , Interactions médicamenteuses , Femelle , Humains , Lopinavir , Mâle , Adulte d'âge moyen , Pyrimidinones/sang , Pyrimidinones/usage thérapeutique , Rifabutine/sang , Rifabutine/usage thérapeutique , Ritonavir/sang , Ritonavir/usage thérapeutiqueRÉSUMÉ
STUDY OBJECTIVE: To determine the feasibility of therapeutic drug monitoring for adjusting low serum antimycobacterial concentrations in patients with both tuberculosis and advanced human immunodeficiency virus (HIV). DESIGN: Retrospective cohort study. DATA SOURCE: De-identified dataset from a tuberculosis clinic. PATIENTS: Twenty-one patients (median age 38 yrs, range 25-68 yrs) with advanced HIV infection (CD4(+) cell count < 100 cells/mm(3)) who received treatment for active tuberculosis between March 2002 and September 2007. MEASUREMENTS AND MAIN RESULTS: We evaluated data based on the practices performed at the tuberculosis clinic. After the daily doses of isoniazid and rifamycins (rifampin or rifabutin) were ingested, serum concentrations were obtained at 2 hours for isoniazid and rifampin, at 3 hours for rifabutin, and, when possible, at 6 hours for all three drugs to detect delayed absorption. Antimycobacterial drug concentrations were compared with published reference levels, and dosages were adjusted to achieve desired concentrations. Costs of monitoring were recorded for all patients. Of the 21 patients, 18 (86%) had low serum concentrations of at least one drug 2 hours after ingestion: 2 (10%) had low isoniazid concentrations, 5 (24%) had low rifamycin concentrations, and 11 (52%) had low serum concentrations of both drugs. The median number of dosage adjustments to attain normal concentrations was 1 (range 0-4 adjustments). The median cost/patient for therapeutic drug monitoring was $619 (range $230-1948). The median final doses to achieve normal concentrations were isoniazid 600 mg/day (range 300-1500 mg/day), rifampin 1050 mg/day (range 600-1200 mg/day), and rifabutin 300 mg (range 150-450 mg) 3 times/week. No patient demonstrated any adverse effects attributed to these higher doses. CONCLUSION: Low serum concentrations of antituberculous drugs, which suggest malabsorption, are common among patients with advanced HIV who also have tuberculosis but can be overcome with higher doses. Therapeutic drug monitoring may be an effective tool to optimize therapy, but needs further study.
Sujet(s)
Antibactériens/sang , Surveillance des médicaments , Infections à VIH/complications , Infections à VIH/traitement médicamenteux , Tuberculose/complications , Tuberculose/traitement médicamenteux , Adulte , Sujet âgé , Antibactériens/administration et posologie , Antirétroviraux/administration et posologie , Études de cohortes , Association de médicaments , Études de faisabilité , Femelle , Humains , Isoniazide/administration et posologie , Isoniazide/sang , Mâle , Adulte d'âge moyen , Études rétrospectives , Rifabutine/administration et posologie , Rifabutine/sang , Rifampicine/administration et posologie , Rifampicine/sangSujet(s)
Antibactériens/effets indésirables , Antifongiques/effets indésirables , Maladies de l'oeil/induit chimiquement , Itraconazole/effets indésirables , Rifabutine/effets indésirables , Sujet âgé , Antifongiques/usage thérapeutique , Endophtalmie/traitement médicamenteux , Humains , Immunocompétence , Itraconazole/usage thérapeutique , Mâle , Broncho-pneumopathie chronique obstructive/traitement médicamenteux , Rifabutine/sang , Résultat thérapeutiqueRÉSUMÉ
Microparticles containing isoniazid and rifabutin were aerosolised using a simple apparatus fabricated from a 15-ml centrifuge tube. The dose available for inhalation by rodents was determined by collecting microparticles emitted at the delivery port. The dose available for inhalation was proportional to durations of exposure ranging from 10 to 90 s (10.5-13.5 CV%) and the weight of powder taken for fluidization (10-50 mg, r2=0.982). The apparatus was then used to administer inhalations of microparticles to mice. Other groups of mice received free rifabutin orally, or by i.v. injection. Rifabutin was estimated in serum and tissues of dosed mice by HPLC. When approximately 20 mg of microparticles were loaded in the apparatus, approximately 2.5 mg were collected at the delivery port in 30 s of operation. Mice inhaled approximately 300 microg of the 2.5 mg emitted at the delivery port. Airway and lung macrophages of mice receiving inhalations for 30 s accumulated 0.38 microg of rifabutin, while the amount in blood serum of these mice was 0.62 microg. In mice receiving 83 microg rifabutin i.v. or orally, the intracellular amounts were 0.06 and 0.07 microg respectively, while the amounts in serum were 1.02 and 0.80 microg. These observations confirmed that inhalation of microparticles targeted airway and lung macrophages.
Sujet(s)
Antituberculeux/administration et posologie , Macrophages/métabolisme , Appareil respiratoire/métabolisme , Rifabutine/administration et posologie , Tests de toxicité/instrumentation , Administration par inhalation , Administration par voie orale , Animaux , Antituberculeux/sang , Antituberculeux/pharmacocinétique , Inspiration , Injections veineuses , Mâle , Souris , Poudres , Appareil respiratoire/cytologie , Rifabutine/sang , Rifabutine/pharmacocinétiqueRÉSUMÉ
Rifabutin (RFB) is administered for treatment of tuberculosis and Mycobacterium avium complex infection, including use for patients coinfected with human immunodeficiency virus (HIV). Increased systemic exposure to RFB and its equipotent active metabolite, 25-O-desacetyl-RFB (dAc-RFB), has been reported during concomitant administration of CYP3A4 inhibitors, including ritonavir (RTV), lopinavir, and amprenavir (APV); therefore, a reduction in the RFB dosage is recommended when it is coadministered with these protease inhibitors. Fosamprenavir (FPV), the phosphate ester prodrug of the HIV type 1 protease inhibitor APV, is administered either with or without RTV. A randomized, open-label, two-period, two-sequence, balanced, crossover drug interaction study was conducted with 22 healthy adult subjects to compare steady-state plasma RFB pharmacokinetic parameters during concomitant administration of FPV-RTV (700/100 mg twice a day [BID]) with a 75%-reduced RFB dose (150 mg every other day [QOD]) to the standard RFB regimen (300 mg once per day [QD]) by geometric least-squares mean ratios. Relative to results with RFB (300 mg QD), coadministration of dose-adjusted RFB with FPV-RTV resulted in an unchanged RFB area under the concentration-time curve for 0 to 48 h (AUC(0-48)) and a 14% decrease in the maximum concentration of drug in plasma (C(max)), whereas the AUC(0-48) and C(max) of dAc-RFB were increased by 11- and 6-fold, respectively, resulting in a 64% increase in the total antimycobacterial AUC(0-48). Relative to historical controls, the plasma APV AUC from 0 h to the end of the dosing interval (AUC(0-tau)) and C(max) were increased approximately 35%, and the concentration at the end of the dosing interval at steady state was unchanged following coadministration of RFB with FPV-RTV. The safety profile of the combination of RFB and FPV-RTV was consistent with previously described events with RFB or FPV-RTV alone. Based on the results of this study, a reduction in the RFB dose by > or =75% (to 150 mg QOD or three times per week) is recommended when it is coadministered with FPV-RTV (700/100 mg BID).
Sujet(s)
Antituberculeux/pharmacocinétique , Carbamates/pharmacocinétique , Organophosphates/pharmacocinétique , Rifabutine/pharmacocinétique , Ritonavir/pharmacocinétique , Sulfonamides/pharmacocinétique , Adulte , Antituberculeux/effets indésirables , Antituberculeux/sang , Aire sous la courbe , Carbamates/effets indésirables , Carbamates/sang , Études croisées , Calendrier d'administration des médicaments , Interactions médicamenteuses , Association de médicaments , Femelle , Furanes , Humains , Mâle , Adulte d'âge moyen , Organophosphates/effets indésirables , Organophosphates/sang , Rifabutine/effets indésirables , Rifabutine/sang , Ritonavir/effets indésirables , Ritonavir/sang , Sulfonamides/effets indésirables , Sulfonamides/sangRÉSUMÉ
Microparticles containing large payloads of two anti-tuberculosis (TB) drugs were prepared and evaluated for suitability as a dry powder inhalation targeting alveolar macrophages. A solution containing one part each of isoniazid and rifabutin, plus two parts poly(lactic acid) (L-PLA) was spray-dried. Drug content and in vitro release were assayed by HPLC, and DSC was used to elucidate release behaviour. Particle size was measured by laser scattering and aerosol characteristics by cascade impaction using a Lovelace impactor. Microparticles were administered to mice using an in-house inhalation apparatus or by intra-tracheal instillation. Drugs in solution were administered orally and by intra-cardiac injection. Flow cytometry and HPLC were used to investigate the specificity and magnitude of targeting macrophages. Microparticles having drug content approximately 50% (w/w), particle size approximately 5 microm and satisfactory aerosol characteristics (median mass aerodynamic diameter, MMAD=3.57 microm; geometric standard deviation, GSD=1.41 microm; fine particle fraction, FPF(<4.6 microm)=78.91+/-8.4%) were obtained in yields of >60%. About 70% of the payload was released in vitro in 10 days. Microparticles targeted macrophages and not epithelial cells on inhalation. Drug concentrations in macrophages were approximately 20 times higher when microparticles were inhaled rather than drug solutions administered. Microparticles were thus deemed suitable for enhanced targeted drug delivery to lung macrophages.
Sujet(s)
Antituberculeux/administration et posologie , Nanoparticules/administration et posologie , Administration par inhalation , Animaux , Antituberculeux/sang , Antituberculeux/pharmacocinétique , Calorimétrie différentielle à balayage , Chromatographie en phase liquide à haute performance , Cytosol/métabolisme , Dessiccation , Préparation de médicament , Cytométrie en flux , Concentration en ions d'hydrogène , Isoniazide/administration et posologie , Isoniazide/sang , Isoniazide/pharmacocinétique , Macrophages alvéolaires/métabolisme , Souris , Taille de particule , Phagocytose , Rifabutine/administration et posologie , Rifabutine/sang , Rifabutine/pharmacocinétique , Solubilité , ComprimésRÉSUMÉ
STUDY OBJECTIVE: To characterize the bidirectional interaction between twice-daily nelfinavir and twice-weekly rifabutin and isoniazid in patients with tuberculosis and human immunodeficiency virus (HIV) infection. DESIGN: Prospective cohort study. SETTING: Three clinical research centers. PATIENTS: Seven patients with HIV-related tuberculosis. INTERVENTION: Rifabutin 300 mg and isoniazid 15 mg/kg (maximum dose 900 mg) twice/week were administered for at least 2 weeks during the continuation phase of tuberculosis treatment. Antiretroviral therapy with nelfinavir 1250 mg twice/day and two nucleoside reverse transcriptase inhibitors was then added. MEASUREMENTS AND MAIN RESULTS: Patients underwent blood sampling for pharmacokinetic analysis during the continuation phase of tuberculosis therapy and after a median of 21 days after the addition of antiretroviral treatment. When rifabutin was coadministered with nelfinavir, its area under the concentration-time curve from 0-21 hours (AUC(0-21)) increased 22% (geometric mean 5.01 microg.hr/ml [90% confidence interval (CI) 3.25-7.71] with nelfinavir vs 4.10 microg.hr/ml [90% CI 3.18-5.27] without nelfinavir; geometric mean ratio 1.22 [90% CI 0.78-1.92]). Also, the AUC(0-21) for the active metabolite, desacetylrifabutin, increased significantly (geometric mean ratio 3.46, 90% CI 1.84-6.47, p=0.009). In the presence of rifabutin, the pharmacokinetic parameters of nelfinavir and its principal metabolite M8 were similar to those of patients not taking rifabutin. No drug interaction between nelfinavir and isoniazid was detected. CONCLUSIONS: Coadministration of rifabutin and isoniazid without dosage adjustment during twice-weekly tuberculosis therapy with nelfinavir-based antiretroviral therapy resulted in rifabutin exposures within the acceptable ranges for safety and efficacy. Therefore, this combination is an appropriate option for the simultaneous treatment of tuberculosis and HIV infection when tuberculosis therapy is given twice weekly.
Sujet(s)
Antibiotiques antituberculeux/pharmacocinétique , Infections à VIH/traitement médicamenteux , Inhibiteurs de protéase du VIH/pharmacocinétique , Nelfinavir/pharmacocinétique , Rifabutine/pharmacocinétique , Tuberculose/traitement médicamenteux , Antibiotiques antituberculeux/effets indésirables , Antibiotiques antituberculeux/usage thérapeutique , Antituberculeux/usage thérapeutique , Aire sous la courbe , Études de cohortes , Interactions médicamenteuses , Association de médicaments , Femelle , Infections à VIH/complications , Inhibiteurs de protéase du VIH/effets indésirables , Inhibiteurs de protéase du VIH/usage thérapeutique , Humains , Isoniazide/usage thérapeutique , Mâle , Nelfinavir/effets indésirables , Nelfinavir/analogues et dérivés , Nelfinavir/sang , Nelfinavir/usage thérapeutique , Études prospectives , Rifabutine/effets indésirables , Rifabutine/analogues et dérivés , Rifabutine/sang , Rifabutine/usage thérapeutique , Tuberculose/complicationsRÉSUMÉ
BACKGROUND: Because of drug-drug interactions mediated by hepatic cytochrome P450, tuberculosis treatment guidelines recommend an increase in rifabutin from 300 mg to 450 or 600 mg when combined with efavirenz-based antiretroviral therapy. To assess this recommendation, rifabutin and efavirenz pharmacokinetic parameters were investigated. METHODS: Plasma concentrations of rifabutin were determined as a baseline control in 15 patients with tuberculosis and human immunodeficiency virus (HIV) infection who were treated with rifabutin 300 mg and isoniazid 15 mg/kg (up to 900 mg) twice weekly. Rifabutin, isoniazid, and efavirenz concentrations were determined after a median of 21 days (interquartile range, 20-34 days) of daily efavirenz-based antiretroviral therapy with twice-weekly rifabutin 600 mg and isoniazid 15 mg/kg. RESULTS: The mean rifabutin area under the concentration-time curve (AUC(0-24)) increased 20% from the baseline value (geometric mean, 5.0 vs. 4.2 microg.h/mL; ratio of geometric means, 1.2 [90% confidence interval, 1.0-1.4]). Also, the mean efavirenz AUC(0-24) in the 15 patients taking concomitant rifabutin 600 mg twice-weekly was 10% higher than that in 35 historical subjects with HIV infection who were not taking rifabutin. Efavirenz-based antiretroviral therapy was effective; HIV load decreased 2.6 log copies/mL, and the median CD4+ T cell count increased from 141 to 240 cells/mm3 after a median of 21 days of efavirenz-based antiretroviral therapy. No statistically significant differences in isoniazid pharmacokinetic parameters were found. CONCLUSIONS: The rifabutin dose increase from 300 mg to 600 mg was adequate to compensate for the efavirenz drug interaction in most patients, and no drug interaction with isoniazid was detected. Efavirenz therapy administered at a standard 600-mg dose achieved adequate plasma concentrations in patients receiving intermittent rifabutin and isoniazid therapy, was generally well tolerated, and demonstrated potent antiretroviral activity.
Sujet(s)
Agents antiVIH/pharmacocinétique , Antibiotiques antituberculeux/pharmacocinétique , Infections à VIH/sang , Infections à VIH/traitement médicamenteux , Oxazines/pharmacocinétique , Rifabutine/pharmacocinétique , Tuberculose/sang , Tuberculose/traitement médicamenteux , Adulte , Alcynes , Agents antiVIH/sang , Antibiotiques antituberculeux/sang , Benzoxazines , Cyclopropanes , Interactions médicamenteuses , Femelle , Infections à VIH/complications , Humains , Mâle , Adulte d'âge moyen , Oxazines/sang , Rifabutine/sang , Tuberculose/complicationsRÉSUMÉ
BACKGROUND: The occurrence of acquired rifamycin resistance despite use of directly observed therapy for tuberculosis is associated with advanced human immunodeficiency virus (HIV) disease and highly intermittent administration of antituberculosis drugs. Beyond these associations, the pathogenesis of acquired rifamycin resistance is unknown. METHODS: We performed a pharmacokinetic substudy of patients in a trial of treatment with twice-weekly rifabutin and isoniazid. RESULTS: A total of 102 (60%) of 169 patients in the treatment trial participated in the pharmacokinetic substudy, including 7 of 8 patients in whom tuberculosis treatment failure or relapse occurred in association with acquired rifamycin-resistant mycobacteria (hereafter, "ARR failure or relapse"). The median rifabutin area under the concentration-time curve (AUC(0-24)) was lower for patients with than for patients without ARR failure or relapse (3.3 vs. 5.2 microg*h/mL; P = .06, by the Mann-Whitney exact test). In a multivariate analysis adjusted for CD4+ T cell count, the mean rifabutin AUC(0-24) was significantly lower for patients with ARR failure or relapse than for other patients (3.0 microg*h/mL [95% confidence interval {CI}, 1.9-4.5] vs. 5.2 microg*h/mL [95% CI, 4.6-5.8]; P = .02, by analysis of covariance). The median isoniazid AUC(0-12) was not significantly associated with ARR failure or relapse (20.6 vs. 28.0 microg*h/mL; P = .24, by the Mann-Whitney exact test). However, in a multivariate logistic regression model that adjusted for the rifabutin AUC(0-24), a lower isoniazid AUC(0-12) was associated with ARR failure or relapse (OR, 10.5; 95% CI, 1.1-100; P = .04). CONCLUSIONS: Lower plasma concentrations of rifabutin and, perhaps, isoniazid were associated with ARR failure or relapse in patients with tuberculosis and HIV infection treated with twice-weekly therapy.