Administration Of Rifampin Research Articles

Selective induction of CYP3A4‐dependent vitamin D catabolism via pregnane X receptor in human hepatocytes and healthy volunteers

Long‐term therapy with certain drugs, especially hPXR ligands, confers an increased risk of osteomalacia that is attributed to vitamin D deficiency. Human CYP24A1 and CYP3A4 can inactivate vitamin D, although their relative contributions appear to be tissue‐specific and not well characterized. In this study, formation of specific metabolites, 4β,25(OH)2D3 (CYP3A4) and 24R,25(OH)2D3 (CYP24A1) from 25OHD3 was measured, along with mRNA levels for these VDR/PXR target genes. In human hepatocytes, treatment with rifampin significantly increased the levels of CYP3A4 but not CYP24A1 mRNA. Cells treated with 25OHD3, after rifampin pretreatment, showed an 8‐fold increased formation of the major metabolite, 4β,25(OH)2D3; this effect was diminished by addition of DHB, a specific CYP3A4 inhibitor. 24R,25(OH)2D3 was a minor metabolite, and its formation occurred predominantly from induction of CYP24A1 via VDR activation. In healthy volunteers, the plasma level of 4β,25(OH)2D3 were increased 60% (p < 0.01) after rifampin administration. In contrast, a small reduction in plasma 1α,25(OH)2D3 (−10%; p = 0.03) and no change in 24R,25(OH)2D3 (−8%; p = 0.09) levels were observed. Analysis of the plasma metabolite/25OHD3 ratios indicated selective induction of the CYP3A4 pathway of 25OHD3 elimination. These results suggest that induction of hepatic CYP3A4 may be important in the etiology of drug‐induced osteomalacia.

Effect of Administration of Moxifloxacin plus Rifampin against Mycobacterium tuberculosis for 7 of 7 Days versus 5 of 7 Days in an In Vitro Pharmacodynamic System

ABSTRACTSome trials administered antituberculosis agents for 5 of 7 days (5/7-day regimen) to optimize adherence. Since moxifloxacin has a longer half-life than rifampin, rifampin concentrations are <1% of the maximum concentration in serum (Cmax) on day 6 and nondetectable on day 7, while concentrations of moxifloxacin remain and are able to induce error-prone replication. We determined if functional moxifloxacin monotherapy for 24 h/week caused resistance. In in vitro pharmacodynamic experiments, Mycobacterium tuberculosis was treated with mean area under the concentration-time curve (AUC) exposures for moxifloxacin and rifampin of 400 and 600 mg/kg/day and exposures equal to 1 standard deviation (SD) above and below the mean values. The drugs were administered on schedules of 7/7 days and 5/7 days. Over the 28-day experiments, bacteria were plated onto antibiotic-free agar to determine the effects of exposure and schedule on the total population. MICs were checked for emergence of resistance. At days 7 and 14, there was a 0.56- to 1.22-log10-CFU/ml greater cell kill with the 7/7-day regimen versus the 5/7-day regimen (low exposure). This difference was not seen for the larger exposures at day 21. At day 23, the low-exposure 5/7-day arm had breakthrough resistance, with the total count increasing to >2 log10 CFU/ml above the low-exposure 7/7-day arm. Pharmacokinetic mismatching of drugs in the therapy of tuberculosis may result in emergence of resistance when a drug holiday is imposed during which there is functional monotherapy and where the remaining agent induces error-prone replication. This is particularly true for the portion of the population where the clearance is higher (1 SD above the mean).

Simulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

Rifampin and carbamazepine have been recommended in the U.S. Food and Drug Administration draft drug interaction guidance as CYP3A4 inducers for clinical drug-drug interaction (DDI) studies. To optimize the dose regimens of these inducers for use in DDI studies, their effect at various doses and dosing durations on the area under the curve (AUC) of multiple probe substrates was simulated using a population-based simulator. A similar assessment of the inducer phenobarbital was also conducted. CYP3A4 induction by all three inducers was previously determined in hepatocytes, and the results were incorporated into simulations. The pharmacokinetics of the three inducers and their associated CYP3A4 drug interactions were predicted and compared with in vivo observations. The predicted C(max) and AUC of all the inducers and substrates correlated closely with those observed clinically. The predicted magnitudes of the DDIs caused by CYP3A4 induction were also in good agreement with the observed clinical results. Comparison of the maximal CYP3A4 induction potential among the three inducers indicated that rifampin is the most potent inducer and is the best choice for clinical CYP3A4 induction DDI studies. Moreover, a near-maximal CYP3A4 DDI was predicted to result from administration of rifampin for approximately 7 days at 450 to 600 mg q.d. or 200 to 300 mg b.i.d. These results suggest optimal dose regimens for clinical trials that maximize the probability of detecting a DDI caused by CYP3A4 induction. The simulation strategy provides the means to predict the induction profiles of compounds in development.

Effects of Rifampin and Ketoconazole on the Pharmacokinetics of Nilotinib in Healthy Participants

Nilotinib (Tasigna), an orally bioavailable second-generation BCR-ABL tyrosine kinase inhibitor, is approved for use in patients with chronic myeloid leukemia in chronic phase and accelerated phase who are resistant or intolerant to prior therapy, including imatinib. Previous in vitro studies indicated that nilotinib metabolism is primarily mediated by CYP3A4. To investigate the effect of CYP3A4 induction and inhibition on nilotinib pharmacokinetics, 2 studies were conducted in healthy volunteers prior to and following treatment with a strong inducer (rifampin) or inhibitor (ketoconazole). In the induction study, administration of rifampin 600 mg once daily for 8 days significantly increased urinary 6β-hydroxycortisol/ cortisol ratio, from a preinduction baseline of 5.8 ± 2.7 to 18.0 ± 10.2 after 8 days of rifampin treatment, confirming an inductive effect on CYP3A4. Nilotinib oral clearance was increased by 4.8-fold, and the maximum serum concentration (C(max)) and area under the serum concentration-time curve (AUC) were decreased by 64% and 80%, respectively, in the induced state compared with baseline. In the inhibition study, ketoconazole 400 mg once daily for 6 days increased the C(max) and AUC of nilotinib by 1.8- and 3-fold, respectively, compared with nilotinib alone. These results indicate that concurrent use of strong CYP3A4 inducers or inhibitors may necessitate dosage adjustments of nilotinib and should be avoided when possible.

Treatment outcomes of patients co-infected with HIV and tuberculosis who received a nevirapine-based antiretroviral regimen: a four-year prospective study

The concurrent use of nevirapine-based antiretroviral therapy (ART) and rifampin-containing anti-tuberculosis regimens for the treatment of HIV and tuberculosis (TB) is common in resource-limited countries. Long-term outcomes of this concurrent treatment are unknown. Seventy HIV-infected patients receiving rifampin for active TB (TB group) and 70 HIV-mono-infected patients (control group) were enrolled to receive nevirapine 400mg/day-based ART. All were followed through 4 years of ART. Plasma HIV-1 RNA and CD4 cell counts were monitored every 12 weeks until 96 weeks, and every 24 weeks thereafter. Of the 140 patients, the median (interquartile range (IQR)) CD4 count was 31 (14-79) cells/mm(3) and median (IQR) plasma HIV-1 RNA was 5.6 (5.2-5.9) log copies/ml at baseline . Thirty-nine (55.7%) patients in the TB group were diagnosed with extrapulmonary/disseminated TB. The median duration of concurrent administration of nevirapine and rifampin was 5.4 (4.6-6.1) months. By intention-to-treat analysis, the percentage of patients who achieved HIV-1 RNA <50 copies/ml was 52.9% in the TB group and 50% in control group (p=0.866; odds ratio 1.121, 95% confidence interval 0.578-2.176); median (IQR) CD4 counts were 352 (271-580) cells/mm(3) and 425 (308-615) cells/mm(3) in the corresponding groups (p=0.238). The proportion of ART discontinuation due to any reason at 1, 2, 3, and 4 years was 21%, 34%, 37%, and 46% in the TB group and 21%, 36%, 43%, and 49% in the control group, respectively (p=0.651). The 4-year mortality rate was 6.4% in both groups. Nevirapine-based ART is an option for HIV-infected patients who receive rifampin in resource-limited countries or those who cannot tolerate efavirenz.

Consensus Document on the Diagnosis, Treatment and Prevention of Tuberculosis

Pulmonary tuberculosis must be suspected in patients with respiratory symptoms longer than 2–3 weeks. Immunosuppression may modify the clinical and radiological presentation. The chest X-ray is highly suggestive of tuberculosis (TB), but is occasionally atypical. The complex radiological tests (CT scan, MRI) are more useful in extrapulmonary TB. At least 3 consecutive representative samples from the clinical location are used for diagnosis, whenever possible. Bacilloscopy and liquid medium cultures are indicated in all cases. Genetic amplification techniques are coadjuvant in moderate or high suspicion of TB. In new cases of TB, administration of isoniazid, rifampin, ethambutol, and pyrazinamide (HREZ) for 2 months and isoniazid plus rifampin for 4 months is recommended. For meningitis cases, treatment should continue for up to 12 months, and up to 9 months in spinal TB with neurological affectation and silicosis. Appropriate adjustments with antiretroviral treatment must be made in HIV patients. Combined therapy is recommended to prevent development of resistance. An antibiogram for first line drugs should be performed in all initial extractions from new patients. Treatment control is one of the most important activities in TB management. The Tuberculin Skin Test (TST) is positive in TB infection when ≥ 5mm, and Interferon-Gamma Release Assays (IGRA) are recommended in combination with TST. The standard treatment schedule for infection is 6 months with isoniazid. In pulmonary TB, respiratory isolation is applied for 3 weeks or until 3 negative bacilloscopy samples are obtained.

Effect of duration and intermittency of rifampin on tuberculosis treatment outcomes: a systematic review and meta-analysis.

Treatment regimens for active tuberculosis (TB) that are intermittent, or use rifampin during only the initial phase, offer practical advantages, but their efficacy has been questioned. We conducted a systematic review of treatment regimens for active TB, to assess the effect of duration and intermittency of rifampin use on TB treatment outcomes. PubMed, Embase, and the Cochrane CENTRAL database for clinical trials were searched for randomized controlled trials, published in English, French, or Spanish, between 1965 and June 2008. Selected studies utilized standardized treatment with rifampin-containing regimens. Studies reported bacteriologically confirmed failure and/or relapse in previously untreated patients with bacteriologically confirmed pulmonary TB. Pooled cumulative incidences of treatment outcomes and association with risk factors were computed with stratified random effects meta-analyses. Meta-regression was performed using a negative binomial regression model. A total of 57 trials with 312 arms and 21,472 participants were included in the analysis. Regimens utilizing rifampin only for the first 1-2 mo had significantly higher rates of failure, relapse, and acquired drug resistance, as compared to regimens that used rifampin for 6 mo. This was particularly evident when there was initial drug resistance to isoniazid, streptomycin, or both. On the other hand, there was little evidence of difference in failure or relapse with daily or intermittent schedules of treatment administration, although there was insufficient published evidence of the efficacy of twice-weekly rifampin administration throughout therapy. TB treatment outcomes were significantly worse with shorter duration of rifampin, or with initial drug resistance to isoniazid and/or streptomycin. Treatment outcomes were similar with all intermittent schedules evaluated, but there is insufficient evidence to support administration of treatment twice weekly throughout therapy.

Therapeutic plasma exchange reveals a color‐coordinated response to cyclosporine‐induced microangiopathic hemolytic anemia and rifampin after stem cell transplant

A 39 year old woman with T/NK-cell lymphoma developed microangiopathic hemolytic anemia (MAHA) associated with cyclosporine A (CSA) toxicity 15 days after allogeneic peripheral blood stem cell transplantation. Her serum creatinine level increased from 0.4 mg/dL pre-transplant to 1.0 and 2.9 mg/dL on days 9 and 15 post-transplant, respectively, leading to cessation of CSA therapy. Peripheral blood smears revealed a dramatic increase in schistocytes (4 per high-power field) on day 14. LDH levels rose from 708 to 4103 U/L on post-transplant days 1 and 15, respectively. Declining hemoglobin concentration and platelet count were attributed initially to the transplant rather than to evolving MAHA. Because of her critical condition, a 5-day course of daily therapeutic plasma exchange (TPE) was initiated as an extreme measure. Plasma removed during the 1st TPE (Figure 1) illustrates the classic tea-color associated with MAHA. During the first 3 days of TPE, CSA levels were 113, 95, and 106 mcg/L. Rifampin, a potent inducer of cytochrome 450 3A4, was administered on days 18 and 19 to promote clearance of CSA. Rifampin stains body fluids a characteristic orange-red color, noted in the plasma removed during the 4th TPE (Figure 2). Plasma color returned to clear yellow by the final day of TPE (Figure 3). Creatinine levels peaked at 4.6 mg/dL on day 19. CSA and creatinine levels declined to 48 mcg/L and 3.4 mg/dL, respectively, the day following completion of TPE and rifampin administration, and further decreased to 34 mcg/L and 1.6 mg/dL 2 days later. Figure 1 Plasma removed during first TPE demonstrating classic tea-colored plasma associated with MAHA. Figure 2 Orange-red plasma removed during fourth TPE after administration of rifampin to promote clearance of CSA. Figure 3 Clear yellow plasma removed during fifth and final TPE procedure.

Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of cytochrome P450s. We describe a physiologically based pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data for model drugs were performed to establish the influence of P-glycoprotein efflux, cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte (F(G)) for 10 cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein in vitro efflux ratios all predicted F(G) values were within 20% of observed in vivo F(G). The presence of P-glycoprotein increased the level of cytochrome 3A drug metabolism by up to 12-fold in the distal intestine. F(G) was highly sensitive to changes in intrinsic metabolic clearance but less sensitive to changes in intestinal drug permeability. The model will be valuable for quantifying aspects of intestinal drug absorption and distribution.

Effect of Rifampin, a Potent Inducer of Drug-Metabolizing Enzymes, on the Pharmacokinetics of Raltegravir

Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor that is metabolized by glucuronidation via UGT1A1 and may be affected by inducers of UGT1A1, such as rifampin (rifampicin). Two pharmacokinetic studies were performed in healthy subjects: study 1 examined the effect of administration of 600-mg rifampin once daily on the pharmacokinetics of a single dose of 400-mg raltegravir, and study 2 examined the effect of 600-mg rifampin once daily on the pharmacokinetics of 800-mg raltegravir twice daily compared to 400-mg raltegravir twice daily without rifampin. Raltegravir coadministered with rifampin resulted in lower plasma raltegravir concentrations: in study 1, the geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) for the plasma raltegravir concentration determined 12 h postdose (C(12)), area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)), and maximum concentration of drug in plasma (C(max)) (400-mg raltegravir plus rifampin/400-mg raltegravir) were 0.39 (0.30, 0.51), 0.60 (0.39, 0.91), and 0.62 (0.37, 1.04), respectively. In study 2, the GMRs and 90% CIs for raltegravir C(12), AUC(0-12), and C(max) (800-mg raltegravir plus rifampin/400-mg raltegravir) were 0.47 (0.36, 0.61), 1.27 (0.94, 1.71), and 1.62 (1.12, 2.33), respectively. Doubling the raltegravir dose to 800 mg when coadministered with rifampin therefore compensates for the effect of rifampin on raltegravir exposure (AUC(0-12)) but does not overcome the effect of rifampin on raltegravir trough concentrations (C(12)). Coadministration of rifampin and raltegravir is not contraindicated; however, caution should be used, since raltegravir trough concentrations in the presence of rifampin are likely to be at the lower limit of clinical experience.

Relative Impact of Genotype and Enzyme Induction on the Metabolic Capacity of CYP2C9 in Healthy Volunteers

Pharmacokinetics in individual subjects is determined by genes and environment. The relative contributions of enzyme induction and inherited genomic variation to cytochrome P450 enzyme 2C9 (CYP2C9) activity are unknown. In 130 volunteers, CYP2C9 activity was measured in vivo using tolbutamide as a probe drug. Tolbutamide was administered orally, and the pharmacokinetics of the drug was analyzed twice--before and after four doses of 450 mg rifampin. Mean total apparent clearances (Cl/F) in the genotype groups CYP2C9*1/*1, *1/*2, *1/*3, *2/*3, and *3/*3 before rifampin were 0.78, 0.74, 0.52, 0.40, and 0.13 l/h, respectively. After rifampin administration, these clearances increased in all genotype groups by a median factor of 1.9 (range 1.1-4.8). The combined effects of genes and environment could be predicted by a simple additive model. Thus, enzyme induction resulted in an approximately twofold difference in CYP2C9 activity, irrespective of the CYP2C9 genotypes. But the difference in activity levels between the CYP2C9*1/*1 and *3/*3 genotypes before the administration of rifampin was sixfold.

Hepatotoxicity and Gastrointestinal Intolerance When Healthy Volunteers Taking Rifampin Add Twice-Daily Atazanavir and Ritonavir

Rifampin is the cornerstone of antituberculosis therapy, but induction of hepatic cytochrome P4503A by rifampin markedly lowers HIV protease inhibitor plasma concentrations. This phase 1, open-label, one-arm study was designed to assess pharmacokinetic interactions and safety of atazanavir, ritonavir, and rifampin among 14 evaluable HIV-seronegative volunteers. The study included 3 sequential periods of study drug dosing, with plasma sampling for pharmacokinetic analyses to occur on the last day of each period. During period 1, participants received rifampin 600 mg every 24 hours for 8 days. During period 2, participants continued rifampin 600 mg every 24 hours, and added atazanavir 300 mg and ritonavir 100 mg every 12 hours, to continue for at least 11 days. During period 3, atazanavir was to be increased to 400 mg every 12 hours. Upon adding atazanavir and ritonavir, the first 3 subjects developed vomiting and transaminase elevations resulting in study drug discontinuation. The study was therefore terminated. Coadministration of rifampin with HIV protease inhibitors may not be a viable treatment option if rifampin administration precedes protease inhibitor initiation. Future studies, which explore concomitant HIV protease inhibitors with rifampin must carefully consider the sequence in which drugs are initiated.

CYP2B6 G516T Polymorphism but Not Rifampin Coadministration Influences Steady-State Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus-Infected Patients in South India

The dose of efavirenz during concomitant rifampin (RMP) administration is a matter of debate. We studied the influence of RMP coadministration on the steady-state pharmacokinetics of efavirenz in human immunodeficiency virus type 1 (HIV-1)-infected patients in South India. Fifty-seven HIV-tuberculosis (TB)-coinfected and 15 HIV-1-infected patients receiving combination antiretroviral therapy (CART) with an efavirenz (600 mg once daily)-containing regimen were recruited. HIV-TB-coinfected patients were receiving treatment with RMP-containing regimens. A complete pharmacokinetic study was conducted with 19 HIV-TB patients on two occasions (with and without RMP). Trough concentrations of efavirenz were measured in the remaining 38 patients during RMP coadministration. The 15 HIV-infected patients underwent complete pharmacokinetic sampling on one occasion. Plasma efavirenz was estimated by high-performance liquid chromatography, and genotyping of CYP2B6 G516T polymorphism was performed by sequencing. Peak and trough concentrations and exposure to efavirenz were significantly higher in TT than in GT and GG genotype patients (P < 0.001). Although RMP coadministration decreased the peak and trough concentrations and exposure to efavirenz by 17.8, 20.4, and 18.6%, respectively, the differences were not statistically significant. The trough concentration of efavirenz was subtherapeutic (less than 1.0 microg/ml) in 6 (8%) of 72 patients. In this South Indian population of HIV-infected patients, CYP2B6 G516T polymorphism but not RMP coadministration significantly influenced the pharmacokinetics of efavirenz; patients with the TT genotype had very high blood levels of efavirenz. While a small proportion of patients had subtherapeutic efavirenz levels, the clinical implications are uncertain, as all had good immunological responses to CART.

Successfully treated intractable pruritus with rifampin in a case of benign recurrent intrahepatic cholestasis.

A 56-year-old gentleman with benign recurrent intrahepatic cholestasis (BRIC) suffered from recurrent episodes of pruritus for over 40years. The treatment prescribed, namely cholestyramine, was minimally effective. However, rifampin 150mg b.i.d promptly and completely relieved his severe pruritus. The diagnosis of BRIC, being a rare condition, may go unrecognized. The severity of the lifelong episodes of intermittent cholestasis with pruritus in BRIC may be extremely distressing to the affected patient. Administration of rifampin during the acute episode of severe pruritus led to a marked improvement in his quality of life.

Population Pharmacokinetics of Rifampin in Pulmonary Tuberculosis Patients, Including a Semimechanistic Model To Describe Variable Absorption

This article describes the population pharmacokinetics of rifampin in South African pulmonary tuberculosis patients. Three datasets containing 2,913 rifampin plasma concentration-time data points, collected from 261 South African pulmonary tuberculosis patients aged 18 to 72 years and weighing 28.5 to 85.5 kg and receiving regular daily treatment that included administration of rifampin (450 to 600 mg) for at least 10 days, were pooled. A compartmental pharmacokinetic model was developed using nonlinear mixed-effects modeling. Variability in the shape of the absorption curve was described using a flexible transit compartment model, in which a delay in the onset of absorption and a gradually changing absorption rate were modeled as the passage of drug through a chain of hypothetical compartments, ultimately reaching the absorption compartment. A previously described implementation was extended to allow its application to multiple-dosing data. The typical population estimate of oral clearance was 19.2 liters x h(-1), while the volume of distribution was estimated to be 53.2 liters. Interindividual variability was estimated to be 52.8% for clearance and 43.4% for volume of distribution. Interoccasional variability was estimated for CL/F (22.5%) and mean transit time during absorption (67.9%). The use of single-drug formulations was found to increase both the mean transit time (by 104%) and clearance (by 23.6%) relative to fixed-dose-combination use. A strong correlation between clearance and volume of distribution suggested substantial variability in bioavailability, which could have clinical implications, given the dependence of treatment effectiveness on exposure. The final model successfully described rifampin pharmacokinetics in the population studied and is suitable for simulation in this context.

Effects of Rifampin and Multidrug Resistance Gene Polymorphism on Concentrations of Moxifloxacin

Treatment regimens combining moxifloxacin and rifampin for drug-susceptible tuberculosis are being studied intensively. However, rifampin induces enzymes that transport and metabolize moxifloxacin. We evaluated the effect of rifampin and the human multidrug resistance gene (MDR1) C3435T polymorphisms (P-glycoprotein) on moxifloxacin pharmacokinetic parameters. This was a single-center, sequential design study with 16 volunteers in which sampling was performed after four daily oral doses of moxifloxacin (400 mg) and again after 10 days of combined rifampin (600 mg) and moxifloxacin. After daily coadministration of rifampin, the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) for moxifloxacin decreased 27%. Average bioequivalence between moxifloxacin coadministered with rifampin and moxifloxacin alone was not demonstrated: the ratio of geometric means (RGM) of the moxifloxacin AUC(0-24) was 73.3 (90% confidence intervals [CI], 64.3, 83.5) (total P value, 0.87 for two one-sided t tests). Peak moxifloxacin concentrations, however, were equivalent: the RGM of the maximum concentration of the drug in serum was 93.6 (90% CI, 80.2, 109.3) (total P value, 0.049). Concentrations of the sulfate conjugate metabolite of moxifloxacin were increased twofold following rifampin coadministration (AUC(0-24), 1.29 versus 2.79 mug.h/ml). Concomitant rifampin administration resulted in a 27% decrease in the mean moxifloxacin AUC(0-24) and a marked increase in the AUC(0-24) of the microbiologically inactive M1 metabolite. Additional studies are required to understand the clinical significance of the moxifloxacin-rifampin interaction.

Dual Effects of Rifampin on the Pharmacokinetics of Atrasentan

The effect of rifampin, a cytochrome P450 3A4 inducer, on the pharmacokinetics of atrasentan was assessed in 12 healthy male subjects in an open-label study. Single doses of atrasentan 10 mg were administered orally on days 1 and 12. Rifampin 600 mg was given once daily from days 4 through 14. On day 12, atrasentan and rifampin were administered simultaneously. Blood samples were collected before and during 72 hours after each atrasentan dose. On average, rifampin increased atrasentan peak plasma concentrations by 150% and reduced its terminal half-life by 77% (P<.05), without affecting the AUC or peak time of atrasentan. Rifampin may affect atrasentan pharmacokinetics by acting as both an inhibitor of organic anion transporting polypeptide-mediated hepatic uptake of atrasentan and an inducer of atrasentan metabolism. The effect of rifampin on atrasentan pharmacokinetics may depend on the time of rifampin administration relative to that of atrasentan.

Rifampin induces alterations in mycophenolic acid glucuronidation and elimination: Implications for drug exposure in renal allograft recipients

Exposure to mycophenolic acid (MPA) and its main metabolites (MPA 7-O-glucuronide [MPAG] and MPA acyl-glucuronide [AcMPAG]) is characterized by a large interindividual and intraindividual variability, resulting in part from variability in glucuronidation (via uridine diphosphate-glucuronosyltransferase isoforms) and excretion via multidrug resistance-associated protein 2 (MRP2). It can be hypothesized that drugs interfering with glucuronidation and excretion will alter (Ac)MPA(G) exposure. This prospective, open-label, nonrandomized, controlled pharmacokinetic interaction study included 8 stable renal allograft recipients, all treated with mycophenolate mofetil. Rifampin (INN, rifampicin), administered once daily (600 mg/d) for 8 days, was used as the probe drug because of its known effects on both uridine diphosphate-glucuronosyltransferase activity and MRP2 transport capacity. A 12-hour pharmacokinetic time-concentration profile was assessed before rifampin administration was started, and this was repeated on the last day of rifampin administration. Total and free MPA, MPAG, and AcMPAG concentrations in plasma and urine were measured by use of HPLC with tandem mass spectrometry detection. Total MPA area under the plasma concentration-time curve (AUC) from 0 to 12 hours decreased significantly after rifampin coadministration (17.5% decrease [95% confidence interval (CI), 5.18%-29.9%]; P=.0234). This was mainly a result of a decrease in total MPA AUC from 6 to 12 hours (32.9% decrease [95% CI, 15.4%-50.4%]; P=.0078), representing decreased enterohepatic recirculation. Free MPA AUC from 6 to 12 hours decreased significantly, by 22.4% (95% CI, 4.71%-49.5%; P=.0391). Total MPAG and AcMPAG AUC from 0 to 12 hours increased by 34.4% (95% CI, 13.5%-55.4%; P=.0156) and 193% (95% CI, 30.3%-355%; P=.0078) respectively. Urinary recovery of MPAG and AcMPAG increased significantly (P=.0078), but renal clearance of these glucuronides did not change after rifampin coadministration. This study demonstrates an interaction between mycophenolate mofetil and rifampin, which is a result of induction of MPA glucuronidation and possibly also rifampin-associated alterations in MRP2-mediated transport of MPAG and AcMPAG. This interaction should be taken into account when rifampin or other drugs influencing pregnane X receptor activity are coadministered with mycophenolate mofetil.

Disposition and sterol-lowering effect of ezetimibe are influenced by single-dose coadministration of rifampin, an inhibitor of multidrug transport proteins

The disposition and sterol-lowering effect of ezetimibe are associated with long-lasting enterosystemic circulation, which is initiated by secretion of ezetimibe and its glucuronide via intestinal P-glycoprotein (P-gp) (ABCB1) and the multidrug resistance-associated protein 2 (MRP2) (ABCC2) into gut lumen. Hepatic uptake and secretion may contribute to recycling. To obtain deeper insight into the intestinal and hepatic processes, the disposition of ezetimibe was studied in the presence of rifampin (INN, rifampicin), a modulator of P-gp, MRP2, and hepatic organic anion (uptake) transporting polypeptides (OATPs) (SLCOs). The disposition of ezetimibe (20 mg orally) alone and after coadministration of rifampin (600 mg orally) was measured in a crossover study of 8 healthy subjects with the SLCO1B1 *1a/*1a genotype. Concentrations of ezetimibe and its glucuronide in serum, urine, and feces, as well as cholesterol, lathosterol, and the plant sterols campesterol and sitosterol in serum, were quantified by use of liquid chromatography and gas chromatography with mass spectrometric detection. After rifampin administration, the maximum serum concentrations of ezetimibe and its glucuronide were significantly elevated (12.0+/-4.20 ng/mL versus 4.67+/-2.72 ng/mL, P=.017, and 282+/-73.8 ng/mL versus 107+/-35.3 ng/mL, P=.012, respectively). The area under the curve of ezetimibe was not affected (102+/-37.6 ng.h/mL versus 140+/-86.3 ng.h/mL, P=not significant), whereas that of the glucuronide was markedly increased (2150+/-687 ng.h/mL versus 1030+/-373 ng.h/mL, P=.012). Renal clearance remained unchanged. Fecal excretion of ezetimibe was markedly decreased (7.6+/-2.2 mg versus 10.4+/-1.8 mg, P=.036), whereas renal excretion of the glucuronide was strongly elevated (4.8+/-1.9 mg versus 2.0+/-1.2 mg, P=.049) after coadministration. The onset of a significant sterol-lowering effect of ezetimibe was significantly shortened by rifampin coadministration. Coadministration of rifampin increases the maximum serum concentrations of ezetimibe but reduces its enterosystemic recycling, most likely by inhibition of the secretion of ezetimibe and its glucuronide via P-gp and MRP2.

Rifampin-induced hypothyroidism

Three euthyroid patients with Hashimoto's thyroiditis developed hypothyroidism after the administration of rifampin. We studied 67 patients with tuberculosis. All of them were treated with rifampin. Of the 67 patients, 42 had negative tests for anti-thyroid antibodies (ATA) and 25 had positive tests for ATA. The diagnosis of Hashimoto's thyroiditis was made on the basis of positive tests for ATA. After the administration of rifampin, TSH levels were not significantly altered in all of the former 42 ATA-negative patients and in 22 of the latter 25 ATA-positives, but TSH levels increased in the other three (Patients 1, 2 and 3) of the latter 25 ATA-positives. Three euthyroid Hashimoto's patients (Patients 1, 2 and 3) developed hypothyroidism after the administration of rifampin. This rifampin-induced hypothyroidism resolved in each, once rifampin was discontinued. A) Patient 1: a 62-yr-old man with lymphoma had pulmonary tuberculosis. After the administration of rifampin, serum TSH increased to 170 mU/l; B) Patient 2: a peritoneal-biopsy specimen containing Langhans' giant cells led to a diagnosis of tuberculous peritonitis in a 66-yr-old woman with ascites. After the administration of rifampin, TSH increased to 12.4 mU/l; C) Patient 3: a 56-yr-old woman with a liver abscess and lymphadenopathy underwent lymph-node biopsy that showed Mycobacterium tuberculosis with caseating granulomas. After the administration of rifampin, TSH increased to 21.3 mU/l. After its administration, Patients 1, 2 and 3 developed hypothyroidism, and received T4. When rifampin was discontinued, the hypothyroidism resolved. After the course of rifampin-therapy had been completed, T4 was discontinued. At-risk patients who receive rifampin may become hypothyroid.