rifampin and Liver-Failure

Tuberculosis (TB) has been a human disease for centuries. Its frequency is increased manyfold in patients with liver cirrhosis. The gold standard of TB management is a 6-mo course of isoniazid, rifampicin, pyrazinamide and ethambutol. Although good results are seen with this treatment in general, the management of patients with underlying cirrhosis is a challenge. The underlying depressed immune response results in alterations in many diagnostic tests. The tests used for latent TB have many flaws in this group of patients. Three of four first-line antitubercular drugs are hepatotoxic and baseline liver function is often disrupted in patients with underlying cirrhosis. Frequency of hepatotoxicity is increased in patients with liver cirrhosis, frequently leading to severe liver failure. There are no established guidelines for the treatment of TB in relation to the severity of liver disease. There is no consensus on the frequency of liver function tests required or the cut-off used to define hepatotoxicity. No specific treatment exists for prevention or treatment of hepatotoxicity, making monitoring even more important. A high risk of multidrug-resistant TB is another major worry due to prolonged and interrupted treatment.

Topics: Antitubercular Agents; Ethambutol; Humans; Immune System Diseases; Isoniazid; Latent Tuberculosis; Liver; Liver Cirrhosis; Liver Diseases; Liver Failure; Liver Function Tests; Liver Transplantation; Prevalence; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Two patients with liver failure secondary to isoniazid hepatotoxicity were successfully treated with orthotopic liver transplantation. A 49-year-old man received isoniazid prophylaxis for a positive tuberculin test, and a 60-year-old woman was treated for active pulmonary tuberculosis with isoniazid, rifampin, and pyrazinamide. Both patients developed hepatic failure 4 and 1.5 months after initiation of antituberculous drug therapy, respectively. Liver transplantation was performed for progressive hepatic failure and was successful in both patients. The patient with active pulmonary tuberculosis was successfully treated with a modified antituberculous drug regimen while taking standard doses of immunosuppressive drugs after transplantation. In conclusion, liver transplantation is feasible and effective therapy for patients with isoniazid-induced hepatic failure, and active pulmonary tuberculosis may represent a relative rather than absolute contraindication to transplantation.

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Hepatic Encephalopathy; Humans; Isoniazid; Liver Failure; Liver Transplantation; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Esaxerenone is a novel, oral, nonsteroidal treatment for hypertension. Physiologically based pharmacokinetic (PBPK) modelling was performed to predict the drug-drug interaction (DDI) effect of cytochrome P450 (CYP)3A modulators on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment.. In our PBPK model, the fraction of esaxerenone metabolised by CYP3A was estimated from mass-balance data and verified and optimised by clinical DDI study results with strong CYP3A modulators. The model was also verified by the observed pharmacokinetics after multiple oral dosing and by the effect of hepatic impairment on esaxerenone pharmacokinetics. The model was applied to predict the DDI effects on esaxerenone pharmacokinetics with untested CYP3A modulators in healthy subjects and with strong CYP3A modulators in subjects with hepatic impairment.. The PBPK model well described esaxerenone pharmacokinetics after multiple oral dosing. The predicted fold changes in esaxerenone plasma exposure after coadministration with strong CYP3A modulators were comparable with the observed data (1.53-fold with itraconazole and 0.31-fold with rifampicin). Predicted DDIs with untested moderate CYP3A modulators were less than the observed DDI with strong CYP3A modulators. The PBPK model also described the effect of hepatic impairment on esaxerenone plasma exposure. The predicted DDI results with strong CYP3A modulators in subjects with hepatic impairment indicate that, for concomitant use of CYP3A modulators, caution is advised for subjects with hepatic impairment, as is for healthy subjects.. The PBPK model developed predicted esaxerenone pharmacokinetics and DDIs and informed concurrent use of esaxerenone with CYP3A modulators.

Topics: Antihypertensive Agents; Area Under Curve; Computer Simulation; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Healthy Volunteers; Humans; Itraconazole; Japan; Liver Failure; Metabolic Clearance Rate; Models, Biological; Pyrroles; Rifampin; Sulfones

A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I disorder. Population pharmacokinetic models for olanzapine and samidorphan were developed using data from 11 clinical studies in healthy subjects or patients with schizophrenia. A 2-compartment disposition model with first-order absorption and elimination and a lag time for absorption adequately described concentration-time profiles of both olanzapine and samidorphan. Age, sex, race, smoking status, and body weight were identified as covariates that impacted the pharmacokinetics of olanzapine. A moderate effect of body weight on samidorphan pharmacokinetics was identified by the model but was not considered clinically meaningful. The effects of food, hepatic or renal impairment, and coadministration with rifampin on the pharmacokinetics of olanzapine and samidorphan, as estimated by the population pharmacokinetic analysis, were consistent with findings from dedicated clinical studies designed to evaluate these specific covariates of interest. Food intake did not have a clinically relevant effect on the pharmacokinetics of olanzapine or samidorphan. Consistent with the known metabolic pathways for olanzapine (primarily via uridine 5'-diphospho-glucuronosyltransferase-mediated direct glucuronidation and cytochrome P450 [CYP]-mediated oxidation) and for samidorphan (predominantly mediated by CYP3A4), coadministration of olanzapine and samidorphan with rifampin, a strong inducer of CYP3A4 and an inducer of uridine 5'-diphospho-glucuronosyltransferase enzymes, significantly decreased the systemic exposure of both olanzapine and samidorphan. Severe renal impairment or moderate hepatic impairment resulted in a modest increase in olanzapine and samidorphan exposure.

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Body Weight; Cigarette Smoking; Cytochrome P-450 CYP3A; Drug Combinations; Female; Food-Drug Interactions; Humans; Liver Failure; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Olanzapine; Racial Groups; Renal Insufficiency; Rifampin; Schizophrenia; Sex Factors; Young Adult

Although active tuberculosis (TB) is considered a contraindication for liver transplantation (LT), this is the only treatment in patients with liver failure and concurrent active TB. We report a case with successful urgent living-donor LT for irreversible liver failure in the presence of active TB.. A 48-year-old man, with a history of decompensated alcoholic liver cirrhosis, was presented with stupor. At admission, his consciousness had deteriorated to semi-coma, and his renal function also rapidly deteriorated to hepatorenal syndrome. A preoperative computed tomography scan of the chest revealed several small cavitary lesions in both upper lobes, and acid-fast bacillus stain from his sputum was graded 2+. Adenosine deaminase levels from ascites were elevated, suggesting TB peritonitis. A first-line anti-TB drug regimen was started immediately (rifampin, isoniazid, levofloxacin, and amikacin). An urgent living-donor LT was performed 2 days later. After LT, the regimen was changed to second-line anti-TB drugs (amikacin, levofloxacin, cycloserine, and pyridoxine). The sputum acid-fast bacillus stain tested negative on postoperative day 10. His liver function remained well preserved, even after the reversion to first-line anti-TB treatment. The patient recovered without any anti-TB medication-related complications and was discharged.. LT can be prudently performed as a life-saving option, particularly for patients with liver failure and concurrent active TB.

Topics: Antitubercular Agents; Humans; Isoniazid; Levofloxacin; Liver Failure; Liver Transplantation; Living Donors; Male; Middle Aged; Rifampin; Tuberculosis

Hepatocellular secretory failure induced by drugs, toxins or transient biliary obstruction may sometimes persist for months after removal of the initiating factor and may then be fatal without liver transplantation. We characterized patients with severe persistent hepatocellular secretory failure (PHSF) and treated them with the pregnane X receptor (PXR) agonist, rifampicin. We also studied the effect of rifampicin on PXR-dependent expression of genes involved in biotransformation and secretion in vitro.. Thirteen patients (age 18-81 years, 6 male) with hepatocellular secretory failure that persisted after removal of the inducing factor (drugs/toxin: 9) or biliary obstruction (4) were identified over 6 years. Six of these patients were screened for ATP8B1 or ABCB11 mutations. All were treated with rifampicin (300 mg daily) for 1-10 weeks. Expression of genes involved in biotransformation and secretion was determined by rtPCR in human hepatocytes and intestinal cells incubated with rifampicin (10 μmol/L).. Serum bilirubin of patients with PHSF ranged from 264 to 755 μmol/L. Normal γGT was found in 10/13 patients of whom 3/6 tested positive for ATP8B1/ABCB11 mutations. Serum bilirubin declined to <33 μmol/L after 1-10 weeks of rifampicin treatment. In vitro, rifampicin PXR-dependently upregulated biotransformation phase 1 (CYP3A4), phase 2 (UGT1A1) and phase 3 (MRP2) enzymes/carriers as well as the basolateral bile salt exporter OSTβ.. Persistent hepatocellular secretory failure may develop in carriers of transporter gene mutations. In severe cases, rifampicin may represent an effective therapeutic option of PHSF. PXR-dependent induction of CYP3A4, UGT1A1, MRP2 and OSTβ could contribute to the anticholestatic effect of rifampicin in PHSF.

Topics: Adenosine Triphosphatases; Adolescent; Adult; Aged; Aged, 80 and over; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bilirubin; Chemical and Drug Induced Liver Injury; Cholestasis; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Female; Genetic Predisposition to Disease; Glucuronosyltransferase; Hep G2 Cells; HT29 Cells; Humans; Liver; Liver Failure; Male; Membrane Transport Proteins; Middle Aged; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Mutation; Pregnane X Receptor; Receptors, Steroid; Rifampin; Risk Factors; Severity of Illness Index; Treatment Outcome; Up-Regulation; Young Adult

A 65-year-old female was started anti-tuberculous therapy for her pulmonary tuberculosis on admission. Liver dysfunction had occurred on 33rd day after starting treatment. AST was elevated to 301 IU/L, and ALT was also elevated to 141 IU/L. Therefore, all medicated drugs were stopped. She had jaundice on 42nd day and liver failure deteriorated. She was medicated with steroids, but she died by liver failure on 64th day. This is a rare case of fatal liver failure due to antituberculous therapy.

Topics: Aged; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Fatal Outcome; Female; Humans; Isoniazid; Liver Failure; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Antitubercular Agents; Diagnosis, Differential; Drug Hypersensitivity; Ethambutol; Exanthema; Fever; Humans; Isoniazid; Liver; Liver Failure; Male; Pyrazinamide; Pyridoxine; Rifampin; Skin; Tuberculosis, Pulmonary

Human hepatocytes were transplanted into urokinase-type plasminogen activator-transgenic SCID mice (uPA/SCID mice), which are immunodeficient and undergo liver failure. The transplanted cells were characterized in terms of their in vivo growth potential and functions. The human hepatocytes progressively repopulated the murine host liver. However, the recipients died when the replacement index (RI) of the human hepatocytes exceeded 50%. The hosts (chimeric mice) survived at RI >50% when treated with a drug that has anti-human complement factor activity, and these mice developed livers with RI values as high as 96%. In total, 36 chimeric mice were generated, and the rate of successful engraftment was as high as 92%. The yield of chimeric mice with RI >70% was 32%. The human hepatocytes in the murine host liver expressed mRNAs for a variety of human cytochrome P450 (hCYP) subtypes, in a manner that was similar to the donor liver. The mRNAs for hCYP3A4 and hCYP1A1/2 were induced in the liver in a CYP type-specific manner when the mice were treated with rifampicin and 3-methylcholanthrene, respectively. These results indicate that human hepatocytes that propagate in mice retain their normal pharmacological responses. We conclude that the chimeric mouse developed in the present study is a useful model for assessing the functions and pharmacological responses of human hepatocytes.

Topics: Adolescent; Adult; Albumins; Animals; Child; Chimera; Complement C3-C5 Convertases; Complement C3a; Cytochrome P-450 Enzyme System; Enzyme Induction; Enzyme Inhibitors; Hepatocytes; Heterozygote; Homozygote; Humans; In Situ Hybridization; Liver; Liver Failure; Male; Methylcholanthrene; Mice; Mice, SCID; Mice, Transgenic; Middle Aged; Rifampin; RNA, Messenger; Transplantation, Heterologous; Urokinase-Type Plasminogen Activator

Topics: Adverse Drug Reaction Reporting Systems; Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Drug Therapy, Combination; Humans; Liver Failure; Pyrazinamide; Rifampin; Tuberculosis; United States

The side effects of rifampicine due to an immunoallergic mechanism are rare and usually observed during discontinued treatment or administration of high doses.. An immediate hypersensitivity reaction with anaphylactic manifestations and increase in IgE occurred in a 39 year-old man suffering from resistant tuberculosis. The reaction occurred within the first hour following a low dose of rifampicin administered in a desensitisation attempt, the outcome of which was favourable after administration of corticosteroids and antihistamines. A type II hypersensitivity reaction occurred in a 76 year-old male patient in the form of thrombopenia on D76 of a twice weekly treatment, diagnosed because of hemoptysis with normalisation of platelet level on withdrawal of rifampicin. An immune complex hypersensitivity reaction was responsible for hepato-renal failure on D68 of twice weekly treatment and required permanent withdrawal of rifampicin and dialysis, which led to subsequent improvement.. These clinical cases illustrate the variability of the hypersensitivity mechanisms observed with rifampicin, the difficulty in imputability tests and methods for immunological confirmation, the interest of continuous treatment which avoids a certain number of these accidents, and that of desensitisation during immediate hypersensitive reactions which permits the continuation this major anti-tuberculosis drug.

Topics: Acute Kidney Injury; Adult; Aged; Anaphylaxis; Antibiotics, Antitubercular; Antigen-Antibody Complex; Desensitization, Immunologic; Drug Hypersensitivity; Humans; Hypersensitivity, Immediate; Liver Failure; Male; Platelet Count; Rifampin; Thrombocytopenia; Time Factors

We present the case of an elderly patient who died of fulminant hepatic failure in the course of receiving 2 months of treatment with pyrazinamide and rifampin for his latent tuberculosis. This 2-month course of treatment for latent tuberculosis is one of four options recently recommended by the Centers for Disease Control and Prevention. We discuss the safety of using this two-drug regimen to treat latent tuberculosis in stable elderly patients.

Topics: Aged; Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Humans; Liver Failure; Male; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

We report the case of a 28-year-old-prostitute from Thailand with HIV infection stage B2 associated with retroperitoneal lymph node tuberculosis. 6 days after the beginning of anti-tuberculous therapy (isoniazid, rifampicin, pyrazinamid and ethambutol) the temperature rose to 40.5 degrees C, diarrhea, vomiting, and tachycardia developed and systolic blood pressure fell to 80 mm Hg. Liver function tests revealed acute hepatic failure (ALT 800 IU/l rising to 1500; serum bilirubin 89 mumol/l rising to 238.0; alkaline phosphatase 199 IU/l; glucose 1.8 mmol/l; prothrombin time 20%). Isoniazid, rifampicin, and pyrazinamid were replaced by streptomycin and PAS. A few days after withdrawal the liver profile returned to normal. Hours after the reintroduction of rifampicin total body erythema, pruritus, vomiting and severe hypotension developed, requiring saline methylprednisolone and epinephrine administration. The next reexposure to intravenous rifampicin produced a rash and was rapidly discontinued. Liver function tests remained normal. Later mild adverse reactions to streptomycin and pyrazinamid occurred, two drugs which had been well tolerated before. Subsequently the diagnosis of adrenal insufficiency was established. After initiation of steroid replacement (50 mg prednisolone) the antituberculous therapy with isoniazid, pyrazinamid and ethambutol was well tolerated. We conclude that the shock in this HIV-infected patient was either due to severe anaphylaxis to rifampicin or acute adrenal insufficiency ensuing on this drug. The reversible fulminant acute hepatic failure represents either an adverse effect of antituberculous drugs, especially hepatotoxic interactions of drug combinations, or an ischemic liver injury during hypotension caused by anaphylaxis. The case illustrates the complex nature of side effects of antituberculous drugs in HIV patients and their aggravation by adrenal insufficiency.

Topics: Adrenal Insufficiency; Adult; Anaphylaxis; Antibiotics, Antitubercular; Female; HIV Infections; Humans; Liver Failure; Prednisolone; Rifampin

Hepatotoxicity by antituberculous drugs is well known. Nonetheless, severe liver involvement is infrequent. Several series of fulminant hepatitis by antituberculous drugs have recently been reported with a much greater frequency than previously reported. The present study describes the authors' experience which, similar to other groups, has shown a marked increase with respect to previous experience. During 1994 5 patients with acute severe hepatitis associated to antituberculous drugs were admitted to the authors' unit. The mean age of the patients was 43 years (range: 25-62). Two patients were healthy HBsAg carriers, one undergoing enzymatic inducer treatment and was anti-HIV positive. Another patient presented compensated liver cirrhosis by HCV. The 5 cases received combined isoniazid and rifampicin and four had also received pyrazinamide. Four patients presented hepatic encephalopathy. Of these cases, three could not undergo emergency liver transplantation because of contraindications and died due to complications of acute severe liver failure. Another patient evolved favorably following emergency liver transplantation. The only patient who presented good evolution with conservative treatment and who did not present hepatic encephalopathy had discontinued isoniazid because of the finding of slight hypertransaminasemia during a routine analytical control. Several risk factors have been reported for the appearance of hepatotoxicity by antituberculous drugs. The factor of greatest clinical importance for the development of severe hepatotoxicity is probably continuation of the treatment once hepatic dysfunction has initiated. The important increase in cases of severe toxicity urges the need for strict analytical monitoring following initiation of treatment.

Topics: Acute Disease; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Hepatic Encephalopathy; Humans; Isoniazid; Liver; Liver Failure; Liver Transplantation; Male; Middle Aged; Pyrazinamide; Rifampin