rifampin and Multiple-Myeloma

Iberdomide is a cereblon E3 ligase modulator capable of redirecting the protein degradation machinery of the cell towards the elimination of target proteins potentially driving therapeutic effects. In vitro studies demonstrated that iberdomide predominantly undergoes oxidative metabolism mediated by cytochrome P450 (CYP) 3A4/5 but had no notable inhibition or induction of CYP enzymes. Consequently, the potential of iberdomide as a victim of drug-drug interactions (DDI) was evaluated in a clinical study with healthy subjects.. A total of 33 males and 5 females with 19 subjects per part were enrolled. Part 1 evaluated the pharmacokinetics (PK) of iberdomide alone (0.6 mg) and when administered with the CYP3A and P-gp inhibitor itraconazole (200 mg twice daily on day 1 and 200 once daily on days 2 through 9). Part 2 evaluated the PK of iberdomide alone (0.6 mg) and with CYP3A4 inducer rifampin (600 mg QD days 1 through 13). Plasma concentrations of iberdomide and the active metabolite M12 were determined by validated liquid chromatography-tandem mass spectrometry assay.. Coadministration of iberdomide with itraconazole increased iberdomide peak plasma concentration (C. Caution should be taken when coadministering iberdomide with strong CYP3A inhibitors. Coadministration of iberdomide with strong CYP3A inducers is not advised.. Clinical trial identification number is NCT02820935 and was registered in July 2016.

Topics: Adult; Area Under Curve; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Healthy Volunteers; Heterocyclic Compounds, 4 or More Rings; Humans; Immunologic Factors; Itraconazole; Lupus Erythematosus, Systemic; Male; Microsomes, Liver; Middle Aged; Morpholines; Multiple Myeloma; Phthalimides; Piperidones; Rifampin; Young Adult

Bortezomib, an antineoplastic agent with proteasome inhibitory activity, is extensively metabolized by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19. Drugs that affect these enzymes may therefore have an impact on the pharmacological profile of bortezomib. This study evaluated the effects of co-administration of a potent CYP3A4 inducer (rifampicin [rifampin]) and a weak CYP3A4 inducer (dexamethasone) on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib.. Patients aged ≥18 years with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma received intravenous bortezomib 1.3 mg/m2, administered on days 1, 4, 8 and 11 of a 21-day cycle, for 3 cycles. In stage 1, patients were randomized (1 : 1) to receive bortezomib alone or in combination with oral rifampicin 600 mg once daily on days 4-10 during cycle 3 only. If the mean area under the plasma concentration-time curve (AUC) of bortezomib was reduced by ≥30% during rifampicin co-administration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40 mg once daily on days 1-4 and days 9-12 during cycle 3 only. Blood samples were collected on days 11 through 14 of cycles 2 and 3 before and after bortezomib administration, at prespecified time points, for pharmacokinetic and pharmacodynamic (proteasome inhibition) assessments.. Twelve patients in the bortezomib-alone arm, six patients in the bortezomib plus rifampicin arm and seven patients in the bortezomib plus dexamethasone arm were included in the pharmacokinetics-evaluable set. Rifampicin reduced the mean AUC from 0 to 72 hours (AUC(72h)) of bortezomib by approximately 45% (223 ng · h/mL in cycle 2 vs 123 ng · h/mL in cycle 3), while dexamethasone had no effect (mean AUC(72h): 179 ng · h/mL in cycle 2 vs 170 ng · h/mL in cycle 3). Proteasome inhibition parameters in peripheral blood were unaffected by rifampicin or dexamethasone. Safety profiles were similar across the treatment arms and consistent with previous experience of bortezomib.. In patients with multiple myeloma or non-Hodgkin's lymphoma, co-administration of rifampicin decreased the exposure to bortezomib but did not affect the proteasome inhibition or safety profiles; co-administration of dexamethasone did not affect the exposure to bortezomib, proteasome inhibition or safety profiles. Concomitant administration of bortezomib with strong CYP3A4 inducers such as rifampicin is not recommended, as it may result in a reduction of the clinical effect, whereas concomitant administration of weak CYP3A4 inducers such as dexamethasone does not affect the pharmacological profile of bortezomib.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Boronic Acids; Bortezomib; Cytochrome P-450 CYP3A; Dexamethasone; Drug Combinations; Enzyme Induction; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Protease Inhibitors; Pyrazines; Rifampin

Pneumatosis intestinalis (PI), defined as intestinal intra- and extramural gas accumulation, is a rare radiographic finding in conditions of intestinal wall damage of varied etiology. Here, we report on a 56-year-old female with multiple myeloma who presented with undulating fever, fluctuating abdominal symptoms, and a distended abdomen 5 months after allogeneic hematopoietic stem cell transplantation (HSCT). Abdominal X-ray and CT scan documented PI with gas accumulation both in the intestinal and colonic bowel walls. Concurrently, thoracic CT revealed mediastinal and bihilar lymphadenopathy associated with bilateral pleural effusions. Microscopy of bronchoalveolar lavage fluid (BALF) revealed acid-fast bacilli, which were identified as Mycobacterium tuberculosis. Tuberculostatic treatment resulted in timely clinical improvement, a complete clearance of the radiological and clinical findings of PI, and the control of the tuberculosis (Tbc), determined by multiple negative BALF results. Taken together, PI occurred as the initial symptom of Tbc in an allogeneic stem cell recipient, achieving complete recovery by tuberculostatic treatment only.

Topics: Antineoplastic Combined Chemotherapy Protocols; Antitubercular Agents; Bronchoalveolar Lavage Fluid; Female; Hematopoietic Stem Cell Transplantation; Humans; Isoniazid; Middle Aged; Multiple Myeloma; Mycobacterium tuberculosis; Pleural Effusion; Pneumatosis Cystoides Intestinalis; Rifampin; Tomography, X-Ray Computed; Treatment Outcome; Tuberculosis, Pulmonary

We hypothesize that a large group of medical conditions of unknown etiology including leukemia, multiple myeloma, myelodysplastic and autoimmune disorders, may be associated with or caused by an obscure group of intracellular obligate parasitic bacteria named Ehrlichia/Anaplasma (EA). Ensconced in the stem cells of the bone marrow, EA may disrupt the normal development and function of many of the cells of immunity, manifesting itself as different syndromes. Recent studies of the activity of EA suggest direct effects on the immune system consistent with the manifestations of leukemia. We reference here three leukemia patients with direct or indirect evidence of EA infection. Moreover, EA have been shown to be most sensitive to rifamycins. Two moribund leukemia patients with levels of platelets and white cells incompatible with life were treated with therapeutic doses of Rifampin. Though they did not survive, their condition improved dramatically for a time, suggesting Rifampin provided some therapeutic benefit. We assert that these results warrant more extensive study.

Topics: Adolescent; Anti-Bacterial Agents; Autoimmune Diseases; Blood Platelets; Ehrlichia; Ehrlichiosis; Female; Humans; Immune System; Leukemia; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Polycythemia Vera; Polymerase Chain Reaction; Rifampin

Topics: Antibiotics, Antitubercular; Diagnosis, Differential; Female; Foot Dermatoses; Humans; Isoniazid; Middle Aged; Multiple Myeloma; Pyoderma Gangrenosum; Rifampin; Tuberculosis, Cutaneous

Acute renal failure developed in a patient with a normal serum creatinine level, after treatment with rifampin was begun for tuberculosis. Renal biopsy revealed an obstructive nephropathy due to tubular casts. Immunoperoxidase and immunofluorescence studies demonstrated the presence of heterogeneous light chains within these casts. This unique drug-induced renal disease is discussed with reference to the literature and to possible analogies with myeloma kidney.

Topics: Acute Kidney Injury; Adult; Humans; Immunoglobulin Light Chains; Kidney; Male; Multiple Myeloma; Rifampin; Tuberculosis, Pulmonary