Phase 1 study to evaluate the effects of rifampin or itraconazole on the pharmacokinetics of limertinib (ASK120067), a novel mutant-selective inhibitor of the epidermal growth factor receptor in healthy Chinese subjects.

BACKGROUND: Limertinib is a novel mutant-selective and irreversible inhibitor of the epidermal growth factor receptor under development. A phase 1 open, two-period, single-sequence, self-controlled, two-part study was initiated to characterize the effects of a strong CYP3A4 inducer (rifampin) or inhibitor (itraconazole) on the pharmacokinetics of limertinib. RESEARCH DESIGN AND METHODS: Twenty-four healthy subjects in each part received a single dose of limertinib alone (160 mg, Part A; 80 mg, Part B) and with multiple doses of rifampin 600 mg once daily (Part A) or itraconazole 200 mg twice daily (Part B). RESULTS: Coadministration of rifampin decreased exposure (area under the plasma concentration-time curve from time 0 to infinity, AUC0-inf) of limertinib and its active metabolite CCB4580030 by 87.86% (geometric least-squares mean [GLSM] ratio, 12.14%; 90% confidence interval [CI], 9.89-14.92) and 66.82% (GLSM ratio, 33.18%; 90% CI, 27.72-39.72), respectively. Coadministration of itraconazole increased the AUC0-inf of limertinib by 289.8% (GLSM ratio, 389.8%; 90% CI, 334.07-454.82), but decreased that of CCB4580030 by 35.96% (GLSM ratio, 64.04%; 90% CI, 50.78-80.77). CONCLUSIONS: Our study demonstrates that the concomitant use of limertinib with strong CYP3A inducers or inhibitors is not recommended. A single dose of limertinib, administered with or without rifampin or itraconazole, is generally safe and well tolerated in healthy Chinese subjects. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05631678.

Single-Dose Rifapentine in Household Contacts of Patients with Leprosy.

BACKGROUND: Previous studies have suggested that a single dose of rifampin has protective effects against leprosy in close contacts of patients with the disease. Rifapentine was shown to have greater bactericidal activity against Mycobacterium leprae than rifampin in murine models of leprosy, but data regarding its effectiveness in preventing leprosy are lacking. METHODS: We conducted a cluster-randomized, controlled trial to investigate whether single-dose rifapentine is effective in preventing leprosy in household contacts of patients with leprosy. The clusters (counties or districts in Southwest China) were assigned to one of three trial groups: single-dose rifapentine, single-dose rifampin, or control (no intervention). The primary outcome was the 4-year cumulative incidence of leprosy among household contacts. RESULTS: A total of 207 clusters comprising 7450 household contacts underwent randomization; 68 clusters (2331 household contacts) were assigned to the rifapentine group, 71 (2760) to the rifampin group, and 68 (2359) to the control group. A total of 24 new cases of leprosy occurred over the 4-year follow-up, for a cumulative incidence of 0.09% (95% confidence interval [CI], 0.02 to 0.34) with rifapentine (2 cases), 0.33% (95% CI, 0.17 to 0.63) with rifampin (9 cases), and 0.55% (95% CI, 0.32 to 0.95) with no intervention (13 cases). In an intention-to-treat analysis, the cumulative incidence in the rifapentine group was 84% lower than that in the control group (cumulative incidence ratio, 0.16; multiplicity-adjusted 95% CI, 0.03 to 0.87; P = 0.02); the cumulative incidence did not differ significantly between the rifampin group and the control group (cumulative incidence ratio, 0.59; multiplicity-adjusted 95% CI, 0.22 to 1.57; P = 0.23). In a per-protocol analysis, the cumulative incidence was 0.05% with rifapentine, 0.19% with rifampin, and 0.63% with no intervention. No severe adverse events were observed. CONCLUSIONS: The incidence of leprosy among household contacts over 4 years was lower with single-dose rifapentine than with no intervention. (Funded by the Ministry of Health of China and the Chinese Academy of Medical Sciences; Chinese Clinical Trial Registry number, ChiCTR-IPR-15007075.).

Improvement of cholestatic episodes in patients with benign recurrent intrahepatic cholestasis (BRIC) treated with rifampicin. A long-term follow-up.

OBJECTIVE: Patients with benign recurrent intrahepatic cholestasis (BRIC) suffer from recurrent episodes of cholestatic jaundice. Treatment options remain limited and are mainly symptomatic. In case reports rifampicin, plasmapheresis, and nasobiliary drainage have been reported to be effective. In this case series, we present long-term experience indicating disease-modifying effects of non-invasive treatment with rifampicin for recurrent cholestasis in BRIC type 1 (BRIC1). MATERIALS AND METHODS: We included all adult BRIC1 patients diagnosed and followed up at a single centre in Bergen, Norway. Data regarding clinical and biochemical features during BRIC attacks with and without rifampicin treatment were retrieved from medical journals and a data registry. RESULTS: Five males with BRIC1 were included. Median age at diagnosis was 22 years (range 15-41). Together they had suffered from 65 cholestatic attacks (including four documented abortive attacks). Twenty-eight attacks were treated with rifampicin alone over the last 12 years; all cases showed symptomatic relief and reduction in the levels of bilirubin and alkaline phosphatase in blood. The attacks treated with rifampicin seemed to have shorter duration and were less likely to result in complications or hospitalization compared to attacks prior to the introduction of rifampicin. No side effects attributable to rifampicin were noted. CONCLUSIONS: Episodic treatment of recurrent BRIC1 attacks with rifampicin seems to ameliorate severity and shorten the duration of attacks. Timely diagnosis and effective treatment are of major importance in BRIC, not only to decrease complications but also improving patients' quality of life.

Using the Food and Drug Administration´s Sentinel System for surveillance of TB infection.

BACKGROUND: We examined patterns in care for individuals treated for latent TB infection (LTBI) in the US Food and Drug Administration´s Sentinel System.METHODS: Using administrative claims data, we identified patients who filled standard LTBI treatment prescriptions during 2008-2019. In these cohorts, we assessed LTBI testing, clinical management, and treatment duration.RESULTS: Among 113,338 patients who filled LTBI prescriptions, 80% (90,377) received isoniazid (INH) only, 19% (21,235) rifampin (RIF) only, and 2% (1,726) INH + rifapentine (RPT). By regimen, the proportion of patients with documented prior testing for TBI was 79%, 54%, and 91%, respectively. Median therapy duration was 84 days (IQR 35-84) for the 3-month once-weekly INH + RPT regimen, 60 days (IQR 30-100) for the 6- to 9-month INH regimen, and 30 days (IQR 2-60) for the 4-month RIF regimen.CONCLUSIONS: Among the cohorts, INH-only was the most commonly prescribed LTBI treatment. Most persons who filled a prescription for LTBI treatment did not have evidence of completing recommended treatment duration. These data further support preferential use of shorter-course regimens such as INH + RPT.

Comparison of three short-course rifamycin-based regimens for the prevention of tuberculosis in patients with end-stage kidney disease: Study protocol for a randomised clinical trial (RIFAKiD-TB trial).

BACKGROUND AND PURPOSE: Screening for and treatment of latent tuberculosis (TB) in patients with end-stage kidney disease (ESKD) are recommended. However, there is limited evidence on safety and treatment completion in this population. The objective of the study is to evaluate three short-course rifamycin-based regimens for the treatment of latent TB in ESKD patients. METHODS: Study design and setting. This is a prospective, open label, randomized clinical trial, that will be conducted at seven teaching hospitals in Spain. Study population, randomization, and interventions. Consecutive adult patients with ESKD requiring treatment for a latent TB infection will be randomly allocated (1:1:1) to receive one of the three treatment regimens of the study: three months of daily isoniazid plus rifampicin (3HR); three months of once-weekly isoniazid plus rifapentine (3HP); or four months of daily rifampicin (4R). Participants will be followed regularly through pre-established visits and a blood test schedule from enrolment to a month after finishing the assigned treatment. Outcomes. The primary outcome will be treatment completion, while the secondary outcomes will be discontinuation of the assigned treatment due to adverse events, related or unrelated to the study treatment; definitive discontinuation of the assigned treatment because of adverse events related to the treatment of the study, and death. Sample size. Two hundred and twenty-five subjects (75 per arm) will be enrolled, which will enable the demonstration, if it exists, of an increase of 0.16 in treatment completion rates either in the 3HP or 4R arm with respect to the 3HR arm. DISCUSSION: Results of this clinical trial will contribute to evidence-based recommendations on the management of latent TB infection in ESKD patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05021731.

Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children.

BACKGROUND: Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen. METHODS: We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment. RESULTS: From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups). CONCLUSIONS: Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.).

Evaluation of CYP2C19 activity using microdosed oral omeprazole in humans.

PURPOSE: To investigate the suitability of microdosed oral omeprazole for predicting CYP2C19 activity in vivo in combination with simultaneous assessment of CYP3A and CYP2D6 activity using both microdosed midazolam and yohimbine. METHODS: An open, fixed-sequence study was carried out in 20 healthy participants. Single microdosed (100 µg) and therapeutic (20 mg) doses of omeprazole were evaluated without comedication and after administration of established CYP2C19 perpetrators fluconazole (inhibition) and rifampicin (induction). To prevent degradation of the uncoated omeprazole microdose, sodium bicarbonate buffer was administered. The pharmacokinetics of omeprazole and its 5-hydroxy-metabolite were assessed as well as the pharmacokinetics of midazolam and yohimbine to estimate CYP3A4 and CYP2D6 activity. RESULTS: Calculated pharmacokinetic parameters after administration of 100 µg and 20 mg omeprazole in healthy subjects suggest dose proportionality. Omeprazole clearance was significantly decreased by fluconazole from 388 [95% CI: 266-565] to 47.2 [42.8-52.0] mL/min after 20 mg omeprazole and even further after 100 µg omeprazole (29.4 [24.5-35.1] mL/min). Rifampicin increased CYP2C19-mediated omeprazole metabolism. The omeprazole hydroxylation index was significantly related to omeprazole clearance for both doses. Both fluconazole and rifampicin altered CYP3A4 activity whereas no change of CYP2D6 activity was observed at all. CONCLUSIONS: Microdosed oral omeprazole is suitable to determine CYP2C19 activity, also during enzyme inhibition and induction. However, the administration of sodium bicarbonate buffer also had a small influence on all victim drugs used. TRIAL REGISTRATION: EudraCT: 2017-004270-34.

Prevention, inhibition, and degradation effects of melittin alone and in combination with vancomycin and rifampin against strong biofilm producer strains of methicillin-resistant Staphylococcus epidermidis.

Methicillin-resistant Staphylococcus epidermidis (MRSE) bacteria are being recognized as true pathogens as they are able to resist methicillin and commonly form biofilms. Recent studies have shown that antimicrobial peptides (AMPs) are promising agents against biofilm-associated bacterial infections. In this study, we aimed to explore the antibiofilm activity of melittin, either alone or in combination with vancomycin and rifampin, against biofilm-producing MRSE strains. Minimum biofilm preventive concentration (MBPC), minimum biofilm inhibition concentration (MBIC), and minimum biofilm eradication concentration (MBEC), as well as fractional biofilm preventive-, inhibitory-, and eradication concentrations (FBPCi, FBICi, and FBECi), were determined for the antimicrobial agents tested. Cytotoxicity and hemolytic activity of melittin at its synergistic concentration were examined on human embryonic kidney cells (HEK-293) and Red Blood Cells (RBCs), respectively. The effect of melittin on the downregulation of biofilm-associated genes was explored using Real-Time PCR. MBPC, MBIC, and MBEC values for melittin were in the range of 0.625-20, 0.625-20, and 10-40 µg/µL, respectively. Melittin showed high synergy (FBPCi, FBICi and FBECi < 0.5). The synergism resulted in a 64-512-fold, 2-16 and 2-8-fold reduction in melittin, rifampicin and vancomycin concentrations, respectively. The synergistic melittin concentration found to be effective did not manifest either cytotoxicity on HEK-293 or hemolytic activity on RBCs. Results showed that melittin downregulated the expression of biofilm-associated icaA, aap, and psm genes in all isolates tested, ranging from 0.04-folds to 2.11-folds for icaA and from 0.05 to 3.76-folds for aap and psm. The preventive and therapeutic indexes of melittin were improved 8-fold when combined with vancomycin and rifampin. Based on these findings, the combination of melittin with conventional antibiotics could be proposed for treating or preventing biofilm-associated MRSE infections.

Interim Guidance: 4-Month Rifapentine-Moxifloxacin Regimen for the Treatment of Drug-Susceptible Pulmonary Tuberculosis - United States, 2022.

On May 5, 2021, CDC's Tuberculosis Trials Consortium and the National Institutes of Health (NIH)-sponsored AIDS Clinical Trials Group (ACTG) published results from a randomized controlled trial indicating that a 4-month regimen containing rifapentine (RPT), moxifloxacin (MOX), isoniazid (INH), and pyrazinamide (PZA) was as effective as the standard 6-month regimen for tuberculosis (TB) treatment (1). On the basis of these findings, CDC recommends the 4-month regimen as a treatment option for U.S. patients aged ≥12 years with drug-susceptible pulmonary TB and provides implementation considerations for this treatment regimen.

Protective Effect of Rifampicin Loaded by HPMA-PLA Nanopolymer on Macrophages Infected with Mycobacterium Tuberculosis.

PURPOSE: This research was designed to investigate the protective effect of rifampicin (RIF) loaded by N-(2-hydroxypropyl) methylacrylamide- (HPMA-) polylactic acid (PLA) nanopolymer on macrophages infected with Mycobacterium tuberculosis (MTB). METHODS: We first induced H37Rv to infect macrophages to build a cell model. Then, the HPMA-PLA nanopolymer loaded with RIF was prepared to treat MTB-infected macrophages. The macrophage activity was tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the nitric oxide (NO) in cells was measured through Griess reagent, and the bacterial activity of MTB was observed via the colony-forming unit (CFU) assay. The inflammation-related factors in cells were detected via the enzyme-linked immunosorbent assay (ELISA), the apoptosis of macrophages was examined via flow cytometry, and the expression of apoptosis-related proteins was determined by western blot (WB). RESULTS: HPMA-PLA had no obvious toxicity to macrophages. The expression of NO and inflammatory factors in macrophages infected with MTB increased significantly, but the apoptosis rate was not significantly different from that of uninfected cells. However, after treatment with HPMA-PLA-RIF or free RIF, the inflammatory reaction of infected cells was inhibited, the expression of NO was decreased, the apoptosis rate was increased, and the bacterial activity in cells was decreased, with statistically significant differences; moreover, HPMA-PLA-RIF was more effective than free RIF. CONCLUSIONS: HPMA-PLA-RIF has a high protective effect on macrophages infected with MTB, with high safety. Its protective mechanism is at least partly through inhibiting the production of NO and inflammatory response, which can inhibit bacterial activity and induce cell apoptosis.

Acute and Chronic Effects of Rifampin on Letermovir Suggest Transporter Inhibition and Induction Contribute to Letermovir Pharmacokinetics.

Rifampin has acute inhibitory and chronic inductive effects that can cause complex drug-drug interactions. Rifampin inhibits transporters including organic-anion-transporting polypeptide (OATP)1B and P-glycoprotein (P-gp), and induces enzymes and transporters including cytochrome P450 3A, UDP-glucuronosyltransferase (UGT)1A, and P-gp. This study aimed to separate inhibitory and inductive effects of rifampin on letermovir disposition and elimination (indicated for cytomegalovirus prophylaxis in hematopoietic stem cell transplant recipients). Letermovir is a substrate of UGT1A1/3, P-gp, and OATP1B, with its clearance primarily mediated by OATP1B. Letermovir (single-dose) administered with rifampin (single-dose) resulted in increased letermovir exposure through transporter inhibition. Chronic coadministration with rifampin (inhibition plus potential OATP1B induction) resulted in modestly decreased letermovir exposure vs. letermovir alone. Letermovir administered 24 hours after the last rifampin dose (potential OATP1B induction) resulted in markedly decreased letermovir exposure. These data suggest rifampin may induce transporters that clear letermovir; the modestly reduced letermovir exposure with chronic rifampin coadministration likely reflects the net effect of inhibition and induction. OATP1B endogenous biomarkers coproporphyrin (CP) I and glycochenodeoxycholic acid-sulfate (GCDCA-S) were also analyzed; their exposures increased after single-dose rifampin plus letermovir, consistent with OATP1B inhibition and prior reports of inhibition by rifampin alone. CP I and GCDCA-S exposures were substantially reduced with letermovir administered 24 hours after the last dose of rifampin vs. letermovir plus chronic rifampin coadministration. This study suggests that OATP1B induction may contribute to reduced letermovir exposure after chronic rifampin administration, although given the complexity of letermovir disposition alternative mechanisms are not fully excluded.

Effects of Cytochrome P450 3A4 Induction and Inhibition on the Pharmacokinetics of BI 425809, a Novel Glycine Transporter 1 Inhibitor.

BACKGROUND AND OBJECTIVE: Increased glycine availability at the synaptic cleft may enhance N-methyl-D-aspartate receptor signalling and provide a promising therapeutic strategy for cognitive impairment associated with schizophrenia. These studies aimed to assess the pharmacokinetics of BI 425809, a potent glycine-transporter-1 inhibitor, when co-administered with a strong cytochrome P450 3A4 (CYP3A4) inhibitor (itraconazole) and inducer (rifampicin). METHODS: In vitro studies using recombinant CYPs, human liver microsomes, and human hepatocytes were conducted to determine the CYP isoforms responsible for BI 425809 metabolism. In addition, two open-label, fixed-treatment period, phase I studies in healthy male volunteers are described. Period 1: participants received oral BI 425809 25 mg (single dose) on day 1; period 2: participants received multiple doses, across 10 days, of oral itraconazole or rifampicin combined with a single dose of oral BI 425809 25 mg on day 4/7 of the itraconazole/rifampicin treatment, respectively. Pharmacokinetic and safety endpoints were assessed in the absence/presence of itraconazole/rifampicin and included area under the concentration-time curve (AUC) over the time interval 0-167 h (AUC0‒167; itraconazole), 0-168 h (AUC0‒168; rifampicin), or 0-infinity (AUC0-∞; rifampicin and itraconazole), maximum measured concentration (Cmax) of BI 425809, and adverse events. RESULTS: In vitro results suggested that CYP3A4 accounted for ≥ 90% of the metabolism of BI 425809. BI 425809 exposure (adjusted geometric mean ratio [%]) was higher in the presence of itraconazole (AUC0‒167: 265.3; AUC0-∞: 597.0; Cmax: 116.1) and lower in the presence of rifampicin (AUC0‒168: 10.3; AUC0-∞: 9.8; Cmax: 37.4) compared with BI 425809 alone. Investigational treatments were well tolerated. CONCLUSIONS: Systemic exposure of BI 425809 was altered in the presence of strong CYP3A4 modulators, corroborating in vitro results that CYP3A4 mediates a major metabolic pathway for BI 425809. TRIAL REGISTRATION NUMBER: NCT02342717 (registered on 15 January 2015) and NCT03082183 (registered on 10 March 2017).

Moxifloxacin Concentrations in the Knee Joint, Tibial Bone, and Soft Tissue When Combined with Rifampicin: A Randomized Porcine Microdialysis Study.

BACKGROUND: Peri and postoperative antibiotics are key adjuvant treatment tools in the management of periprosthetic joint infection (PJI). The aim of this study was to evaluate the effect of rifampicin on the area under the moxifloxacin concentration-time curve from 0 to 24 hours (AUC0-24) in the synovial fluid of the knee joint, tibial bone, and adjacent subcutaneous tissue under steady-state conditions using microdialysis in a porcine model. METHODS: Twenty female pigs were randomized to receive oral treatment with moxifloxacin monotherapy (Group A, n = 10) of 400 mg once daily for 3 days or a combination therapy (Group B, n = 10) of 400 mg of moxifloxacin once daily for 3 days and 450 mg of rifampicin twice daily for 7 days. Microdialysis was used for sampling the synovial fluid of the knee joint, tibial cancellous and cortical bone, and adjacent subcutaneous tissues. Plasma samples were taken as a reference. Measurements were obtained for 24 hours. RESULTS: Coadministration of moxifloxacin and rifampicin resulted in reductions of the moxifloxacin AUC0-24 in all targeted tissue compartments by 67% to 85% (p < 0.05). The corresponding change in plasma was 20% (p = 0.49). For both groups, the tissue penetration (the ratio of tissue free fraction AUC0-24 to plasma free fraction AUC0-24 [fAUCtissue/fAUCplasma]) was incomplete in all investigated compartments. The highest moxifloxacin tissue penetration was in the knee joint synovial fluid: 0.59 (Group A) and 0.24 (Group B). The lowest tissue penetration was in the cortical bone: 0.17 (Group A) and 0.03 (Group B). CONCLUSIONS: We found a significant reduction of the moxifloxacin concentration, expressed as the AUC0-24, in tissues relevant to acute PJI treatment when coadministered with rifampicin. CLINICAL RELEVANCE: The concentrations within the targeted tissue compartments were reduced significantly more than the concentrations in plasma, which may be particularly important as plasma concentrations are used in clinical practice to assess moxifloxacin treatment sufficiency.

Rifampin and ritonavir increase oral availability and elacridar enhances overall exposure and brain accumulation of the NTRK inhibitor larotrectinib.

INTRODUCTION: Larotrectinib is an FDA-approved oral small-molecule inhibitor for neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive cancer treatment. Here larotrectinib pharmacokinetic behavior upon co-administration with prototypical inhibitors of the efflux transporters ABCB1/ABCG2 (elacridar), the SLCO1A/1B (OATP1A/1B) uptake transporters (rifampin), and the drug-metabolizing enzyme CYP3A (ritonavir), respectively, was investigated. METHODS: Inhibitors were orally administered prior to oral larotrectinib (10 mg/kg) to relevant genetically modified mouse models. Larotrectinib plasma and tissue homogenate concentrations were measured by a liquid chromatography-tandem mass spectrometric assay. RESULTS: Elacridar increased oral availability (2.7-fold) and markedly improved brain-to-plasma ratios (5.0-fold) of larotrectinib in wild-type mice. Mouse (m)Oatp1a/1b but not hepatic transgenic human (h)OATP1B1 or -1B3 restricted larotrectinib oral availability and affected its tissue distribution. Rifampin enhanced larotrectinib oral availability not only in wild-type mice (1.9-fold), but surprisingly also in Slco1a/1b-/- mice (1.7-fold). Similarly, ritonavir increased the larotrectinib plasma exposure in both wild-type (1.5-fold) and Cyp3a-/- mice (1.7-fold). Intriguingly, both rifampin and ritonavir decreased liver and/or intestinal larotrectinib levels in all related experimental groups, suggesting additional inhibition of enterohepatic Abcb1a/1b activity. CONCLUSIONS: Elacridar enhances both larotrectinib plasma and tissue exposure and especially relative brain penetration, which might be therapeutically relevant. Hepatic mOatp1a/1b but not hOATP1B1 or -1B3 transported larotrectinib. Additionally, rifampin enhances larotrectinib systemic exposure, most likely by inhibiting mOatp1a/1b, but probably also hepatic and/or intestinal mAbcb1. Similar to rifampin, dual-inhibition functions of ritonavir affecting both CYP3A enzymes and enterohepatic Abcb1 transporters enhanced larotrectinib oral availability. The obtained insights may be used to further optimize the clinical-therapeutic application of larotrectinib.

Leveraging Human Plasma-Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Cytochrome P450 3A4 by Modafinil.

Preparations of plasma-derived small extracellular vesicles (sEVs) were deployed as liquid biopsy to study cytochrome P450 (CYP) 3A4 (CYP3A4) induction following modafinil 400 mg once daily × 14 days (young healthy volunteers, N = 10 subjects). Induction was confirmed using the 4ß-hydroxycholesterol-to-cholesterol (4ßHC/C) ratio, a plasma CYP3A4/5 biomarker, with a mean 2.1-fold increase (Day 15 vs. Day 1; 90% confidence interval (CI) = 1.8-2.3; P value = 0.0004). Proteomic analysis revealed the induction (mean Day 15 vs. Day 1 fold-increase (90% CI)) of both liver (1.3 (1.1-1.5), P value = 0.014) and nonliver (1.9 (1.6-2.2), P value = 0.04) sEV CYP3A4 protein expression. In CYP3A5 nonexpresser subjects, the baseline (pre-dose) 4ßHC/C plasma ratio was more highly correlated with liver sEVs (r = 0.937, P value = 0.001) than nonliver sEVs (r = 0.619, P value = 0.101) CYP3A4 protein expression. When CYP3A5 expressers (CYP3A5*1/*3) were included, the correlation with liver sEVs (r = 0.761, P value = 0.011) and nonliver sEVs (r = 0.391, P value = 0.264) CYP3A4 protein was weaker. Although modafinil-induced changes in plasma 4ßHC/C ratio did not correlate with sEVs CYP3A4 protein expression, the individual subject sEVs proteomic data were used successfully to predict victim drug (midazolam, triazolam, dextromethorphan, 17α-ethinylestradiol, and abemaciclib) area under the plasma concentration-time curve (AUC) ratios (AUCRs) following modafinil. Based on the AUCR values, modafinil was classified as a weak to moderate CYP3A4 inducer (vs. rifampicin). For the first time, it was possible to deploy plasma-derived sEVs to study CYP3A4 induction beyond rifampicin, a more potent CYP3A4 inducer.

Treatment of spinal tuberculosis in rabbits using bovine serum albumin nanoparticles loaded with isoniazid and rifampicin.

OBJECTIVE: To evaluate the clinical efficacy of bovine serum albumin nanoparticles loaded with isoniazid and rifampicin (INH-RFP-BSA-NPs) in the treatment of spinal tuberculosis in rabbits. METHODS: 35 spinal tuberculosis rabbit models were grouped into three groups, including 14 in group A and group B respectively and 7 in group C.All rabbits in group A were treated by INH-RFP-BSA-NPs's injection and in group B were treated with classic dosage form of INH and RFP, while in group C normal saline was given as the blank control. After intervention, the body weighing and CT scan, as well as concentration's measurement of INH and RFP in blood and tissues, were performed in all rabbits at the time of the 6thweek and 12th week, respectively. RESULTS: In group A, rabbits' weight increased by 0.44 kg and 0.27 kg within 6 weeks and 12 weeks' treatment respectively. The bactericidal concentrations of 1.64 µg•g-1 for INH and 21.36 µg•g-1 for RFP were measured in focus vertebral body 6 weeks post-injection and six weeks later the concentrations of INH and RFP in vertebral body still maintained at the level of 1.96 µg•g-1 and 22.35 µg•g-1respectively. After 12 weeks therapy, CT-scanned showed all the necrotic tissue was replaced by normal bone tissue. In group B, all rabbits had no significant increment of body weight and 4 rabbits had paralysis of hind leg. The concentrations of INH and RFP in vertebral body and focus were much lower than group A. CT-scanned showed the focus vertebral body was only partially repaired after 12 weeks' therapy. CONCLUSION: The INH-RFP-BSA-NPs has the characteristics of sustained release in vivo and target biodistribution in focus vertebral body. Its therapeutic effect in rabbit spinal tuberculosis is much better than common INH and RFP.