Clinical relevance of rifampicin-moxifloxacin interaction in isoniazid resistant/intolerant tuberculosis patients.

Moxifloxacin is an attractive drug for the treatment of isoniazid-resistant rifampicin-susceptible tuberculosis (TB) or drug-susceptible TB complicated by isoniazid intolerance. However, co-administration with rifampicin decreases moxifloxacin exposure. It remains unclear whether this drug-drug interaction has clinical implications. This retrospective study in a Dutch TB centre investigated how rifampicin affected moxifloxacin exposure in patients with isoniazid-resistant or –intolerant TB. Moxifloxacin exposures were measured between 2015 and 2020 in 31 patients with isoniazid-resistant or –intolerant TB receiving rifampicin, and 20 TB patients receiving moxifloxacin without rifampicin. Moxifloxacin exposure, i.e. area under the concentration-time curve (AUC 0-24h ), and attainment of AUC 0-24h /minimal inhibitory concentration (MIC) > 100 were investigated for 400 mg moxifloxacin and 600 mg rifampicin, and increased doses of moxifloxacin (600 mg) or rifampicin (900 mg). Moxifloxacin AUC 0–24h and peak concentration with a 400 mg dose were decreased when rifampicin was co-administered compared to moxifloxacin alone (ratio of geometric means 0.61 (90% CI (0.53, 0.70) and 0.81 (90% CI (0.70, 0.94), respectively). Among patients receiving rifampicin, 65% attained an AUC 0-24h /MIC > 100 for moxifloxacin compared to 78% of patients receiving moxifloxacin alone; this difference was not significant. Seven out of eight patients receiving an increased dose of 600 mg moxifloxacin reached the target AUC 0-24h /MIC > 100. This study showed a clinically significant 39% decrease in moxifloxacin exposure when rifampicin was co-administered. Moxifloxacin dose adjustment may compensate for this drug-drug interaction. Further exploring the impact of higher doses of these drugs in patients with isoniazid resistance or intolerance is paramount.

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Faculty of 1000 evaluation for Lack of a clinically significant drug-drug interaction in healthy volunteers between the HCV protease inhibitor boceprevir and the HIV integrase inhibitor raltegravir.

F1000 - Post-publication peer review of the biomedical literature ◽

10.3410/f.717958759.793470403 ◽

2013 ◽

Author(s):

Glenn Tillotson

Keyword(s):

Drug Interaction ◽

Protease Inhibitor ◽

Healthy Volunteers ◽

Integrase Inhibitor ◽

Hiv Integrase ◽

Hcv Protease ◽

Drug Drug Interaction ◽

Clinically Significant

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Ginsenoside Absorption Rate and Extent Enhancement of Black Ginseng (CJ EnerG) over Red Ginseng in Healthy Adults

Pharmaceutics ◽

10.3390/pharmaceutics13040487 ◽

2021 ◽

Vol 13 (4) ◽

pp. 487

Author(s):

Saebyul Yoo ◽

Bom-I Park ◽

Do-hyun Kim ◽

Sooyoung Lee ◽

Seung-hoon Lee ◽

...

Keyword(s):

Clinical Trial ◽

Molecular Weight ◽

Absorption Rate ◽

Systemic Exposure ◽

Red Ginseng ◽

Double Blind ◽

Time Curve ◽

Concentration Time ◽

Black Ginseng ◽

Clinically Significant

Red ginseng (RG) and black ginseng (BG, CJ EnerG) were prepared from fresh ginseng using one and nine cycles of steaming and drying, respectively. This process reduces the molecular weight (MW) of ginsenoside-active compounds in ginseng by removing sugar moieties from their dammaranes. We compared the pharmacokinetic characteristics of ginsenosides between BG comprising mainly low-MW ginsenosides (Rg3, Rg5, Rk1, and Rh1) and RG that predominantly contains high-MW ginsenosides (Rb1, Rb2, Rc, Rd, Re, and Rg1). The safety profiles and tolerability were also studied using a randomized, double-blind, single-dose, crossover clinical trial. A combination of Rb1, Rg1, and Rg3, well-known representative and functional RG components, exhibited a 1-h faster absorption rate (Tmax) and 58% higher exposure (24-h area under the concentration–time curve, AUC24) in BG than in RG. Furthermore, the combination of Rg3, Rg5, and Rk1, the major and most efficient components in BG, displayed 824% higher absorption (AUC24) in BG than in RG. The total ginsenoside showed a 5-h rapid intestinal absorption (Tmax) and 79% greater systemic exposure (AUC24) in BG than in RG. No clinically significant findings were observed in terms of safety or tolerability. Thus, BG extract was more effective than RG extract.

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Pharmacokinetic Interactions between the Hormonal Emergency Contraception, Levonorgestrel (Plan B), and Efavirenz

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/2012/137192 ◽

2012 ◽

Vol 2012 ◽

pp. 1-4 ◽

Cited By ~ 45

Author(s):

Monica L. Carten ◽

Jennifer J. Kiser ◽

Awewura Kwara ◽

Samantha Mawhinney ◽

Susan Cu-Uvin

Keyword(s):

Geometric Mean ◽

Liver Function Tests ◽

Open Label ◽

Time Curve ◽

Geometric Means ◽

Concentration Time ◽

Plan B ◽

Effective Contraception ◽

Grade 3 ◽

Hiv Negative

Objectives. Compare the Plan B levonorgestrel (LNG) area under the concentration- time curve (AUC12) prior to and with efavirenz (EFV).Design. Prospective, open-label, single-arm, equivalence study.Methods. Healthy HIV-negative subjects underwent 12 hr intensive pharmacokinetic (PK) sampling following single dose LNG alone and after 14 days of EFV. Geometric means, Geometric Mean Ratios, and 90% confidence intervals (CI) are reported for PK Parameters.T-tests were utilized. Clinical parameters and liver function tests (LFTs) were assessed.Results. 24 women enrolled and 21 completed the study. With EFV, LNG AUC12was reduced 56% (95% CI: 49%, 62%) from 42.9 to 17.8 ng*hr/mL, and maximum concentration (Cmax⁡) was reduced 41% (95% CI: 33%, 50%) from 8.4 to 4.6 ng/mL. LNG was well tolerated with no grade 3 or 4 treatment-related toxicities.Conclusions. EFV significantly reduced LNG exposures. Higher LNG doses may be required with EFV. These results reinforce the importance of effective contraception in women taking EFV.

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The Impact of Isoniazid Resistance on the Treatment Outcomes of Smear Positive Re-Treatment Tuberculosis Patients in the State of Andhra Pradesh, India

PLoS ONE ◽

10.1371/journal.pone.0076189 ◽

2013 ◽

Vol 8 (10) ◽

pp. e76189 ◽

Cited By ~ 14

Author(s):

Dorai Deepa ◽

Shanta Achanta ◽

Jyoti Jaju ◽

Koteswara Rao ◽

Rani Samyukta ◽

...

Keyword(s):

Treatment Outcomes ◽

Andhra Pradesh ◽

The State ◽

Isoniazid Resistance ◽

Tuberculosis Patients ◽

The Impact

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Determinants of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Pharmacokinetics in a Cohort of Tuberculosis Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.50.4.1170-1177.2006 ◽

2006 ◽

Vol 50 (4) ◽

pp. 1170-1177 ◽

Cited By ~ 136

Author(s):

Helen McIlleron ◽

Peter Wash ◽

André Burger ◽

Jennifer Norman ◽

Peter I. Folb ◽

...

Keyword(s):

Antituberculosis Drug ◽

Time Curve ◽

Tuberculosis Patients ◽

Treatment Regimens ◽

Concentration Time ◽

Antituberculosis Treatment ◽

Drug Concentrations ◽

Patients At Risk ◽

History Of ◽

Dosing Strategy

ABSTRACT Evaluation of sources of pharmacokinetic variation can facilitate optimization of tuberculosis treatment regimens by identification of avoidable sources of variation and of risk factors for low or high drug concentrations in patients. Our objective was to describe the pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in a cohort of tuberculosis patients established on first-line treatment regimens and to evaluate the determinants of pharmacokinetic variation. Plasma concentration-time profiles were determined for each of the drugs in 142 patients with drug-sensitive pulmonary tuberculosis after 2 months of daily treatment in hospital. Pharmacokinetic measures were described by noncompartmental analysis. Multiple linear regression was used to evaluate the patient and the treatment factors associated with variation of the area under the concentration-time curve from 0 to 8 h. Several factors independently associated with variations in antituberculosis drug concentrations were identified: human immunodeficiency virus infection was associated with 39% and 27% reductions for rifampin and ethambutol, respectively; formulation factors were determinants of rifampin and isoniazid bioavailability; female patients had increased rifampin and isoniazid concentrations but reduced ethambutol concentrations; older patients had higher levels of isoniazid and ethambutol; patients with a history of previous antituberculosis treatment had lower ethambutol concentrations; and the dose per kilogram of body weight was associated with the concentrations of all four agents. Further studies are required to assess the implications of variations in antituberculosis drug concentrations for efficacy and safety before decisions are made to change the dosing strategy in patients at risk.

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Lack of Effect of Simultaneously Administered Didanosine Encapsulated Enteric Bead Formulation (Videx EC) on Oral Absorption of Indinavir, Ketoconazole, or Ciprofloxacin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.2.385-391.2002 ◽

2002 ◽

Vol 46 (2) ◽

pp. 385-391 ◽

Cited By ~ 30

Author(s):

Bharat D. Damle ◽

Vanaja Mummaneni ◽

Sanjeev Kaul ◽

Catherine Knupp

Keyword(s):

Oral Absorption ◽

Historical Data ◽

Point Estimate ◽

Open Label ◽

Time Curve ◽

Geometric Means ◽

Point Estimates ◽

Concentration Time ◽

Crossover Studies ◽

Post Hoc

ABSTRACT Didanosine formulation that contains a buffer to prevent it from acid-mediated degradation can result in a significant decrease in the oral absorption of certain drugs because of interactions with antacids. An enteric formulation of didanosine is unlikely to cause such drug interactions because it lacks antacids. This study was undertaken to determine whether the enteric bead formulation of didanosine (Videx EC) influences the bioavailability of indinavir, ketoconazole, and ciprofloxacin, three drugs that are representative of a broader class of drugs affected by interaction with antacids. Healthy subjects of either gender were enrolled in three separate open-label, single-dose, two-way crossover studies. Subjects were randomized to treatment A (800 mg of indinavir, 200 mg of ketoconazole, or 750 mg of ciprofloxacin) or treatment B (same dose of indinavir, ketoconazole, or ciprofloxacin, but with 400 mg of didanosine as an encapsulated enteric bead formulation). A lack of interaction was concluded if the 90% confidence interval (CI) of the ratio of the geometric means of log-transformed C max and AUC0-∞ values (i.e., values for the area under the concentration-time curve from time zero to infinity) of indinavir, ketoconazole, and ciprofloxacin were contained entirely between 0.75 and 1.33. For indinavir (n = 23), the point estimate (90% CI; minimum, maximum) of the ratios of C max and AUC0-∞ values were 0.99 (0.91, 1.06) and 0.96 (0.91, 1.02), respectively. In the ketoconazole study, 3 of 24 subjects showed anomalous absorption of ketoconazole (i.e., an ∼8-fold-lower AUC compared to historical data), which was the reference treatment. A post hoc analysis performed after these three subjects were excluded indicated that the point estimates (90% CI) of the ratios of Cmax and AUC0-∞ values were 0.99 (0.86, 1.14) and 0.97 (0.85, 1.10), respectively. For ciprofloxacin (n = 16), the point estimate (90% CI) of the ratios of C max and AUC0-∞ values were 0.92 (0.79, 1.07) and 0.91 (0.76, 1.08), respectively. All three studies clearly indicated a lack of interaction. The T max and t 1/2 for indinavir, ketoconazole, and ciprofloxacin were similar between treatments. Our results showed that the lack of interaction of didanosine encapsulated enteric bead formulation with indinavir, ketoconazole, and ciprofloxacin indicates that this enteric formulation of didanosine can be concomitantly administered with drugs whose bioavailability is known to be reduced by interaction with antacids.

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Phase I and Pharmacokinetic Study of Temozolomide on a Daily-for-5-Days Schedule in Patients With Advanced Solid Malignancies

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.8.2604 ◽

1999 ◽

Vol 17 (8) ◽

pp. 2604-2604 ◽

Cited By ~ 83

Author(s):

Lisa A. Hammond ◽

John R. Eckardt ◽

Sharyn D. Baker ◽

S. Gail Eckhardt ◽

Margaret Dugan ◽

...

Keyword(s):

Oral Dose ◽

Single Oral Dose ◽

Hematologic Toxicity ◽

Targeted Therapeutics ◽

Time Curve ◽

Concentration Time ◽

Solid Malignancies ◽

Cumulative Rate ◽

Heavily Pretreated ◽

Higher Doses

PURPOSE: To determine the principal toxicities, characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-for-5-days schedule, and recommend a dose for subsequent disease-directed studies in both minimally pretreated (MP) and heavily pretreated (HP) patients. PATIENTS AND METHODS: Patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150, and 150 to 200 mg/m2/d in separate cohorts of MP and HP patients. PK plasma was sampled on days 1 and 5. TMZ concentrations were analyzed and pertinent PK parameters were related to the principal toxicities of TMZ in PD analyses. RESULTS: Twenty-four patients were treated with 85 courses of TMZ. Thrombocytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive effects was unacceptably high at TMZ doses exceeding 150 mg/m2/d in both MP and HP patients. TMZ was absorbed rapidly with maximum concentrations achieved in 0.90 hours, on average, and elimination was rapid, with a half-life and systemic clearance rate (ClS/F) averaging 1.8 hours and 115 mL/min/m2, respectively. When clearance was normalized to body-surface area (BSA), interpatient variability in ClS/F was reduced from 20% to 13% on day 1 and from 16% to 10% on day 5. Patients who experienced DLT had significantly higher maximum drug concentration (median 16 v 9.5 μg/mL, P = .0084) and area under the concentration-time curve (median 36 v 23 μg-h/mL, P = .0019) values on day 5. CONCLUSION: Prior myelosuppressive therapy was not a determinant of toxicity. TMZ 150 mg/m2/d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by MP and HP patients, with higher doses resulting in unacceptably high rates of severe hematologic toxicity. TMZ doses should be individualized according to BSA rather than use of a prespecified oral dose for all individuals. TMZ is an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies.

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