HIV-1 Coinfection Does Not Reduce Exposure to Rifampin, Isoniazid, and Pyrazinamide in South African Tuberculosis Outpatients

ABSTRACTThere are contrasting data in the literature about antituberculosis plasma drug concentrations in HIV-1-coinfected patients. We report the pharmacokinetics of rifampin, isoniazid, and pyrazinamide in a cohort of patients being treated for active tuberculosis, the majority of whom were coinfected with HIV-1 and had commenced antiretroviral therapy within 2 months of starting antituberculosis treatment. We also examined the association between antituberculosis drug concentrations and reported drug side effects at the 2-month clinical review. One hundred patients with pulmonary tuberculosis (65% coinfected with HIV-1) were intensively sampled to determine rifampin, isoniazid, and pyrazinamide plasma concentrations after 7 to 8 weeks of a daily quadruple-therapy regimen dosed according to World Health Organization (WHO) weight bands. Pharmacokinetic parameters were determined for each patient by using nonlinear mixed-effects models. HIV-1-coinfected patients had lower clearance rates for rifampin (21% decrease) and isoniazid (23% decrease) than HIV-1-uninfected patients, with resulting higher areas under the concentration-time curve from 0 to 24 h (AUC0–24) and maximum concentrations of drug in serum (Cmax). Antiretroviral therapy (ART) that included double-standard-dose lopinavir/ritonavir further lowered rifampin clearance, by 46%, and increased the AUC0–24. The current uniform dosing (per kilogram of body weight) across WHO weight bands was associated with a trend of decreased pharmacokinetic exposures for the lowest weight band. Use of fat-free mass as opposed to total body weight for allometric scaling of clearance significantly improved the model. Ambulant HIV-1-coinfected patients, the majority of whom were coprescribed ART, did not have reduced antituberculosis drug concentrations compared to HIV-1-uninfected patients.

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Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02600-15 ◽

2016 ◽

Vol 60 (4) ◽

pp. 2171-2179 ◽

Cited By ~ 27

Author(s):

A. Bekker ◽

H. S. Schaaf ◽

H. R. Draper ◽

L. van der Laan ◽

S. Murray ◽

...

Keyword(s):

Drug Disposition ◽

Treatment Guidelines ◽

Geometric Mean ◽

Plasma Concentrations ◽

World Health ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Data ◽

Maximum Plasma ◽

Antituberculosis Treatment ◽

The Mean

ABSTRACTThere are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive pharmacokinetic sampling was performed in infants routinely receiving antituberculosis treatment, including rifampin, isoniazid, pyrazinamide, and ethambutol, using World Health Organization-recommended doses. Regulatory-approved single-drug formulations, including two rifampin suspensions, were used on the sampling day. Assays were conducted using liquid chromatography-mass spectrometry; pharmacokinetic parameters were generated using noncompartmental analysis. Thirty-nine infants were studied; 14 (36%) had culture-confirmed tuberculosis. Fifteen (38%) were premature (<37 weeks gestation); 5 (13%) were HIV infected. The mean corrected age and weight were 6.6 months and 6.45 kg, respectively. The mean maximum plasma concentrations (Cmax) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 μg/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 μg/ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC0–8) were 12.1, 24.7, 239.4, and 5.1 μg · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed inCmax(geometric mean ratio [GMR],2.55; 95% confidence interval [CI], 1.47 to 4.41;P= 0.001) and AUC0–8(GMR, 2.52; 95% CI, 1.34 to 4.73;P= 0.005). HIV status was associated with lower pyrazinamideCmax(GMR, 0.85; 95% CI, 0.75 to 0.96;P= 0.013) and AUC0–8(GMR, 0.79; 95% CI, 0.69 to 0.90;P< 0.001) values. No other important differences were observed due to age, weight, prematurity, ethnicity, or gender. In summary, isoniazid and pyrazinamide concentrations in infants compared well with proposed adult target concentrations; ethambutol concentrations were lower but similar to previously reported pediatric studies. The low rifampin exposures require further investigation. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637558.)

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A Pilot Study of Immune Activation and Rifampin Absorption in HIV-Infected Patients without Tuberculosis Infection: A Short Report

Tuberculosis Research and Treatment ◽

10.1155/2017/2140974 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7

Author(s):

Christopher Vinnard ◽

Isabel Manley ◽

Brittney Scott ◽

Mariana Bernui ◽

Joella Adams ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Pilot Study ◽

Bacterial Translocation ◽

Immune Activation ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Short Report ◽

Hiv Viral Load ◽

Time Curve ◽

Immunodeficiency Virus

Background. Rifampin malabsorption is frequently observed in tuberculosis patients coinfected with human immunodeficiency virus (HIV) but cannot be predicted by patient factors such as CD4+ T cell count or HIV viral load. Methods. We sought to describe the relationship between HIV-associated immune activation, measures of gut absorptive capacity and permeability, and rifampin pharmacokinetic parameters in a pilot study of 6 HIV-infected, tuberculosis-uninfected patients who were naïve to antiretroviral therapy. Results. The median rifampin area under the concentration-versus-time curve during the 8-hour observation period was 42.8 mg·hr/L (range: 21.2 to 57.6), with a median peak concentration of 10.1 mg/L (range: 5.3 to 12.5). We observed delayed rifampin absorption, with a time to maximum concentration greater than 2 hours, in 2 of 6 participants. There was a trend towards increased plasma concentrations of sCD14, a marker of monocyte activation in response to bacterial translocation, among participants with delayed rifampin absorption compared to participants with rapid absorption (p=0.06). Conclusions. Delayed rifampin absorption may be associated with elevated markers of bacterial translocation among HIV-infected individuals naïve to antiretroviral therapy. This trial is registered with NCT01845298.

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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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Association of Suboptimal Antiretroviral Therapy Adherence With Inflammation in Virologically Suppressed Individuals Enrolled in the SMART Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx275 ◽

2017 ◽

Vol 5 (1) ◽

Cited By ~ 4

Author(s):

Jose R Castillo-Mancilla ◽

Andrew N Phillips ◽

James D Neaton ◽

Jacqueline Neuhaus ◽

Simon Collins ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Confidence Interval ◽

Cohort Studies ◽

Plasma Concentrations ◽

Virologic Suppression ◽

Art Adherence ◽

Antiretroviral Therapy Adherence ◽

Smart Study ◽

Hiv 1 ◽

D Dimer

Abstract Suboptimal (ie, <100%) antiretroviral therapy (ART) adherence has been associated with heightened inflammation in cohort studies, even among people with virologic suppression. We aimed to evaluate this association among participants in the Strategies for Management of Antiretroviral Therapy (SMART) study who had virologic suppression (HIV-1 VL < 200 copies/mL) at enrollment. Based on self-reported adherence (7-day recall), plasma concentrations of interleukin 6 and D-dimer were 9% (95% confidence interval [CI], 1%–18%; P = .02) and 11% (95% CI, 1%–22%; P = .03) higher in participants who reported suboptimal vs 100% adherence, respectively. These findings confirm previous observations and support the hypothesis that suboptimal ART adherence, even in the context of virologic suppression, may have significant biological consequences. ClinicalTrials.gov number NCT00027352

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Plasma Drug Level Validates Self-Reported Adherence but Predicts Limited Specificity for Nonadherence to Antiretroviral Therapy

ISRN Pharmacology ◽

10.5402/2012/274978 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Robert Balikuddembe ◽

Joshua Kayiwa ◽

David Musoke ◽

Muhammad Ntale ◽

Steven Baveewo ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Low Income ◽

Plasma Levels ◽

Plasma Concentrations ◽

Drug Level ◽

Low Income Countries ◽

Plasma Drug ◽

Cross Sectional ◽

Drug Concentrations ◽

Emergence Of Resistance

Introduction. Adherence to antiretroviral therapy (ART) in low-income countries is mainly assessed by self-reported adherence (S-RA) without drug level determination. Nonadherence is an important factor in the emergence of resistance to ART, presenting a need for drug level determination. Objective. We set out to establish the relationship between plasma stavudine levels and S-RA and validate S-RA against the actual plasma drug concentrations. Methods. A cross-sectional investigation involving 234 patients in Uganda. Stavudine plasma levels were determined using high-performance liquid chromatography. We compared categories of plasma levels of stavudine with S-RA using multivariable logistic regression models. Results. Overall, 194/234 patients had S-RA ≥ 95% (good adherence) and 166/234 had stavudine plasma concentrations ≥ 36 nmol/L (therapeuticconcentration). Patients with good S-RA were eight times more likely to have stavudine levels within therapeutic concentration (Adjusted Odds Ratio: 7.7, 95% Confidence Interval: 3.5–7.0). However, of the 194 patients with good S-RA, 21.7% had below therapeutic concentrations. S-RA had high sensitivity for adherence (91.6%), but limited specificity for intrinsic poor adherence (38.2%). Conclusions. S-RA is a good tool for assessing adherence, but has low specificity in detecting nonadherence, which has implications for emergence of resistance.

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Are Prophylactic and Therapeutic Target Concentrations Different?: the Case of Lopinavir-Ritonavir or Lamivudine Administered to Infants for Prevention of Mother-to-Child HIV-1 Transmission during Breastfeeding

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01869-16 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 2

Author(s):

Frantz Foissac ◽

Jörn Blume ◽

Jean-Marc Tréluyer ◽

Thorkild Tylleskär ◽

Chipepo Kankasa ◽

...

Keyword(s):

South African ◽

Population Analysis ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Pharmacokinetic Parameters ◽

Breastfed Infants ◽

Trough Concentrations ◽

Therapeutic Doses ◽

Mother To Child ◽

Hiv 1

ABSTRACT The ANRS 12174 trial assessed the efficacy and tolerance of lopinavir (LPV)-ritonavir (LPV/r) prophylaxis versus those of lamivudine (3TC) prophylaxis administered to breastfed infants whose HIV-infected mothers were not on antiretroviral therapy. In this substudy, we assessed LPV/r and 3TC pharmacokinetics to evaluate the percentage of infants with therapeutic plasma concentrations and to discuss these data in the context of a prophylactic treatment. Infants from the South African trial site underwent blood sampling for pharmacokinetic study at weeks 6, 26, and 38 of life. We applied a Bayesian approach to derive the 3TC and LPV pharmacokinetic parameters on the basis of previously published pharmacokinetic models for HIV-infected children. We analyzed 114 LPV and 180 3TC plasma concentrations from 69 infants and 92 infants, respectively. A total of 30 LPV and 20 3TC observations were considered missing doses and discarded from the Bayesian analysis. The overall population analysis showed that 30 to 40% of the infants did not reach therapeutic targets, regardless of treatment group. The median LPV trough concentrations at weeks 6, 26, and 38 were 2.8 mg/liter (interquartile range [IQR], 1.7 to 4.4 mg/liter), 5.6 mg/liter (IQR, 3.2 to 7.7 mg/liter), and 3.4 mg/liter (IQR, 2.3 to 7.3 mg/liter), respectively. The median 3TC area under the curve from 0 to 12 h after the last drug intake were 5.6 mg · h/liter (IQR, 4.1 to 7.8 mg · h/liter), 5.9 mg · h/liter (IQR, 5.1 to 7.5 mg · h/liter), and 7.3 mg · h/liter (IQR, 4.9 to 8.5 mg · h/liter) at weeks 6, 26, and 38, respectively. Use of the therapeutic doses recommended by the WHO would have resulted in a higher proportion of infants achieving the targets. However, no HIV-1 infection was reported among these infants. These results suggest that the prophylactic targets for both 3TC and LPV may be lower than the therapeutic ones. For treatment, the WHO dosing guidelines should be suitable to maintain values above the therapeutic pharmacokinetic targets in most infants. (This study has been registered at ClinicalTrials.gov under identifier NCT00640263.)

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Comparative Study on Pharmacokinetics of Four Long-Acting Injectable Formulations of Enrofloxacin in Pigs

Frontiers in Veterinary Science ◽

10.3389/fvets.2020.604628 ◽

2021 ◽

Vol 7 ◽

Author(s):

Salah Uddin Ahmad ◽

Jichao Sun ◽

Fusheng Cheng ◽

Bing Li ◽

Safia Arbab ◽

...

Keyword(s):

Comparative Study ◽

High Performance ◽

Pasteurella Multocida ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Reference Formulation ◽

Time Curve ◽

Drug Concentrations ◽

Long Acting

A comparative study on pharmacokinetics of four long-acting enrofloxacin injectable formulations was investigated in 36 healthy pigs after intramuscular injection according to the recommended single dose @ 2.5 mg/kg body weight. The drug concentrations in the plasma were computed using high-performance liquid chromatography (HPLC) with fluorescence detection. WinNonLin5.2.1 software was used to analyze the experimental data and compared it under one-way ANOVA using SPSS software with a 95% confidence interval (CI). The main pharmacokinetic parameters, that is, the maximum plasma concentrations (Cmax), the time to maximum concentration (Tmax), area under the time curve concentration (AUCall) and Terminal half-life (T1/2) were 733.84 ± 129.87, 917.00 ± 240.13, 694.84 ± 163.49, 621.98 ± 227.25 ng/ml, 2.19 ± 0.0.66, 1.50 ± 0.37, 2.89 ± 0.24, 0.34 ± 0.13 h, 7754.43 ± 2887.16, 8084.11 ± 1543.98, 7369.42 ± 2334.99, 4194.10 ± 1186.62 ng h/ml, 10.48 ± 2.72, 10.37 ± 2.38, 10.20 ± 2.81, and 10.61 ± 0.86 h for 10% enrofloxacin (Alkali), 20% enrofloxacin (Acidic), Yangkang and control drug Nuokang® respectively. There were significant differences among Cmax, Tmax, and AUCall of three formulations compare with that of the reference formulation. No significant differences were observed among the T1/2 for tested formulations compare with the reference formulation. The pharmacokinetic parameters showed that the tested formulations were somewhat better compared to the reference one. The calculated PK/PD indices were effective for bacteria such as Actinobacillus pleuropneumoniae and Pasteurella multocida with values higher than the cut-off points (Cmax/MIC90≥10–12 and AUC/MIC90 ≥ 125). However, they were not effective against bacteria like Haemophilus parasuis, Streptococcus suis, E. coli, and Bordetella bronchiseptica where lower values were obtained.

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Abstract 350: Influence of HIV-1 Infection and Antiretroviral Therapy on the Coagulation System

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a350 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Kevin Fasing ◽

Brian R Weil ◽

Kyle J Diehl ◽

Jared J Greiner ◽

Brian L Stauffer ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Factor Viii ◽

Tissue Factor ◽

Plasma Concentrations ◽

Tissue Type ◽

Factor Vii ◽

Coagulation System ◽

Factor X ◽

Thrombotic Risk ◽

Hiv 1

HIV-1-infected individuals have a two- to four-fold greater incidence of cardiovascular disease and atherothrombotic events compared with the general population. The mechanisms responsible for this heightened cardiovascular risk are not fully understood. We have previously reported that the capacity of the endothelium to release tissue-type plasminogen activator (t-PA), the primary activator of fibrinolysis and a key endogenous defense mechanism against intravascular fibrin deposition and thrombosis, is impaired in HIV-1-seropositive adults. Whether diminished fibrinolytic activity is coupled with a hypercoagulative state in this population is unknown. Elevations in specific coagulation markers such as tissue factor and Factor VII are associated with increased thrombotic risk. The experimental aim of this study was to determine the influence of HIV-1 infection and antiretroviral therapy (ART) on markers of coagulation. To address this aim we studied 33 men: 16 HIV-1-seronegative (age: 41±3 yr); 7 HIV-1-seropositive treatment-naïve (34±2 yr); and 10 HIV-1-seropositive receiving ART (42±3 yr; efavirenz-based regimen). All subjects were non-obese, normotensive and free of overt cardiometabolic disease. Circulating concentrations of tissue factor, Factor VII, Factor VIII and Factor X were determined by immunoassay. There were no significant differences in plasma concentrations of tissue factor (32+3 vs 40+3 pg/mL), Factor VII (103+9 vs 100+5 %), Factor VIII (111+13 vs 117+8 %) and Factor X (89+5 vs 91+2 %) between HIV-1-seropositive treatment-naïve and healthy men. Moreover, there was no influence of ART on these circulating markers. Plasma tissue factor (41+5 pg/mL), Factor VII (107+6 %), Factor VIII (103+7 %) and Factor X (90+3%) were similar in the HIV-1-seropositive receiving ART compared with HIV-1-seropositive treatment-naïve and seronegative groups. These data suggest that neither HIV-1 infection per se nor ART are associated with unfavorable changes in specific coagulation markers. Thus, changes in the coagulation system that have been linked to increased thrombotic burden are not apparent in HIV-1-seropositive adults.

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Pharmacokinetics of Ethionamide in Children

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00379-11 ◽

2011 ◽

Vol 55 (10) ◽

pp. 4594-4600 ◽

Cited By ~ 20

Author(s):

S. Thee ◽

H. I. Seifart ◽

B. Rosenkranz ◽

A. C. Hesseling ◽

K. Magdorf ◽

...

Keyword(s):

Body Weight ◽

Oral Dose ◽

Age Groups ◽

Serum Levels ◽

Pharmacokinetic Parameters ◽

Concomitant Treatment ◽

Older Children ◽

Maximum Serum ◽

Antituberculosis Treatment ◽

Dose Recommendations

ABSTRACTEthionamide (ETH), a second-line antituberculosis drug, is frequently used in treating childhood tuberculosis. Data supporting ETH dose recommendations in children are limited. The aim of this study was to determine the pharmacokinetic parameters for ETH in children on antituberculosis treatment including ETH. ETH serum levels were prospectively assessed in 31 children in 3 age groups (0 to 2 years, 2 to 6 years, and 6 to 12 years). Within each age group, half received rifampin (RMP). Following an oral dose of ETH (15 to 20 mg/kg of body weight), blood samples were collected at 0, 1, 2, 3, 4, and 6 h following 1 and 4 months of ETH therapy. The maximum serum concentration (Cmax), time toCmax(Tmax), and area under the time-concentration curve from 0 to 6 h (AUC0–6) were calculated. Younger children were exposed to lower ETH concentrations than older children at the same mg/kg body weight dose. Age correlated significantly with the AUC after both 1 month (r= 0.50,P= 0.001) and 4 months (r= 0.63,P= 0.001) of therapy. There was no difference in the AUC orCmaxbetween children receiving concomitant treatment with RMP and those who did not. Time on treatment did not influence the pharmacokinetic parameters of ETH following 1 and 4 months of therapy. HIV infection was associated with lower ETH exposure. In conclusion, ETH at an oral dose of 15 to 20 mg/kg results in sufficient serum concentrations compared to current adult recommended levels in the majority of children across all age groups. ETH levels were influenced by young age and HIV status but were not affected by concomitant RMP treatment and duration of therapy.

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