Reduced Antituberculosis Drug Concentrations in HIV-Infected Patients Who Are Men or Have Low Weight: Implications for International Dosing Guidelines

McIlleron, Helen; Rustomjee, Roxana; Vahedi, Mahnaz; Mthiyane, Thuli; Denti, Paolo; Connolly, Catherine; Rida, Wasima; Pym, Alexander S.; Smith, Peter J.; Onyebujoh, Philip

doi:10.1128/aac.05526-11

Cited by 90 publications

(104 citation statements)

References 37 publications

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“…Their baseline characteristics are presented in Table 1, and further information can be found in the previous report (12). The median weight, FFM, and height were 55.2 kg, 42.2 kg, and 1.59 m, respectively.…”

Section: Demographicsmentioning

confidence: 99%

“…Additionally, a sample was collected at approximately 12 h before the 15th dose. Details of plasma separation and storage and quantitation of drug concentrations were as reported before (12). The lower limit of quantitation was 0.1 mg/liter.…”

Section: Methodsmentioning

confidence: 99%

“…Extensive details of this study, including design, patient selection, and dose administration, have been reported before (12). Two four-drug fixed-dose combinations (FDCs) were administered; each tablet contained 150 mg of rifampin, 75 mg of isoniazid, 400 mg of pyrazinamide, and 275 mg of ethambutol.…”

Section: Methodsmentioning

confidence: 99%

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Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction

Chirehwa

Rustomjee

Mthiyane

et al. 2016

Antimicrob Agents Chemother

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Rifampin is a key sterilizing drug in the treatment of tuberculosis (TB). It induces its own metabolism, but neither the onset nor the extent of autoinduction has been adequately described. Currently, the World Health Organization recommends a rifampin dose of 8 to 12 mg/kg of body weight, which is believed to be suboptimal, and higher doses may potentially improve treatment outcomes. However, a nonlinear increase in exposure may be observed because of saturation of hepatic extraction and hence this should be taken into consideration when a dose increase is implemented. Intensive pharmacokinetic (PK) data from 61 HIV-TBcoinfected patients in South Africa were collected at four visits, on days 1, 8, 15, and 29, after initiation of treatment. Data were analyzed by population nonlinear mixed-effects modeling. Rifampin PKs were best described by using a transit compartment absorption and a well-stirred liver model with saturation of hepatic extraction, including a first-pass effect. Autoinduction was characterized by using an exponential-maturation model: hepatic clearance almost doubled from the baseline to steady state, with a half-life of around 4. Rifampin is a key drug in the treatment of tuberculosis (TB), and the World Health Organization (WHO) currently recommends weight-adjusted doses of 8 to 12 mg/kg daily. Despite its being used in the treatment of TB for nearly 50 years, there is evidence that current rifampin exposures may be suboptimal. Rifampin's efficacy is exposure dependent (1-3); therefore, the efficacy and toxicity of higher doses are under investigation. Recent reports show that larger doses of rifampin are well tolerated by humans (4) and may improve treatment outcomes, as well as reduce the treatment duration from the current 6 months (5, 6).Rifampin is mainly hepatically cleared, and it undergoes extensive first-pass metabolism (7), whose saturation with higher doses has been reported since early pharmacokinetic (PK) studies (8). Thus, when the rifampin dose is increased above a certain level, a more-than-proportional increase in the plasma rifampin concentration results. Rifampin also induces its own metabolism via the pregnane X receptor (9), a phenomenon known as clearance autoinduction, resulting in less exposure at steady state than after a single dose.Previous studies have proposed rifampin PK models (10), but those trying to characterize clearance autoinduction have done so mostly by relying on only two PK sampling occasions (11), which limited their ability to characterize the process. Nonlinearity in a dose-exposure relationship suggesting saturation of rifampin clearance has been reported (8). However, a population PK model has not jointly described the autoinduction and hepatic extraction (E H ) of rifampin. In this study, we analyzed rich data from an intensive sampling scheme to develop a rifampin PK model for TB patients that accounts for both clearance autoinduction and saturation of E H . This model was then employed to explore changes in rifampin exposure when doses are incr...

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Section: Demographicsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction

Chirehwa

Rustomjee

Mthiyane

et al. 2016

Antimicrob Agents Chemother

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“…Low rifampin exposure among undernourished TB HIV-coinfected patients has been reported previously; a study by Polasa et al assessing rifampin kinetics in undernourished individuals shows that AUC and C max were reduced in undernourished individuals compared to individuals with normal BMI (9). McIlleron et al also reported reduced rifampin exposure among undernourished HIV-coinfected TB patients in studies from South Africa (8,35). A recent study from South Africa by Pasipanodya et al has also shown that serum drug concentrations predicted clinical outcome in TB patients and that low rifampin and isoniazid C max and AUC preceded therapy failure and occurrence of multidrug resistance or extremely drug-resistant TB (36).…”

Section: Discussionmentioning

confidence: 82%

Nutritional Supplementation Increases Rifampin Exposure among Tuberculosis Patients Coinfected with HIV

Jeremiah

Denti

Cosson

et al. 2014

Antimicrob Agents Chemother

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f Nutritional supplementation to tuberculosis (TB) patients has been associated with increased weight and reduced mortality, but its effect on the pharmacokinetics of first-line anti-TB drugs is unknown. 2 ) were randomized to receive nutritional supplementation during the intensive phase of TB treatment. Rifampin plasma concentrations were determined after 1 week and 2 months of treatment. The effects of nutritional supplementation, HIV, time on treatment, body weight, and SLCO1B1 rs4149032 genotype were examined using a population pharmacokinetic model. The model adjusted for body size via allometric scaling, accounted for clearance autoinduction, and detected an increase in bioavailability (؉14%) for the patients in the continuation phase. HIV coinfection in patients not receiving the supplementation was found to decrease bioavailability by 21.8%, with a median maximum concentration of drug in serum (C max ) and area under the concentration-time curve from 0 to 24 h (AUC 0 -24 ) of 5.6 g/ml and 28.6 g · h/ml, respectively. HIV-coinfected patients on nutritional supplementation achieved higher C max and AUC 0 -24 values of 6.4 g/ml and 31.6 g · h/ml, respectively, and only 13.3% bioavailability reduction. No effect of the SLCO1B1 rs4149032 genotype was observed. In conclusion, nutritional supplementation during the first 2 months of TB treatment reduces the decrease in rifampin exposure observed in HIV-coinfected patients but does not affect exposure in HIV-uninfected patients. If confirmed in other studies, the use of defined nutritional supplementation in HIV-coinfected TB patients should be considered in TB control programs. (This study has the controlled trial registration number ISRCTN 16552219.)

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“…Our sample size was small and many factors may have influenced the pharmacokinetics, including extremes of weight and days on treatment. [29] The lack of a control group may also be viewed as a limitation of our study. We used historical pharmacokinetic data in our analysis, as it was deemed impractical and unethical to subject 10 healthy volunteers to 7 days of TB treatment, a nasogastric feeding tube and 24 hours of pharmacokinetic sampling.…”

Section: Fig 2 Isoniazid Plasma Concentration Over Time (0 -24 Hourmentioning

confidence: 99%

The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care

et al. 2013

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Background. There is a paucity of data on the pharmacokinetics of fixed-dose combination enteral antituberculosis treatment in critically ill patients. Objectives. To establish the pharmacokinetic profile of a fixed-dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol given according to weight via a nasogastric tube to patients admitted to an intensive care unit (ICU). Methods. We conducted a prospective, observational study on 10 patients (mean age 32 years, 6 male) admitted to an ICU and treated for tuberculosis (TB). Serum concentrations of the drugs were determined at eight predetermined intervals over 24 hours by means of highperformance liquid chromatography. Results. The therapeutic maximum plasma concentration (C max ) for rifampicin at time to peak concentration was achieved in only 4 patients, whereas 2 did not achieve therapeutic C max for isoniazid. No patient reached sub-therapeutic C max for pyrazinamide (6 were within and 4 above therapeutic range). Three patients reached sub-therapeutic C max for ethambutol, and 6 patients were within and 1 above the therapeutic range. Patients with a sub-therapeutic rifampicin level had a higher mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score (p=0.03) and a lower estimated glomerular filtration rate (GFR) (p=0.03). Conclusions. A fixed-dose combination tablet, crushed and mixed with water, given according to weight via a nasogastric tube to patients with TB admitted to an ICU resulted in sub-therapeutic rifampicin plasma concentrations in the majority of patients, whereas the other drugs had a more favourable pharmacokinetic profile. Patients with a sub-therapeutic rifampicin concentration had a higher APACHE II score and a lower estimated GFR, which may contribute to suboptimal outcomes in critically ill patients. Studies in other settings have reported similar proportions of patients with 'sub-therapeutic' rifampicin concentrations.

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Reduced Antituberculosis Drug Concentrations in HIV-Infected Patients Who Are Men or Have Low Weight: Implications for International Dosing Guidelines

Cited by 90 publications

References 37 publications

Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction

Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction

Nutritional Supplementation Increases Rifampin Exposure among Tuberculosis Patients Coinfected with HIV

The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care

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