A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children

Schipani, Alessandro; Pertinez, Henry; Mlota, Rachel; Molyneux, Elizabeth; López, Núria; Dzinjalamala, Fraction K.; Oosterhout, Joep J. van; Ward, Stephen A.; Khoo, Saye; Davies, Geraint R.

doi:10.1111/bcp.12848

Cited by 23 publications

(27 citation statements)

References 35 publications

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“…Consequently, in 2010, WHO recommended increased pediatric dosages for isoniazid (7-15 mg/kg), rifampicin (10-20 mg/kg), pyrazinamide (30-40 mg/kg), and ethambutol (15-25 mg/kg), which are higher than the adult recommended dosages (4-6, 8-12, 20-30, and 15-20 mg/kg, respectively) [2]. To date, few studies have evaluated the pharmacokinetics of the WHO revised dosages in children [79,[84][85][86][87][88]. Much additional work is needed to characterize the pharmacokinetics and pharmacodynamics of the four first-line anti-TB drugs in pediatric patients.…”

Section: Pediatric Patientsmentioning

confidence: 99%

Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring

Verbeeck

Günther²,

Kibuule

et al. 2016

Eur J Clin Pharmacol

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Section: Pediatric Patientsmentioning

confidence: 99%

Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring

Verbeeck

Günther²,

Kibuule

et al. 2016

Eur J Clin Pharmacol

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“…There are already several population PK models for rifampicin, including models that do not include any structural nonlinearity in PK parameters, a model including structural components describing autoinduction, and a model including structural components for autoinduction and a nonlinear increase in exposure . All of these were based on the 10 mg/kg rifampicin dose.…”

mentioning

confidence: 99%

“…9 Rifampicin activates the nuclear pregnane X receptor (PXR), which leads to increased gene transcription of several systemic and presystemic metabolizing enzymes and drug transporters. 11 There are already several population PK models for rifampicin, including models that do not include any structural nonlinearity in PK parameters, 12,13 a model including structural components describing autoinduction, 14 and a model including structural components for autoinduction and a nonlinear increase in exposure. 10 All of these were based on the 10 mg/kg rifampicin dose.…”

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confidence: 99%

A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses

Svensson

Aarnoutse

Diacon

et al. 2017

Clin Pharma and Therapeutics

149

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Accumulating evidence suggests that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics, and antimycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty‐three pulmonary tuberculosis patients received 10, 20, 25, 30, 35, or 40 mg/kg rifampicin daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol in the second week. This study aimed at characterizing rifampicin pharmacokinetics observed in HIGHRIF1 using nonlinear mixed effects modeling. The final population pharmacokinetic model included an enzyme turnover model accounting for time‐dependent elimination due to autoinduction, concentration‐dependent clearance, and dose‐dependent bioavailability. The relationship between clearance and concentration was characterized by a Michaelis–Menten relationship. The relationship between bioavailability and dose was described using an Emax relationship. The model will be key in determining exposure–response relationships for rifampicin and should be considered when designing future trials and when treating future patients with high‐dose rifampicin.

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“…The PubMed search resulted in 271 hits. Twelve population PK models of rifampicin from between 1997 and 2017 were identified [10,[30][31][32][33][34][35][36][37][38][39][40]. No additional relevant publications were found in the references of the selected articles.…”

Section: Identification Of Models (Step 2)mentioning

confidence: 99%

Personalized Tuberculosis Treatment Through Model-Informed Dosing of Rifampicin

Beek¹,

Heine²,

Keizer³

et al. 2019

Clin Pharmacokinet

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Background and objective This study proposes a model-informed approach for therapeutic drug monitoring (TDM) of rifampicin to improve tuberculosis (TB) treatment. Methods Two datasets from pulmonary TB patients were used: a pharmacokinetic study (34 patients, 373 samples), and TDM data (96 patients, 391 samples) collected at Radboud University Medical Center, The Netherlands. Nine suitable population pharmacokinetic models of rifampicin were identified in the literature and evaluated on the datasets. A model developed by Svensson et al. was found to be the most suitable based on graphical goodness of fit, residual diagnostics, and predictive performance. Prediction of individual area under the concentration-time curve from time zero to 24 h (AUC 24) and maximum concentration (C max) employing various sampling strategies was compared with a previously established linear regression TDM strategy, using sampling at 2, 4, and 6 h, in terms of bias and precision (mean error [ME] and root mean square error [RMSE]). Results A sampling strategy using 2-and 4-h blood collection was selected to be the most suitable. The bias and precision of the two strategies were comparable, except that the linear regression strategy was more biased in prediction of the AUC 24 than the model-informed approach (ME of 9.9% and 1.5%, respectively). A comparison of resulting dose advice, using predictions on a simulated dataset, showed no significant difference in sensitivity or specificity between the two methods. The model was successfully implemented in the InsightRX precision dosing platform. Conclusion Blood sampling at 2 and 4 h, combined with model-based prediction, can be used instead of the currently used linear regression strategy, shortening the sampling by 2 h and one sampling point without performance loss while simultaneously offering flexibility in sampling times. Key Points We propose a new model-informed therapeutic drug monitoring method for rifampicin. The proposed method uses only two blood samples at 2 and 4 h after dosing. In contrast to linear regression-based methods, the proposed method allows for flexible sampling times and prediction of optimal dose adjustment.

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A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children

Cited by 23 publications

References 35 publications

Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring

Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring

A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses

Personalized Tuberculosis Treatment Through Model-Informed Dosing of Rifampicin

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