Pharmacokinetics Of Rifampicin Research Articles

Population Pharmacokinetic Analyses of Isoniazid in Tuberculosis Treatment: a Systematic Review

The aims of this systematic review are to provide knowledge concerning population pharmacokinetics of isoniazid (INH) and to identify factors influencing INH pharmacokinetic variability. Pubmed and Embase databases were systematically searched from inception to July, 2017. Relevant articles from reference lists were also included. All population pharmacokinetic studies of INH written in English, conducted in human (either healthy subjects or pulmonary tuberculosis patients) were included in this review. Ten studies were included in this review. Most studies characterized a two-compartment model with first-order kinetics for INH with a transit-compartment model for absorption suggested. Frequently reported significant predictors for INH clearance is NAT2 acetylator types (slow/intermediate/fast), while weight is a significant covariate for INH volume of distribution (both central and peripheral). In children, enzyme maturation had a profound affect on INH clearance.
 Keywords:
 Population pharmacokinetics, Isoniazid.
 References
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Kinzig-Schippers et al., Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses?, Antimicrobial Agents and Chemotherapy 49(5) (2005), 1733-1738. https://doi.org/10.1128/aac.49.5.1733-1738.2005 [16] J.J. Kiser et al., Isoniazid pharmacokinetics, pharmacodynamics, and dosing in South African infants, Therapeutic Drug Monitoring 34(4) (2012) 446-451. https://doi.org/10.1097/ftd.0b013e31825c4bc3 [17] L. Lalande, Population modeling and simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of isoniazid in lungs, Antimicrobial Agents and Chemotherapy 59(9) (2015) 5181-5189. https://doi.org/10.1128/aac.00462-15 [18] C. Magis-Escurra et al., Population pharmacokinetics and limited sampling strategy for first-line tuberculosis drugs and moxifloxacin, International Journal of Antimicrobial Agents 44(3) (2014) 229-234. https://doi.org/10.1016/j.ijantimicag.2014.04.019 [19] C.A. Peloquin et al., Population pharmacokinetic modeling of isoniazid, rifampin, and pyrazinamide, Antimicrobial Agents and Chemotherapy 41(12) (1997) 2670-2679. https://doi.org/10.1128/aac.41.12.2670 [20] K.Y. Seng et al., Population pharmacokinetic analysis of isoniazid, acetylisoniazid, and isonicotinic acid in healthy volunteers, Antimicrobial Agents and Chemotherapy 59(11) (2015) 6791-6799. https://doi.org/10.1128/aac.01244-15 [21] J.J. Wilkins et al., Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients, British Journal of Clinical Pharmacology 72(1) (2011) 51-62. https://doi.org/10.1111/j.1365-2125.2011.03940.x [22] S.P. 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Relationship among genetic polymorphism of SLCO1B1, rifampicin exposure and clinical outcomes in patients with active pulmonary tuberculosis.

Rifampicin is a key drug for the treatment of tuberculosis (TB). Little is known for the relationship between the rifampicin pharmacokinetics and genetic polymorphisms in the Asian population. We aimed to investigate relationship between genetic polymorphism of SLCO1B1 and rifampicin exposure and its impact on clinical outcomes in Korean patients with active pulmonary TB. From February 2016 to December 2019, patients with active pulmonary TB who were taking rifampicin for >1 week were prospectively enrolled. Serial or 1-time blood sampling was conducted to determine rifampicin concentrations. The genotype of 4 single nucleotide polymorphisms of SLCO1B1 was determined. To estimate the drug clearance and exposure, population pharmacokinetics analysis was conducted. Clinical outcomes such as time to acid-fast bacteria culture conversion, chest radiograph score changes from baseline, and all-cause mortality were also evaluated. The exposure among different SLCO1B1 genotype was compared and relationship between drug exposure and clinical outcomes were explored. A total of 105 patients (70 males and 35 females) were included in the final analysis. The mean age of patients was 55.4years. The mean drug clearance and exposure were 13.6L/h and 57.9mgh/L, respectively. The genetic polymorphisms of SLCO1B1 were not related to rifampicin clearance or exposure. As the rifampicin exposure increased, the chest radiographs improved significantly, but the duration of acid-fast bacteria culture conversion was not related to the drug exposure. SLCO1B1 gene polymorphisms did not influence rifampicin concentrations and clinical outcomes in Korean patients with active pulmonary TB.

Pharmacokinetics of rifampicin after repeated intra-tracheal administration of amorphous and crystalline powder formulations to Sprague Dawley rats

Rifampicin is one of the key drugs used to treat tuberculosis and is currently used orally. The use of higher oral doses of rifampicin is desired for better therapeutic efficacy, but this is accompanied by increased risk of systemic toxicity thus limiting its recommended oral dose to 10 mg/kg per day. Inhaled delivery of rifampicin is a potential alternative mode of delivery, to achieve high drug concentrations in both the lung and potentially the systemic circulation. In addition, rifampicin exists either as amorphous or crystalline particles, which may show different pharmacokinetic behaviour. However, disposition behaviour of amorphous and crystalline rifampicin formulations after inhaled high-dose delivery is unknown. In this study, rifampicin pharmacokinetics after intra-tracheal administration of carrier-free, amorphous and crystalline powder formulations to Sprague Dawley rats were evaluated. The formulations were administered once daily for seven days by oral, intra-tracheal and oral plus intra-tracheal delivery, and the pharmacokinetics were studied on day 0 and day 6. Intra-tracheal administration of the amorphous formulation resulted in a higher area under the plasma concentration curve (AUC) compared to the crystalline formulation. For both formulations, the intra-tracheal delivery led to significantly higher AUC compared to the oral delivery at the same dose suggesting higher rifampicin bioavailability from the inhaled route. Increasing the intra-tracheal dose resulted in a more than dose proportional AUC suggesting non-linear pharmacokinetics of rifampicin from the inhaled route. Upon repeated administration for seven days, no significant decrease in the AUCs were observed suggesting the absence of rifampicin induced enzyme auto-induction in this study. The present study suggests an advantage of inhaled delivery of rifampicin in achieving higher drug bioavailability compared to the oral route.

The potential of microdialysis to estimate rifampicin concentrations in the lung of guinea pigs.

Optimised pre-clinical models are required for TB drug development to better predict the pharmacokinetics of anti-tuberculosis (anti-TB) drugs to shorten the time taken for novel drugs and combinations to be approved for clinical trial. Microdialysis can be used to measure unbound drug concentrations in awake freely moving animals in order to describe the pharmacokinetics of drugs in the organs as a continuous sampling technique. The aim of this work was to develop and optimise the microdialysis methodology in guinea pigs to better understand the pharmacokinetics of rifampicin in the lung. In vitro experiments were performed before progressing into in vivo studies because the recovery (concentration of the drug in the tissue fluid related to that in the collected dialysate) of rifampicin was dependent on a variety of experimental conditions. Mass spectrometry of the dialysate was used to determine the impact of flow rate, perfusion fluid and the molecular weight cut-off and membrane length of probes on the recovery of rifampicin at physiologically relevant concentrations. Following determination of probe efficiency and identification of a correlation between rifampicin concentrations in the lung and skeletal muscle, experiments were conducted to measure rifampicin in the sacrospinalis of guinea pigs using microdialysis. Lung concentrations of rifampicin were estimated from the rifampicin concentrations measured in the sacrospinalis. These studies suggest the potential usefulness of the microdialysis methodology to determine drug concentrations of selected anti-TB drugs to support new TB drug development.

The Impact of First-Line Anti-Tubercular Drugs' Pharmacokinetics on Treatment Outcome: A Systematic Review.

BackgroundTuberculosis remains the major public health problem besides tremendous efforts to combat it. Most tuberculosis patients are treated with a standard dose of first-line anti-TB drugs. The cure rate, however, varies from patient to patient. Various factors have been related to anti-TB treatment failure. In recent years, studies associating lower plasma concentrations of anti-TB drugs with poor treatment outcomes are emerging although the results are inconclusive.ObjectiveInvestigate the impact of first-line anti-tubercular drugs pharmacokinetics on treatment outcome.MethodsA systematic search of Pubmed, EMBASE, Web of Science, and the Cochrane Library for articles published in the English language between January 2010 to June 2020 was conducted to identify eligible studies describing associations of first-line anti-tubercular drug pharmacokinetics with treatment outcomes. The primary outcomes considered were pharmacokinetics parameter results and its association with treatment outcome.ResultsThe search identified 1754 articles of which twelve articles; ten prospective observational studies and two controlled clinical trials fulfilled the eligibility criteria. The majority of the studies showed target concentrations for the first-line anti-tubercular drugs below the current standard range. Among the twelve studies, eleven studies assessed rifampicin pharmacokinetics of which eight reported association of drug concentration and treatment outcomes. Similarly, four out of eight and three out of seven reported drug concentration and treatment outcome association for isoniazid and pyrazinamide, respectively. Despite the low plasma concentration, a favorable treatment outcome was achieved for the bulk of the patients. Irrespective of the inconsistency, an increase in exposure to rifampicin improved the outcome, and lower rifampicin, isoniazid, and pyrazinamide concentration are associated with poor outcome. No data are available for ethambutol associating its pharmacokinetics with treatment outcomes.ConclusionThe pharmacokinetics of first-line antitubercular drugs can influence treatment outcomes. Further controlled clinical studies are, however, required to establish these relationships.

Drug exposure of first-line anti-tuberculosis drugs in China: A prospective pharmacological cohort study.

Exploring the need for optimization of drug exposure to improve tuberculosis (TB) treatment outcome is of great importance. We aimed to describe drug exposure at steady state as well as the population pharmacokinetics (PK) of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) in Chinese TB patients. A prospective multicentre PK study of RIF, INH and PZA was conducted in China between January 2015 and December 2017. Six blood samples were collected from each subject for drug concentration measurement. Nonlinear mixed effect analyses were used to develop population PK models. In total, 217 patients were included. Positive correlations between body weight, clearance and volume of distribution were identified for RIF and PZA, whereas body weight only influenced clearance for INH. In addition, males had higher RIF clearance and thus lower RIF exposure than women. Acetylator status was significantly associated with INH clearance as INH exposure in intermediate and fast acetylators was significantly lower than in slow acetylators, especially in low-weight bands. Simulations also showed significantly lower drug exposures in low-weight bands for all three drugs. Patients weighing <38 kg were respectively exposed to 30.4%, 45.9% and 18.0% lower area under the concentration-time curve of RIF, INH and PZA than those weighing ≥70 kg. Higher doses by addition of one fixed-dose combination tablet or 150 mg INH were simulated and found to be effective in improving INH drug exposures, especially in low-weight bands. PK variability of first-line anti-TB drugs is common in Chinese TB patients. The developed population PK models can be used to optimize drug exposures in Chinese patients. Moreover, standard dosing needs to be adjusted to increase target attainment.

Intrapulmonary Pharmacokinetics of First-line Anti-tuberculosis Drugs in Malawian Patients With Tuberculosis.

BackgroundFurther work is required to understand the intrapulmonary pharmacokinetics of first-line anti-tuberculosis drugs. This study aimed to describe the plasma and intrapulmonary pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol, and explore relationships with clinical treatment outcomes in patients with pulmonary tuberculosis.MethodsMalawian adults with a first presentation of microbiologically confirmed pulmonary tuberculosis received standard 6-month first-line therapy. Plasma and intrapulmonary samples were collected 8 and 16 weeks into treatment and drug concentrations measured in plasma, lung/airway epithelial lining fluid (ELF), and alveolar cells. Population pharmacokinetic modeling generated estimates of drug exposure (Cmax and AUC) from individual-level post hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics.ResultsOne-hundred fifty-seven patients (58% HIV coinfected) participated. Despite standard weight-based dosing, peak plasma concentrations of first-line drugs were below therapeutic drug-monitoring targets. Rifampicin concentrations were low in all 3 compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in ELF and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6-fold (95% CI, 11.2–18.0-fold) and 49.8-fold (95% CI, 34.2–65.3-fold) higher in ELF than plasma, respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cell–plasma ratio, 15.0; 95% CI, 11.4–18.6). Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response.ConclusionsWe report differential drug concentrations between plasma and the lung. While plasma concentrations were below therapeutic monitoring targets, accumulation of drugs at the site of disease may explain the success of the first-line regimen. The low rifampicin concentrations observed in all compartments lend strong support for ongoing clinical trials of high-dose rifampicin regimens.

Individualized Dosing With High Inter-Occasion Variability Is Correctly Handled With Model-Informed Precision Dosing-Using Rifampicin as an Example.

Rifampicin exhibits complexities in its pharmacokinetics (PK), including high inter-occasion variability (IOV), which is challenging for dose individualization. Model-informed precision dosing (MIPD) can be used to optimize individual doses. In this simulation-based study we investigated the magnitude of IOV in rifampicin PK on an exposure level, the impact of not acknowledging IOV when performing MIPD, and the number of sampling occasions needed to forecast the dose. Subjects with drug-susceptible tuberculosis (TB) were simulated from a previously developed population PK model. To explore the magnitude of IOV, the area under the plasma concentration-time curve from time zero up to 24 h (AUC0–24h) after 35 mg/kg in the typical individual was simulated for 1,000 sampling occasions at steady-state. The impact of ignoring IOV for dose predictions was investigated by comparing the prediction error of a MIPD approach including IOV to an approach ignoring IOV. Furthermore, the number of sampling occasions needed to predict individual doses using a MIPD approach was assessed. The AUC0–24h in the typical individual varied substantially between simulated sampling occasions [95% prediction interval (PI): 122.2 to 331.2 h mg/L], equivalent to an IOV in AUC0–24h of 25.8%, compared to an inter-individual variability of 25.4%. The median of the individual prediction errors using a MIPD approach incorporating IOV was 0% (75% PI: −14.6% to 0.0%), and the PI for the individual prediction errors was narrower with than without IOV (median: 0%, 75% PI: −14.6% to 20.0%). The most common target dose in this population was forecasted correctly in 95% of the subjects when IOV was included in MIPD. In subjects where doses were not predicted optimally, a lower dose was predicted compared to the target, which is favorable from a safety perspective. Moreover, the imprecision (relative root mean square error) and bias in predicted doses using MIPD with IOV decreased statistically significant when a second sampling occasion was added (difference in imprecision: −9.1%, bias: −7.7%), but only marginally including a third (difference in imprecision: −0.1%, bias: −0.1%). In conclusion, a large variability in exposure of rifampicin between occasions was shown. In order to forecast the individual dose correctly, IOV must be acknowledged which can be achieved using a MIPD approach with PK information from at least two sampling occasions.

The Population Pharmacokinetics of Rifampicin in Japanese Pulmonary Tuberculosis Patients.

In Japan, tuberculosis has been recognized as one of the major infections requiring urgent measures because of its high morbidity rate even now especially in elderly people suffering from tuberculosis during the past epidemic and its reactivation. Hence, many Japanese clinicians have made efforts to suppress the onset of tuberculosis and treat it effectively. The objectives of this study are to (1) identify covariate(s) that may explain the variation of rifampicin, which is the key antitubercular agent, under the steady-state by evaluating its population pharmacokinetics and (2) to propose an appropriate dosing method of rifampicin to Japanese patients. For this purpose, serum concentration-time data were obtained from 138 patients receiving rifampicin (300-450 mg) and isoniazid (300-400 mg) every day over 14 days, and analyzed using nonlinear mixed effects model. Thereby, population pharmacokinetic parameters were estimated followed by elucidating relations between the parameters and statistical factors. The analysis adopted one-compartment model including Lag-time by assuming that the absorption process is 0+1st order. The analyses demonstrate that meal affected the bioavailability, primary absorption rate constant, and zero order absorption time in the constructed model. A body weight calculated from the power model was selected as the covariate by the Stepwise Covariate Model method and found to highly affect the clearance in the range from -31.6% to 47.4%. We conclude that the dose in Japanese tuberculous patients can be well estimated by the power model formula and should be taken into consideration when rifampicin is administered.

Population Pharmacokinetics of Rifampicin on Pulmonary Tuberculosis Patients

Abstract: This study aimed to establish a reasonable population pharmacokinetic model for rifampicin taken orally by patients with pulmonary tuberculosis, estimate pharmacokinetic parameters as well as influencing covariates. Blood samples of patients were collected at day 10 – 14 after commencing treatment. Time – concentration data were handled using non-linear mixed-effect model with Monolix 2018. An one-compartment, linear elimination, absorption with transit compartments model was found to be the most suitable for rifampicin. Volume of distribution (33,5 L) and clearance (9,62 L) were found to be influenced by fat-free mass (calculated using Janmahasatian’s method). Absorption-related parameters (Ktr, mean transit time and Ka) were found to have high inter-individual variability.&#x0D; Keywords&#x0D; Rifampicin, population pharmacokinetics, pulmonary tuberculosis.&#x0D; References&#x0D; [1] Christian Lienhardt et al, Target regimen profiles for treatment of tuberculosis: a WHO document (2017).[2] J.G. Pasipanodya et al, Serum drug concentrations predictive of pulmonary tuberculosis outcomes, The Journal of infectious diseases 208(9) (2013) 1464-1473. https://doi.org/10.1093/infdis/jit352[3] Jonathan Reynolds, Scott K Heysell (2014), Understanding pharmacokinetics to improve tuberculosis treatment outcome, Expert opinion on drug metabolism &amp; toxicology 10(6) (2014) 813-823. https://doi.org/10.1517/17425255.2014.895813[4] E.F. Egelund, A.B. Barth, C.A. Peloquin (2011), Population pharmacokinetics and its role in anti-tuberculosis drug development and optimization of treatment, Current pharmaceutical design 17(27) (2017) 2889-2899. https://doi.org/10.2174/138161211797470246.[5] J.F. Murray, D.E. Schraufnagel, P.C. Hopewell, Treatment of tuberculosis. A historical perspective, Annals of the American Thoracic Society 12(12) (2015) 1749-1759. https://doi.org/10.1513/AnnalsATS.201509-632PS[6] K.E. Stott, et al, Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis, Journal of Antimicrobial Chemotherapy 73(9) (2018) 2305-2313. https://doi.org/10.1093/jac/dky152.[7] Le Thi Luyen, Ta Manh Hung et al, Simultaneous Determination of Pyrazinamide, Rifampicin, Ethambutol, Isoniazid and Acetyl Isoniazid in Human Plasma by LC-MS/MS Method, Journal of Applied Pharmaceutical Science 8(09) (2018) 061-073. https://doi.org/ 10.7324/JAPS.2018.8910.[8] M.T. Chirehwa et al, Model-based evaluation of higher doses of rifampin using a semimechanistic model incorporating autoinduction and saturation of hepatic extraction, Antimicrobial agents and chemotherapy 60(1) (2016) 487-494. https://doi.org/10.1128/AAC.01830-15.[9] Paolo Denti et al, A population pharmacokinetic model for rifampicin auto-induction, The 3rd international workshop on clinical pharmacology of TB drugs (2010).[10] Y. Jing et al, Population pharmacokinetics of rifampicin in Chinese patients with pulmonary tuberculosis, The Journal of Clinical Pharmacology 56(5) (2016) 622-627. https://doi.org/10.1002/jcph.643.[11] S.R.C. Milán et al, Population pharmacokinetics of rifampicin in Mexican patients with tuberculosis, Journal of clinical pharmacy and therapeutics 38(1) (2013) 56-61. https://doi.org/10.1111/jcpt.12016.[12] Anushka Naidoo et al, Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis, Pharmacogenomics(00) (2013). https://doi.org/10.2217/pgs-2018-0166.[13] Neesha Rockwood et al, HIV-1 coinfection does not reduce exposure to rifampin, isoniazid, and pyrazinamide in South African tuberculosis outpatients, Antimicrobial agents and chemotherapy 60(10) (2016) 6050-6059. https://doi.org/10.1128/AAC.00480-16.[14] Alessandro Schipani et al, A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children, British Journal of Clinical Pharmacology 81(4) (2016) 679-687. https://doi.org/10.1111/bcp.12848.[15] Kok-Yong Seng et al, Population pharmacokinetics of rifampicin and 25-deacetyl-rifampicin in healthy Asian adults, Journal of Antimicrobial Chemotherapy 70(12) (2015) 3298-3306. https://doi.org/10.1093/jac/dkv268.[16] J.J. Wilkins et al, Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption, Antimicrobial agents and chemotherapy 52(6) (2008)2138-2148. https://dx.doi.org/10.1128%2FAAC.00461-07.[17] Sylvain Goutelle et al, Population modeling and Monte Carlo simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of rifampin in lungs, Antimicrobial agents and chemotherapy 53(7) (2009) 2974-2981. https://doi.org/10.1128/AAC.01520-08.[18] R.M. Savic et al, Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies, Journal of pharmacokinetics and pharmacodynamics 34(5) (2007) 711-726. https://doi.org/10.1007/s10928-007-9066-0.[19] B.J. Anderson, N.H.G. Holford, Mechanism-based concepts of size and maturity in pharmacokinetics, Annu. Rev. Pharmacol. Toxicol 48 (2008) 303-332. https://doi.org/10.1146/annurev.pharmtox.48.113006.094708.[20] Kok-Yong Seng et al, Population pharmacokinetic analysis of isoniazid, acetyl-isoniazid and isonicotinic acid in healthy volunteers, Antimicrobial agents and chemotherapy, pp. AAC. (2015) 01244-15. https://doi.org/10.1128/AAC.01244-15.[21] Sarayut Janmahasatian et al, Quantification of lean bodyweight, Clinical pharmacokinetics 44(10), (2005) 1051-1065. https://doi.org/10.2165/00003088-200544100-00004.[22] Kidola Jeremiah et al, Nutritional supplementation increases rifampin exposure among tuberculosis patients coinfected with HIV, Antimicrobial agents and chemotherapy 58(6) (2014) 3468-3474. https://doi.org/10.1128/AAC.02307-13&#x0D;

Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB-rifampicin sensitivity among Ugandan patients.

Suboptimal anti-TB drugs exposure may cause multidrug-resistant TB. The role of African predominant SLCO1B1 variant alleles on rifampicin pharmacokinetics and the subsequent effect on the occurrence of Mycobacterium tuberculosis-rifampicin sensitivity needs to be defined. We describe the rifampicin population pharmacokinetics profile and investigate the relevance of SLCO1B1 genotypes to rifampicin pharmacokinetics and rifampicin-TB sensitivity status. Fifty patients with TB (n=25 with rifampicin-resistant TB and n=25 with rifampicin-susceptible TB) were genotyped for SLOC1B1 rs4149032 (g.38664C>T), SLOC1B1*1B (c.388A>G) and SLOC1B1*5 (c.521T>C). Steady state plasma rifampicin levels were determined among patients infected with rifampicin-sensitive TB. Data were analysed using NONMEM to estimate population rifampicin pharmacokinetics as well as the effect of SLOC1B1 genotypes on rifampicin pharmacokinetics and on rifampicin-TB sensitivity status. Overall allele frequencies of SLOC1B1 rs4149032, *1B and *5 were 0.66, 0.90 and 0.01, respectively. Median (IQR) Cmax and Tmax were 10.2 (8.1-12.5) mg/L and 1.7 (1.125-2.218) h, respectively. Twenty-four percent of patients exhibited Cmax below the recommended 8-24mg/L range. SLOC1B1 genotypes, gender and age did not influence rifampicin pharmacokinetics or TB-rifampicin sensitivity. Although SLOC1B1 genotype, age and gender do not influence either rifampicin pharmacokinetics or rifampicin-TB sensitivity status, one in every four Ugandan TB patients achieve subtherapeutic plasma rifampicin concentrations.

Development and Evaluation of Physiologically Based Pharmacokinetic Drug-Disease Models for Predicting Rifampicin Exposure in Tuberculosis and Cirrhosis Populations.

The physiologically based pharmacokinetic (PBPK) approach facilitates the construction of novel drug–disease models by allowing incorporation of relevant pathophysiological changes. The aim of the present work was to explore and identify the differences in rifampicin pharmacokinetics (PK) after the application of its single dose in healthy and diseased populations by using PBPK drug–disease models. The Simcyp® simulator was used as a platform for modeling and simulation. The model development process was initiated by predicting rifampicin PK in healthy population after intravenous (i.v) and oral administration. Subsequent to successful evaluation in healthy population, the pathophysiological changes in tuberculosis and cirrhosis population were incorporated into the developed model for predicting rifampicin PK in these populations. The model evaluation was performed by using visual predictive checks and the comparison of mean observed/predicted ratios (ratio(Obs/pred)) of the PK parameters. The predicted PK parameters in the healthy population were in adequate harmony with the reported clinical data. The incorporation of pathophysiological changes in albumin concentration in the tuberculosis population revealed improved prediction of clearance. The developed PBPK drug–disease models have efficiently described rifampicin PK in tuberculosis and cirrhosis populations after administering single drug dose, as the ratio(Obs/pred) for all the PK parameters were within a two-fold error range. The mechanistic nature of the developed PBPK models may facilitate their extension to other diseases and drugs.

Individualised dosing algorithm and personalised treatment of high-dose rifampicin for tuberculosis.

To propose new exposure targets for Bayesian dose optimisation suited for high-dose rifampicin and to apply them using measured plasma concentrations coupled with a Bayesian forecasting algorithm allowing predictions of future doses, considering rifampicin's auto-induction, saturable pharmacokinetics and high interoccasion variability. Rifampicin exposure targets for Bayesian dose optimisation were defined based on literature data on safety and anti-mycobacterial activity in relation to rifampicin's pharmacokinetics i.e. highest plasma concentration up to 24hours and area under the plasma concentration-time curve up to 24hours (AUC0-24h ). Targets were suggested with and without considering minimum inhibitory concentration (MIC) information. Individual optimal doses were predicted for patients treated with rifampicin (10mg/kg) using the targets with Bayesian forecasting together with sparse measurements of rifampicin plasma concentrations and baseline rifampicin MIC. The suggested exposure target for Bayesian dose optimisation was a steady state AUC0-24h of 181-214h×mg/L. The observed MICs ranged from 0.016-0.125mg/L (mode: 0.064mg/L). The predicted optimal dose in patients using the suggested target ranged from 1200-3000mg (20-50mg/kg) with a mode of 1800mg (30mg/kg, n=24). The predicted optimal doses when taking MIC into account were highly dependent on the known technical variability of measured individual MIC and the dose was substantially lower compared to when using the AUC0-24h -only target. A new up-to-date exposure target for Bayesian dose optimisation suited for high-dose rifampicin was derived. Using measured plasma concentrations coupled with Bayesian forecasting allowed prediction of the future dose whilst accounting for the auto-induction, saturable pharmacokinetics and high between-occasion variability of rifampicin.

Rifampicin Bioavailability in Fixed-Dose Combinations for Tuberculosis Treatment: Evidence and Policy Actions

Purpose: The pharmacokinetics (PK) of anti-tuberculosis drugs, including their bioavailability (BA), significantly impacts the efficacy and effectiveness of tuberculosis (TB) treatment regimens. Rifampicin, one of the most important drugs in the treatment of drug-sensitive tuberculosis, has been used increasingly in fixed-dose combinations (FDCs). This paper reviews and analyzes available data on BA and PK of rifampicin with a focus on FDCs, from published studies and reports. Methods: Using PubMed as the primary database, Cochrane and other relevant databases, a systematic review of literature was conducted to identify studies on the bioavailability and efficacy of rifampicin in FDCs versus single drug formulations. A number of keywords including “bioavailability”, “rifampicin”, “fixed dose combinations”, and “pharmacokinetics” were used in various combinations. The search covered the period 1980 to 2016. Priority was given to articles on rifampicin bioavailability in fixed dose combinations used in the program setting, and human studies that used the World Health Organization (WHO) approved BA/PK protocol and sample size (≥22 patients). Findings: More than 450 original peer-reviewed articles, reviews and reports, were assessed for this analysis. Eleven papers, which included data from high-TB-burden countries (South Africa, India, and China), raised significant concerns about rifampicin bioavailability within FDCs; the authors of the studies discussed multiple factors associated with low bioavailability, including drug formulation and quality, storage environment, patient factors, and concomitant diseases. Implications: Recent studies and reviews point to the problem of low bioavailability of rifampicin in fixed dose combinations. However, in the field, it remains a hidden or unrecognized factor leading to poor treatment outcomes. It is difficult to study the issue thoroughly unless there is awareness among TB program personnel of its existence, and adequate laboratory and research support is available to national tuberculosis programs (NTPs). In stemming the tide of tuberculosis multi-drug resistance (MDR) and extensive drug resistance (XDR), it is paramount to ensure that rifampicin bioavailability is adequate in FDCs, and to detect and address any deviation from recommended target ranges. There is a need for strategies to minimize the undesirable clinical effects of reduced rifampicin bioavailability in FDCs, and for effective utilization of quality-assured drugs within NTPs programs; these can help NTPs support effective case management in line with the international TB care standards, while taking into consideration the factors affecting drug absorption and therapeutic concentration.

Evolution of rifampicin treatment for tuberculosis

Rifampicin was discovered in 1965 and remains one of the most important drugs in tuberculosis treatment that is valued for its sterilizing activity and ability to shorten treatment. Antimicrobial activity of rifampicin was initially proved in vitro; subsequently numerous in vivo studies showed the bactericidal properties and dose-dependent effect of rifampicin. Rifampicin was first during the late 1960s to treat patients suffering from chronic drug-resistant pulmonary TB. Decades later, rifampicin continues to be studied with particular emphasis on whether higher doses could shorten the duration of treatment without increasing relapse or having adverse effects. Lesion-specific drug penetration and pharmacokinetics of rifampicin are improving our understanding of effective concentration while potentially refining drug regimen designs. Another prospective aspect of high-dose rifampicin is its potential use in treating discrepant mutation thereby eliminating the need for MDR treatment. To date, several clinical trials have shown the safety, efficacy, and tolerability of high-dose rifampicin. Currently, high-dose rifampicin has been used successfully in a routine clinical setting for the treatment of high-risk patients. However, the WHO and other relevant policy makers have not committed to implementing a controlled rollout thereof. This review describes the course that rifampicin has travelled to the present-day exploration of high-dose rifampicin treatment.

Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis.

The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6months when combined with pyrazinamide in the first 2months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600mg (8-12mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of ≥ 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600mg. Rifampicin maximum (peak) concentration (Cmax) > 8.2μg/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of ≥ 8µg/mL. A higher rifampicin Cmax is required for severe forms TB such as TB meningitis, with Cmax ≥ 22 μg/mL and area under the concentration-time curve (AUC) from time zero to 6h (AUC6) ≥ 70μg·h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35mg/kg were found to be safe and well-tolerated over a period of 12weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as Cmax/MIC (minimum inhibitory concentration) and AUC/MIC.

Attainment of target rifampicin concentrations in cerebrospinal fluid during treatment of tuberculous meningitis

ObjectiveThere is considerable uncertainty regarding the optimal use of rifampicin for the treatment of tuberculous (TB) meningitis. A pharmacokinetic modeling and simulation study of rifampicin concentrations in cerebrospinal fluid (CSF) during TB meningitis treatment was performed in this study. MethodsParameters for rifampicin pharmacokinetics in CSF were estimated using individual-level rifampicin pharmacokinetic data, and the model was externally validated in three separate patient cohorts. Monte Carlo simulations of rifampicin serum and CSF concentrations were performed. The area under the rifampicin CSF concentration-versus-time curve during 24 h (AUC0–24) relative to the minimum inhibitory concentration (MIC) served as the pharmacodynamic target. ResultsAcross all simulated patients on the first treatment day, 85% attained the target AUC0–24/MIC ratio of 30 under a weight-based dosing scheme approximating 10 mg/kg. At the rifampicin MIC of 0.5 mg/l, the probability of AUC0–24/MIC target attainment was 26%. With an intensified dosing strategy corresponding to 20 mg/kg, target attainment increased to 99%, including 93% with a MIC of 0.5 mg/l. ConclusionsUnder standard dosing guidelines, few TB meningitis patients would be expected to attain therapeutic rifampicin exposures in CSF when the MIC is ≥0.5 mg/l. Either downward adjustment of the rifampicin MIC breakpoint in the context of TB meningitis, or intensified rifampicin dosing upwards of 20 mg/kg/day, would reflect the likelihood of pharmacodynamic target attainment in CSF.

Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis.

We report the prevalence and effect of genetic variability on pharmacokinetic parameters of isoniazid and rifampicin. Genotypes for SLCO1B1, NAT2, PXR, ABCB1and UGT1A genes were determined using a TaqMan® Genotyping OpenArray™. Nonlinear mixed-effects models were used to describe drug pharmacokinetics. Among 172 patients, 18, 43 and 34% were classified as rapid, intermediate and slow NAT2 acetylators, respectively. Of the 58 patients contributing drug concentrations, rapid and intermediate acetylators had 2.3- and 1.6-times faster isoniazid clearance than slow acetylators. No association was observed between rifampicin pharmacokinetics and SLCO1B1, ABCB1, UGT1Aor PXR genotypes. Clinical relevance of the effects of genetic variation on isoniazid concentrations and low first-line tuberculosis drug exposures observed require further investigation.

Intra-individual effects of food upon the pharmacokinetics of rifampicin and isoniazid.

Poor response to TB therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic parameters can be affected by comorbidities or the interaction of drugs with food. This study aimed to determine the effect of food intake upon pharmacokinetics of rifampicin and isoniazid in a Peruvian population with TB. Rifampicin and isoniazid levels were analysed at 2, 4 and 6 h after drug intake in both fasting and non-fasting states using LC-MS methods. Sixty patients participated in the study. The median rifampicin Cmax and AUC0-6 were higher during fasting than non-fasting: 7.02 versus 6.59 mg/L (P = 0.054) and 28.64 versus 24.31 mg·h/L (P = 0.002). There was a statistically significant delay overall of non-fasting Tmax compared with the fasting state Tmax (P = 0.005). In the multivariate analysis, besides the effect of fasting, Cmax for females was 20% higher than for males (P = 0.03). Concerning isoniazid, there were significant differences in the Cmax during non-fasting (median = 3.51 mg/L) compared with fasting (4.54 mg/L). The isoniazid dose received had an effect upon the isoniazid levels (1.26, P = 0.038). In the multivariate analysis, isoniazid exposure during fasting was found to be 14% higher than during non-fasting (CI = 1.02-1.28, P < 0.001). Neither radiological extent of the disease nor consumption of food with drug intake nor pharmacokinetics of rifampicin or isoniazid was associated with a poorer treatment outcome. Rifampicin in particular and isoniazid pharmacokinetics were significantly affected by the intake of the drug with food between and within individuals.

Effects of tannins in Galla Chinensis on pharmacokinetics of rifampicin in vivo and in vitro

This study was aimed to explore the effects of tannins in Galla Chinensis on rifampicin in vivo. In the experiment in vitro, UV spectrophotometry and high performance liquid chromatography (HPLC) were used to investigate the solubility of rifampin in pH 1.3, 6.8, artificial gastric juice environment and artificial intestinal fluid environment as well as the effects of tannins on solubility of rifampin in the above conditions. In the experiment in vivo, the process of rifampicin was studied after intragastric administration of rifampicin and rifampicin+ tannins in Galla Chinensis, and then the pharmacokinetic parameters were calculated. The results showed that rifampicin was constantly precipitated in the artificial gastric juice environment over time, and nearly 85% of the rifampicin was precipitated after 6 hours; it showed a good solubility in the artificial intestinal juice environment. After adding the said tannins, the concentration of rifampicin was decreased significantly in both environments, and the concentration of rifampicin in artificial intestinal juice remained relatively stable, while that in artificial gastric juice remained the original downward trend. The pharmacokinetic parameters displayed that as compared with rifampicin alone, AUC0-t and Cmax were decreased significantly, MRT0-t slowed down significantly, Tmax doubled to 7.0 h and the bioavailability was only 31.65% in rifampicin + tannins in Galla Chinensis group. The experiment indicated rifampicin had a poor solubility in acidic environment and the decrease of bioavailability of rifampicin when in combination with tannin was mainly due to the reduction of rifampicin solubility in intestinal tract by complexation of rifampicin with tannin, thus affecting its absorption in intestinal tract. Therefore, rifampicin and the Chinese herbal medicines or Chinese patent medicines rich in tannin should not be taken simultaneously.