Publications by authors named "Rob E Aarnoutse"

108 Publications

Tricyclic antidepressants for major depressive disorder: a comprehensive evaluation of current practice in the Netherlands.

BMC Psychiatry 2021 10 1;21(1):481. Epub 2021 Oct 1.

Department of Psychiatry, Radboud University Medical Center, Reinier Postlaan 10, 6500, HB, Nijmegen, The Netherlands.

Background: Traditionally tricyclic antidepressants (TCAs) have an important place in treatment of major depressive disorder (MDD). Today, often other antidepressant medications are considered as first step in the pharmacological treatment of MDD, mainly because they are associated with less adverse effects, whereby the position of TCAs appears unclear. In this study we aimed to examine the current practice of TCAs in treatment of unipolar MDD.

Methods: A mixed methods approach was applied. First, a selection of leading international and national guidelines was reviewed. Second, actual TCA prescription was examined by analyzing health records of 75 MDD patients treated with the TCAs nortriptyline, clomipramine or imipramine in different centers in the Netherlands. Third, promotors and barriers influencing the choice for TCAs and dosing strategies were explored using semi-structured interviews with 24 Dutch psychiatrists.

Results: Clinical practice guidelines were sometimes indirective and inconsistent with each other. Health records revealed that most patients (71%) attained therapeutic plasma concentrations within two months of TCA use. Patients who achieved therapeutic plasma concentrations reached them on average after 19.6 days (SD 10.9). Both health records and interviews indicated that therapeutic nortriptyline concentrations were attained faster compared to other TCAs. Various factors were identified influencing the choice for TCAs and dosing by psychiatrists.

Conclusions: Guideline recommendations and clinical practice regarding TCA prescription for MDD vary. To increase consistency in clinical practice we recommend development of an up-to-date guideline integrating selection and dosing of TCAs, including the roles of therapeutic drug monitoring and pharmacogenetics. Such a guideline is currently lacking and would contribute to optimal TCA treatment, whereby efficacy and tolerability may be increased.
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http://dx.doi.org/10.1186/s12888-021-03490-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487125PMC
October 2021

Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling.

J Clin Pharmacol 2021 Sep 23. Epub 2021 Sep 23.

Department of Pharmacy, Radboud Institute for Health Sciences & Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.

Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, coadministration with the cornerstone TB drug rifampicin results in suboptimal plasma exposure. We aimed to gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically based pharmacokinetic model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate pharmacokinetic parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P-glycoprotein in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin-glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration-time curve (AUC) of moxifloxacin (400 mg once daily) with and without rifampicin (600 mg once daily) were in accordance with clinically observed data (predicted/observed [P/O] ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual patients with TB as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios, 1.04-1.52) and the multiple dose model to children with TB (P/O AUC ratio, 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin pharmacokinetics and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further physiologically based pharmacokinetic refinement.
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http://dx.doi.org/10.1002/jcph.1972DOI Listing
September 2021

Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial.

J Antimicrob Chemother 2021 Nov;76(12):3237-3246

Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town 8000, South Africa.

Background: Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children.

Objectives: To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB.

Patients And Methods: The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0-12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1-14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L·h, the geometric mean area under the concentration-time curve from 0 to 24 h (AUC0-24) among adults receiving a 35 mg/kg dose].

Results: Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range = 0.4-11.7). Evaluated doses were ∼35 mg/kg (days 1-14) and ∼50 mg/kg (day 15) for cohort 2 and ∼60 mg/kg (days 1-14) and ∼75 mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65-70 mg/kg rifampicin dose was needed in children to reach the target exposure.

Conclusions: High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.
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http://dx.doi.org/10.1093/jac/dkab336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598292PMC
November 2021

Pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents treated for tuberculous meningitis.

Arch Dis Child 2021 Jun 28. Epub 2021 Jun 28.

Division of Pediatric Respirology, Department of Child Health, Faculty of Medicine, Universitas Padjadjaran, Hasan Sadikin Hospital, Bandung, Indonesia.

Objective: To assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM).

Design: Prospective observational pharmacokinetic study with an exploratory pharmacokinetic/pharmacodynamic analysis.

Setting: Hasan Sadikin Hospital, Bandung, Indonesia.

Patients: Individuals aged 0-18 years clinically diagnosed with TBM and receiving first-line anti-tuberculosis drug dosages according to revised WHO-recommended treatment guidelines.

Interventions: Plasma and cerebrospinal fluid (CSF) concentrations of isoniazid, rifampicin and pyrazinamide were assessed on days 2 and 10 of treatment.

Main Outcome Measures: Plasma exposures during the daily dosing interval (AUC), peak plasma concentrations ( ) and CSF concentrations.

Results: Among 20 eligible patients, geometric mean AUC of isoniazid, rifampicin and pyrazinamide was 18.5, 66.9 and 315.5 hour∙mg/L on day 2; and 14.5, 71.8 and 328.4 hour∙mg/L on day 10, respectively. Large interindividual variabilities were observed in AUC and of all drugs. All patients had suboptimal rifampicin AUC for TBM treatment indication and very low rifampicin CSF concentrations. Four patients developed grade 2-3 drug-induced liver injury (DILI) within the first 4 weeks of treatment, in whom anti-tuberculosis drugs were temporarily stopped, and no DILI recurred after reintroduction of rifampicin and isoniazid. AUC of isoniazid, rifampicin and pyrazinamide along with of isoniazid and pyrazinamide on day 10 were higher in patients who developed DILI than those without DILI (p<0.05).

Conclusion: Higher rifampicin doses are strongly warranted in treatment of children and adolescents with TBM. The association between higher plasma concentrations of isoniazid, rifampicin and pyrazinamide and the development of DILI needs confirmatory studies.
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http://dx.doi.org/10.1136/archdischild-2020-321426DOI Listing
June 2021

Effect of Digital Adherence Tools on Adherence to Antiretroviral Treatment Among Adults Living With HIV in Kilimanjaro, Tanzania: A Randomized Controlled Trial.

J Acquir Immune Defic Syndr 2021 08;87(5):1136-1144

Radboudumc, Radboud Institute for Health Sciences, Department of Pharmacy, Nijmegen, the Netherlands.

Background: Lifelong adherence to antiretroviral treatment remains challenging for people living with HIV (PLHIV). The aim of this study was to investigate whether any of 2 digital adherence tools could improve adherence among PLHIV in Kilimanjaro, Tanzania.

Methods: We performed a parallel 3-arm, nonblinded, randomized controlled trial with 1:1:1 allocation. We included adults aged between 18 and 65 years, living in Kilimanjaro region, and who were on antiretroviral treatment for at least 6 months. Their adherence, as judged by the study nurses, had to be suboptimal. In one arm, participants received reminder short message service (SMS) texts, followed by a question SMS. In the second arm, participants received a real-time medication monitoring (RTMM) device (Wisepill) with SMS reminders. In the third arm, participants received standard care only. The primary outcome of mean adherence over 48 weeks was compared between arms using between-group t tests in a modified intention-to-treat analysis.

Results: In each arm, we randomized 83 participants: data of 82 participants in the RTMM arm, 80 in the SMS arm, and 81 in the standard care arm were analyzed. The average (over 48 weeks) adherence in the SMS, RTMM, and control arms was 89.6%, 90.6%, and 87.9% for pharmacy refill; 95.9%, 95.0%, and 95.2% for self-report in the past week; and 97.5%, 96.6%, and 96.9% for self-report in the past month, respectively (P values not statistically significant).

Conclusions: Receiving reminder SMS or RTMM combined with feedback about adherence levels and discussion of strategies to overcome barriers to adherence did not improve adherence to treatment and treatment outcome in PLHIV.

Clinical Trial Number: PACTR201712002844286.
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http://dx.doi.org/10.1097/QAI.0000000000002695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263131PMC
August 2021

Correction to: A Model-Informed Method for the Purpose of Precision Dosing of Isoniazid in Pulmonary Tuberculosis.

Clin Pharmacokinet 2021 Jul;60(7):955

Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein zuid 10, 864, 6500 HB, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1007/s40262-021-01018-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249269PMC
July 2021

"I Wish to Continue Receiving the Reminder Short Messaging Service": A Mixed Methods Study on the Acceptability of Digital Adherence Tools Among Adults Living with HIV on Antiretroviral Treatment in Tanzania.

Patient Prefer Adherence 2021 9;15:559-568. Epub 2021 Mar 9.

Kilimanjaro Clinical Research Institute, Moshi, Tanzania.

Introduction: Digital Adherence Tools (DAT) to promote adherence to antiretroviral treatment (ART) for HIV are being increasingly adopted globally, however their effectiveness and acceptability in limited resource settings has been challenging. In this study, we examine the acceptability of DATs to improve adherence to ART.

Methods: This study was part of a three-arm randomized controlled trial (REMIND) which investigated the effect of two different DAT's: SMS text messages (SMS) or real-time medication monitoring (RTMM) on treatment adherence; compared to standard of care. Exit interviews and in-depth interviews were conducted at 48 weeks follow-up, to collect data on their experiences (successes, challenges, and barriers) and behaviours regarding the implementation of the interventions. Translated transcripts, memos and field notes were imported to NVivo software version 12. We used a thematic framework analysis which drew from Sekhon's theoretical framework of acceptability (TFA), which comprises of seven constructs (affective attitude, perceived burden, perceived effectiveness, ethicality, self-efficacy, intervention coherence and opportunity costs).

Results: Of the 166 participants enrolled, 143 (86%) were interviewed (68 in the SMS arm and 75 in the RTMM arm). Participants were highly satisfied (98%) with the DAT system and the majority of them reported it motivated them to take their medication (99%). The majority of participants reported they were confident in their ability to comply with the intervention and understood how the intervention worked (97%). Very few reported negatively about the devices (carrying the device), with only 6% reporting that they did not feel comfortable and 8% had ethical concerns with the SMS-content A few participants reported challenges with their connectivity/network and that the visits were too time-consuming. A few participants reported that they incurred extra cost for the sake of the study.

Conclusion: Overall, the acceptability of these DATs was high. However, several factors may hamper their acceptability including the content and number of SMS, carrying the devices and the network availability.
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http://dx.doi.org/10.2147/PPA.S290079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955743PMC
March 2021

Population Pharmacokinetics and Bayesian Dose Adjustment to Advance TDM of Anti-TB Drugs.

Clin Pharmacokinet 2021 06 6;60(6):685-710. Epub 2021 Mar 6.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Tuberculosis (TB) is still the number one cause of death due to an infectious disease. Pharmacokinetics and pharmacodynamics of anti-TB drugs are key in the optimization of TB treatment and help to prevent slow response to treatment, acquired drug resistance, and adverse drug effects. The aim of this review was to provide an update on the pharmacokinetics and pharmacodynamics of anti-TB drugs and to show how population pharmacokinetics and Bayesian dose adjustment can be used to optimize treatment. We cover aspects on preclinical, clinical, and population pharmacokinetics of different drugs used for drug-susceptible TB and multidrug-resistant TB. Moreover, we include available data to support therapeutic drug monitoring of these drugs and known pharmacokinetic and pharmacodynamic targets that can be used for optimization of therapy. We have identified a wide range of population pharmacokinetic models for first- and second-line drugs used for TB, which included models built on NONMEM, Pmetrics, ADAPT, MWPharm, Monolix, Phoenix, and NPEM2 software. The first population models were built for isoniazid and rifampicin; however, in recent years, more data have emerged for both new anti-TB drugs, but also for defining targets of older anti-TB drugs. Since the introduction of therapeutic drug monitoring for TB over 3 decades ago, further development of therapeutic drug monitoring in TB next steps will again depend on academic and clinical initiatives. We recommend close collaboration between researchers and the World Health Organization to provide important guideline updates regarding therapeutic drug monitoring and pharmacokinetics/pharmacodynamics.
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http://dx.doi.org/10.1007/s40262-021-00997-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935699PMC
June 2021

A Model-Informed Method for the Purpose of Precision Dosing of Isoniazid in Pulmonary Tuberculosis.

Clin Pharmacokinet 2021 07 22;60(7):943-953. Epub 2021 Feb 22.

Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein zuid 10, 864, 6500 HB, Nijmegen, The Netherlands.

Background And Objective: This study aimed to develop and evaluate a population pharmacokinetic model and limited sampling strategy for isoniazid to be used in model-based therapeutic drug monitoring.

Methods: A population pharmacokinetic model was developed based on isoniazid and acetyl-isoniazid pharmacokinetic data from seven studies with in total 466 patients from three continents. Three limited sampling strategies were tested based on the available sampling times in the dataset and practical considerations. The tested limited sampling strategies sampled at 2, 4, and 6 h, 2 and 4 h, and 2 h after dosing. The model-predicted area under the concentration-time curve from 0 to 24 h (AUC) and the peak concentration from the limited sampling strategies were compared to predictions using the full pharmacokinetic curve. Bias and precision were assessed using the mean error (ME) and the root mean square error (RMSE), both expressed as a percentage of the mean model-predicted AUC or peak concentration on the full pharmacokinetic curve.

Results: Performance of the developed model was acceptable and the uncertainty in parameter estimations was generally low (the highest relative standard error was 39% coefficient of variation). The limited sampling strategy with sampling at 2 and 4 h was determined as most suitable with an ME of 1.1% and RMSE of 23.4% for AUC prediction, and ME of 2.7% and RMSE of 23.8% for peak concentration prediction. For the performance of this strategy, it is important that data on both isoniazid and acetyl-isoniazid are used. If only data on isoniazid are available, a limited sampling strategy using 2, 4, and 6 h can be employed with an ME of 1.7% and RMSE of 20.9% for AUC prediction, and ME of 1.2% and RMSE of 23.8% for peak concentration prediction.

Conclusions: A model-based therapeutic drug monitoring strategy for personalized dosing of isoniazid using sampling at 2 and 4 h after dosing was successfully developed. Prospective evaluation of this strategy will show how it performs in a clinical therapeutic drug monitoring setting.
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http://dx.doi.org/10.1007/s40262-020-00971-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249295PMC
July 2021

Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg rifampicin.

Eur Respir J 2021 07 8;58(1). Epub 2021 Jul 8.

Dept of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Accumulating data indicate that higher rifampicin doses are more effective and shorten tuberculosis (TB) treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 7- and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Here we report the results of the final cohorts of PanACEA HIGHRIF1, a dose escalation study in treatment-naive adult smear-positive patients with TB.

Methods: Patients received, in consecutive cohorts, 40 or 50 mg·kg rifampicin once daily in monotherapy (day 1-7), supplemented with standard dose isoniazid, pyrazinamide and ethambutol between days 8 and 14.

Results: In the 40 mg·kg cohort (n=15), 13 patients experienced a total of 36 adverse events during monotherapy, resulting in one treatment discontinuation. In the 50 mg·kg cohort (n=17), all patients experienced adverse events during monotherapy, 93 in total; 11 patients withdrew or stopped study medication. Adverse events were mostly mild/moderate and tolerability rather than safety related, gastrointestinal disorders, pruritis, hyperbilirubinaemia and jaundice. There was a more than proportional increase in the rifampicin geometric mean area under the plasma concentration-time curve from time 0 to 12 h (AUC) for 50 mg·kg compared with 40 mg·kg; 571 (range 320-995) 387 (range 201-847) mg·L·h, while peak exposures saw proportional increases. Protein-unbound exposure after 50 mg·kg (11% (range 8-17%)) was comparable with lower rifampicin doses. Rifampicin exposures and bilirubin concentrations were correlated (Spearman's ρ=0.670 on day 3, p<0.001). EBA increased considerably with dose, with the highest seen after 50 mg·kg: 14-day EBA -0.427 (95% CI -0.500- -0.355) logCFU·mL·day.

Conclusion: Although associated with an increased bactericidal effect, the 50 mg·kg dose was not well tolerated. Rifampicin at 40 mg·kg was well tolerated and therefore selected for evaluation in a phase IIc treatment-shortening trial.
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http://dx.doi.org/10.1183/13993003.00955-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411896PMC
July 2021

High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study).

Wellcome Open Res 2019 25;4:190. Epub 2020 Aug 25.

Infectious Diseases Institute, Mulago College of Health Sciences, Kampala, PO Box 22418, Uganda.

Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. ISRCTN15668391 (17/06/2019).
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http://dx.doi.org/10.12688/wellcomeopenres.15565.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542255PMC
August 2020

Returning of antiretroviral medication dispensed over a period of 8 months suggests non-adherence despite full adherence according to real time medication monitoring.

AIDS Res Ther 2020 09 10;17(1):57. Epub 2020 Sep 10.

Kilimanjaro Clinical Research Institute, Kilimanjaro Christian Medical Centre, Moshi, United Republic of Tanzania.

Real-time medication monitoring (RTMM) may potentially enhance adherence to antiretroviral treatment (ART). We describe a participant in an ongoing trial who, shortly after completing trial participation, died of cryptococcal meningitis despite high levels of adherence according to self-report, pill-counts and RTMM (> 99%). However, she evidenced consistently high HIV viral load throughout the 48-week study follow-up. Subsequently, her relatives unsolicitedly returned eight months' dispensed ART medication that she was supposed to have taken. This brief report illustrates the challenges of adherence measurements including RTMM, and reinforces the need to combine adherence assessments with viral load monitoring in HIV care.
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http://dx.doi.org/10.1186/s12981-020-00313-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488262PMC
September 2020

Pharmacokinetics of antiretroviral and tuberculosis drugs in children with HIV/TB co-infection: a systematic review.

J Antimicrob Chemother 2020 12;75(12):3433-3457

Radboud University Medical Center, Radboud Institute for Health Sciences, Department of Pharmacy, Nijmegen, The Netherlands.

Introduction: Management of concomitant use of ART and TB drugs is difficult because of the many drug-drug interactions (DDIs) between the medications. This systematic review provides an overview of the current state of knowledge about the pharmacokinetics (PK) of ART and TB treatment in children with HIV/TB co-infection, and identifies knowledge gaps.

Methods: We searched Embase and PubMed, and systematically searched abstract books of relevant conferences, following PRISMA guidelines. Studies not reporting PK parameters, investigating medicines that are not available any longer or not including children with HIV/TB co-infection were excluded. All studies were assessed for quality.

Results: In total, 47 studies met the inclusion criteria. No dose adjustments are necessary for efavirenz during concomitant first-line TB treatment use, but intersubject PK variability was high, especially in children <3 years of age. Super-boosted lopinavir/ritonavir (ratio 1:1) resulted in adequate lopinavir trough concentrations during rifampicin co-administration. Double-dosed raltegravir can be given with rifampicin in children >4 weeks old as well as twice-daily dolutegravir (instead of once daily) in children older than 6 years. Exposure to some TB drugs (ethambutol and rifampicin) was reduced in the setting of HIV infection, regardless of ART use. Only limited PK data of second-line TB drugs with ART in children who are HIV infected have been published.

Conclusions: Whereas integrase inhibitors seem favourable in older children, there are limited options for ART in young children (<3 years) receiving rifampicin-based TB therapy. The PK of TB drugs in HIV-infected children warrants further research.
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http://dx.doi.org/10.1093/jac/dkaa328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662174PMC
December 2020

Rifampicin Transport by OATP1B1 Variants.

Antimicrob Agents Chemother 2020 09 21;64(10). Epub 2020 Sep 21.

Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Single nucleotide polymorphisms in the OATP1B1 transporter have been suggested to partially explain the large interindividual variation in rifampicin exposure. HEK293 cells overexpressing wild-type (WT) or OATP1B1 variants *1b, *4, *5, and *15 were used to determine the rifampicin intrinsic clearance. For OATP1B1*5 and *15, a 36% and 42% reduction in intrinsic clearance, respectively, compared to WT was found. We consider that these differences in intrinsic clearance most likely have minor clinical implications.
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http://dx.doi.org/10.1128/AAC.00955-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508598PMC
September 2020

Technical and Psychosocial Challenges of mHealth Usage for Antiretroviral Therapy Adherence Among People Living With HIV in a Resource-Limited Setting: Case Series.

JMIR Form Res 2020 Jun 10;4(6):e14649. Epub 2020 Jun 10.

Kilimanjaro Clinical Research Institute, Kilimanjaro Christian Medical Centre, Moshi, United Republic of Tanzania.

Background: Mobile communication has been found to improve antiretroviral therapy (ART) adherence among people living with HIV. In an ongoing randomized clinical trial, 2 mobile communication strategies (ie, sending SMS text messages and real-time medication monitoring [RTMM]) were used to improve adherence to ART among people living with HIV in Tanzania. We noticed remarkable discrepancies between self-reported adherence and adherence recorded by SMS text messaging or RTMM among some of the first trial participants.

Objective: Our objective was to describe these cases and the observed discrepancies in more detail, to serve as a useful illustration of some of the challenges in using mobile health in resource-limited settings.

Methods: In an ongoing randomized trial, adults living with HIV from two HIV treatment centers in Tanzania who were suspected of low levels of adherence were randomly assigned in a 1:1:1 ratio to receive (1) SMS text message reminders, (2) an RTMM device, or (3) no additional intervention to standard HIV care. During bimonthly study visits, the participants self-reported their level of adherence, received feedback about their level of adherence based on SMS text messaging or RTMM, and discussed strategies to overcome adherence problems with nurses providing HIV care. For the purpose of this report, we selected people living with HIV who had completed 5 follow-up visits and consistently reported more than 95% adherence, while SMS text messaging or RTMM recorded lower than 75% adherence. The participants were invited for a short, face-to-face in-depth interview to explore reasons for this discrepancy.

Results: At the time of this analysis, 26 participants had completed follow-up. Six of these evidenced the above-mentioned discrepancies, with an average adherence of 46% based on SMS text messaging or RTMM, while self-reported adherence was 98%. Five of these 6 participants insisted that their adherence to ART was good, with 4 reporting that their adherence to properly using the monitoring device was low. Three participants mentioned concerns about involuntary disclosure of HIV status as a main reason for low adherence to using the device. Two participants were still depending on other reminder cues despite receiving SMS text message or RTMM reminders. Poor network coverage caused low adherence in 1 participant.

Conclusions: Psychosocial barriers were reported as importantly contributing to low adherence, both with respect to use of ART and proper use of the adherence-monitoring device. This case series illustrates that when introducing new digital adherence monitoring technology, researchers should consider psychosocial barriers and distinguish between adherence to device use and adherence to treatment.

Trial Registration: Pan African Clinical Trials Registry PACTR201712002844286; https://tinyurl.com/y98q4p3l.
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http://dx.doi.org/10.2196/14649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315367PMC
June 2020

Preclinical models to optimize treatment of tuberculous meningitis - A systematic review.

Tuberculosis (Edinb) 2020 05 31;122:101924. Epub 2020 Mar 31.

Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525, GA, Nijmegen, the Netherlands. Electronic address:

Tuberculous meningitis (TBM) is the most devastating form of TB, resulting in death or neurological disability in up to 50% of patients affected. Treatment is similar to that of pulmonary TB, despite poor cerebrospinal fluid (CSF) penetration of the cornerstone anti-TB drug rifampicin. Considering TBM pathology, it is critical that optimal drug concentrations are reached in the meninges, brain and/or the surrounding CSF. These type of data are difficult to collect in TBM patients. This review aims to identify and describe a preclinical model representative for human TBM which can provide the indispensable data needed for future pharmacological characterization and prioritization of new TBM regimens in the clinical setting. We reviewed existing literature on treatment of TBM in preclinical models: only eight articles, all animal studies, could be identified. None of the animal models completely recapitulated human disease and in most of the animal studies key pharmacokinetic data were missing, making the comparison with human exposure and CNS distribution, and the study of pharmacokinetic-pharmacodynamic relationships impossible. Another 18 articles were identified using other bacteria to induce meningitis with treatment including anti-TB drugs (predominantly rifampicin, moxifloxacin and levofloxacin). Of these articles the pharmacokinetics, i.e. plasma exposure and CSF:plasma ratios, of TB drugs in meningitis could be evaluated. Exposures (except for levofloxacin) agreed with human exposures and also most CSF:plasma ratios agreed with ratios in humans. Considering the lack of an ideal preclinical pharmacological TBM model, we suggest a combination of 1. basic physicochemical drug data combined with 2. in vitro pharmacokinetic and efficacy data, 3. an animal model with adequate pharmacokinetic sampling, microdialysis or imaging of drug distribution, all as a base for 4. physiologically based pharmacokinetic (PBPK) modelling to predict response to TB drugs in treatment of TBM.
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http://dx.doi.org/10.1016/j.tube.2020.101924DOI Listing
May 2020

Feasibility of SMS to remind pregnant and breastfeeding women living with HIV to take antiretroviral treatment in Kilimanjaro region, Tanzania: a pilot study.

East Afr Health Res J 2020 26;4(2):140-148. Epub 2020 Nov 26.

Kilimanjaro Clinical Research Institute, Moshi, Tanzania, United Republic of.

Background: Pregnant and breastfeeding Women Living with HIV (WLHIV) often have difficulties in reaching adequate levels of adherence (>95%) to Antiretroviral treatment. "Forgetting" is the most commonly mentioned reason. Sending reminders via SMS is expected to improve adherence. We conducted a pilot study to investigate acceptability, user experience and technical feasibility of sending reminder-SMS to WLHIV.

Methods: This was a 6-months observational pilot-study among WLHIV attending antenatal and postnatal care at Kilimanjaro Christian Medical Centre in Moshi, Tanzania. Women received a reminder-SMS 30 minutes before usual time of intake. One hour later, they received an SMS asking whether they took medication to which they could reply with 'Yes' or 'No'. Messages were sent 3 times a week on randomly chosen days to prevent reliance on daily messages. We calculated the percentage of number of SMS delivered, failed to be delivered, and replied to. We analysed feedback from exit-interviews about experience with the SMS-reminders.

Results: 25 women were enrolled (age 18-45), 2 were lost to follow up. 5,054 messages were sent of which 53 failed to be delivered (1%). 1,880 SMS were sent with a question if medication was taken; 1,012 (54%) messages were replied to, of which 1,003 (99%) were replied with 'YES' and closely to 'YES', and a total of 9 (1%) with 'NO' and 'closely to NO'. 868 messages (46%) were not responded to due to either dropout, change of phone number, loss of phone or network failure. Results from 18 interviews showed that 16 (89%) women were satisfied with SMS reminders. 2 (11%) were concerned about unwanted disclosure because of the content 'don't forget to take medication' and one reported other privacy issues (6%). 3 (17%) women experienced stigma.

Conclusion: 99%of SMS being delivered indicates that SMS reminders in this resource-limited setting are technically feasible. However, concerns regarding privacy were noted, specifically the risk of unwanted disclosure and the experience of stigma. Participants indicated that being made aware of their adherence, motivated them to adhere better. However, personalised and more neutral content of the SMS might be a way to improving the intervention.
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http://dx.doi.org/10.24248/eahrj.v4i2.637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279205PMC
November 2020

Model-Based Meta-analysis of Rifampicin Exposure and Mortality in Indonesian Tuberculous Meningitis Trials.

Clin Infect Dis 2020 11;71(8):1817-1823

Department of Pharmacy, Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Intensified antimicrobial treatment with higher rifampicin doses may improve outcome of tuberculous meningitis, but the desirable exposure and necessary dose are unknown. Our objective was to characterize the relationship between rifampicin exposures and mortality in order to identify optimal dosing for tuberculous meningitis.

Methods: An individual patient meta-analysis was performed on data from 3 Indonesian randomized controlled phase 2 trials comparing oral rifampicin 450 mg (~10 mg/kg) to intensified regimens including 750-1350 mg orally, or a 600-mg intravenous infusion. Pharmacokinetic data from plasma and cerebrospinal fluid (CSF) were analyzed with nonlinear mixed-effects modeling. Six-month survival was described with parametric time-to-event models.

Results: Pharmacokinetic analyses included 133 individuals (1150 concentration measurements, 170 from CSF). The final model featured 2 disposition compartments, saturable clearance, and autoinduction. Rifampicin CSF concentrations were described by a partition coefficient (5.5%; 95% confidence interval [CI], 4.5%-6.4%) and half-life for distribution plasma to CSF (2.1 hours; 95% CI, 1.3-2.9 hours). Higher CSF protein concentration increased the partition coefficient. Survival of 148 individuals (58 died, 15 dropouts) was well described by an exponentially declining hazard, with lower age, higher baseline Glasgow Coma Scale score, and higher individual rifampicin plasma exposure reducing the hazard. Simulations predicted an increase in 6-month survival from approximately 50% to approximately 70% upon increasing the oral rifampicin dose from 10 to 30 mg/kg, and predicted that even higher doses would further improve survival.

Conclusions: Higher rifampicin exposure substantially decreased the risk of death, and the maximal effect was not reached within the studied range. We suggest a rifampicin dose of at least 30 mg/kg to be investigated in phase 3 clinical trials.
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http://dx.doi.org/10.1093/cid/ciz1071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643733PMC
November 2020

Effect of diabetes mellitus on TB drug concentrations in Tanzanian patients.

J Antimicrob Chemother 2019 12;74(12):3537-3545

Radboud university medical center, Department of Pharmacy & Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Background: Diabetes mellitus (DM) is associated with poor TB treatment outcome. Previous studies examining the effect of DM on TB drug concentrations yielded conflicting results. No studies have been conducted to date in an African population.

Objectives: To compare exposure to TB drugs in Tanzanian TB patients with and without DM.

Patients And Methods: A prospective pharmacokinetic study was performed among 20 diabetic and 20 non-diabetic Tanzanian TB patients during the intensive phase of TB treatment. Plasma pharmacokinetic parameters of isoniazid, rifampicin, pyrazinamide and ethambutol were compared using an independent-sample t-test on log-transformed data. Multiple linear regression analysis was performed to assess the effects of DM, gender, age, weight, HIV status and acetylator status on exposure to TB drugs.

Results: A trend was shown for 25% lower total exposure (AUC0-24) to rifampicin among diabetics versus non-diabetics (29.9 versus 39.9 mg·h/L, P=0.052). The AUC0-24 and peak concentration (Cmax) of isoniazid were also lower in diabetic TB patients (5.4 versus 10.6 mg·h/L, P=0.015 and 1.6 versus 2.8 mg/L, P=0.013). Pyrazinamide AUC0-24 and Cmax values were non-significantly lower among diabetics (P=0.08 and 0.09). In multivariate analyses, DM remained an independent predictor of exposure to isoniazid and rifampicin, next to acetylator status for isoniazid.

Conclusions: There is a need for individualized dosing of isoniazid and rifampicin based on plasma concentration measurements (therapeutic drug monitoring) and for clinical trials on higher doses of these TB drugs in patients with TB and DM.
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http://dx.doi.org/10.1093/jac/dkz368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183353PMC
December 2019

Successful Systemic and Topical Treatment of Mycobacterium abscessus Otomastoiditis.

Antimicrob Agents Chemother 2019 12 20;64(1). Epub 2019 Dec 20.

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands

is an extensively drug-resistant opportunistic pathogen that can cause chronic otomastoiditis. There are no evidence-based treatment regimens for this severe infection. We treated four children with otomastoiditis with a structured regimen of topical imipenem and tigecycline, intravenous imipenem and tigecycline, and oral clofazimine and azithromycin and adjunctive surgery. This structured approach led to cure, with 1 year of follow-up after treatment. Adverse events were frequent, mostly caused by tigecycline.
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http://dx.doi.org/10.1128/AAC.01203-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187624PMC
December 2019

Implementation and effectiveness of evriMED with short messages service (SMS) reminders and tailored feedback compared to standard care on adherence to treatment among tuberculosis patients in Kilimanjaro, Tanzania: proposal for a cluster randomized controlled trial.

Trials 2019 Jul 12;20(1):426. Epub 2019 Jul 12.

Department of Clinical Pharmacology, RadboudUMC, Nijmegen, the Netherlands.

Background: Adherence to tuberculosis (TB) treatment is challenging because of many factors. The World Health Organization has recommended the use of digital adherence monitoring technologies in its End TB Strategy. However, evidence on improving adherence is limited. EvriMED is a real-time medication-monitoring device which was found to be feasible and acceptable in a few studies in Asia. In Tanzania, however, there may be challenges in implementing evriMED due to stigmatization, network and power access, accuracy, and cost effectiveness, which may have implications for treatment outcome. We propose a pragmatic cluster randomized trial to investigate the effectiveness of evriMED with reminder cues and tailored feedback on adherence to TB treatment in Kilimanjaro, Tanzania.

Methods/design: We will create clusters in Kilimanjaro based on level of health care facility. Clusters will be randomized in an intervention arm, where evriMED will be implemented, or a control arm, where standard practice directly observed treatment will be followed. TB patients in intervention clusters will take their medication from the evriMED pillbox and receive tailored feedback. We will use the 'Stages of Change' model, which assumes that a person has to go through the stages of pre-contemplation, contemplation, preparation, action, and evaluation to change behavior for tailored feedback on adherence reports from the device.

Discussion: If the intervention shows a significant effect on adherence and the devices are accepted, accurate, and sustainable, the intervention can be scaled up within the National Tuberculosis Programmes.

Trial Registration: Pan African Clinical Trials Registry, PACTR201811755733759 . Registered on 8 November 2018.
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http://dx.doi.org/10.1186/s13063-019-3483-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626331PMC
July 2019

Optimal Sampling Strategies for Therapeutic Drug Monitoring of First-Line Tuberculosis Drugs in Patients with Tuberculosis.

Clin Pharmacokinet 2019 11;58(11):1445-1454

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands.

Background: The 24-h area under the concentration-time curve (AUC)/minimal inhibitory concentration ratio is the best predictive pharmacokinetic/pharmacodynamic (PK/PD) parameter of the efficacy of first-line anti-tuberculosis (TB) drugs. An optimal sampling strategy (OSS) is useful for accurately estimating AUC; however, OSS has not been developed in the fed state or in the early phase of treatment for first-line anti-TB drugs.

Methods: An OSS for the prediction of AUC of isoniazid, rifampicin, ethambutol and pyrazinamide was developed for TB patients starting treatment. A prospective, randomized, crossover trial was performed during the first 3 days of treatment in which first-line anti-TB drugs were administered either intravenously or in fasting or fed conditions. The PK data were used to develop OSS with best subset selection multiple linear regression. The OSS was internally validated using a jackknife analysis and externally validated with other patients from different ethnicities and in a steady state of treatment.

Results: OSS using time points of 2, 4 and 8 h post-dose performed best. Bias was < 5% and imprecision was < 15% for all drugs except ethambutol in the fed condition. External validation showed that OSS cannot be used for rifampicin in steady state conditions.

Conclusion: OSS at 2, 4 and 8 h post-dose enabled an accurate and precise prediction of AUC values of first-line anti-TB drugs in this population.

Trial Registration: ClinicalTrials.gov (NCT02121314).
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http://dx.doi.org/10.1007/s40262-019-00763-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856034PMC
November 2019

Personalized Tuberculosis Treatment Through Model-Informed Dosing of Rifampicin.

Clin Pharmacokinet 2019 06;58(6):815-826

Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

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) and maximum concentration (C) 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 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.
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http://dx.doi.org/10.1007/s40262-018-00732-2DOI Listing
June 2019

A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant non-tuberculous mycobacteria.

J Antimicrob Chemother 2019 04;74(4):935-943

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Non-tuberculous mycobacteria (NTM) infections are hard to treat. New antimicrobial drugs and smarter combination regimens are needed.

Objectives: Our aim was to determine the in vitro activity of bedaquiline against NTM and assess its synergy with established antimycobacterials.

Methods: We determined MICs of bedaquiline for clinically relevant NTM species and Mycobacterium tuberculosis by broth microdilution for 30 isolates. Synergy testing was performed using the chequerboard method for 22 reference strains and clinical isolates of Mycobacterium abscessus (MAB) and Mycobacterium avium complex (MAC). Time-kill kinetics (TK) assays with resistance monitoring of bedaquiline alone and combined with clofazimine were performed for MAB CIP 104536 and M. avium ATCC 700898; bedaquiline/clarithromycin combinations were evaluated against M. avium ATCC 700898. Interactions were assessed for TK experiments based on Bliss independence.

Results: Bedaquiline had modest activity against tested NTM, with MICs between <0.007 and 1 mg/L. Bedaquiline showed no interaction with tested drugs against MAB or MAC. Lowest mean fractional inhibitory concentration index (FICI) values were 0.79 with clofazimine for MAB and 0.97 with clofazimine and 0.82 with clarithromycin for MAC. In TK assays, bedaquiline showed a bacteriostatic effect. Clofazimine extended the bacteriostatic activity of bedaquiline against MAB and yielded a slight bactericidal effect against M. avium. The bedaquiline/clofazimine combination slowed emergence of bedaquiline resistance for M. avium but promoted it for MAB. Relative to Bliss independence, bedaquiline/clofazimine showed synergistic interaction over time for MAB and no interaction for M. avium and bedaquiline/clarithromycin showed antagonistic interaction for M. avium.

Conclusions: Following these in vitro data, a bedaquiline/clofazimine combination might add activity to MAB and MAC treatment. The bedaquiline/clarithromycin combination might have lower activity compared with bedaquiline alone for MAC treatment.
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http://dx.doi.org/10.1093/jac/dky526DOI Listing
April 2019

Protein binding of rifampicin is not saturated when using high-dose rifampicin.

J Antimicrob Chemother 2019 04;74(4):986-990

Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.

Background: Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations.

Objectives: To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin.

Methods: Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64 mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10 mg/kg daily) or high-dose (35 mg/kg) rifampicin up to steady-state. The performance of total AUC0-24 to predict unbound AUC0-24 was evaluated.

Results: The in vitro free fraction of rifampicin remained unaltered (∼9%) up to 21 mg/L and increased up to 13% at 41 mg/L and 17% at 64 mg/L rifampicin. The highest (peak) concentration in vivo was 39.1 mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC0-24in vivo was 13.3% (range = 8.1%-24.9%) and 11.1% (range = 8.6%-13.6%) for the standard group and the high-dose group, respectively (P = 0.214). Prediction of unbound AUC0-24 based on total AUC0-24 resulted in a bias of -0.05% and an imprecision of 13.2%.

Conclusions: Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.
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http://dx.doi.org/10.1093/jac/dky527DOI Listing
April 2019

Rifampicin Alters Metformin Plasma Exposure but Not Blood Glucose Levels in Diabetic Tuberculosis Patients.

Clin Pharmacol Ther 2019 03 29;105(3):730-737. Epub 2018 Oct 29.

Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.

The pharmacokinetic (PK) and clinical implications of combining metformin with rifampicin are relevant to increasing numbers of patients with diabetic tuberculosis (TB) across the world and are yet unclear. We assessed the impact of rifampicin on metformin PKs and its glucose-lowering effect in patients with diabetic TB by measuring plasma metformin and blood glucose during and after TB treatment. Rifampicin increased metformin exposure: plasma area under the plasma concentration-time curve from time point 0 to the end of the dosing interval (AUC ) and peak plasma concentration (C ) geometric mean ratio (GMR; during vs. after TB treatment) were 1.28 (90% confidence interval (CI) 1.13-1.44) and 1.19 (90% CI 1.02-1.38; n = 22). The metformin glucose-lowering efficacy did not change (Δglucose - C ; P = 0.890; n = 18). Thus, we conclude that additional glucose monitoring in this population is not warranted. Finally, 57% of patients on metformin and rifampicin, and 38% of patients on metformin alone experienced gastrointestinal adverse effects. Considering this observation, we advise patients to take metformin and rifampicin with food and preferably separated in time. Clinicians could consider metoclopramide if gastrointestinal adverse effects occur.
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http://dx.doi.org/10.1002/cpt.1232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587702PMC
March 2019

The stability of antimycobacterial drugs in media used for drug susceptibility testing.

Diagn Microbiol Infect Dis 2018 Dec 27;92(4):305-308. Epub 2018 Jun 27.

Department of Medical Microbiology, Radboud University Medical Center, PO Box 9101, 6500HB Nijmegen, the Netherlands. Electronic address:

The emergence of drug-resistant tuberculosis and disease caused by nontuberculous mycobacteria has increased the need for accurate drug susceptibility testing of mycobacteria. The stability of the tested drugs in relevant test media have been understudied. We assessed the stability of isoniazid, rifampicin, clarithromycin, linezolid and amikacin in Middlebrook 7H9 medium and that of clarithromycin, amikacin and cefoxitin in the cation-adjusted Mueller Hinton broth. We used ultra-performance liquid chromatography (UPLC) methods for rifampicin and isoniazid and a microbiological assay for rifampicin, clarithromycin, amikacin, cefoxitin and linezolid. Rifampicin and isoniazid concentrations in Middlebrook 7H9 medium had decreased by 92% and 54% after 7 days. The microbiological assay revealed decreases in drug concentration of ≥75% (rifampicin, clarithromycin, cefoxitin) and 60% (linezolid) after 14 days. With the exception of amikacin, all antimycobacterial drugs were unstable during 14 days of incubation in the preferred media for DST. Drug stability may influence minimum inhibitory concentration measurements.
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http://dx.doi.org/10.1016/j.diagmicrobio.2018.06.015DOI Listing
December 2018

Assessment of the Additional Value of Verapamil to a Moxifloxacin and Linezolid Combination Regimen in a Murine Tuberculosis Model.

Antimicrob Agents Chemother 2018 09 27;62(9). Epub 2018 Aug 27.

Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Centre, Rotterdam, the Netherlands.

The favorable treatment outcome rate for multidrug-resistant tuberculosis (MDR-TB) is only 54%, and therefore new drug regimens are urgently needed. In this study, we evaluated the activity of the combination of moxifloxacin and linezolid as a possible new MDR-TB regimen in a murine TB model and the value of the addition of the efflux pump inhibitor verapamil to this backbone. BALB/c mice were infected with drug-sensitive and were treated with human-equivalent doses of moxifloxacin (200 mg/kg of body weight) and linezolid (100 mg/kg) with or without verapamil (12.5 mg/kg) for 12 weeks. Pharmacokinetic parameters were collected during treatment at the steady state. After 12 weeks of treatment, a statistically significant decline in mycobacterial load in the lungs was observed with the moxifloxacin-linezolid regimen with and without verapamil (5.9 and 5.0 log CFU, respectively), but sterilization was not achieved yet. The spleens of all mice were culture negative after 12 weeks of treatment with both treatment modalities, and the addition of verapamil caused a significant reduction in relapse (14/14 positive spleens without versus 9/15 with verapamil, = 0.017). In conclusion, treatment with a combination regimen of moxifloxacin and linezolid showed a strong decline in mycobacterial load in the mice. The addition of verapamil to this backbone had a modest additional effect in terms of reducing mycobacterial load in the lung as well as reducing the spleen relapse rate. These results warrant further studies on the role of efflux pump inhibition in improving the efficacy of MDR-TB backbone regimens.
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http://dx.doi.org/10.1128/AAC.01354-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125510PMC
September 2018

Evaluation of dried blood spot sampling for pharmacokinetic research and therapeutic drug monitoring of anti-tuberculosis drugs in children.

Int J Antimicrob Agents 2018 Jul 8;52(1):109-113. Epub 2018 May 8.

Radboud University Medical Center-Dekkerswald, Department of Pulmonary Diseases, Groesbeek, The Netherlands. Electronic address:

Background: Dried blood spot (DBS) sampling for pharmacokinetic (PK) studies and therapeutic drug monitoring have unique advantages over venous sampling. This study aimed to evaluate a DBS method for first-line anti-tuberculosis drugs in children, and DBS sampling to assess PK parameters.

Methods: Paraguayan children were treated according to the revised paediatric dosing scheme of the World Health Organization. A PK curve was performed both with DBS sampling and conventional venous sampling for rifampicin, pyrazinamide and ethambutol. Passing-Bablok regression, Bland-Altman plots and predictive performance evaluation were used to assess agreement between DBS and plasma concentrations. The percentages of patients attaining population PK values for C and AUC were calculated.

Results: After use of a conversion factor, Passing-Bablok regression showed no significant proportional or systematic bias between DBS and plasma concentrations. Bland-Altman plots showed that 95% of the ratios of the DBS predicted:observed plasma concentrations lay between 0.6 and 1.4 for rifampicin, 0.5 and 1.6 for pyrazinamide and -0.4 and 2.8 for ethambutol. DBS measurements showed acceptable predictive performance for rifampicin and pyrazinamide, but not for ethambutol. Assessment of C target attainment was 62.5% for isoniazid, 25% for rifampicin, 100% for pyrazinamide and 75% for ethambutol.

Conclusion: For rifampicin and pyrazinamide, the DBS method was accurate in predicting plasma concentrations, and was used successfully for PK parameter assessment. However, predicting ethambutol plasma concentrations with DBS measurement was associated with too much imprecision. Despite higher dosing, only 25% of the population reached average target adult rifampicin exposures.
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http://dx.doi.org/10.1016/j.ijantimicag.2018.04.020DOI Listing
July 2018
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