MDR-PK Studies


Pharmacokinetics and toxicity of the second-line anti-TB drugs in HIV-infected and uninfected children

Funder: NIH, NICHD

Principal Investigator: Anneke C. Hesseling

Multidrug-resistant tuberculosis (MDR-TB; i.e. resistance to both rifampicin and isoniazid) is an emerging global epidemic, and requires treatment with second-line anti-TB medications.  Although second-line anti-TB drugs are routinely given and recommeded in children, there is limited information available to inform the accurate dosing in young and in HIV-infected children, who may have altered drug metabolism and drug-drug interactions. There are limited data on the toxicity of these anti-TB drugs in children, who are typically treated for 18-24 months for drug-resistant tuberculosis (DR-TB).  The long-term goal of our project is to improve the health of children with DR-TB in need of second-line antituberculosis drugs, through studying the pharmacokinetics (PK), safety profile and toxicity of commonly used second-line anti-TB drugs in children with and without HIV co-infection.

This study is a prospective, longitudinal, hospital-based, observational PK study in HIV-infected and uninfected children aged 0-15 years who are routinely receiving chemotherapy or chemoprophylaxis for the treatment or prevention of DR-TB.  The target enrolment is 318 children consecutively over 3.5 years for intensive PK sampling of second-line anti-TB drugs. HIV-infected children will also have PK sampling of antiretrovirals done. We will follow children on routine treatment for DR disease until treatment completion for clinical outcomes including TB treatment response and drug adverse effects. An equal number of HIV-infected children without anti-TB therapy will be enrolled to allow for comparison of the effect of second-line TB drugs on ARV levels in HIV-infected children.

By the end of 2014, 230 total participants had already been enrolled. This study has helped build significant capacity at our group for the implementation of these specialized and high-impact types of clinical studies in children.  As there is very little existing data on the PK of most of these drugs in children, the results of this study are already informing current dosing recommendations for the second-line TB drugs.  We expect the analysis and dissemination of results on some of the key second-line drugs in 2015.

The project is also building on excellent collaborations with colleagues in South African and internationally.

Pharmacokinetics and Toxicity of Ofloxacin, Levofloxacin and Moxifloxacin in HIV-Infected and Uninfected Children with Tuberculosis

Principal investigator: Steffi Thee

The fluoroquinolone antibiotics ofloxacin, levofloxacin, and moxifloxacin are key components of treatment regimens for drug-resistant TB, though there is limited data on dosing and toxicity of these drugs in children.  This open label crossover design study is a sub-study of the main MDR PK Study, and aims to assess the pharmacokinetics and cardiotoxicity of ofloxacin, levofloxacin (<8 years of age), and moxifloxacin (>8 years of age) in children with drug-resistant TB. Serum was collected prior to, and at 1, 2, 4, 6 and 8 hours post-dose. Maximum serum concentration (Cmax), time to Cmax (Tmax) and area under the time-concentration curve from 0-8 hours (AUC0-8) were calculated. A 12-lead ECG was done 3 hours post-dose, at the putative Tmax. The study began in 2012 and completed enrolment in 2014.

Analysis of the ofloxacin and levofloxacin group was completed in 2013. Among 22 children receiving drug-resistant tuberculosis prophylaxis or treatment, serum concentrations following oral doses of levofloxacin (15 mg/kg of body weight) and ofloxacin (20 mg/kg) were lower than those expected from existing pediatric data, possibly due to differences in the formulations (crushed tablets). Drug exposures were lower than those in adults following standard doses and below the proposed pharmacodynamic targets, likely due to more rapid elimination in children. No QT prolongation was observed. These results were published in 2014 (Thee S, et al. Antimicrobial Agents and Chemotherapy. 2014;58 (5):2948-51.).

Analysis of the group receiving moxifloxacin was completed in 2014. Twenty-three children aged 7-15 years of age receiving moxifloxacin 10 mg/kg/day as part of their MDR-TB treatment were included. We found low serum moxifloxacin concentrations (AUC of 17.24 [IQR, 14.47–21.99] μg*h/mL) compared with adults receiving 400 mg moxifloxacin daily. (AUC 40-60 μg*h/mL). HIV-infected children had lower concentrations compared to HIV-uninfected children, though the numbers were small. Moxifloxacin was well tolerated, with adverse effect mostly mild and non-persistent.  Higher moxifloxacin dosages may be required in children.  These results were published in early 2015 (Thee S, et al. Clin Infect Dis. 2015;60 (4):549-56.).

 Influence of lignocaine on the pharmacokinetics and tolerability of intramuscular amikacin: a double-blind randomized cross-over trial

Principal Investigator: Penelope C. Rose

Current treatment regimens for MDR-TB recommend the use of the second-line injectable TB drugs. These drugs are given by a daily, painful, intramuscular injection, often for up to 6 months. Giving the injections mixed with the local anaesthetic agent lignocaine could decrease the pain associated with these injections, but may also influence the pharmacokinetics of the injectable.

This uses a randomized crossover design in which patients with MDR-TB routinely receiving amikacin will receive their routine amikacin injections both with and without lignocaine. The pain during each injection and the amikacin concentrations is recorded and analyzed to assess whether lignocaine reduces the injection pain and whether it causes clinically relevant changes in the amikacin pharmacokinetics.

We expect to complete enrolment and analysis in 2015. These results could be used to recommend the routine addition of lignocaine to the second-line injectables to reduce the pain from these poorly tolerated injections.

Pediatric Tuberculosis: Enabling early detection of children at-risk for treatment failure (Dried-blood spot [DBS] sub-study)

Principal investigator: Anneke C. Hesseling, South Africa, in collaboration with Susan Abdel Rahman, Mercy Children’s Hospital, Kansas City, Missouri, USA

Funder: Thrasher Research Fund

Both sub-therapeutic and supra-therapeutic drug concentrations pose risks to children treated for MDR-TB. The only way to guarantee that children are achieving desirable drug concentrations is to measure drug levels at the point-of-care, which is currently not feasible via traditional venipuncture-based methods. TB drug monitoring can provide point-of-care clinicians with objective data to guide treatment in the children for whom they provide care. This is of special concern given the high rates of toxicity observed in children receiving the 2nd line TB drugs. DBS assays will not only enhance clinical care but enable the conduct of population-based PK studies in large groups of children for whom we currently have limited information on the relationship between dose and exposure. Once published, DBS technology will be available for immediate application by practitioners managing children with DR-TB and can conceivably impact every pediatric TB patient residing in a community that has access to filter paper and a postal system.

This is a collaboration between the DTTC and the University of Missouri-Kansas City School of Medicine. The hypothesis of this study is that dried blood spots (DBS) can be used to facilitate TB drug monitoring in children that reside in resource-constrained settings. The specific aims are: 1 – To develop and validate methods for DBS analysis of drugs used to treat DR-TB in children; 2 – Evaluate the feasibility of DBS monitoring at the point of care for children with DR-TB. The study will develop DBS assays for drugs used to treat DR-TB and field-test the technology in an “ideal” treatment setting where venous blood concentrations are already planned. The primary and secondary outcomes for this study are to establish concordance in anti-TB concentrations between venous blood and DBS and define the impact of remote collection, shipping and handling on DBS performance, respectively. The study began enrolling at the end of 2014.

Otsuka Studies 232 and 233

Principal Investigator: Anneke Hesseling

Funder: Otsuka Pharmaceuticals

Children with MDR-TB can have good outcomes when receiving high-quality individualized treatment, however regimens are long, associated with frequent serious adverse events, and often require prolonged hospitalization. Better tolerated and shorter treatment regimens are urgently needed. Delamanid is a novel TB drug recently approved by the European Medicines Authority (EMA) for the treatment of MDR-TB in adults, but has not yet been studied in children.

Study 242-12-232 is titled Phase 1, Open-label, multiple-dose, age de-escalation trial to assess the pharmacokinetics, safety and tolerability of delamanid (OPC 67683) in pediatric multidrug-resistant tuberculosis patients on therapy with an optimized background regimen of anti-tuberculosis drugs. This study aims to determine the pharmacokinetics and safety of delamanid given over a short period to children with MDR-TB, in combination with an optimized treatment regimen.

Study 242-12-233, titled Phase 2, Open-label, multiple-dose trial to assess the safety, tolerability, pharmacokinetics, and efficacy of delamanid (OPC 67683) in pediatric multidrug-resistant tuberculosis patients on therapy with an optimized background regimen of anti-tuberculosis drugs over a 6 month treatment period.  Children completing the Phase 1 study are encouraged to roll-over into this Phase 2 study, which will provide additional information on the pharmacokinetics of delamanid and important information on its safety when used long-term.

These are the first studies of a novel TB drug in children, and are being implemented at a site in the Philippines and here at the DTTC.  Enrolment at the DTTC began in 2014, and is ongoing. This is the first paediatric-specific trial of a novel TB drug. Data generates from this study could have a significant impact on the development of shorter duration injectable sparing drug regimens for MDR-TB in children.

Tuberculosis in pregnancy: Disease spectrum and treatment outcome amongst HIV-infected and -uninfected pregnant South African women.

Principal investigator: Adrie Bekker

Funder: TREAT TB and USAID

TB and HIV are major global health problems commonly affecting pregnant women in high-burden TB/HIV settings. TB in pregnancy has not been well investigated to date. This study aimed to describe the burden, TB disease spectrum and treatment outcome in pregnant women with TB. During 2014, 74 mothers presenting at Tygerberg Hospital, Cape Town were diagnosed with TB; 70 % were HIV co-infected. HIV co-infection was associated with high mortality in both mothers and newborns. In pregnancy, TB often presents atypically and the diagnosis is frequently delayed, highlighting the need for antenatal TB screening as well as during the postpartum period. A proportion of HIV co-infected pregnant women presented with severe forms of extra-pulmonary TB, complicating the diagnosis and contributing to poor outcome. Both TB and HIV were associated with low birth weight and prematurity births in infants, highlighting the increased morbidity in infants in the presence of maternal TB. Five (7%) maternal deaths occurred, and 41 (55%) of women had a favourable TB treatment outcome.

Pharmacokinetics and toxicity of first-line anti-TB drugs in infants (“Treat Infant TB”)

Principal investigator: Adrie Bekker

Funder: TB Alliance (STEP-TB, Unitaid)

More than 90% of children treated for TB have drug-susceptible TB, and require treatment with the “first-line” TB drugs. There are limited data on the appropriate dosing of the first-line anti-TB drugs in infants (< 12 months of age), despite revised WHO dosing recommendations issued in 2010, recommending considerably higher doses of rifampicin, pyrazinamide and isoniazid in children.  This gap in knowledge prompted us to conduct a pharmacokinetic study of the first-line anti-TB drugs in infants. The aim of the study was to establish what the drug exposure is in infants   when dosed with WHO-recommended doses of TB drugs. Infants are at extremely high risk of developing TB disease if exposed to TB, and undergo many developmental changes influencing absorption, metabolism and elimination of drugs.  Between April-December 2014, we enrolled 40 infants and completed pharmacokinetic sampling. Long-term follow-up is ongoing and data analysis will be completed during 2015. Information gained from this study will inform paediatric TB treatment guidelines in infants.