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The Pediatric Tuberculosis Treatment Pipeline: Beyond Pharmacokinetics and Safety Data

July 15, 2016

By Lindsay McKenna

INTRODUCTION

The roster of enrolling and planned pediatric tuberculosis (TB) treatment studies is growing. Emerging results from pharmacokinetics (PK) and safety studies continue to inform optimal dosing strategies in children and to highlight areas in need of further investigation. New pediatric formulations continue to advance to market, and consensus has begun to form around the need for efficacy studies of simplified multidrug-resistant TB (MDR-TB) treatment regimens in children.

PEDIATRIC PIPELINE OVERVIEW

Studies that are under way or starting soon will evaluate preventive therapy for children exposed to MDR-TB and treatment shortening for less severe forms of drug-sensitive TB (DS-TB) in children, as well as fill gaps in PK and safety data that are necessary to optimize treatment, including in HIV-positive children and children with MDR-TB. Table 1 provides an overview of ongoing and planned pediatric TB prevention and treatment studies.

Table 1. Ongoing and Planned TB Prevention and Treatment Studies in Children

Study/Regimen

Status

Population(s)

Sponsor(s)

PREVENTION

P4v9

4 months of self-administered daily rifampin for prevention of TB

NCT00170209*

Enrollment complete; results expected 2016

HIV-positive and HIV-negative infants, children, and adolescents 0–17 years old with LTBI

CIHR, McGill University

TBTC 35

PK and safety of rifapentine/isoniazid FDC for prevention of TB

Planned; opening 2017

HIV-positive and HIV-negative infants, children, and adolescents 0–12 years old with LTBI

TBTC, Sanofi

TB-CHAMP

6 months of levofloxacin vs. placebo for prevention of MDR-TB (substudy planned using delamanid for child contacts of FQ-R TB patients)

Planned; opening 2016

HIV-positive or HIV-negative infant and child household contacts 0–5 years old; children ≤5 years old will get new pediatric formulation

BMRC, Wellcome Trust, DFID, SA MRC

ACTG A5300/IMPAACT P2003 (PHOENIx)

6 months of delamanid vs. isoniazid for prevention of MDR-TB

Planned; opening late 2016/early 2017

High-risk (HIV+, TST+, or <5 years) infant, child,  adolescent, and adult household contacts of index patient with MDR-TB

NIAID

V-QUIN

6 months of levofloxacin vs. placebo for prevention of MDR-TB

Planned; opening 2016

HIV-positive or HIV-negative adult household contacts; phased inclusion of infant, child, and adolescent contacts

NHMRC

TREATMENT – NEW DRUGS

232

PK and safety of delamanid; OBR for treatment of MDR-TB

NCT01856634*

Enrolling; final results expected 2018

HIV-negative infants, children, and adolescents 0–17 years old with MDR-TB; children ≤5 years old will get pediatric formulation

Otsuka

233

6 months of delamanid; OBR for treatment of MDR-TB

NCT01859923*

Enrolling; final results expected 2020

HIV-negative infants, children, and adolescents 0–17 years old with MDR-TB; children ≤5 years old will get pediatric formulation

Otsuka

IMPAACT P2005

PK and safety of delamanid; all oral OBR for treatment of MDR-TB

Planned

HIV-positive or HIV-negative infants, children, and adolescents 0–18 years old with MDR-TB

NIAID

JANSSEN C211

PK and safety of bedaquiline; OBR for treatment of MDR-TB

NCT02354014*

Enrolling

HIV-negative infants, children, and adolescents 0–18 years old with MDR-TB; children ≤12 years old will get pediatric formulation

Janssen, UNITAID/TB Alliance (STEP-TB Project)

IMPAACT P1108

PK and safety of bedaquiline; OBR for treatment of MDR-TB

Planned; opening 2016

HIV-positive or HIV-negative infants, children, and adolescents 0–18 years old with MDR-TB

NIAID

TREATMENT – EXISTING DRUGS

Treat Infant TB

PK and safety of FLDs using 2010 WHO dosing guidelines for treatment of TB

Enrollment complete; results presented 2015

HIV-positive or HIV-negative infants <12 months old with TB

UNITAID/TB Alliance (STEP-TB Project)

PK-PTBHIV01

PK of FLDs using 2010 WHO dosing guidelines for treatment of TB

NCT01687504*

Enrollment complete; interim results presented 2015; final results expected 2016

HIV-positive or HIV-negative children 3 months to 14 years old with TB

NICHD

OptiRif Kids

PK, safety, and dose optimization of rifampin for treatment of TB

Planned; opening 2016

HIV-positive or HIV-negative infants and children ≤5 years old with TB

TB Alliance

SHINE

4 vs. 6 months using 2010 WHO dosing guideline–adjusted FLD FDCs for treatment of minimal TB

Planned; opening 2016

HIV-positive or HIV-negative infants, children, and adolescents 0–16 years old with minimal TB

BMRC, DFID, Wellcome Trust, UCL

TBM-KIDS

Safety and efficacy of high-dose rifampin ± levofloxacin for treatment of TBM

Planned; opening 2016

HIV-positive or HIV-negative infants and children with TBM

 

NICHD

MDR-PK 1

PK and safety of SLDs for treatment of MDR-TB

Enrollment complete; interim results presented; final results expected 2016

HIV-positive or HIV-negative infants, children, and adolescents with MDR-TB or LTBI

NICHD

MDR-PK 2

PK, safety, and dose optimization of SLDs for treatment of MDR-TB

Enrolling; results expected 2020

HIV-positive or HIV-negative infants, children, and adolescents with MDR-TB

NICHD, SA MRC

COTREATMENT WITH ARVS           

DATiC

PK of FLDs using 2010 WHO dosing guidelines for treatment of TB and interactions with lopinavir/ritonavir and nevirapine

NCT01637558*

Enrolling; results expected 2017

HIV-positive or HIV-negative infants, children, and adolescents 0–12 years old with TB

NICHD

IMPAACT P1106

PK of rifampin and isoniazid with nevirapine or lopinavir/ritonavir

NCT02383849*

Enrolling; results expected 2018

HIV-positive or HIV-negative low-birth-weight/ premature infants

NIAID, NICHD

PK and safety of nevirapine with rifampin-containing TB treatment

NCT01699633*

Enrolling; results expected 2017

HIV-positive children 3 months to 3 years old with TB

NICHD

IMPAACT P1070

PK and safety of efavirenz with rifampin-containing TB treatment

NCT00802802*

Enrollment complete; results presented 2016

HIV-positive children 3 months to <3 years old with TB

NIAID, NICHD

PK and safety of efavirenz with rifampin-containing TB treatment

NCT01704144*

Enrolling; results expected 2017

HIV-positive children and adolescents 3–14 years old with TB

NICHD

HIVPED001

PK and safety of superboosted lopinavir/ritonavir (1:1) with rifampin-containing TB treatment

NCT02348177*

Enrolling; interim results presented 2015; final results expected 2016

HIV-positive infants and children with TB weighing 3–15 kg; DNDi developing stand-alone ritonavir booster formulation

DNDi, AFD, UBS Optimus Foundation, MSF

IMPAACT P1101

PK and safety of raltegravir with rifampin-containing TB treatment

NCT01751568*

Enrolling; results expected 2018

ARV-naive, HIV-positive children and adolescents 2–12 years old with TB

NIAID

*U.S. National Institutes of Health (NIH) clinical trial identifiers; for more information, go to ClinicalTrials.gov.

AFD: French Development Agency
ART: antiretroviral therapy
ARV: antiretroviral
BMRC: British Medical Research Council
CIHR: Canadian Institutes of Health Research
DFID: Department for International Development (United Kingdom)
DNDi: Drugs for Neglected Diseases
FDC: fixed-dose combination
FLD: first-line drug
FQ-R: fluoroquinolone-resistant
IMPAACT: International Maternal, Pediatric, Adolescent AIDS Clinical Trials Group, NIH
LTBI: latent tuberculosis infection
MDR-TB: Multidrug-resistant tuberculosis
MSF: Médecins Sans Frontières
NHMRC: National Health and Medical Research Council (Australia)
NIAID: National Institute of Allergy and Infectious Diseases, NIH
NICHD: National Institute of Child Health and Human Development, NIH
OBR: optimized background regimen
PK: pharmacokinetics
SA MRC: South African Medical Research Council
SLD: second-line drug
TB: tuberculosis
TBM: tuberculous meningitis
TBTC: Tuberculosis Trials Consortium, U.S. Centers for Disease Control and Prevention
TST: tuberculin skin test
UBS: Union Bank of Switzerland
UCL: University College London
WHO: World Health Organization

TB drugs and regimens with proven efficacy in adults have long been assumed to work at least equally as well in children. Typically, PK and safety studies are conducted in children only to inform appropriate dosing and to confirm safety and tolerability; efficacy studies are therefore not usually considered to be necessary.

However, given the paucibacillary nature of TB disease in children (characterized by fewer TB bacteria in the body), it might be possible to achieve a cure using shorter, milder regimens than those that are necessary in adults. This logic underpins SHINE, a study to evaluate whether it is possible to shorten standard first-line treatment from six to four months for less severe forms of pulmonary and extrapulmonary TB in children. There is an urgent need to conduct a similar evaluation to shorten treatment for children with less severe MDR-TB; conversations about what this regimen and study might look like are ongoing. Regimens for children with more severe forms of TB with higher bacterial loads, such as disseminated or HIV-associated TB, should also be studied.

RESEARCH UPDATES

Data from ongoing pediatric PK and safety studies continue to contribute findings that are important for optimizing TB treatment for children. Here we present recent research updates and discuss remaining research needs for first-line, second-line, and new TB drugs in children. For a comprehensive discussion of available evidence and recommended doses for TB drugs in children, see the review Antituberculosis Drugs in Children, from Schaaf, Garcia-Prats, and Donald.1

First-Line Drugs

A study of first-line treatment in infants in Cape Town, South Africa (Treat Infant TB; N = 39), using doses recommended by the WHO, found that 35 mg/kg (recommended range: 30–40 mg/kg) of pyrazinamide and 15 mg/kg (recommended range: 10–20 mg/kg) of isoniazid achieved drug exposures in infants that are comparable to those in adults. Exposures following 15 mg/kg (recommended range: 10–20 mg/kg) of rifampin and 20 mg/kg (recommended range: 15–25 mg/kg) of ethambutol were lower than those achieved in adults. HIV-positive infants taking ARVs (abacavir, lamivudine, and lopinavir/ritonavir) achieved lower pyrazinamide and ethambutol exposures than did HIV-negative infants.2,3

Another study of first-line treatment using WHO-recommended doses in Durban, South Africa, in children 10 years old or younger found exposures for rifampin, isoniazid, and pyrazinamide below those associated with optimal microbiological and clinical outcomes in adults.4

A study of first-line treatment in infants and children in Ghana (PK-PTBHIV01; N = 62; 47% of children less than five years old), again using WHO-recommended doses, found that 59% of children had low exposures to rifampin and 52% of children had low exposures to ethambutol.5,6

A recent study in Vietnamese children 15 years of age or younger found rifampin concentrations in cerebrospinal fluid below the minimum inhibitory concentration (minimum drug concentration required to inhibit mycobacterial growth) for almost all children treated for TB meningitis using pre-2010 WHO-recommended doses.7 These findings support planned work to investigate the use of higher doses of rifampin for TB meningitis (TBM-KIDS). Further research is urgently needed to establish optimal drug combinations and doses for the treatment of pediatric TB meningitis.

Despite good treatment outcomes, investigators continue to find lower drug exposures measured by Cmax (peak drug exposure) and area under the curve (AUC, or total drug exposure) in children compared with adults. It is important to note a recently demonstrated association between low TB drug levels and poor outcomes in children. A study in India comparing PK for rifampin, isoniazid, and pyrazinamide in HIV-positive and HIV-negative children receiving thrice-weekly TB treatment found that the Cmax of rifampin and pyrazinamide significantly affected TB treatment outcomes.8 These findings support the higher and daily doses recommended by the WHO and underscore the need to identify PK targets that correlate with good outcomes in children and the drug doses that are necessary to achieve them. Low rifampin exposures in children are of special concern for the treatment of more severe forms of TB and in light of plans to evaluate shorter regimens.

Children experience a broad spectrum of TB disease, ranging from severe TB (e.g., TB meningitis) in young children to limited pulmonary disease to cavitary disease in adolescents. Optimal drug doses and treatment durations likely differ by disease type (extent and location). It is critical to determine which PK values correlate most precisely with efficacy for TB drugs in children. This information is necessary to optimize pediatric dosing, which is especially important in the context of simplified and shortened regimens for DS-TB and drug-resistant TB (DR-TB) and in treating more severe forms of TB.

Findings from these studies point to the need for investigations to determine PK targets for children, especially considering differences in bacterial burden and severity and location of disease; to elucidate optimal age- and weight-based dosing schedules in infants and young children; and to optimize dosing for first-line TB drugs in children younger than five years. In addition, as investigators continue to study higher doses of rifampin in adults without finding toxicity (see Tuberculosis Treatment Pipeline), higher doses should be considered in children and evaluated in future PK and safety studies. Some work is already under way or being planned, including a study to evaluate the PK and safety of higher doses of rifampin in children 0–12 years old with severe and nonsevere forms of TB (OptiRif Kids). This dose-finding and safety study will explore the drug doses in children necessary to achieve the PK exposures shown to be safe, well tolerated, and associated with improved TB killing activity in recent adult studies.9

Cotreatment with ARVs

Rifampin (a rifamycin) induces drug metabolism by increasing the amount of drug-metabolizing enzymes in the liver.10 As a result, rifampin interacts with many other drugs, including anti-HIV compounds such as the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine and the protease inhibitors lopinavir and ritonavir. Studies are necessary to characterize these drug-drug interactions and to determine whether dose adjustments are necessary or contraindications exist.

Efavirenz, which has minimal interactions with rifampin, is an important treatment option for people coinfected with TB and HIV, but PK variability and formulation issues have precluded its use in children younger than three years. A PK study using higher doses of efavirenz (65 mg/kg) in TB/HIV-coinfected children 3–36 months old (P1070) found therapeutic efavirenz concentrations in children with fast metabolism of drugs processed by the cytochrome P450 2B6 enzyme (encoded by the CYP2B6 gene). The investigators concluded that a lower dose is likely to be necessary for TB/HIV-coinfected children with slow CYP2B6 metabolism.11 This study demonstrates that optimal exposure to efavirenz can be achieved in coinfected children younger than three years but requires pretreatment genotyping with pharmacogenomic assays that are expensive and not widely available.

A study of rifabutin, an alternative to rifampin that is more forgiving in adults on protease inhibitor–based antitretroviral therapy (ART), in HIV-positive children younger than five years receiving lopinavir/ritonavir closed early due to safety concerns. In the six children who completed the study prior to closure, rifabutin dosed at 5 mg/kg three times a week resulted in lower AUC and Cmax values for rifabutin and its metabolite compared with those in adults receiving the recommended dose of 150 mg rifabutin daily. In addition, high rates of severe transient neutropenia (characterized by low concentrations of white blood cells that are important for fighting infections) were observed.12 It is unclear whether a safe and effective rifabutin dose exists for TB/HIV-coinfected children on protease inhibitor–based ART.

Interim results from a study evaluating superboosted lopinavir/ritonavir administered in a ratio of 1:1 (standard lopinavir/ritonavir is administered in a ratio of 4:1) with rifampin-containing TB treatment to infants and young children (HIVPED001) found that exposures to lopinavir/ritonavir (1:1) with rifampin were not inferior to exposures to lopinavir/ritonavir (4:1) without rifampin. Virological efficacy and safety were also comparable. However, problems with existing lopinavir/ritonavir formulations and tolerability remain.13

Given the challenges presented by interactions between protease inhibitors and rifamycins, integrase inhibitors may provide a good alternative for young TB/HIV-coinfected children. PK and safety studies for integrase inhibitors, notably dolutegravir and raltegravir, are under way for children and infants14 (see Pediatric Antiretroviral Pipeline), and the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network is planning to evaluate the PK and safety of raltegravir administered with rifampin-containing anti-TB treatment to children 2–12 years old (P1101).

Second-Line Drugs

In addition to the preliminary PK and safety data covered by previous reports,15,16 further analyses from MDR-PK 1, which completed enrollment in 2015, are presented here for ofloxacin, levofloxacin, and amikacin. More data will be disseminated throughout 2016, including those on moxifloxacin and linezolid.

Children given ofloxacin at 15–20 mg/kg as whole or crushed tablets for treatment (N = 55) or prevention (N = 30) of MDR-TB had peak exposures slightly lower than, but comparable to, those achieved in adults. Total exposures were far below the targets achieved in adults—likely because of more rapid drug clearance in children. Higher Cmax values were observed in children receiving crushed versus whole tablets (statistically insignificant), but AUCs remained unaffected. Peak exposures were higher among younger children, but increased with total exposure and weight. No difference was observed in children coinfected with HIV. Ofloxacin appeared to be safe, with no grade 3 or 4 adverse events in 46 children followed for a median of 150 days.17,18 Of the fluoroquinolones, moxifloxacin and levofloxacin are generally considered to be superior to ofloxacin, but given cost, availability, and formulation constraints, ofloxacin is still used in children in some settings.

Previously published data on levofloxacin dosed at 15 mg/kg in children show low drug exposures compared with those achieved in adults.19 Using additional PK data from children given levofloxacin at 15 mg/kg and 20 mg/kg (N = 109) and pharmacometric modeling, researchers have determined that the 20 mg/kg dose more closely approximates adult exposures.20 However, there is room to further optimize levofloxacin exposures in children, and studies are under way (MDR-PK 2).

Age influenced the AUC, but not the Cmax, when amikacin was given to children (N = 96) at 15–20 mg/kg (recommended range: 15–30 mg/kg). There was no effect on exposure by HIV status. Based on these and earlier data, to achieve exposures similar to those in adults, the investigators suggest that amikacin be given to children at a dose of 18–20 mg/kg.21 Hearing loss (associated with cumulative amikacin exposure) has not yet been analyzed in this cohort, but has been previously reported in up to 24% of children in this setting.22

Further analyses of the data collected in MDR-PK 1 are planned for high-dose isoniazid, ethionamide, para-aminosalicylic acid, and linezolid. MDR-PK 2, which opened in October 2015, will build on the evidence collected in MDR-PK 1 to further optimize the use of key second-line drugs in children, including moxifloxacin, levofloxacin, and linezolid. MDR-PK 2 incorporates a crossover design to allow for the collection of PK data on moxifloxacin and levofloxacin in children across all ages; children younger than eight years are typically only given levofloxacin due to the limitations of the existing formulation of moxifloxacin, a large unscored tablet that is bitter when crushed. MDR-PK 2 will look more closely at bioavailability when moxifloxacin and levofloxacin are administered as whole tablets versus crushed tablets or extemporaneously prepared solutions.23

The PK and safety data presented here and still being collected are critical to informing dosing for first- and second-line TB drugs in children. However, several ongoing or planned treatment-shortening studies in adults use higher doses of key first- and second-line drugs (see Tuberculosis Treatment Pipeline). It is imperative that these treatment-shortening studies collect data on ideal PK values in adults, as this information is necessary to inform appropriate, evidence-based dosing in children.

In May 2016, the WHO issued an update to its guidelines for treating MDR-TB. Based on data in adults, the guidelines recommend that children with confirmed rifampin-resistant or MDR-TB be given the same consideration for treatment with a shorter MDR-TB treatment regimen as adults.24 However, this recommendation is likely to have limited reach given the challenges of obtaining viable samples for microbiologically confirmed diagnosis of TB in children (see Tuberculosis Diagnostics Pipeline). Another pediatric recommendation that was included in the WHO’s 2016 update to the MDR-TB treatment guidelines and is likely to have much broader implications is for the exclusion of injectable agents from regimens for children with nonsevere disease.25 This recommendation was based on consideration of the potential harms associated with the injectable agents, namely hearing loss and pain with administration, and meta-analysis of individual patient data, which points to insignificant differences in rates of treatment success among children with clinically diagnosed and nonsevere disease treated with or without an injectable agent.26

New Drugs

After one year of follow-up for the first age cohort (12–17 year olds) enrolled in C232/C233 (a pediatric PK and safety study of delamanid in HIV-negative children), Otsuka found six months of twice-daily delamanid administered at 100 mg to be safe and well tolerated. Delamanid exposures in the adolescent cohort were slightly higher than but comparable to, those achieved in adults, suggesting that the standard adult dose for delamanid is adequate for adolescents.27

Follow-up for the second age cohort (6–11 year olds), who received 50 mg of delamanid twice daily, is ongoing, and enrollment for the third cohort (3–5 year olds), using the pediatric formulation, is half completed. A modification to Otsuka’s Pediatric Investigation Plan, agreed to by the European Medicines Agency (EMA), will allow for the final cohort (0–2 year olds) to enroll in parallel. This sets an important precedent for the parallel enrollment of pediatric cohorts, which is expected to help expedite access to new drugs for younger children.28 Despite the encouraging pace at which Otsuka’s pediatric investigations are progressing and the recent inclusion of delamanid in the Global Drug Facility (GDF) catalogue, delamanid has been registered only in the European Union, Japan, and South Korea. Routine access is likely to be an issue for years to come (see Tuberculosis Treatment Pipeline).

The WHO is planning an update to its guidance on the programmatic use of delamanid before the end of 2016 and will consider the available PK and safety data in children as young as six years.29 Rapid release of its guidelines will be necessary to ensure that policy is not a barrier to access for children. In the meantime, the Sentinel Project on Pediatric Drug-Resistant Tuberculosis has released rapid clinical advice on the use of delamanid and bedaquiline in children.30 Country programs shouldn’t wait, but many programs will not procure or use delamanid for children without formal recommendation from the WHO in the form of updated treatment guidelines. This underscores the importance of WHO processes that allow for more rapid review and incorporation of emerging data into guidelines for children.

In contrast, bedaquiline is much more widely available to adults under programmatic conditions, but children have virtually no access to it due to lack of data. Janssen’s PK and safety study of bedaquiline in HIV-negative children (C211), which has been in development for over five years, finally opened to enrollment in May 2016.31 Janssen’s lack of experience setting up pediatric MDR-TB studies, the paucity of adequately prepared trial sites independent of those participating in established pediatric research networks like the IMPAACT Network, and apparent pushback from regulators were among the reported causes of the study’s severely delayed start.32 In an effort to expedite the study, Janssen is now exploring additional trial sites in Ethiopia, India, and the Philippines.33

To further hasten the investigation of bedaquiline in children, Janssen should make its pediatric formulation available free of charge for complementary studies, including P1108, a pediatric PK and safety study of bedaquiline that will include HIV-positive and HIV-negative children with MDR-TB.34


Box 1. Inclusion of Pregnant Women in TB Research

An estimated 3.2 million women develop TB each year; conservative models estimate that 216,500 of them are also pregnant, but these data are not collected.35 TB is one of the leading non-obstetric causes of death among pregnant women, accounting for 28% of maternal deaths globally.36 Currently, treatment of TB during pregnancy is done with minimal specific guidance and with a lack of information on the effects of physiological and metabolic changes that occur during pregnancy on drug metabolism and achieved drug exposures. Pregnant women are systematically excluded from TB research, and, as a result, clinicians are forced to use old and sometimes new TB drug regimens in pregnant women with TB without any guidance on safety, efficacy, or dose adjustments—or, even worse, to deny them treatment for lack of options.

An expert panel convened by the NIH recently published a consensus statement advocating for the earlier inclusion of pregnant and postpartum women in TB drug trials and outlining priority research needs.37 The few ongoing or planned TB prevention and treatment studies in pregnant women are presented in table 2.

In line with a 1994 report by the Institute of Medicine, which recommends that pregnant women be “presumed eligible for participation in clinical studies,”38 TB researchers should assume inclusion, and then, on an individual trial basis, think carefully about safety and whether the balance of risks and benefits warrants the exclusion of pregnant women from TB drug trials. In fact, expert consensus statements, regulatory frameworks, and guidance documents already exist to facilitate the appropriate and earlier inclusion of pregnant women in research.

Additionally, a registry, similar to the Antiretroviral Pregnancy Registry, should be established for pregnant women with TB to prospectively monitor birth defects in infants exposed to TB drugs in utero, provide early warning of major teratogenicity (ability to induce congenital malformations), and help estimate risk of birth defects. In the absence of clinical trials data, a TB registry is critical for informing the safe treatment and prevention of TB in pregnant women and their children.39


Table 2. Ongoing and Planned TB Prevention and Treatment Studies in Pregnant Women

Trial

Phase

TB type

Study purpose

PREVENTION

IMPAACT P1078 (TB APPRISE)

NCT01494038*

IV

DS-TBI

To evaluate antepartum vs. postpartum isoniazid preventive therapy in HIV-positive women

IMPAACT P2001

NCT02651259*

I/II

DS-TBI

To evaluate the pharmacokinetics and safety of once-weekly rifapentine and isoniazid in pregnant and postpartum women with and without HIV

TREATMENT

IMPAACT P1026s

NCT00042289*

IV

DS-/DR-TB

To evaluate the pharmacokinetics of first- and second-line TB drugs with and without ARVs in pregnant women

ACTG A5338

NCT02412436*

IV

DS-TB

To evaluate the pharmacokinetic interactions among depo-medroxyprogesterone acetate, rifampin, and efavirenz in women co-infected with HIV and TB

TB pregnancy registry

IV

DS-/DR-TB

To evaluate maternal and infant treatment and safety outcomes from clinical research databases (planned)

*U.S. NIH clinical trial identifiers; for more information, go to ClinicalTrials.gov.

DR-TB: drug-resistant tuberculosis
DS-TB: drug-sensitive tuberculosis

DS-TBI: drug-sensitive tuberculosis infection

PEDIATRIC FORMULATIONS IN THE PIPELINE

In dose or form, preexisting pediatric formulations and preparations of TB drugs have been inadequate.40 However, new pediatric fixed-dose combinations (FDCs) provide a rare occasion for celebration. Anticipated additional advances in pediatric formulation development should be approached with tempered optimism, as much remains to be done. Table 3, presented at the end of this section, provides an overview of the pediatric formulations new to market and in development.

First-Line Drugs

Five years after the WHO increased the recommended doses for first-line TB drugs in children, and following significant investments by UNITAID and work by the TB Alliance and partners under the STEP-TB project grant, Macleods has introduced new pediatric FDCs.

Macleods’s FDCs of HRZ (isoniazid, rifampin, and pyrazinamide) and HR (isoniazid and rifampin) are now available through the GDF and have been successfully registered in Côte d’Ivoire and India. Registrations are pending in Botswana, Burkina Faso, Cambodia, Cameroon, Congo, Ethiopia, Ghana, Kenya, Mozambique, Nigeria, the Philippines, Tanzania, Uganda, Vietnam, Zambia, and Zimbabwe.41 Registration is stalled in South Africa, as the Medicines Control Council requires bioequivalence work to be conducted in-country.42 Rollout of the new pediatric FDCs is anticipated in Kenya and the Philippines before the end of 2016 and as part of a 100-site pilot program in India.43 Macleods has also received orders from Papua New Guinea and Kiribati and an inquiry from Zimbabwe.44

Other companies, including Lupin, Sanofi, Sandoz, and Svizera, are working on developing and introducing their own versions, albeit at varying paces and at the mercy of review and approval times of country regulatory authorities and WHO prequalification—a mechanism put in place to ensure and monitor the quality of medications procured in bulk—and in the absence of approval by a Stringent Regulatory Authority, a requirement of manufacturers to sell medications through the GDF.

Work to increase awareness and facilitate uptake of the new pediatric FDCs is being led by the TB Alliance, the WHO Global TB Program, and the WHO Department of Essential Medicines and Health Products. The UNITAID-funded STEP-TB project will come to an end in 2016, but UNITAID will continue to promote scale-up of the new pediatric treatment options and to support a more sustainable market, and it has issued a call for relevant proposals.45

Sanofi, the sponsor of rifapentine (indicated in the United States, in combination with isoniazid, for latent TB infection in children as young as two years), will perform a bioavailability and safety study of the components of its mango-flavored, fixed-dose dispersible of rifapentine and isoniazid and of a rifapentine stand-alone dispersible to facilitate dose adjustments in young children before the end of 2016. The Tuberculosis Trials Consortium will use these formulations in its pediatric PK and safety study of three months of once-weekly rifapentine and isoniazid (3HP) to prevent TB in children. The study (S35) is expected to open in 2017, and HIV-positive children on select ARV regimens will be eligible for participation.46,47 Unfortunately, rifapentine is still registered only in the United States; Sanofi has a long way to go to ensure wider access for adults and children (see Tuberculosis Prevention Pipeline).

Second-Line TB Drugs

Encouragingly, in August 2015, the WHO Expert Review Panel (ERP) issued an invitation to manufacturers to submit an expression of interest (EOI) to the WHO prequalification team for pediatric formulations of several second-line TB drugs, including cycloserine, levofloxacin, moxifloxacin, linezolid, and ethionamide.48 Macleods expects to register pediatric formulations of these second-line drugs before the end of 2016.49 A pediatric formulation of clofazimine was not included in the invitation for EOI, but should be immediately added considering its increasingly important role as a component of MDR-TB treatment and trials of shortened regimens. A scored-dispersible or other novel pediatric formulation of clofazimine is urgently needed to facilitate dosing in small children; an invitation for an EOI from the WHO ERP for a pediatric formulation of clofazimine is a necessary first step. It is critical that these new formulations undergo palatability and acceptability evaluations in children and that their quality be assured.

Still, even with the invited EOI and continued investments by Macleods to bring pediatric formulations for second-line TB drugs to market, without updated WHO dosing guidelines, future uptake by country programs is likely to be severely limited. The first time the WHO recommended doses for second-line TB drugs in children was 2006. In 2010, the WHO issued Rapid Advice: Treatment of Tuberculosis in Children,50 which recommended increased doses of first-line TB drugs in children; in 2014, it updated its Guidance for National Tuberculosis Programs on the Management of Tuberculosis in Children.51 Yet neither of these updates considered data that have emerged for the use of second-line TB drugs in children since 2006. In fact, existing WHO guidelines do not include a recommended pediatric dose for clofazimine at all. The WHO should immediately take the steps necessary to issue updated, comprehensive, and evidence-based dosing guidelines for second-line TB drugs in children.

New Drugs

Otsuka is using 5 mg and 25 mg dispersible tablets of delamanid in strawberry and cherry flavors in its PK and safety study, which is now enrolling children under five years of age (232; 233).

The bioavailability study for Janssen’s 20 mg dispersible tablet of bedaquiline has long been completed, and Janssen’s pediatric study finally opened to enrollment in May 2016. A second bioavailability study to evaluate differences between crushed and whole tablets of the adult formulation of bedaquiline (bedaquiline-crush) is under regulatory review in South Africa.52 Without access to Janssen’s pediatric formulation, these data are necessary to inform IMPAACT’s planned PK and safety study of bedaquiline in children, including those with HIV (P1108). Data from bedaquiline-crush will also be important to inform use of bedaquiline in children during the time between when evidence from pediatric PK and safety studies is available and when the pediatric formulation enters the market.

Table 3. Pediatric Formulations Newly Marketed and in Development

Drug

Dose

Formulation

Company

First-line drugs         

Fixed-dose combinations

H: isoniazid

R: rifampin

Z: pyrazinamide

P: rifapentine

HRZ: 50/75/150 mg

HR: 50/75 mg

Dispersible tablets

Macleods

HRZ: 50/75/150 mg

HR: 50/75 mg

Dispersible tablets

Lupin

HRZ: 50/75/150 mg

HR: 50/75 mg

Dispersible tablets

Sandoz

HRZ: 50/75/150 mg

HR: 50/75 mg

HP: 150/150 mg

Dispersible tablets

Sanofi

HRZ: 50/75/150 mg

HR: 50/75 mg

Dispersible tablets

Svizera

Ethambutol

100 mg

Dispersible tablet

Macleods

Isoniazid

100 mg

Dispersible tablet

Macleods

Pyrazinamide

150 mg

Dispersible tablet

Macleods

Rifapentine

100 mg

Dispersible tablet

Sanofi

Second-line and new drugs

Bedaquiline

20 mg

Dispersible tablet

Janssen

Cycloserine

125 mg

Mini capsule

Macleods

Delamanid

20 mg

5 mg

Dispersible tablets

Otsuka

Ethionamide

125 mg

Scored dispersible tablet

Macleods

Levofloxacin

100 mg

Scored dispersible tablet

Macleods

Linezolid

150 mg

Dispersible tablet

Macleods

Moxifloxacin

100 mg

Scored dispersible tablet

Macleods

 

RECOMMENDATIONS

In recent years, significant strides have been made in pediatric TB research and development (R&D). Yet much work remains to collect critically important data in children, to increase access to the new pediatric FDCs, and to expedite development of, and access to, pediatric formulations for new and second-line TB drugs.

For researchers

  • Consider children when planning adult studies. Building PK investigations into studies that evaluate higher doses of TB drugs in adults is necessary to inform future PK targets in children.
  • Determine which PK value(s) correlate best with efficacy for TB drugs in children and establish PK targets based on adult data, taking into consideration the variability in severity and type of TB disease among, and challenges defining efficacy in, children.
  • Enroll children two years of age and younger in pediatric studies, as this is the period during which drug disposition changes the most for children, increasing risk for high or low drug exposures.
  • Include HIV-positive children in studies of new TB drugs and regimens.
  • Include pregnant women in studies of new TB drugs and regimens.

For policy makers

  • Incorporate emerging data into guidelines for children more rapidly, especially those for new and second-line TB drugs in children.

For regulatory authorities

  • Enforce more thoughtful requirements to ensure comprehensive and timely investigations of TB drugs in children. Mandatory and time-bound pediatric investigational plans that also require studies in HIV-positive children will help to shrink the persisting evidence and access gaps that exist between adults and children for new TB drugs.53
  • Follow the important precedent set by the EMA and allow parallel enrollment of pediatric cohorts in PK and safety studies.
  • Be transparent and clear about requirements to register pediatric formulations for both existing and new drugs.
  • When possible and appropriate, consider waived requirements and registration fees to facilitate access.

For donors

  • Maintain and adequately fund momentum in pediatric TB drug R&D, for which global investments totaled $11.6 million in 2014.54 Recent attacks on the budget for and AIDS research priorities of the NIH are particularly concerning for pediatric TB R&D. Not only is the NIH the leading funder, but its investments support studies that are critical to improving treatment of pediatric TB and to filling both long-standing and new gaps in pediatric PK and safety data, especially for HIV-positive children taking ARVs.55
  • Further attention to and investments in pediatric TB trial infrastructure and site capacity development are urgently needed to support the increasingly full research agenda for prevention and treatment of TB in children.
  • UNITAID, whose investments have led to the market introduction of appropriately dosed FDCs of first-line TB drugs for children, and whose planned investments will ensure global uptake of these new formulations, should invest in a project modeled after STEP-TB that is focused on expediting development and market introduction of pediatric formulations of second-line TB drugs.

ACKNOWLEDGMENTS

Many thanks to all of the investigators and sponsors who provided information and feedback that aided the development of this chapter. Special acknowledgment is owed to Dr. Anneke Hesseling for her thoughtful review and to Dr. Kelly Dooley for her help finessing the language and points related to pharmacokinetics.



REFERENCES

  1. Schaaf HS, Garcia-Prats AJ, Donald PR. Antituberculosis drugs in children. Clin Pharmacol Ther. 2015 Sep;98(3):252–65. doi: 10.1002/cpt.164.
  2. Bekker A, Schaaf HS, Draper HR, et al. Pharmacokinetics and treatment of first-line anti tuberculosis drugs in infants. Presented at: Maternal and infant TB: advancing our understanding of pathogenesis, treatment and prevention [symposium 08] at 46th Union World Conference on Lung Health; 2015 December 4; Cape Town, South Africa.
  3. Bekker A, Schaaf HS, Draper HR, et al. Pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in infants dosed according to revised WHO-recommended treatment guidelines. Antimicrob Agents Chemother. 2016 Apr:60(4):2171–79. doi: 10.1128/AAC.02600-15.
  4. Hiruy H, Rogers Z, Mbowane C, et al. Subtherapeutic concentrations of first-line anti-TB drugs in South African children treated according to current guidelines: the PHATISA study. J Antimicrob Chemother 2015;70:1115–1123. doi: 10.1093/jac/dku478.
  5. Kwara A, Enimil A, Yang H, et al. Pharmacokinetics of first-line antituberculosis drugs in children with tuberculosis with and without HIV co-infection (Abstract OA-424-05). Oral abstract presented at: 46th Union World Conference on Lung Health; 2015 December; Cape Town, South Africa.
  6. Kwara A, Enimil A, Gillani FS, et al. Pharmacokinetics of first-line antituberculosis drugs using WHO revised dosage in children with tuberculosis with and without HIV coinfection. J Pediatric Infect Dis Soc. 2015 May 26. doi: 10.1093/jpids/piv035. [Epub ahead of print]
  7. Pouplin T, Duc Bang N, Van Toi P, et al. Naïve-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis. BMC Infect Dis. 2016;16(1):144. doi: 10.1186/s12879-016-1470-x.
  8. Ramachandran G, Kumar AKH, Kannan T, et al. Low serum concentrations of rifampicin and pyrazinamide associated with poor treatment outcomes in children with tuberculosis related to HIV status. Ped Infect Dis J. 2016 May;35(5):530–34. doi: 10.1097/INF.0000000000001069.
  9. Boeree MJ, Diacon AH, Dawson R, et al. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med. 2015 May 1;191(9):1058–65.
  10. Baciewicz AM, Self TH. Rifampin drug interactions. Arch Intern Med. 1984 Aug;144(8):1667–71.
  11. Bolton C, Samson P, Capparelli E, et al. Optimal use of efavirenz in HIV+/TB+ co-infected children aged 3 to ≤24 months (Abstract 458). Poster abstract presented at: Conference on Retroviruses and Opportunistic Infections; 2016 February; Boston, MA. Available from: http://www.croiconference.org/sessions/optimal-use-efavirenz-hiv-tb-coinfected-children-aged-3-24-months.
  12. Moultrie H, McIlleron H, Sawry S, et al. Pharmacokinetics and safety of rifabutin in young HIV-infected children receiving rifabutin and lopinavir/ritonavir. J Antimicrob Chemother. 2015 Feb;70(2):543–9. doi: 10.1093/jac/dku382.
  13. Rabie H, Denti P, Lee J, et al. Pharmacokinetics of lopinavir/ritonavir super-boosting in infants and young children co-infected with HIV and TB. Presented at: 7th International Workshop on HIV Pediatrics at 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention; 2015 July 17–18; Vancouver, Canada. Available from: http://www.dndi.org/wp-content/uploads/2015/06/Rabie_PediatricHIVWorkshop_Pharmacokinetics-lopinavirritonavir_2015.pdf.
  14. Clayden P. The pediatric antiretroviral pipeline. In: Clayden P, Collins S, Frick M, et al.; i-Base/Treatment Action Group. 2015 pipeline report. New York: Treatment Action Group; 2015. Available from: http://www.pipelinereport.org/2015/pediatric-arvs.
  15. McKenna L. Playing catch-up: pediatric tuberculosis treatment pipeline. In: Clayden P, Collins S, Daniels C, et al.; i-Base/Treatment Action Group. 2014 pipeline report. New York: Treatment Action Group; 2014. p. 217-32. Available from: http://www.pipelinereport.org/2014/pediatric-tb-treatment.
  16. McKenna L. Momentum in the pediatric tuberculosis treatment pipeline. In: Clayden P, Collins S, Frick M, et al.; i-Base/Treatment Action Group. 2015 pipeline report. New York: Treatment Action Group; 2015. p. 137-52. Available from: http://www.pipelinereport.org/2015/tb-pediatrics.
  17. Garcia-Prats AJ, Draper HR, Thee S, et al. The pharmacokinetics and safety of ofloxacin for drug-resistant tuberculosis in children (Abstract OA-479-06). Oral abstract presented at: 46th Union World Conference on Lung Health; 2015 December; Cape Town, South Africa.
  18. Garcia-Prats AJ, Draper HR, Thee S, et al. The pharmacokinetics and safety of ofloxacin in children with drug-resistant tuberculosis. Antimicrob Agents Chemother. 2015 Oct; 59(10):6073–79. doi: 10.1128/AAC.01404-15.
  19. Thee S, Garcia-Prats AJ, McIlleron HM, et al. Pharmacokinetics of ofloxacin and levofloxacin for prevention and treatment of multidrug-resistant tuberculosis in children. Antimicrob Agents Chemother. 2014 May; 58(5):2948–51. doi: 10.1128/AAC.02755-13.
  20. Garcia-Prats AJ, Schaaf HS. Emerging data on PK and safety of levofloxacin and amikacin informs care and design of new regimens. Presented at: Building on emerging knowledge to develop novel regimens for pediatric drug-resistant TB [symposium 27] at 46th Union World Conference on Lung Health; 2015 December 5; Cape Town, South Africa.
  21. Ibid.
  22. Seddon JA, Thee S, Jacobs K, et al. Hearing loss in children treated for multidrug-resistant tuberculosis. J Infect. 2013 Apr;68(4):320–29. doi: 10.1016/j.jinf.2012.09.002.
  23. Garcia-Prats, Anthony (Desmond Tutu TB Center, Stellenbosch, South Africa). Personal communication with: Lindsay McKenna (Treatment Action Group, New York, NY). 2016 March 23.
  24. World Health Organization. 2016 Update: WHO treatment guidelines for drug-resistant tuberculosis. Geneva: World Health Organization; 2016. Available from: www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/resources/.
  25. Ibid.
  26. Ibid.
  27. Hafkin, J. Long-term safety, tolerability, and pharmacokinetics of delamanid in children aged 12–17 years (Abstract EP-115-04). Poster abstract presented at: 46th Union World Conference on Lung Health; 2015 December; Cape Town, South Africa.
  28. Hafkin, J. Delamanid update. Presented at: 2016 Critical Path to TB Drug Regimens Workshop; 2016 April 5; Washington, D.C.
  29. The Sentinel Project on Pediatric Drug-Resistant Tuberculosis and Treatment Action Group. Request to update WHO recommendations on delamanid to include children [Open letter to World Health Organization]. 2016 March 24. Available from: http://www.tbonline.info/media/uploads/documents/signed_delamanid_letter.pdf.
  30. The Sentinel Project on Pediatric Drug-resistant Tuberculosis. Rapid clinical advice: the use of delamanid and bedaquiline for children with drug-resistant tuberculosis. Boston: The Sentinel Project; 2016. Available from: http://sentinel-project.org/2016/05/16/advancing-access-for-new-tb-drugs-for-children/.
  31. Theeuwes, Myriam (Janssen Pharmaceuticals, Beerse, Belgium). Personal communication with: Mark Harrington (Treatment Action Group, New York, NY). 2016 May 17.
  32. Kambili, Chrispin (Janssen Global Public Health, NJ). Personal communication with: the Global Tuberculosis Community Advisory Board during its 9th semi-annual meeting; 2016 November 30; Cape Town, South Africa.
  33. Theeuwes, M. Personal communication with: Mark Harrington.
  34. McKenna L, Ruiz-Mingote L. Janssen’s pediatric study remains an “open issue” [correspondence]. Eur Respir J. Forthcoming 2016.
  35. Mathad, Jyoti. Current research on pathophysiology, immunology, and treatment of TB in pregnant women. Presented at: Maternal and infant TB: advancing our understanding of pathogenesis, treatment and prevention [symposium 8] at 46th Union World Conference on Lung Health; 2015 December 4; Cape Town, South Africa.
  36. Sugarman J, Colvin C, Moran AC, Oxlade O. Tuberculosis in pregnancy: an estimate of the global burden of disease. Lancet Glob Health. 2014 Dec;2(12):e710–6. doi: 10.1016/S2214-109X(14)70330-4.
  37. Gupta A, Mathad JS, Abdel-Rahman SM, et al. Towards earlier inclusion of pregnant and postpartum women in tuberculosis drug trials: consensus statements from an international expert panel. Clin Infect Dis. 2016 Mar 15;62(6):761–9. doi: 10.1093/cid/civ991.
  38. Drapkin Lyerly A, Little MA, Faden R. The second wave: toward responsible inclusion of pregnant women in research. Int J Fem Approached Bioeth. 2008;1(2):5–22. doi: 10.1353/ijf.0.0047.
  39. Global TB Community Advisory Board, Community Partners, Community Research Advisors Group, Treatment Action Group, and Women’s HIV Research Collaborative. Letter to support the establishment of a tuberculosis registry for pregnant women. 2015 December 15. Available from: http://www.treatmentactiongroup.org/sites/g/files/g450272/f/201601/NIH%20Letter_Pregnancy%20Registry_Final.pdf.
  40. Brigden G, Furin J, Van Gulik C, Marais B. Getting it right for children: improving tuberculosis treatment access and new treatment options. Expert Review Anti Infect Ther. 2015 Apr;13(4)451–61. doi: 10.1586/14787210.2015.1015991.
  41. Agarwal, Vijay (Macleods Pharmaceuticals, Mumbai, India). Personal communication with: Lindsay McKenna (Treatment Action Group, New York, NY). 2016 January 31.
  42. Hesseling, Anneke (Stellenbosch University, Stellenbosch, South Africa). Personal communication with: Lindsay McKenna (Treatment Action Group, New York, NY). 2016 May 19.
  43. Usherenko, Irina (Global Alliance for TB Drug Development, New York, NY). Personal communication with: Lindsay McKenna (Treatment Action Group, New York, NY). 2016 April 5.
  44. Agarwal, Vijay (Macleods Pharmaceuticals, Mumbai, India). Personal communication with: Lindsay McKenna (Treatment Action Group, New York, NY). 2016 April 20.
  45. UNITAID. Call for proposals for the area for intervention: Scale-up of better TB treatment in children [Internet]. (cited 2016 April 11). Available from: http://www.unitaid.eu/en/how/call-for-proposals.
  46. Villarino, ME, Scott NA, Weis SE, et al. Treatment for preventing tuberculosis in children and adolescents. JAMA Pediatr. 2015 Jan 12. doi:10.1001/jamapediatrics.2014.3158.
  47. Sterling TR, Scott NA, Miro JM, et al. Three months of weekly rifapentine plus isoniazid for treatment of M. tuberculosis infection in HIV co-infected persons. AIDS. 2016 Mar 17. doi: 10.1097/QAD.0000000000001098. [Epub ahead of print]
  48. World Health Organization. 13th invitation to manufacturers of antituberculosis medicines to submit an expression of interest for product evaluation to the WHO prequalification team– medicines [Internet]. August 2015 (cited 2016 April 12). Available from: http://apps.who.int/prequal/info_applicants/eoi/2015/EOI-TuberculosisV13_1.pdf.
  49. Agarwal, V. Personal communication with: Lindsay McKenna. 2016 January 31.
  50. World Health Organization. Rapid advice: treatment of tuberculosis in children. Geneva: World Health Organization; 2010. Available from: http://apps.who.int/iris/bitstream/10665/44444/1/9789241500449_eng.pdf. (Accessed 2016 April 12)
  51. World Health Organization. Guidance for national tuberculosis programs on the management of tuberculosis in children. Geneva: World Health Organization; 2014. Available from: http://www.who.int/tb/publications/childtb_guidelines/en/. (Accessed 2016 April 12)
  52. Garcia-Prats, A. Personal communication with: Lindsay McKenna. 2016 March 23.
  53. McKenna L. Momentum in the pediatric tuberculosis treatment pipeline.
  54. Frick M. 2015 report on tuberculosis research funding trends, 2005–2014. New York: Treatment Action Group; 2015. Available from: http://www.treatmentactiongroup.org/tbrd2015. (Accessed 2016 April 12)
  55. McKenna L. Momentum in the pediatric tuberculosis treatment pipeline.