The paediatric tuberculosis treatment pipeline: beyond pharmacokinetics and safety data
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.
4 months of self-administered daily rifampin for prevention of TBNCT00170209*
|Enrollment complete; results expected 2016||HIV-positive and HIV-negative infants, children, and adolescents 0–17 years old with LTBI||CIHR, McGill University|
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|
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|
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|
PK and safety of delamanid; OBR for treatment of MDR-TB
|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|
6 months of delamanid; OBR for treatment of MDR-TB
|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|
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|
PK and safety of bedaquiline; OBR for treatment of MDR-TB
|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)|
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 of FLDs using 2010 WHO dosing guidelines for treatment of TB
|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|
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|
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|
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|
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|
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|
PK of FLDs using 2010 WHO dosing guidelines for treatment of TB and interactions with lopinavir/ritonavir and nevirapine
|Enrolling; results expected 2017||HIV-positive or HIV-negative infants, children, and adolescents 0–12 years old with TB||NICHD|
PK of rifampin and isoniazid with nevirapine or lopinavir/ritonavir
|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
|Enrolling; results expected 2017||HIV-positive children 3 months to 3 years old with TB||NICHD|
PK and safety of efavirenz with rifampin-containing TB treatment
|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
|Enrolling; results expected 2017||HIV-positive children and adolescents 3–14 years old with TB||NICHD|
PK and safety of superboosted lopinavir/ritonavir (1:1) with rifampin-containing TB treatment
|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|
PK and safety of raltegravir with rifampin-containing TB treatment
|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
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
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
SA MRC: South African Medical Research Council
SLD: second-line drug
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.
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. 
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. 
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.  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.  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. 
Cotreatment with ARVs
Rifampin (a rifamycin) induces drug metabolism by increasing the amount of drug-metabolizing enzymes in the liver.  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.  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.  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. 
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 infants  (see Pediatric Antiretroviral Pipeline in 2016 Pipeline Report), 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).
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.  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.  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.  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.
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. 
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.  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.  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. 
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. 
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.  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.  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.  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.  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.  In an effort to expedite the study, Janssen is now exploring additional trial sites in Ethiopia, India, and the Philippines. 
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. 
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.  TB is one of the leading non-obstetric causes of death among pregnant women, accounting for 28% of maternal deaths globally.  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.  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,”  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. 
|Trial||Phase||TB type||Study purpose|
|IV||DS-TBI||To evaluate antepartum vs. postpartum isoniazid preventive therapy in HIV-positive women|
|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|
|IV||DS-/DR-TB||To evaluate the pharmacokinetics of first- and second-line TB drugs with and without ARVs in pregnant women|
|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)|
|*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.  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.
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.  Registration is stalled in South Africa, as the Medicines Control Council requires bioequivalence work to be conducted in-country.  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.  Macleods has also received orders from Papua New Guinea and Kiribati and an inquiry from Zimbabwe. 
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. 
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.  Macleods expects to register pediatric formulations of these second-line drugs before the end of 2016.  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,  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.  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.
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.  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.
|Fixed-dose combinationsH: isoniazid
|HRZ: 50/75/150 mg
HR: 50/75 mg
|HRZ: 50/75/150 mg
HR: 50/75 mg
|HRZ: 50/75/150 mg
HR: 50/75 mg
|HRZ: 50/75/150 mg
HR: 50/75 mg
HP: 150/150 mg
|HRZ: 50/75/150 mg
HR: 50/75 mg
|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 mg5 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|
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.
- 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. 
- 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.
- Maintain and adequately fund momentum in pediatric TB drug R&D, for which global investments totaled $11.6 million in 2014.  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. 
- 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.
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.
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