Paediatric TB: glimpses of PK data and a potential new approach to drug development

There is also a need to ensure that any new developments for adults are speedily tested for paediatric use. Three presentations at the 43rd Union World Conference presented findings from pharmacokinetic (PK) evaluations of TB drugs in children and a novel approach to paediatric drug development. [1, 2, 3]

PK of second line TB treatment in children

There is virtually no data on second-line TB drug dosing in children. Child friendly formulations are not usually available and the doses using divided and/or crushed tablets are uncertain. PK data on which to base optimal dosing is lacking. Also, second-line drugs are more toxic than those used in first line treatment and adverse events are hard to monitor in children. TB drugs are also frequently used with antiretrovirals in TB/HIV coinfected children.

Annekke Hessling from the Department of Paediatrics and Child Health, University of Stellenbosch, Cape Town, described a large ongoing study to characterise PK and toxicity of second-line TB drugs for treatment and prevention of drug resistant TB in HIV positive and negative children, by age and HIV status. She presented preliminary data for three second-line TB drugs: ethionamide, amikacin and ofloxacin.

This ambitious study will be running over the next five years with an enrollment target of 276 children. Age matched HIV positive children not on TB treatment will be enrolled as controls (42 receiving efavirenz and 22 lopinavir/r). The drugs under evaluation are: ethionamide, terizidone, ofloxacin, levofloxacin, moxifloxacin, amikacin, high dose isoniazid (INH), PAS, linezolid and capreomycin. The study includes intensive PK sampling, clinical follow up until treatment completion for children with active TB, cross sectional PK data from children receiving prophylaxis and toxicity monitoring.

Dr Hessling presented data from HIV positive and negative children, receiving routine treatment or prophylaxis for MDR TB, from December 2011 to September 2011. Children with severe anaemia (Hb <8g/dL) and/or weighing <5 kg were excluded.

Directly observed, exact doses were administered using the upper limit of the recommended doses following a standard breakfast: ethionamide 20 mg/kg (recommended dose 15 – 20 mg/kg/day), amikacin 20 mg/kg (15 – 22.5 or 30 mg/kg/day) and ofloxacin (15 – 20 mg/kg/day). Intensive sampling was performed at 0, 1, 2, 4, 6 and 8 hours post dose and C-max, T-max, AUC0-8 and t1/2 were compared to adult targets.

Seventy children (46 with TB disease and 24 receiving prophylaxis) were in the study group. Respectively, 12, 15 and 19 children in the disease group were age <2, 2 – 5 and 6 – 15 years. Only children < 5 years are prophylaxed for TB, of these 6 were <2 and 18 were 2 – 5 years old. Overall, 12 (26.7%) children in the TB disease group were HIV positive and receiving ART. About 70% of the children with TB disease had pulmonary TB and the remainder had extra pulmonary TB or both.

The PK evaluation for ethionamide, revealed HIV negative children with higher C-max in the 0 – 2 years age group than the other two groups (median 7.66 vs approximately 5 ug/mL) but this was not significant; T-max peaked sooner and achieved higher target levels earlier (mean 1.80 hours vs 3.15 in the oldest age group, p=0.001), although overall exposure (AUC) was similar across age groups. HIV positive children had lower levels than HIV negative ones (median 4.86 vs 6.37 ug.h/mL, p=0.051). Dr Hessling noted that a larger sample size would probably show lower AUC as well. She described the finding that younger children peaked higher and earlier as “quite surprising” as the only other study that has looked at ethionamide PK in children by age group showed the opposite, she suggested that this might be due to crushing the tablets. The lower levels seen with HIV positive children compared to negative is consistent with that observed previously. Although adult targets are unclear, the MIC achieved in children was similar or above that of adults.

For amakacin, Cmax was lower in the youngest group than the other two (median 43.65 vs approximately 49 μg/mL), T-max was lower (mean 1.00 vs approximately 1.13 hours) and AUC lower (median 103.85 vs 159.25 ug.h/mL in the oldest group, p=0.016). Levels did not differ by HIV status. At a dose of 20 mg/kg per day all children exceeded the adult target (Cmax 35 – 40 ug/mL). Dr Hessling suggested that perhaps 15 mg/kg, less frequent dosing and TDM should be evaluated particularly with relation to toxicities (amakacin can cause irreversible deafness). Interim data at a median of just over five months follow up showed hearing loss in 3/28 children, all with levels exceeding the adult target C-max. She also noted its low early bacterial activity, although it is given for MDR-TB, this compounded with its high toxicity, make it, “not such a wonderful drug”.

Giving ofloxacin achieved higher Cmax in the youngest versus oldest groups (median 9.4 vs 7.16 ug/mL), higher and earlier mean peak in Tmax (1.42 vs 2.60 hours, p=0.39) and similar overall exposure. This drug is given routinely as prophylaxis for MDR-TB and levels were higher in this group but this might be an age effect as it is given only to younger children. There was no difference by HIV status and adult targets were achieved.

This study is ongoing and will result in a very large and important data set.

Izoniazid PK in neonates and infants

In a related presentation, Adrie Bekke from the Stellenbosch group presented data from a study conducted to determine INH PK parameters at a dose of 10 mg/kg/day in low birth weight infants (<2500 g), and to define the PK of INH in relation to the N-acetyltransferase-2 (NAT2)-genotype

INH is recommended as prophylaxis for TB-exposed infants. There are limited data to guide dosing in neonates and no PK data for low birth weight infants. In 2009, WHO recommended higher doses of TB drugs for children (INH 10-15 mg/kg/day) but there is uncertainty about the correct dose for this very young population.

The study was prospective, with longitudinal intensive PK sampling, measuring INH serum concentrations at 2, 3, 4 and 5 hours post-dose and conducted at Tygerberg Hospital, Stellenbosch.

Twenty low birth weight infants were included in the evaluation, of which 14 (70%) were male, 16 (80%) were HIV-exposed and 13 (65%) were preterm. The infants were a median gestational age of 35 weeks (IQR 34-38) and weight of 1874 grams (IQR 1366-2105).

Of the 20 infants, 5 were homozygous slow, 11 heterozygous fast/slow, and 4 homozygous fast NAT2-genotype. There was a median elimination constant rate, Cmax, Tmax, AUC2-5 and half-life of 0.13 h-1, 5.64 μg/mL, 2.02 hours, 13.62 μg.h/mL and 5.55 hours, respectively.

All of the infants achieved adult target INH values, which range between 3 and 5 ug/ml, 2 hours post dose. Measured alanine aminotransferase (ALT) values were generally normal apart from one grade 1 and one grade 2 elevated result, which returned to normal at 6 months.

Dr Bekke noted that as the low birth weight infants achieved adult, if not higher, targets the upper range of the WHO recommended dose (15 mg/kg/day) of INH might be too high for this population. The NAT2 expression on the clearance of INH appears to be delayed, supporting immature enzyme maturation and cautions the administration of higher dosing. The limited safety data was reassuring. More work is urgently needed looking at TB drug dosing in infants.

A novel approach for the evaluation of new TB drugs in children

Researchers from the TB Alliance and the Stellenbosch group have been looking at a novel approach for speeding access to new TB drugs and regimens in infants and young children. Carl Mendel presented the proposed framework for this evaluation.

TB Alliance are a not for profit product development partnership. It will soon be appropriate to begin trials in children for at least one of the drugs that are currently being studied in adults.

Dr Mendel first summarised what is known about developing TB drugs for children. He explained that trials with efficacy as the primary endpoint are not required for children as power would be prohibitive and at least similar efficacy to adults is assumed. Matching PK to that in adults has proven to be safe and effective. But trials in children cannot begin until the adult dose has been established and safety and efficacy demonstrated in this population – what is controversial is when this is.

The researchers currently have several open questions including whether DS and DR TB patients should be distinguished and how closely should PK in children match that of adults particularly with paediatric formulations that are not always bioequivalent.

When to begin paediatric trials needs to balance the risk with beginning early: the drug might fail in adults or toxicities could be first seen in children, to that with starting late: a drug already on the market might be used in children without adequate information or a drug might be delayed in this population. He suggested that for a drug without particular safety concerns, the group consider as soon as two months safety and efficacy data are available in adults to be appropriate.

The traditional approach to collecting PK and then safety data in children is sequentially in de-escalated weight bands. This approach is conservative and experience in older children might not mitigate the risk in younger groups as differences are caused by changes in metabolism at different ages. Drugs to be used mainly by children are not developed in this way.

The TB Alliance plan proposes hospitalised TB patients in all age groups receive single dose for initial PK (based on adult dose and modeling) on top of background therapy, which is a small and manageable risk. Next step would be 14 day multiple dose PK also in hospitalised TB patients.

This approach means that approval for the youngest children would not be delayed – 0-2 is a critical age for TB and has a huge and unmet need for treatments. It is important though that studying the older group is not delayed if paediatric formulations are not available for the younger ones.

Dr Mendel concluded that this approach could provide faster information for registration and he noted that both the FDA and EMA have indicated that they are open to considering it.

References:

1. Hessling A et al. Pharmacokinetics of second line TB therapy in children. Tuberculosis treatment considerations for neonates and infants. 43rd Union World Conference on Lung Health, 13 – 17 November 2012, Kuala Lumpur, Malaysia. Symposium 19.
   http://uwclh.conference2web.com/content/1894?from_view=all&view_address=sessions%3D380
2. Bekker A et al. Tuberculosis treatment considerations for neonates and infants. 43rd Union World Conference on Lung Health, 13 – 17 November 2012, Kuala Lumpur, Malaysia. Symposium 19.
   http://uwclh.conference2web.com/content/1902?from_view=all&view_address=sessions%3D380
3. Mendel CM et al. A framework for the evaluation of new TB drugs in children. 43rd Union World Conference on Lung Health, 13 – 17 November 2012, Kuala Lumpur, Malaysia.

Source: HIV i-Base: HIV Treatment Bulletin: February 2013