Pharmacokinetics of old and new TB drugs for children

1 February 2016. Related: Conference reports, PK and drug interactions, TB coinfection, World Conference on Lung Health 46th 2015.

Polly Clayden, HIV i-Base

Several presentations at the 44th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease showed pharmacokinetic (PK) data for anti-tuberculosis (TB) drugs in children.

These included new data on first-line drugs in infancy – a time of rapid growth and developmental changes that potentially influences drug disposition – at World Health Organisation (WHO) recommended higher dosing (since the revision in 2009).

Emerging data on drugs to treat children with multidrug resistant (MDR) TB – from an excellent ongoing programme in Cape Town – as well as the first on delamanid in older children was also shown.

First-line drugs in infants

Infants starting routine first-line TB treatment in Cape Town with WHO-recommended dosing had very low rifampicin (RMP) exposure. Pyrazinamide (PZA) and isoniazid (INH) concentrations met adult target concentrations. Ethambutol (EMB) exposure was similar to that reported from other paediatric studies but lower than adult targets. [1, 2]

This evaluation was conducted between March 2014 and March 2015, to determine the PK of RMP, INH, PZA +/- EMB in infants at respective doses of: 10 (10 to15), 15 (10 to 20), 35 (30 to 40), and 20 (15 to 25) mg/kg/day. Drug concentrations were determined by validated liquid chromatography mass spectrometry and PK parameters calculated using non-compartmental analysis.

The investigators performed intensive PK plasma sampling in infants receiving fixed dose combination (FDC) tablets. They collected samples at: baseline (0 hours), 1, 2, 4, 6 and 8 hours post-dosing. Infants received approved single TB drug formulations on the day of PK sampling, including two different RMP suspensions.

There were 39 infants included in the study: 26 (67%) (74%) male, 29 black, 14 (36%) with culture-confirmed TB, 15 (38%) premature, 22 (56%) HIV-exposed and 5 (13%) were coinfected with HIV. Their mean age was 6.6 months (SD 3.3), and weight 6.45 kg (SD 1.67). All 39 infants received RMP, INH and PZA and 16 (41%) also received EMB.

Plasma Cmax for RMP, INH, PZA and EMB was 2.9, 7.92, 41.9 and 1.26 ug/mL; AUC0-8 was 12.12, 24.68, 239.4 and 5.09 ug.h/mL, respectively.

Adjusted for age and weight, results for the two RMP formulations differed: Cmax GMR 2.55 (95% CI: 1.47 to 4.41), p=0.001; and AUC0-8 GMR 2.52 (95% CI: 1.34 to 4.73), p=0.005.

HIV coinfection was associated with a lower PZA Cmax and AUC0-8: GMR 0.85 (95% CI: 0.75 to 0.96), p=0.013; and GMR 0.79 (95% CI: 0.69 to 0.90), p=0.001, respectively.

The investigators reported no other significant differences associated with age, weight, prematurity, ethnicity or gender. The majority (85%) of infants had favorable TB treatment outcomes.

There were very low RMP exposures in infants, even when dosed at 15mg/kg/day. PZA and INH concentrations compared well to adult targets. EMB exposure was lower than suggested adult target concentrations, but equivalent to other paediatric studies.

The investigators concluded that the low RMP concentrations observed in infants require further investigation, particularly in the context of future treatment shortening trials in children.

First-line drugs in infants and older children

Related data from Ghana showed, despite the use of revised WHO drug doses, low RMP and EMB Cmax were common among Ghanaian children with TB. [3]

Children aged 3 months to 14 years old receiving first-line TB treatment for at least 4 weeks had samples collected pre-dose, and 1, 2, 4, and 8 hours post-dose.

Of 62 children, 32 (51.6%) were male, median age (IQR) was 5.2 (2.8-8.9) years, 29 (46.8%) were less than five years old and 28 (45.2%) were coinfected with HIV.

The median (IQR) Cmax was 4.8 (3.7 to 6.4) ug/mL for INH, 6.3 (3.5 to 8.8) ug/mL for RMP, 28.6 (21.8 to 35.6) ug/mL for PZA and 1.9 (0.9 to 3.1) ug/mL for EMB.

Cmax below the lower limit of the reference range was considered to be low: INH 3 to 6 ug/mL, RMP 8 to 24 ug/mL, PZA 20 to 60 ug/mL, and EMB 2 to 6 ug/mL.

Including only the children who received the revised WHO doses, the proportions with low Cmax were: INH 13.7% (n=51); RIF 58.8% (n=51), PZA 17.9% (n=56) and EMB 51.8% (n=56).

In multivariate analysis, younger age, OR 1.23, p=0.023, and lower RMP dose, OR 1.28, p=0.004, were associated with low Cmax <8 ug/mL. Shorter height, OR 1.05, p=0.011, was associated with low PZA Cmax <20 mg/mL. Shorter height OR 1.04, p=0.009, was associated with low EMB Cmax <2 mg/mL. None of the factors evaluated affected INH concentrations.

The investigators concluded their findings suggest that higher RMP and EMB doses than currently recommended are necessary to achieve target Cmax in children.

Levofloxacin and amikacin for MDR-TB

Early data from suggested that an amikacin dose of 18-20 mg/kg and levofloxacin of 20 mg/kg should probably be given to children. [4]

Levofloxacin is the most frequently used fluoroquinolone for MDR-TB treatment and prevention in young children. It is currently dosed at 10-15mg/kg once daily.

The second-line injectable TB drugs are used routinely in MDR-TB treatment regimens, at a recommended paediatric once daily dose of 15-30 mg/kg. The PK of levofloxacin and the injectables have not been well characterised in children with MDR-TB.

Up to a quarter of children receiving injectables long-term will have permanent hearing loss. This severe adverse event is likely related to the total cumulative drug exposure.

The Department of Paediatrics and Child Health, University of Stellenbosch, Cape Town – that also performed the infant first-line PK study above – has 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. [5, 6] The group showed emerging data from this study on the PK of amikacin and levofloxacin (the later using pharmacometric modelling).

The investigators previously reported PK and short-term safety data on amikacin PK in 28 children with MDR-TB at an intramuscular (IM) dose of 20 mg/kg showed a median Cmax of 47.1 ug/mL, which is above the currently proposed target Cmax of 35-45 ug/mL in a large proportion of children evaluated.

Their previous data on levofloxacin dosed at of 15 mg/kg in 22 young children with MDR-TB showed a median Cmax of 6.79 mg/mL and a median AUC0-inf of 32.9 ug.h/mL. These values are below those seen in adults following the currently recommended 750 mg once-daily dose: Cmax 8.6 ug/mL, AUC0-24 90.7 ug.h/mL.

Further evaluation of amikacin dosed at 20 mg/kg and 15 mg/kg in 96 children found age to have a significant influence on IM amikacin by AUC but not by Cmax. There was no effect by HIV-status or nutritional status (WfA).

The investigators suggested that in order to achieve target adult Cmax of at least 35 ug/mL, an IM amikacin dose of 18-20 mg/kg should probably be given.

They noted that as the majority of children achieved a Cmax of >35 ug/mL at 20mg/kg daily, care should be taken not to exceed this dose unless TDM is available, as hearing loss is associated with cumulative amikacin exposure. They have not yet analysed hearing loss in this cohort.

Levofloxacin was dosed at 15 mg/kg and 20 mg/kg in 109 children and using modelling the investigators found the 20 mg/kg dose more closely approximates adult exposures than 15 mg/kg.

Ofloxacin for MDR-TB

Ofloxacin exposures after a 20 mg/kg dose were low compared with adult targets in a further presentation from the Stellenbosch group. [7]

Ofloxacin is another fluoroquinolone used for the treatment of MDR-TB. Although it is gradually being replaced by levofoxacin and moxifloxacin, ofloxacin is still widely available. It is not known whether the current internationally recommended paediatric dose of 15-20mg/kg meets target adult exposures. After a standard 800mg dose in adults, median PK values are: AUC0-24 103 (48 to 755) ug.h/mL, Cmax 10.5 (8.0 to 14.3) ug/mL, and CL/F 0.12 L/h/kg.

In this study the investigators assessed a 20mg/kg dose of ofloxacin. Plasma samples were collected pre-dose and at 1, 2, 4, 8 and either 6 or 11 hours post-dose.

Of 85 children <15 years old with a median age of 3.4 years, 11 (13%) were coinfected with HIV and 14 (18%) underweight.

Mean (range) Cmax and AUC0-8 were 8.97 ug/mL (2.47 to 14.40) and 44.2 ug.h/mL (12.1 to 75.8), respectively; AUC0-24 was 66.7 ug.h/mL (18.8 to120.7) and half-life was 3.47h (1.89 to 6.95), CL/F was 0.33 L/h/kg (0.10 to1.04). The investigators reported more rapid clearance in younger children, p=0.001.

In multivariate analysis each additional kg of body weight increased AUC by 1.46 ug.h/L, p=0.006. Cmax also associated with age (p=0.005) and weight (p=0.029) but the investigators suggested that this should be interpreted cautiously.

The investigators noted that crushing tablets did not affect the overall bioavailability of ofloxacin. HIV and malnutrition had no effect. The investigators are using these data to simulate optimal dosing to achieve adult targets. But, despite low exposures the outcomes (not presented) were good at this dose raising questions about adult targets.

Delamanid for MDR-TB

Exposure to delamanid 100 mg twice daily was safe and well tolerated in adolescents with MDR-TB. Plasma concentrations in this age group were within the range seen in adult studies, suggesting that the current standard adult dose is adequate for this age group. [8]

Data were from a phase 2, open-label, uncontrolled, trial of delamanid in children with MDR-TB aged 12 17 conducted at De La Salle Health Sciences Institute and Lung Center of the Philippines.

Delamanid was given with an optimised background regimen (OBR) for six months followed by OBR alone as recommended by WHO. The investigators performed clinical and safety assessments approximately every 2-4 weeks for up to one year. Sparse PK sampling for concentrations of delamanid and DM-6705 (a key delamanid metabolite) were conducted on days: 1, 14, 56, 98, 154, 182, 189, 196, 203, 210, and 238.

Nine participants were screened and seven enrolled in this study. Six (86%) had confirmed MDR-TB, and one (14%) probable MDR-TB. All seven participants (100%) had pulmonary disease, and six (86%) had previously received treatment for TB. The median age was 15 years (13 to 17); four were male, three female; median weight and BMI were 38.5 (26-45) kg and 15.9 kg/m2 (15-20), respectively.

No participants discontinued before the end of the study but one had delamanid withdrawn due to non-adherence and subsequent pregnancy. There were no serious adverse events reported. The most common adverse event reported was headache, reported in five participants (71.4%). No one experienced an absolute QTcF greater than 500ms.

During delamanid treatment, the median Cmax ranged from 354 to 657ng/mL. Compared to adults, median delamanid concentrations were higher in this age group but within the adult range. Median DM-6705 levels were lower than in adults.

Delamanid is now being assessed in children younger than 12 years of age.

Comment

More data is needed to confirm the delamanid results; n=7 is very small for a drug with relatively high PK variability.

Anneke Hesseling from the Stellenbosch group gave an excellent overview on planned and ongoing paediatric trials for MDR-TB identifying research priorities. [9] These included injectable-sparing, shorter and less toxic regimens and evolving adult targets. The presentation is online.

References:

Unless stated otherwise, references are to the programme and abstracts of the 44th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease, 2 – 6 December 2015, Cape Town.

1. Bekker A et al. The pharmacokinetics and treatment of first-line TB drugs for infants. 44th World Lung Conference, Cape Town, 2015. Symposium 8.
   http://tinyurl.com/hmba7c6
   http://html5.slideonline.eu/event/15UNION/presentation/56a880a2a2195c4c12ffaa4c/309/4:3/the-pharmacokinetics-and-treatment-of-first-line-tb-drugs-for-infants
2. Bekker A et al. Pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol in South African infants at revised WHO recommended dosing guidelines. 44th World Lung Conference, Cape Town, 2015. Poster abstract PC-1081-05.
3. Kwara A et al. Pharmacokinetics of first-line antituberculosis drugs in children with tuberculosis with and without HIV coinfection. 44th World Lung Conference, Cape Town, 2015. Oral abstract OA-424-05.
   http://tinyurl.com/j8co5rm
   http://html5.slideonline.eu/event/15UNION/presentation/56a880a2a2195c4c12ffab33///pharmacokinetics-of-first-line-antituberculosis-drugs-in-children-with-tuberculosis-with-and-without-hiv-coinfection-english
4. Garcia-Prats A. Emerging data on PK and safety of levofloxacin and amikacin informs care and design of new regimens. 44th World Lung Conference, Cape Town, 2015. Symposium 27.
5. Clayden P. Pharmacokinetics and safety of moxifloxacin in children. HTB. 29 January 2015.
   https://i-base.info/htb/27733
6. Clayden P. Preventing and treating TB in children – more baby steps. HTB. 1 December 2013.
   https://i-base.info/htb/24037
7. Garcia-Prats A et al. The pharmacokinetics and safety of ofloxacin for drug-resistant tuberculosis in children. 44th World Lung Conference, Cape Town, 2015. Oral abstract OA-479-06.
   http://tinyurl.com/ja46pxl
   http://html5.slideonline.eu/event/15UNION/presentation/56a880a2a2195c4c12ffac0c///the-pharmacokinetics-and-safety-of-ofloxacin-for-drug-resistant-tuberculosis-in-children
8. Hafkin J et al. Long-term safety, tolerability, and pharmacokinetics of delamanid in children aged 12-17 years. 44th World Lung Conference, Cape Town, 2015. Poster abstract EP-115-04.
9. Hessling AC. Update on MDR-TB treatment in children. 44th World Lung Conference, Cape Town, 2015.
   http://tinyurl.com/z36p98g
   http://html5.slideonline.eu/event/15UNION/presentation/56a880a2a2195c4c12ffaaca/404/4:3/update-on-planned-and-ongoing-trials-on-mdr-tb-prevention-and-treatment-in-children