{"id":27733,"date":"2015-01-29T12:27:33","date_gmt":"2015-01-29T12:27:33","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=27733"},"modified":"2015-01-30T17:42:06","modified_gmt":"2015-01-30T17:42:06","slug":"pharmacokinetics-and-safety-of-moxifloxacin-in-children","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/27733","title":{"rendered":"Pharmacokinetics and safety of moxifloxacin in children"},"content":{"rendered":"

<\/strong>\"45th<\/strong>Polly Clayden, HIV i-Base<\/p>\n

Moxifloxacin concentrations were lower in children than adults according to pharmacokinetic (PK) data presented at the 45th Union World Conference on Lung Health.<\/strong> [1]<\/p>\n

The Desmond Tutu centre at Stellenbosch University, Cape Town has a large, ongoing study looking at PK and safety of second line anti-TB drugs in HIV positive and negative children with drug resistant (DR)-TB. We have reported data from this programme presented at previous Union meetings. [2, 3]<\/p>\n

Late-generation fluoroquinalones \u2013 moxifloxacin and levofloxacin \u2013 are potent against multi-drug resistant (MDR)-TB. South African guidelines recommend moxifloxacin for children >20kg and >8 years old and levofloxacin for those <20kg and <8 years old.<\/p>\n

Moxifloxacin is currently considered the most potent against MDR-TB. It has 90% bioavailability, food has little effect on absorption: about 50% is metabolised by the liver, about 20% is excreted unchanged in urine and 25% in faeces.<\/p>\n

Currently only 400 mg tablets are available. The moxifloxacin WHO-recommended daily dose is 7.5 \u2013 10 mg\/kg.<\/p>\n

Following a standard 400 mg oral dose in adults, PK values have been described in the literature as follows: AUC0-24 40 \u2013 60 ug*h\/mL, Cmax 4 \u2013 6 ug\/mL, Tmax 1 -2 hours, and T1\/2 of 6\u201310 hours.<\/p>\n

Pharmacodynamic (PD) targets of fluoroquinalones: AUC0-24\/MIC, target 100 and Cmax\/MIC target 8 \u2013 10.<\/p>\n

Steffi Thee presented findings from a nested study in the large MDR-TB drug PK one, conducted to describe the PK of moxifloxacin and to characterise the tolerability and safety of the drug.<\/p>\n

HIV positive and negative children 8 \u2013 15 years of age, receiving moxifloxacin as part of routine MDR-TB treatment, were enrolled; those with lab-documented anaemia (Hb <8 g\/d\/L) were excluded.<\/p>\n

Moxifloxacin was dosed at 10 mg\/kg and taken on an empty stomach with all anti-TB medications. Intensive PK sampling (0, 1, 2, 4, 8 and 6 or 11 hours) of moxifloxacin at steady state (2 \u2013 8 weeks) was performed. Liquid chromatograpy-tandem mass spectrometry was used in the evaluation; all assays were conducted at the University of Cape Town Clinical Pharmacology Department.<\/p>\n

Routine and laboratory safety assessments were conducted monthly for the first 6 months of treatment, then every 2 months until completion. Liver function tests, creatinine and complete blood cell counts were performed on children receiving antiretrovirals or linezolid; thyroid function was measured in children receiving ethionamide or PAS. Cardiotoxicity was measured. Adverse events were graded using DAIDS criteria.<\/p>\n

Dr Thee presented data from 23 children. At baseline they were a median age of 11.1 years (IQR 9.2 \u2013 12.0) and weight of 28.9kg (range 21 \u2013 66 kg). Nine (39.1%) were boys; 13 (56.5%) and 10 (43.5%) were defined as black and coloured ethnicity respectively; 11 (47.8%) had experienced a previous TB episode or treatment; 12 (52.2%) had a known TB source case; 19 (82.6%) had a bacteriologically confirmed TB diagnosis and 4 (17.4%) a probable TB diagnosis; 14 (60.9%) had pulmonary TB, 3 (13.0%) extra-pulmonary TB and 6 (26.1%) had both; 6 (26.1%) children were HIV positive; and 3 (13.0%) had weight-for-age z-score <-2.0%.<\/p>\n

Dr Thee reported that the evaluation found the moxifloxacin Cmax in children nearly approximated that with a 400 mg adult dose but the AUC was substantially lower. Table 1 shows moxifloxacin PK parameters by HIV status, nutritional status and administration method.<\/p>\n\n\n\n\n\n\n\n
Table 1: Moxifloxacin PK parameters by HIV status, nutritional status and administration method<\/caption>\n
PK Parameter<\/th>\nCmax (ug\/mL)<\/th>\nTmax (h)<\/th>\nAUC0-8 (ug*h\/mL)<\/th>\n<\/tr>\n
<\/td>\nn<\/th>\nMedian (IQR)<\/th>\np-value<\/th>\nMedian (range)<\/th>\np-value<\/th>\nMedian (IQR)<\/th>\np-value<\/th>\n<\/tr>\n
HIV positiveHIV negative<\/td>\n617<\/td>\n2.83 (2.36 \u2013 2.94)3.21 (2.95 \u2013 3.82)<\/td>\n0.08<\/td>\n2.0 (1.0 \u2013 4.0)4.0 (1.0 \u2013 8.0)<\/td>\n0.33<\/td>\n13.19 (11.8 \u2013 15.9)19.98 (16.71- 25.21)<\/td>\n0.003<\/td>\n<\/tr>\n
WAZ > \u00ad\u20132.0WAZ <\u20132.0 (UWA)<\/td>\n203<\/td>\n3.08 (2.87 \u2013 3.71)2.78 (1.99 \u2013 4.06)<\/td>\n0.41<\/td>\n2.0 (1.0 \u2013 8.0)2.0 (1.0 \u2013 8.0)<\/td>\n0.59<\/td>\n18.76 (16.43 \u2013 23.6)14.47 (9.95 \u2013 15.9)<\/td>\n0.045<\/td>\n<\/tr>\n
Whole drugCrushed drug<\/td>\n203<\/td>\n2.96 (2.82 \u2013 3.71)3.21 (3.08 \u2013 4.06)<\/td>\n0.29<\/td>\n3.0 (1.0 \u2013 8.0)1.0 (1.0 \u2013 2.0)<\/td>\n0.047<\/td>\n17.36 (14.93 \u2013 23.6)17.24 (14.47\u2013 19.53)<\/td>\n0.72<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Using MIC90 0.5 mg\/L, the PD targets were not achieved: mean AUC0-24\/MIC(IQR), 56.1 (SD 25.1) vs target 100 and mean Cmax\/MIC(IQR) 6.5 (SD 1.5) vs target 8 \u2013 10.<\/p>\n

ECG was performed in 12 children. The mean QT interval was 362 ms (SD 40 ms) and mean QTc 403ms (SD 30 ms). None had QTc interval >450 ms.<\/p>\n

One child had a grade 3 ALT elevation possible related to moxifloxican, all other adverse events were mild and not persistent grade 1 or 2.<\/p>\n

Dr Thee suggested that future directions should include: dose optimisation of moxifloxacin in more child-friendly regimens and formulations, investigation into formulation effects on bioavailability, and evaluation of larger cohorts for safety assessment and further investigation into clinical covariates, including HIV coinfection.<\/p>\n

Comment<\/h3>\n

The large five year study of second-line treatment has an enrollment target of about 300 children. Age matched HIV positive children who are not on TB treatment are enrolled as controls.<\/strong><\/p>\n

The drugs under evaluation are: ethionamide, terizidone, ofloxacin, levofloxacin, moxifloxacin, amikacin, high dose isoniazid (INH), PAS, linezolid and capreomycin. The group will be looking at delamanid and bedaquiline and novel TB drugs as they become available for children.<\/strong><\/p>\n

References:<\/p>\n

    \n
  1. Clayden P. Paediatric TB: glimpses of PK data and a potential new approach to drug development. HTB, January\/February 2013.
    \nhttps:\/\/i-base.info\/htb\/20861<\/a><\/li>\n
  2. Clayden P. Preventing and treating TB in children \u2013 more baby steps. HTB, November\/December 2013.
    \n    https:\/\/i-base.info\/htb\/24037<\/a><\/li>\n
  3. Thee S. The pharmacokinetics and safety of moxiflixacin in HIV-infected and HIV uninfected children with MDR-tuberculosis. 45th Union World Conference on Lung Health. Barcelona, Spain. 28 October \u2013 1 November, 2014. Symposium abstracts, Saturday, 1 November S49.
    \n    http:\/\/slideonline.eu\/recordings\/2014\/14union<\/a><\/li>\n<\/ol>\n
    \u00a0<\/strong><\/div>\n","protected":false},"excerpt":{"rendered":"

    Polly Clayden, HIV i-Base Moxifloxacin concentrations were lower in children than adults according to pharmacokinetic (PK) data presented at the 45th Union World Conference on Lung Health. [1] The Desmond Tutu centre at Stellenbosch University, Cape Town has a large, …<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,32,34],"tags":[200],"class_list":["post-27733","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-paediatric-care","category-pk-and-drug-interactions","tag-world-conference-on-lung-health-45th-2014"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/27733","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=27733"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/27733\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=27733"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=27733"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=27733"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}