University of Liverpool audit of paediatric TDM
Polly Clayden, HIV i-Base
In an oral presentation, Sara Gibbons, from the University of Liverpool, Pharmacology and Therapeutics, presented data from the groups therapeutic drug monitoring (TDM) service .
Data from the Collaborative HIV Paediatric Study (CHIPS) Cohort – that includes 757 children in the UK and Ireland – show that 73% of HIV-positive children have received antiretroviral therapy. A previous CHIPS analysis has found that 40.5% children in this cohort had been under-dosed during their drug history .
Pharmacokinetic data of antiretroviral drugs in this population are limited. Additionally appropriate paediatric antiretroviral formulations are not always available, leading to frequent unlicensed and off-label use. In Europe, of the 11 PI or NNRTI formulations available to treat adults, 8 are licensed for paediatric use, but with age restrictions ranging from 2 months to 16 years.
The investigators performed a retrospective audit on TDM requests (1999-2005) from the UK and Ireland where the patient was <18 years at the time of request. Data were classified by age, with patients grouped according to British National Formulary guidelines for dosing in children (i.e. neonates=up to 1 month; infants=up to 1 year; younger children=1-5 years; older children=6-12 years; adolescents=over 12 years). The variability in drug concentrations and the relationship between concentrations and age were evaluated.
The investigators noted that 20.6% of requests had missing data, in particular, time post dose, frequency of dose and amount of dose. They reported difficulty in accessing dose/kg or dose m2 as 16.8% of patients weights were not recorded.
During the period of analysis the Liverpool group received 911 requests for TDM. They found that the three most frequently requested drugs were lopinavir/r (35.0%), nevirapine (27.1%) and efavirenz (19.9%). Unlicensed drugs for paediatric use accounted for 16.8% of requests. Stratified by age: 4.0% neonates, 8.0% infants, 26.3% young children, 33.9% older children and 27.8% adolescents, made up the requests.
Plasma concentrations (at any time post dose) falling below adult targets are shown in Table 1.
Table 1: Plasma concetrations falling below target
|Drug||Neonates||Infants||Young children||Older children||Adolescents|
|Lopinavir||–||16% (4/24)||19.4% (18/93)||19.0% (19/100)||25.5% (25/98)|
|Nevirapine||46.95 (15/32)||44.4% (20/45)||22.2% (22/99)||20.0% (9/43)||21.4% (6/28)|
|Efavirenz||–||–||25.9% (7/27)||19.5% (22/113)||26.8% (11/41)|
The investigators found that plasma concentrations below target were frequently also below the limits of quantification (LOQ), in patients receiving lopinavir/r. For lopinavir/r, the absolute percentages below the LOQ were 8.3% infants, 15.1% young children, 17.0% older children 6-12 years and 19.4% adolescents. Percentages for nevirapine were 4.4% infants, 6.1% young children, 9.3% older children and 10.7% adolescents. They noted that the lack of information regarding previous doses limits the use of these data for rigorous population PK analysis.
They concluded that although these data are limited by small sample sizes and potential selection bias, they found greater variability in paediatric drug concentrations than adults. Infants may be particularly at risk for under-dosing especially with nevirapine and adult target values may not be appropriate for paediatric populations. They added that drug formulations might be an additional barrier to achieving adequate concentrations.
The BMJ paper on underdosing concludes:
Three key points emerge. Firstly, rigorous pharmacokinetic and pharmacodynamic data for children are needed before drug licensure. Secondly, effective formal systems for early appraisal, dissemination, and implementation of important modifications to treatment recommendations are needed universally. Thirdly, improved methods of pharmacovigilance are needed to monitor drug utilisation, efficacy and toxicity after drug licensing.
The European Union and the United States have recently committed to promoting research specific to childrens medicines while protecting children as participants in clinical trials.
The UK Department of Health has launched the Medicines for Children Research Network (www.liv.ac.uk/mcrn), which aims to develop closer links between the drugs industry, regulators, families, and paediatricians, links that will be needed to meet the challenges of developing and manufacturing appropriate paediatric drugs (www.hivforum.org). Our study shows that, even for paediatric HIVa new disease with rapid drug development and good dialogue between all these partiesantiretroviral dosing seems to have similar problems to the ones that antibiotics have always had. The Medicines for Children Research Network initiative to tackle these issues is timely. 
- Gibbons S, Back D, Khoo S. An audit of TDM in paediatric subjects from the UK and Ireland. 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abs 8.
- Menson EN, Walker S, Sharland M et al. Underdosing of antiretrovirals in UK and Irish children with HIV as an example of problems in prescribing medicines to children, 1997-2005: cohort study. BMJ 2006 332: 1183-1187.